Chronic exposure to low frequency noise at moderate levels causes impaired balance in mice.

PubMed

Tamura, Haruka; Ohgami, Nobutaka; Yajima, Ichiro; Iida, Machiko; Ohgami, Kyoko; Fujii, Noriko; Itabe, Hiroyuki; Kusudo, Tastuya; Yamashita, Hitoshi; Kato, Masashi

2012-01-01

We are routinely exposed to low frequency noise (LFN; below 0.5 kHz) at moderate levels of 60-70 dB sound pressure level (SPL) generated from various sources in occupational and daily environments. LFN has been reported to affect balance in humans. However, there is limited information about the influence of chronic exposure to LFN at moderate levels for balance. In this study, we investigated whether chronic exposure to LFN at a moderate level of 70 dB SPL affects the vestibule, which is one of the organs responsible for balance in mice. Wild-type ICR mice were exposed for 1 month to LFN (0.1 kHz) and high frequency noise (HFN; 16 kHz) at 70 dB SPL at a distance of approximately 10-20 cm. Behavior analyses including rotarod, beam-crossing and footprint analyses showed impairments of balance in LFN-exposed mice but not in non-exposed mice or HFN-exposed mice. Immunohistochemical analysis showed a decreased number of vestibular hair cells and increased levels of oxidative stress in LFN-exposed mice compared to those in non-exposed mice. Our results suggest that chronic exposure to LFN at moderate levels causes impaired balance involving morphological impairments of the vestibule with enhanced levels of oxidative stress. Thus, the results of this study indicate the importance of considering the risk of chronic exposure to LFN at a moderate level for imbalance.

Chronic Exposure to Low Frequency Noise at Moderate Levels Causes Impaired Balance in Mice

PubMed Central

Tamura, Haruka; Ohgami, Nobutaka; Yajima, Ichiro; Iida, Machiko; Ohgami, Kyoko; Fujii, Noriko; Itabe, Hiroyuki; Kusudo, Tastuya; Yamashita, Hitoshi; Kato, Masashi

2012-01-01

We are routinely exposed to low frequency noise (LFN; below 0.5 kHz) at moderate levels of 60–70 dB sound pressure level (SPL) generated from various sources in occupational and daily environments. LFN has been reported to affect balance in humans. However, there is limited information about the influence of chronic exposure to LFN at moderate levels for balance. In this study, we investigated whether chronic exposure to LFN at a moderate level of 70 dB SPL affects the vestibule, which is one of the organs responsible for balance in mice. Wild-type ICR mice were exposed for 1 month to LFN (0.1 kHz) and high frequency noise (HFN; 16 kHz) at 70 dB SPL at a distance of approximately 10–20 cm. Behavior analyses including rotarod, beam-crossing and footprint analyses showed impairments of balance in LFN-exposed mice but not in non-exposed mice or HFN-exposed mice. Immunohistochemical analysis showed a decreased number of vestibular hair cells and increased levels of oxidative stress in LFN-exposed mice compared to those in non-exposed mice. Our results suggest that chronic exposure to LFN at moderate levels causes impaired balance involving morphological impairments of the vestibule with enhanced levels of oxidative stress. Thus, the results of this study indicate the importance of considering the risk of chronic exposure to LFN at a moderate level for imbalance. PMID:22768129

Corticosterone levels and behavioral changes induced by simultaneous exposure to chronic social stress and enriched environments in NMRI male mice.

PubMed

Mesa-Gresa, Patricia; Ramos-Campos, Marta; Redolat, Rosa

2016-05-01

Environmental enrichment (EE) is an experimental model which is believed to counteract some of the effects induced by stressors, although few studies have exposed rodents simultaneously to EE and stress. Our aim was to compare the short- and long-term effects of different housing conditions in mice submitted to chronic stress. 128 NMRI male mice arrived at our laboratory on postnatal day (PND) 21. During Phase I (PND 28), animals were randomly assigned to four experimental conditions: 1) EE+STRESS: mice housed in EE and submitted to social stress (n=32); 2) EE+NO STRESS: mice housed in EE without stress (n=32); 3) SE+STRESS: mice maintained in standard conditions (SE) and submitted to social stress (n=32); and 4) SE+NO STRESS (n=32). At the end of Phase I (PND 77), one cohort of 32 animals was used for behavioral assessment whereas another cohort of 32 was sacrificed for corticosterone analysis. Results indicated that EE animals showed less body weight, higher water and food intake, diminished anxiety response and decreased motor and exploratory behavior than SE mice. Mice exposed to stress gained less body weight, showed higher food and fluid intake and displayed decreased exploratory behavior than non-stressed mice. Furthermore, EE+STRESS group displayed significantly higher corticosterone levels than EE+NO STRESS group whereas EE+NO STRESS group showed lower levels than SE+NO STRESS. On PND 83, Phase II of the study began. Animals (n=96) were assigned to two different housing conditions: EE (n=48) and SE (n=48). On PND 112, corticosterone analysis (n=32) and behavioral study (n=64) were done. The factor "Housing Phase II" reached statistical significance. Results indicated that EE animals showed lower body weight and higher fluid intake than SE group, as well as decreased anxiety. No clear effects on motor and exploratory behavior or learning were observed. When long-term effects were analyzed, results indicated that "Initial Housing" condition was significant: animals allocated in EE during Phase I of the study showed higher corticosterone levels, lower body weight and higher fluid intake than SE mice. "Initial Stress" had significant long-term actions on food intake and exploratory behavior: animals initially reared under stress conditions displayed higher food intake and lower exploration levels on the hole-board test than non-stressed mice. In the elevated plus-maze, there were significant interactions between factors "Initial Housing" and "Initial Stress". These factors did not reach statistical significance for motor activity or learning task. We can conclude that both short- and long-term effects of housing conditions are evident for corticosterone levels, body weight and fluid intake. Social stress induced short-term effects on body weight, food and fluid intake and exploratory behavior whereas long-acting effects were reflected on food intake and exploratory behavior. Further studies are needed in order to explore more in depth behavioral and physiological consequences of social stress and environmental enrichment. Copyright © 2016. Published by Elsevier Inc.

Serotonin2C receptors in the nucleus accumbens are involved in enhanced alcohol-drinking behavior

PubMed Central

Yoshimoto, Kanji; Watanabe, Yoshihisa; Tanaka, Masaki; Kimura, Minoru

2012-01-01

Dopamine and serotonin (5-HT) in the nucleus accumbens (ACC) and ventral tegmental area of the mesoaccumbens reward pathways have been implicated in the mechanisms underlying development of alcohol dependence. We used a C57BL/6J mouse model with increased voluntary alcohol-drinking behavior by exposing the mice to alcohol vapor for 20 consecutive days. In the alcohol-exposed mice, the expression of 5-HT2C receptor mRNA increased in the ACC, caudate nucleus and putamen, dorsal raphe nucleus (DRN), hippocampus and lateral hypothalamus, while the protein level of 5-HT2C receptor significantly increased in the ACC. The expression of 5-HT7 receptor mRNA increased in the ACC and DRN. Contents of 5-HT decreased in the ACC shell (ACCS) and DRN of the alcohol-exposed mice. The basal extracellular releases of dopamine (DA) and 5-HT in the ACCS increased more in the alcohol-exposed mice than in alcohol-naïve mice. The magnitude of the alcohol-induced ACCS DA and 5-HT release in the alcohol-exposed mice was increased compared with the control mice. Intraperitoneal (i.p.) administration or local injection into ACCS of the 5-HT2C receptor antagonist, SB-242084, suppressed voluntary alcohol-drinking behavior in the alcohol-exposed mice. But the i.p. administration of the 5-HT7 receptor antagonist, SB-258719, did not have significant effects on alcohol-drinking behavior in the alcohol-exposed mice. The effects of the 5-HT2C receptor antagonist were not observed in the air-exposed control mice. These results suggest that adaptations of the 5-HT system, especially the upregulation of 5-HT2C receptors in the ACCS, are involved in the development of enhanced voluntary alcohol-drinking behavior. PMID:22512261

Temporal analysis of oxidative effects on the pulmonary inflammatory response in mice exposed to cigarette smoke.

PubMed

Campos, Keila Karine Duarte; Manso, Rafaela Gontijo; Gonçalves, Evandro Guedes; Silva, Marcelo Eustáquio; de Lima, Wanderson Geraldo; Menezes, Cristiane Alves Silva; Bezerra, Frank Silva

2013-01-01

The most common factor related to the chronic obstructive pulmonary disease (COPD) development is the chronic smoking habit. Our study describes the temporal kinesis of pulmonary cellular influx through BALF analyses of mice acutely exposed to cigarette smoke (CS), the oxidative damage and antioxidative enzyme activities. Thirty-six mice (C57BL/6, 8weeks old, male) were divided in 6 groups: the control group (CG), exposed to ambient air, and the other 30 mice were exposed to CS. Mice exposed to CS presented, especially after the third day of exposure, different cellular subpopulations in BALF. The oxidative damage was significantly higher in CS exposed groups compared to CG. Our data showed that the evaluated inflammatory cells, observed after three days of CS exposure, indicate that this time point could be relevant to studies focusing on these cellular subpopulation activities and confirm the oxidative stress even in a short term CS exposure. Copyright © 2013 Elsevier Inc. All rights reserved.

Exposure to neonatal cigarette smoke causes durable lung changes but does not potentiate cigarette smoke–induced chronic obstructive pulmonary disease in adult mice

PubMed Central

McGrath-Morrow, Sharon; Malhotra, Deepti; Lauer, Thomas; Collaco, J. Michael; Mitzner, Wayne; Neptune, Enid; Wise, Robert; Biswal, Shyam

2016-01-01

The impact of early childhood cigarette smoke (CS) exposure on CS-induced chronic obstructive pulmonary disease (COPD) is unknown. This study was performed to evaluate the individual and combined effects of neonatal and adult CS exposure on lung structure, function, and gene expression in adult mice. To model a childhood CS exposure, neonatal C57/B6 mice were exposed to 14 days of CS (Neo CS). At 10 weeks of age, Neo CS and control mice were exposed to 4 months of CS. Pulmonary function tests, bronchoalveolar lavage, and lung morphometry were measured and gene expression profiling was performed on lung tissue. Mean chord lengths and lung volumes were increased in neonatal and/or adult CS-exposed mice. Differences in immune, cornified envelope protein, muscle, and erythrocyte genes were found in CS-exposed lung. Neonatal CS exposure caused durable structural and functional changes in the adult lung but did not potentiate CS-induced COPD changes. Cornified envelope protein gene expression was decreased in all CS-exposed mice, whereas myosin and erythrocyte gene expression was increased in mice exposed to both neonatal and adult CS, suggesting an adaptive response. Additional studies may be warranted to determine the utility of these genes as biomarkers of respiratory outcomes. PMID:21649527

MORPHOLOGICAL AND HISTOCHEMICAL CHANGES IN THE SPLEEN AND LYMPH NODE OF WHITE MICE IN RESPONSE TO RADIATION AND ANTIGENIC EFFECTS (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akopova, V.A.

1961-01-01

Research was carried out on 90 white ntice subjected to x irradiation (Series I), vaccination with a brucellosis vaccine (Series II), and to a combined action of these factors (Series III and IV). The spleen and lymph nodes were studied both morphologically and histochemically. When exposing the mice to a total x-ray dose of 335 r, visible destructive changes and the lowering of desoxyribonucleic and ribonucleic acid level were found to occur in the spleen and lymph nodes. In the case of a single vaccination of the mice with the brucellosis vaccine, a certain vaccinal hyperplasia was observed in themore » spleen and lymph nodes, the level of desoxyribonucleic and ribonucleic acid being normal. In vaccinating the white mice, following total irradiation, destructive changes along with a gradual lowering of desoxyribonucleic and ribonucleic acid level are observed in the spleen and lymph nodes. The total x irradiation following a singie vaccination with the brucellosis vaccine, brings about slight destructive changes along with a simultaneous reticular hyperplasia in the spleen and lymph nodes. The levels of desoxyribonucleic and ribonucleic acids are high at all times. (auth)« less

Synergistic effect of EMF-BEMER-type pulsed weak electromagnetic field and HPMA-bound doxorubicin on mouse EL4 T-cell lymphoma.

PubMed

Říhová, Blanka; Etrych, Tomáš; Šírová, Milada; Tomala, Jakub; Ulbrich, Karel; Kovář, Marek

2011-12-01

We have investigated the effects of low-frequency pulsed electromagnetic field (LF-EMF) produced by BEMER device on experimental mouse T-cell lymphoma EL4 growing on conventional and/or athymic (nude) mice. Exposure to EMF-BEMER slowed down the growth of tumor mass and prolonged the survival of experimental animals. The effect was more pronounced in immuno-compromised nude mice compared to conventional ones. Acceleration of tumor growth was never observed. No measurable levels of Hsp 70 or increased levels of specific anti-EL4 antibodies were detected in the serum taken from experimental mice before and at different intervals during the experiment, i.e. before solid tumor appeared, at the time of its aggressive growth, and at the terminal stage of the disease. A significant synergizing antitumor effect was seen when EL4 tumor-bearing mice were simultaneously exposed to EMF-BEMER and treated with suboptimal dose of synthetic HPMA copolymer-based doxorubicin, DOX(HYD)-HPMA. Such a combination may be especially useful for heavily treated patients suffering from advanced tumor and requiring additional aggressive chemotherapy which, however, at that time could represent almost life-threatening way of medication.

Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Last, Jerold A.; Gohil, Kishorchandra; Mathrani, Vivek C.

2005-10-15

Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkersmore » of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-{kappa}B in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.« less

Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes.

PubMed

Last, Jerold A; Gohil, Kishorchandra; Mathrani, Vivek C; Kenyon, Nicholas J

2005-10-15

Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-kappaB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.

NTP Toxicology and Carcinogenesis Studies of l-Epinephrine Hydrochloride (CAS No. 55-31-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

PubMed

1990-03-01

l-Epinephrine, an endogenous neurotransmitter hormone, is widely used for the treatment of allergic and respiratory disorders. NTP Toxicology and Carcinogenesis studies of epinephrine hydrochloride were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to an aerosol containing epinephrine hydrochloride for 14 days, 13 weeks, 15 months, or 2 years. During the 14-day and 13-week studies, control animals were exposed to dilute aerosols of hydrochloric acid (pH 2.8), whereas during the 15-month and 2-year studies, controls were exposed to aerosols of water. Genetic toxicology studies of epinephrine were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: Rats and mice were exposed to 0 or 12.5-200 mg/m3 epinephrine hydrochloride. Deaths occurred in male rats exposed to 12.5 mg/m3 or more and in females exposed to 25 mg/m3 or more. Deaths of mice occurred at concentrations of 50 mg/m3 or higher. Compound-related clinical signs included an increased respiratory rate in all groups of epinephrine-exposed rats and mice. At higher concentrations (100 and 200 mg/m3), excessive lacrimation and dyspnea in rats and exaggerated visual and auditory reflexes in mice were observed. Thirteen-Week Studies: Rats and mice were exposed to 0 or 2.5-40 mg/m3 epinephrine hydrochloride. Deaths in rats and mice were not concentration related. Final mean body weights of chemically exposed and hydrochloric acid aerosol control rats and mice were generally similar. Increased respiratory rates were noted in rats and mice exposed to 40 mg/m3. Heart and adrenal gland weights of rats and mice and liver weights of mice exposed to 40 mg/m3 were greater than those of aerosol controls. Squamous metaplasia occurred in the respiratory epithelium of the nasal mucosa of rats and mice exposed to 40 mg/m3. Degenerative lesions of the laryngeal muscle were seen in male and female rats exposed to 20 or 40 mg/m3. Inflammation in the glandular stomach was seen in male and female mice exposed to 10, 20, and 40 mg/m3, and uterine atrophy was seen in 7/10 female mice exposed to 40 mg/m3. Two-year studies were conducted by exposing groups of 60 rats or each sex to 0, 1.5, or 5 mg/m3 epinephrine hydrochloride, 5 days per week for 103 weeks. Groups of 60 mice of each sex were exposed to 0, 1.5, or 3 mg/m3 epinephrine hydrochloride, 5 days per week for 104 weeks. Use of these exposure concentrations represented a departure from the usual practice of utilizing doses equivalent to one-half the maximum tolerated dose (MTD) and the MTD for 2-year carcinogenicity studies. Thus, although the dose levels exceeded maximum human therapeutic use levels (normalized to body weight and surface area), they were less than one-half the MTD. Fifteen-Month Studies: Results of hematologic analyses did not show compound-related changes. Absolute liver weights for exposed mice (3 mg/m3) and rats (5 mg/m3) and relative liver weights for exposed rats (5 mg/m3) were significantly lower than those for controls. The absolute kidney weights for mice exposed to 3 mg/m3 and the kidney weight to body weight ratio for male mice exposed to 3 mg/m3 were significantly lower than those for controls. No compound-related lesions were seen in rats or mice. Body Weights and Survival in the Two-Year Studies: Mean body weights and survival of exposed and control rats and mice were similar (survival, rats--male: control, 33/50; 1.5 mg/m3, 27/50; 5 mg/m3, 32/50; female: 32/50; 29/50; 30/50; mice--male: control, 33/50; 1.5 mg/m3, 34/50; 3 mg/m3, 36/50; female: 32/50; 35/50; 34/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Suppurative inflammation of the nasal mucosa, dilatation of the nasal glands (Bowman's and septal), and hyperplasia of the respiratory epithelium were seen at increased incidences in male rats exposed to 5 mg/m3 and in female rats exposed to 1.5 or 5 mg/m3. Hyaline degeneration of the olfactory epithelium in male mice and suppurative inflammation of the nasal passage and hyaline degeneration of the respiratory epithelium in female mice were increased in the 1.5 and 3 mg/m3 groups compared with controls. No neoplasms seen in these studies were considered related to chemical exposure. Genetic Toxicology: Salmonella gene mutation tests with l-epinephrine yielded negative results in strain TA100 in the presence of exogenous metabolic activation (S9) and equivocal results in the absence of S9. No mutagenic activity was observed in strains TA98, TA1535, or TA1537 with or without S9. The responses observed in the CHO cell assay for induction of sister chromatid exchanges were considered to be negative and equivocal in the presence and absence of S9 activation, respectively. l-Epinephrine did not induce chromosomal aberrations in CHO cells with or without S9. Conclusions: Under the conditions of these 2-year studies, no carcinogenic effects were observed in male or female F344/N rats exposed to aerosols containing 1.5 or 5 mg/m3 l-epinephrine hydrochloride for 2 years or in B6C3F1 mice exposed to 1.5 or 3 mg/m3 l-epinephrine hydrochloride for 2 years. However, these studies were considered to be inadequate studies of carcinogenic activity because the concentrations used, which were chosen to represent multiples of therapeutic doses, were considered too low for the animals to have received an adequate systemic challenge from the compound. Synonyms: adrenaline hydrochloride; 4-(1-hydroxy-2-(methylamino)ethyl)-1,2-benzenediol; (-)3,4-dihydroxy-a-((methylamino)methyl)benzyl alcohol hydrochloride; methylaminoethanol catechol hydrochloride Trade names for epinephrine formulations: Primatene®. Mist; Sus-Phrine®.; Epipen®.; Supravenin Hydrochloride®.; Bronkaid®.

Early life persistent vitamin D deficiency exacerbates ...

EPA Pesticide Factsheets

Epidemiological and animal data have conclusively linked adverse cardiovascular outcomes to air pollution exposure. As such, cardiovascular function is maintained by adequate levels of certain essential micronutrients like vitamin D. Unfortunately, vitamin D deficiency (VDD) has become highly prevalent in the United States, as well as in the world, even affecting otherwise healthy individuals. My initial studies showed that VDD alters cardiac function, increases cardiac arrhythmia and HRV (i.e. indirect measure of autonomic tone) in mice; this response is further exacerbated after smog exposure. VDD has been shown to alter the responsiveness of transient receptor potential A1 (TRPA1) channels, which we have previously shown to be involved in cardiopulmonary dysfunction to acrolein, which is a ubiquitous air pollutant and potent TRPA1 agonist. The effect of VDD on TRPA1-induced air pollution responses is not known and is the purpose of this study. 3-week old mice were placed on a VDD or normal diet (ND) for 19 weeks and then implanted with radiotelemeters for the measurement of heart rate, electrocardiogram and HRV. Mice were exposed to filtered air then acrolein for 3 hours each on separate days. During exposure, ventilatory function and ECG were simultaneously recorded. Acrolein increased parasympathetic tone in ND mice, but not VDD mice during exposure. However, acrolein caused cardiac arrhythmias only in VDD mice during exposure. Similar to previous studies,

[Influence of electromagnetic radiation on toxicity of Vipera lebetina obtusa venom].

PubMed

Abiev, G A; Babaev, E I; Topchieva, Sh A; Chumburidze, T B; Nemsitsveridze, N G

2009-11-01

The aim of the article was to study the effect of electromagnetic radiation on toxicity of Vipera lebetina obtusa venom. It was found that mice intoxicated with snake venom, with moderate to high exposure to electromagnetic radiation and mice intoxicated with venom, which had not been exposed to the radiation showed the same symptoms of intoxication and death. At the same time, the longevity of mice intoxicated with venom exposed to electromagnetic radiation was higher. The longevity of mice in control group was 25+/-5 min. The longevity of mice intoxicated with exposed to electromagnetic radiation snake venom was from 29 to 60 min. The research showed that the longevity of mice intoxicated with snake venom rose with the level of electromagnetic radiation intensity the snake was exposed to. Accordingly, snake venom, with exposure to high intensity electromagnetic radiation is less toxic.

Apocynin and ebselen reduce influenza A virus-induced lung inflammation in cigarette smoke-exposed mice.

PubMed

Oostwoud, L C; Gunasinghe, P; Seow, H J; Ye, J M; Selemidis, S; Bozinovski, S; Vlahos, R

2016-02-15

Influenza A virus (IAV) infections are a common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Oxidative stress is increased in COPD, IAV-induced lung inflammation and AECOPD. Therefore, we investigated whether targeting oxidative stress with the Nox2 oxidase inhibitors and ROS scavengers, apocynin and ebselen could ameliorate lung inflammation in a mouse model of AECOPD. Male BALB/c mice were exposed to cigarette smoke (CS) generated from 9 cigarettes per day for 4 days. On day 5, mice were infected with 1 × 10(4.5) PFUs of the IAV Mem71 (H3N1). BALF inflammation, viral titers, superoxide production and whole lung cytokine, chemokine and protease mRNA expression were assessed 3 and 7 days post infection. IAV infection resulted in a greater increase in BALF inflammation in mice that had been exposed to CS compared to non-smoking mice. This increase in BALF inflammation in CS-exposed mice caused by IAV infection was associated with elevated gene expression of pro-inflammatory cytokines, chemokines and proteases, compared to CS alone mice. Apocynin and ebselen significantly reduced the exacerbated BALF inflammation and pro-inflammatory cytokine, chemokine and protease expression caused by IAV infection in CS mice. Targeting oxidative stress using apocynin and ebselen reduces IAV-induced lung inflammation in CS-exposed mice and may be therapeutically exploited to alleviate AECOPD.

Survival and endogenous colony formation in irradiated mice grafted with normal or infectious mononucleosis bone marrow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Louwagie, A. C.; Verwilghen, R. L.

1973-07-01

Mice were exposed to 850 or 975 rad of whole-body radiation; three hr later mice were given normal human bone marrow, infectious mononucleosis bone marrow, or cells from malignant blood diseases. The surviving mice were killed at day 9 and the spleen nodules were counted. Some mice were also given antihuman antilymphocytic serum (ALS). In mice exposed to 975 rad, the highest survival was observed in mice grafted with infectious mononucleosis bone marrow, while none of the animals grafted with cells from malignant blood diseases survived 9 days. In mice exposed to 850 rad, grafting of normal or infectious mononucleosismore » bone marrow markedly decreased the survival. Endogenous spleen colonies were induced in all animals grafted with normal or infectious mononucleosis bone marrow. (HLW)« less

Enhanced taurine release in cell-damaging conditions in the developing and ageing mouse hippocampus.

PubMed

Saransaari, P; Oja, S S

1997-08-01

Taurine has been shown to be essential for neuronal development and survival in the central nervous system. The release of preloaded [3H]taurine was studied in hippocampal slices from seven-day-, three-month- and 18-22-month-old mice in cell-damaging conditions. The slices were superfused in hypoxic, hypoglycemic and ischemic conditions and exposed to free radicals and oxidative stress. The release of taurine was greatly enhanced in the above conditions in all age groups, except in oxidative stress. The release was large in ischemia, particularly in the hippocampus of aged mice. Potassium stimulation was still able to release taurine in cell-damaging conditions in immature mice, whereas in adult and aged animals the release was so substantial that this additional stimulus failed to work. Taurine release was partially Ca2+-dependent in all cases. The massive release of the inhibitory amino acid taurine in ischemic conditions could act neuroprotectively, counteracting in several ways the effects of simultaneous release of excitatory amino acids. This protection could be of great importance in developing brain tissue, while also having an effect in aged brains.

A C-terminal cyclic 8-13 neurotensin fragment analog appears less exposed to neprilysin when it crosses the blood-brain barrier than the cerebrospinal fluid-brain barrier in mice.

PubMed

Van Kemmel, F M; Dubuc, I; Bourdel, E; Fehrentz, J A; Martinez, J; Costentin, J

1996-10-11

A C-terminal cyclic 8-13 neurotensin fragment analog. JMV 1193, a direct agonist of central neurotensin receptors, is able to cross both the cerebrospinal fluid-brain barrier and the blood-brain barrier. When administered intracerebroventricularly (i.c.v.), its hypothermic effect was potentiated by the enkephalinase inhibition induced either by thiorphan (simultaneous intracerebroventricular administration of 10 micrograms) or by the thiorphan prodrug. acetorphan (intravenous (i.v.) administration of 10 mg/kg). Such a potentiation was not observed when both JMV 1193 and acetorphan were administered intravenously. Therefore it appears that the sensitivity of JMV 1193 to enkephalinase depends on its route of administration. It is exposed to this peptidase after i.c.v. injection (when crossing the cerebrospinal fluid-brain barrier), while it is not after i.v. administration (when crossing the blood-brain barrier).

Metabolite signatures in hydrophilic extracts of mouse lungs exposed to cigarette smoke revealed by 1H NMR metabolomics investigation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Jian Z.; Wang, Xuan; Feng, Ju

Herein, 1H-NMR metabolomics are carried out to evaluate the changes of metabolites in lungs of mice exposed to cigarette smoke. It is found that the concentrations of adenosine derivatives (i.e. ATP, ADP and AMP), inosine and uridine are significantly fluctuated in the lungs of mice exposed to cigarette smoke compared with those of controls regardless the mouse is obese or regular weight. The decreased ATP, ADP, AMP and elevated inosine predict that the deaminases in charge of adenosine derivatives to inosine derivatives conversion are altered in lungs of mice exposed to cigarette smoke. Transcriptional analysis reveals that the concentrations ofmore » adenosine monophosphate deaminase and adenosine deaminase are different in the lungs of mice exposed to cigarette smoke, confirming the prediction from metabolomics studies. We also found, for the first time, that the ratio of glycerophosphocholine (GPC) to phosphocholine (PC) is significantly increased in the lungs of obese mice compared with regular weight mice. The ratio of GPC/PC is further elevated in the lungs of obese group by cigarette smoke exposure. Since GPC/PC ratio is a known biomarker for cancer, these results may suggest that obese group is more susceptible to lung cancer when exposed to cigarette smoke.« less

Metabolite signatures in hydrophilic extracts of mouse lungs exposed to cigarette smoke revealed by 1H NMR metabolomics investigation

DOE PAGES

Hu, Jian Z.; Wang, Xuan; Feng, Ju; ...

2015-05-12

Herein, 1H-NMR metabolomics are carried out to evaluate the changes of metabolites in lungs of mice exposed to cigarette smoke. It is found that the concentrations of adenosine derivatives (i.e. ATP, ADP and AMP), inosine and uridine are significantly fluctuated in the lungs of mice exposed to cigarette smoke compared with those of controls regardless the mouse is obese or regular weight. The decreased ATP, ADP, AMP and elevated inosine predict that the deaminases in charge of adenosine derivatives to inosine derivatives conversion are altered in lungs of mice exposed to cigarette smoke. Transcriptional analysis reveals that the concentrations ofmore » adenosine monophosphate deaminase and adenosine deaminase are different in the lungs of mice exposed to cigarette smoke, confirming the prediction from metabolomics studies. We also found, for the first time, that the ratio of glycerophosphocholine (GPC) to phosphocholine (PC) is significantly increased in the lungs of obese mice compared with regular weight mice. The ratio of GPC/PC is further elevated in the lungs of obese group by cigarette smoke exposure. Since GPC/PC ratio is a known biomarker for cancer, these results may suggest that obese group is more susceptible to lung cancer when exposed to cigarette smoke.« less

The Lung Inflammation and Skeletal Muscle Wasting Induced by Subchronic Cigarette Smoke Exposure Are Not Altered by a High-Fat Diet in Mice

PubMed Central

Hansen, Michelle J.; Chen, Hui; Jones, Jessica E.; Langenbach, Shenna Y.; Vlahos, Ross; Gualano, Rosa C.; Morris, Margaret J.; Anderson, Gary P.

2013-01-01

Obesity and cigarette smoking independently constitute major preventable causes of morbidity and mortality and obesity is known to worsen lung inflammation in asthma. Paradoxically, higher body mass index (BMI) is associated with reduced mortality in smoking induced COPD whereas low BMI increases mortality risk. To date, no study has investigated the effect of a dietary-induced obesity and cigarette smoke exposure on the lung inflammation and loss of skeletal muscle mass in mice. Male BALB/c mice were exposed to 4 cigarettes/day, 6 days/week for 7 weeks, or sham handled. Mice consumed either standard laboratory chow (3.5 kcal/g, 12% fat) or a high fat diet (HFD, 4.3 kcal/g, 32% fat). Mice exposed to cigarette smoke for 7 weeks had significantly more inflammatory cells in the BALF (P<0.05) and the mRNA expression of pro-inflammatory cytokines and chemokines was significantly increased (P<0.05); HFD had no effect on these parameters. Sham- and smoke-exposed mice consuming the HFD were significantly heavier than chow fed animals (12 and 13%, respectively; P<0.05). Conversely, chow and HFD fed mice exposed to cigarette smoke weighed 16 and 15% less, respectively, compared to sham animals (P<0.05). The skeletal muscles (soleus, tibialis anterior and gastrocnemius) of cigarette smoke-exposed mice weighed significantly less than sham-exposed mice (P<0.05) and the HFD had no protective effect. For the first time we report that cigarette smoke exposure significantly decreased insulin-like growth factor-1 (IGF-1) mRNA expression in the gastrocnemius and tibialis anterior and IGF-1 protein in the gastrocnemius (P<0.05). We have also shown that cigarette smoke exposure reduced circulating IGF-1 levels. IL-6 mRNA expression was significantly elevated in all three skeletal muscles of chow fed smoke-exposed mice (P<0.05). In conclusion, these findings suggest that a down-regulation in local IGF-1 may be responsible for the loss of skeletal muscle mass following cigarette smoke exposure in mice. PMID:24260397

Silymarin inhibits ultraviolet radiation-induced immune suppression through DNA repair-dependent activation of dendritic cells and stimulation of effector T cells

PubMed Central

Vaid, Mudit; Prasad, Ram; Singh, Tripti; Elmets, Craig A.; Xu, Hui; Katiyar, Santosh K.

2013-01-01

Silymarin inhibits UVB-induced immunosuppression in mouse skin. To identify the molecular mechanisms underlying this effect, we used an adoptive transfer approach in which dendritic cells (DCs) from the draining lymph nodes of donor mice that had been UVB-exposed and sensitized to 2,4,-dinitrofluorobenzene (DNFB) were transferred into naïve recipient mice. The contact hypersensitivity (CHS) response of the recipient mice to DNFB was then measured. When DCs were obtained from UVB-exposed donor mice that were not treated with silymarin, the CHS response was suppressed confirming the role of DCs in the UVB-induced immunosuppression. Silymarin treatment of UVB-exposed donor mice relieved this suppression of the CHS response in the recipients. Silymarin treatment was associated with rapid repair of UVB-induced cyclobutane pyrimidine dimers (CPDs) in DCs and silymarin treatment did not prevent UV-induced immunosuppression in XPA-deficient mice which are unable to repair UV-induced DNA damage. The CHS response in mice receiving DCs from silymarin-treated UV-exposed donor mice also was associated with enhanced secretion of Th1-type cytokines and stimulation of T cells. Adoptive transfer of T cells revealed that transfer of either CD8+ or CD4+ cells from silymarin-treated, UVB-exposed donors resulted in enhancement of the CHS response. Cell culture study showed enhanced secretion of IL-2 and IFNγ by CD8+ T cells, and reduced secretion of Th2 cytokines by CD4+ cells, obtained from silymarin-treated UVB-exposed mice. These data suggest that DNA repair-dependent functional activation of DCs, a reduction in CD4+ regulatory T-cell activity, and stimulation of CD8+ effector T cells contribute to silymarin-mediated inhibition of UVB-induced immunosuppression. PMID:23395695

Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life

PubMed Central

Smith, Dani; Aherrera, Angela; Lopez, Armando; Neptune, Enid; Winickoff, Jonathan P.; Klein, Jonathan D.; Chen, Gang; Lazarus, Philip; Collaco, Joseph M.; McGrath-Morrow, Sharon A.

2015-01-01

Nicotine exposure has been associated with an increased likelihood of developing attention deficit hyperactivity disorder (ADHD) in offspring of mothers who smoked during pregnancy. The goal of this study was to determine if exposure to E-cigarette nicotine vapors during late prenatal and early postnatal life altered behavior in adult mice. Methods Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG) or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains. Results Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not. Conclusion Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth. PMID:26372012

Intermittent calorie restriction largely counteracts the adverse health effects of a moderate-fat diet in aging C57BL/6J mice.

PubMed

Rusli, Fenni; Lute, Carolien; Boekschoten, Mark V; van Dijk, Miriam; van Norren, Klaske; Menke, Aswin L; Müller, Michael; Steegenga, Wilma T

2017-05-01

Calorie restriction (CR) has been shown to extend life- and health-span in model species. For most humans, a life-long CR diet is too arduous to adhere to. The aim of this study was to explore whether weekly intermittent CR can (1) provide long-term beneficial effects and (2) counteract diet-induced obesity in male aging mice. In this study, we have exposed C57Bl/6J mice for 24 months to an intermittent (INT) diet, alternating weekly between CR of a control diet and ad libitum moderate-fat (MF) feeding. This weekly intermittent CR significantly counteracted the adverse effects of the MF diet on mortality, body weight, and liver health markers in 24-month-old male mice. Hepatic gene expression profiles of INT-exposed animals appeared much more comparable to CR- than to MF-exposed mice. At 12 months of age, a subgroup of MF-exposed mice was transferred to the INT diet. Gene expression profiles in the liver of the 24-month-old diet switch mice were highly similar to the INT-exposed mice. However, a small subset of genes was consistently changed by the MF diet during the first phase of life. Weekly intermittent CR largely, but not completely, reversed adverse effects caused by a MF diet. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Abnormal epithelial structure and chronic lung inflammation after repair of chlorine-induced airway injury

PubMed Central

Mo, Yiqun; Chen, Jing; Humphrey, David M.; Fodah, Ramy A.; Warawa, Jonathan M.

2014-01-01

Chlorine is a toxic gas used in a variety of industrial processes and is considered a chemical threat agent. High-level chlorine exposure causes acute lung injury, but the long-term effects of acute chlorine exposure are unclear. Here we characterized chronic pulmonary changes following acute chlorine exposure in mice. A/J mice were exposed to 240 parts per million-hour chlorine or sham-exposed to air. Chlorine inhalation caused sloughing of bronchial epithelium 1 day after chlorine exposure, which was repaired with restoration of a pseudostratified epithelium by day 7. The repaired epithelium contained an abnormal distribution of epithelial cells containing clusters of club or ciliated cells rather than the uniformly interspersed pattern of these cells in unexposed mice. Although the damaged epithelium in A/J mice was repaired rapidly, and minimal airway fibrosis was observed, chlorine-exposed mice developed pneumonitis characterized by infiltration of alveoli with neutrophils and prominent, large, foamy macrophages. Levels of CXCL1/KC, CXCL5/LPS-induced CXC chemokine, granulocyte colony-stimulating factor, and VEGF in bronchoalveolar (BAL) fluid from chlorine-exposed mice showed steadily increasing trends over time. BAL protein levels were increased on day 4 and remained elevated out to day 28. The number of bacteria cultured from lungs of chlorine-exposed mice 4 wk after exposure was not increased compared with sham-exposed mice, indicating that the observed pneumonitis was not driven by bacterial infection of the lung. The results indicate that acute chlorine exposure may cause chronic abnormalities in the lungs despite rapid repair of injured epithelium. PMID:25398987

Abnormal epithelial structure and chronic lung inflammation after repair of chlorine-induced airway injury.

PubMed

Mo, Yiqun; Chen, Jing; Humphrey, David M; Fodah, Ramy A; Warawa, Jonathan M; Hoyle, Gary W

2015-01-15

Chlorine is a toxic gas used in a variety of industrial processes and is considered a chemical threat agent. High-level chlorine exposure causes acute lung injury, but the long-term effects of acute chlorine exposure are unclear. Here we characterized chronic pulmonary changes following acute chlorine exposure in mice. A/J mice were exposed to 240 parts per million-hour chlorine or sham-exposed to air. Chlorine inhalation caused sloughing of bronchial epithelium 1 day after chlorine exposure, which was repaired with restoration of a pseudostratified epithelium by day 7. The repaired epithelium contained an abnormal distribution of epithelial cells containing clusters of club or ciliated cells rather than the uniformly interspersed pattern of these cells in unexposed mice. Although the damaged epithelium in A/J mice was repaired rapidly, and minimal airway fibrosis was observed, chlorine-exposed mice developed pneumonitis characterized by infiltration of alveoli with neutrophils and prominent, large, foamy macrophages. Levels of CXCL1/KC, CXCL5/LPS-induced CXC chemokine, granulocyte colony-stimulating factor, and VEGF in bronchoalveolar (BAL) fluid from chlorine-exposed mice showed steadily increasing trends over time. BAL protein levels were increased on day 4 and remained elevated out to day 28. The number of bacteria cultured from lungs of chlorine-exposed mice 4 wk after exposure was not increased compared with sham-exposed mice, indicating that the observed pneumonitis was not driven by bacterial infection of the lung. The results indicate that acute chlorine exposure may cause chronic abnormalities in the lungs despite rapid repair of injured epithelium. Copyright © 2015 the American Physiological Society.

Chronic cigarette smoke causes oxidative damage and apoptosis to retinal pigmented epithelial cells in mice.

PubMed

Fujihara, Masashi; Nagai, Norihiro; Sussan, Thomas E; Biswal, Shyam; Handa, James T

2008-09-01

The purpose of this study was to determine whether mice exposed to chronic cigarette smoke develop features of early age-related macular degeneration (AMD). Two month old C57Bl6 mice were exposed to either filtered air or cigarette smoke in a smoking chamber for 5 h/day, 5 days/week for 6 months. Eyes were fixed in 2.5% glutaraldehyde/2% paraformaldehyde and examined for ultrastructural changes by transmission electron microscopy. The contralateral eye was fixed in 2% paraformaldehyde and examined for oxidative injury to the retinal pigmented epithelium (RPE) by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG) immunolabeling and apoptosis by TUNEL labeling. Mice exposed to cigarette smoke had immunolabeling for 8-OHdG in 85+/-3.7% of RPE cells counted compared to 9.5+/-3.9% in controls (p<0.00001). Bruch membrane was thicker in mice exposed to smoke (1086+/-332 nm) than those raised in air (543+/-132 nm; p = 0.0069). The two most pronounced ultrastructural changes (severity grading scale from 0-3) seen were a loss of basal infoldings (mean difference in grade = 1.98; p<0.0001), and an increase in intracellular vacuoles (mean difference in grade = 1.7; p<0.0001). Ultrastructural changes to Bruch membrane in cigarette-smoke exposed mice were smaller in magnitude but consistently demonstrated significantly higher grade injury in cigarette-exposed mice, including basal laminar deposits (mean difference in grade = 0.54; p<0.0001), increased outer collagenous layer deposits (mean difference in grade = 0.59; p = 0.002), and increased basal laminar deposit continuity (mean difference in grade = 0.4; p<0.0001). TUNEL assay showed a higher percentage of apoptotic RPE from mice exposed to cigarette smoke (average 8.0+/-1.1%) than room air (average 0+/-0%; p = 0.043). Mice exposed to chronic cigarette smoke develop evidence of oxidative damage with ultrastructural degeneration to the RPE and Bruch membrane, and RPE cell apoptosis. This model could be useful for studying the mechanism of smoke induced changes during early AMD.

Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes

PubMed Central

2014-01-01

Background Engineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation. Results Twenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms. Conclusions These data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT. PMID:24405760

Protective propensity of bacoside A and bromelain on renal cholinesterases, γ-Aminobutyric acid and serotonin level of Mus musculus intoxicated with dichlorvos.

PubMed

Agarwal, Sonam; Chaudhary, Bharti; Bist, Renu

2017-01-05

Current study established a protective action of bacoside A and bromelain against the toxic effects of dichlorvos in kidneys of mice. Experimental design included five groups. The first group was control. Mice of groups II, III and IV were administered doses of dichlorvos, bromelain and bacoside A respectively. In group V, mice were treated with both the antioxidants (bacoside A and bromelain) and dichlorvos. After 21 days of exposure of different doses, levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), γ-aminobutyric acid (GABA) and serotonin were measured in renal tissues. Dichlorvos significantly reduced the kidney AChE (p < 0.001), BChE (p < 0.01) and GABA level (p < 0.01) compared to control. A simultaneous significant elevation in the serotonin level (p < 0.01) was recorded after dichlorvos exposure. Concomitant exposure of bacoside A and bromelain followed by dichlorvos treatment in group V not only restored, but increased the renal cholinesterases and GABA level. Meanwhile, a significant decline in serotonin level (p < 0.001) was revealed, compared to dichlorvos exposed mice. Bacoside A and bromelain occupy a tremendous antioxidant action in the mice kidneys and a combination of the same ameliorates the renal toxicity induced by dichlorvos. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

NTP Toxicology and Carcinogenesis Studies of Molybdenum Trioxide (CAS No. 1313-27-5) in F344 Rats and B6C3F1 Mice (Inhalation Studies).

PubMed

1997-04-01

Molybdenum is an essential element for the function of nitrogenase in plants and as a cofactor for enzymes including xanthine oxidoreductase, aldehyde oxidase, and sulfide oxidase in animals. Molybdenum trioxide is used primarily as an additive to steel and corrosion-resistant alloys. It is also used as a chemical intermediate for molybdenum products; an industrial catalyst; a pigment; a crop nutrient; components of glass, ceramics, and enamels; a flame retardant for polyester and polyvinyl chloride resins; and a reagent in chemical analyses. Molybdenum trioxide was nominated by the NCI for toxicity and carcinogenicity studies as a representative inorganic molybdenum compound. The production of molybdenum trioxide is the largest of all the molybdenum compounds examined. Male and female F344/N rats and B6C3F1 mice were exposed to molybdenum trioxide (approximately 99% pure) by inhalation for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 3, 10, 30, 100, or 300 mg molybdenum trioxide/m(3). Rats were exposed for 6 hours per day, 5 days per week, for a total of 10 exposure days during a 14-day period. All rats survived to the end of the study. The final mean body weights of male rats exposed to 100 mg/m(3) and male and female rats exposed to 300 mg/m(3) were significantly lower than those of the control groups. Male rats exposed to 300 mg/m(3) lost weight during the study. There were no clinical findings related to exposure to molybdenum trioxide. No chemical-related lesions were observed. 14-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 3, 10, 30, 100, or 300 mg molybdenum trioxide/m(3). Mice were exposed 6 hours per day, 5 days per week, for a total of 10 exposure days during a 14-day period. All mice survived to the end of the study. Final mean body weights of male and female mice exposed to 300 mg/m(3) were significantly lower than those of the control groups. Male mice exposed to 300 mg/m(3) lost weight during the study. There were no clinical findings related to exposure to molybdenum trioxide. No chemical-related lesions were observed. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to molybdenum trioxide by inhalation at concentrations of 0, 1, 3, 10, 30, or 100 mg/m(3) for 6.5 hours per day, 5 days per week, for 13 weeks. All rats survived to the end of the study. The final mean body weights of exposed rats were similar to those of the control groups. No clinical findings related to molybdenum trioxide exposure were observed. There were no significant chemical-related differences in absolute or relative organ weights, hematology or clinical chemistry parameters, sperm counts or motility, or liver copper concentrations between control and exposed rats. No chemical-related lesions were observed. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to molybdenum trioxide by inhalation at concentrations of 0, 1, 3, 10, 30, or 100 mg/m(3) for 6.5 hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weights of exposed mice were similar to those of the control groups. There were no chemical-related clinical findings. There were no significant differences in absolute or relative organ weights or sperm counts or motility between control and exposed mice. There were significant increases in liver copper concentrations in female mice exposed to 30 mg/m(3) and in male and female mice exposed to 100 mg/m(3) compared to those of the control groups. No chemical-related lesions were observed. 2-YEAR STUDIES IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to molybdenum trioxide by inhalation at concentrations of 0, 10, 30, or 100 mg/m(3). Rats were exposed for 6 hours per day, 5 days per week, for 106 weeks. Survival, Body Weights, and Special Studies: Survival rates of exposed maleed male and female rats were similar to those of the control groups. Mean body weights of exposed groups of male and female rats were similar to those of the control groups throughout the study. There was a significant exposure-dependent increase in blood molybdenum concentration in exposed rats. Blood concentrations of molybdenum in exposed male rats were greater than those in exposed female rats. There were no toxicologically significant differences in bone density or curvature between control and exposed rats. Pathology Findings: The incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were increased in male rats with a marginally significant positive trend. No increase in the incidences of lung neoplasms occurred in female rats. Incidences of chronic alveolar inflammation in male and female rats exposed to 30 or 100 mg/m(3) were significantly greater than those in the control groups. No nasal or laryngeal neoplasms were attributed to exposure to molybdenum trioxide. Incidences of hyaline degeneration in the nasal respiratory epithelium in 30 and 100 mg/m(3) males and in all exposed groups of females were significantly greater than those in the control groups. The incidences of hyaline degeneration in the nasal olfactory epithelium of all exposed groups of females were significantly greater than that in the control group. In the larynx, incidences of squamous metaplasia of the epithelium lining the base of the epiglottis in all exposed groups of male and female rats were significantly greater than those in the control groups and increased with increasing exposure concentration. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were exposed to molybdenum trioxide by inhalation at concentrations of 0, 10, 30, or 100 mg/m(3). Mice were exposed for 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Special Studies: The survival rate of male mice exposed to 30 mg/m(3) was marginally lower than that of the control group; survival rates of 10 and 100 mg/m(3) males and of all exposed groups of females were similar to those of the control groups. Mean body weights of exposed male mice were generally similar to those of the control group throughout the study. Mean body weights of exposed female mice were generally greater than those of the control group from week 11 until the end of the study. There was a significant exposure-dependent increase in blood molybdenum concentration in exposed mice. There were no toxicologically significant differences in bone density or curvature between control and exposed mice. Pathology Findings: The incidences of alveolar/bronchiolar carcinoma in all exposed groups of males were significantly greater than that in the control group. Incidences of alveolar/bronchiolar adenoma in females in the 30 and 100 mg/m(3) groups were significantly greater than that in the control group. Incidences of alveolar/bronchiolar adenoma or carcinoma (combined) in 10 and 30 mg/m(3) males and in 100 mg/m(3) females were significantly greater than those in the control groups and exceeded the historical control ranges for 2-year NTP inhalation studies. Incidences of metaplasia of the alveolar epithelium of minimal severity in the centriacinar region of the lung were significantly increased in all exposed groups of mice. The incidences of histiocyte cellular infiltration in all exposed groups of males were significantly greater than that in the control group. Incidences of hyaline degeneration of the respiratory epithelium of the nasal cavity in 100 mg/m(3) males and females and hyaline degeneration of the olfactory epithelium of the nasal cavity in 100 mg/m(3) females were significantly greater than those in the control groups. The incidences of squamous metaplasia of the epithelium lining the base of the epiglottis were significantly increased in all exposed groups of males and females. In both male and female mice, the incidences of hyperplasia of the laryngeal epithelium in level II of the larynx increased with increasing exposure concentration. The increase was statistically significant only in mice exposed to 100 mg/m(3) with 82% of male and 70% of female mice affected. GENETIC TOXICOLOGY: Molybdenum trioxide was not mutagenic in any of five strains of Salmonella typhimurium, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells in vitro. All tests were conducted with and without S9 metabolic activation enzymes. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of molybdenum trioxide in male F344/N rats based on a marginally significant positive trend of alveolar/bronchiolar adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of molybdenum trioxide in female F344/N rats exposed to 10, 30, or 100 mg/m(3). There was some evidence of carcinogenic activity of molybdenum trioxide in male B6C3F1 mice based on increased incidences of alveolar/bronchiolar carcinoma and adenoma or carcinoma (combined). There was some evidence of carcinogenic activity of molybdenum trioxide in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenoma and adenoma or carcinoma (combined). Exposure of male and female rats to molybdenum trioxide by inhalation resulted in increased incidences of chronic alveolar inflammation, hyaline degeneration of the respiratory epithelium, hyaline degeneration of the olfactory epithelium (females), and squamous metaplasia of the epiglottis. Exposure of male and female mice to molybdenum trioxide by inhalation resulted in increased incidences of metaplasia of the alveolar epithelium, histiocyte cellular infiltration (males), hyaline degeneration of the respiratory epithelium, hyaline degeneration of the olfactory epithelium (females), squamous metaplasia of the epiglottis, and hyperplasia of the larynx. Synonyms: Molybdic oxide; molybdic trioxide; molybdic anhydride; molybdenum (VI) oxide; molybdenum peroxide; molybdic acid anhydride; molybdenum anhydride; natural molybdite; molybdena

Social Isolation-Induced Territorial Aggression in Male Offspring Is Enhanced by Exposure to Diesel Exhaust during Pregnancy

PubMed Central

Yokota, Satoshi; Oshio, Shigeru; Moriya, Nozomu; Takeda, Ken

2016-01-01

Diesel exhaust particles are a major component of ambient particulate matter, and concern about the health effects of exposure to ambient particulate matter is growing. Previously, we found that in utero exposure to diesel exhaust affected locomotor activity and motor coordination, but there are also indications that such exposure may contribute to increased aggression in offspring. Therefore, the aim of the present study was to test the effects of prenatal diesel exhaust exposure on social isolation-induced territorial aggression. Pregnant mice were exposed to low concentrations of diesel exhaust (DE; mass concentration of 90 μg/m3: DE group: n = 15) or clean air (control group: n = 15) for 8 h/day during gestation. Basal locomotion of male offspring was measured at 10 weeks of age. Thereafter, male offspring were individually housed for 2 weeks and subsequently assessed for aggression using the resident−intruder test at 12 weeks of age, and blood and brain tissue were collected from the male offspring on the following day for measuring serum testosterone levels and neurochemical analysis. There were no significant differences in locomotion between control and DE-exposed mice. However, DE-exposed mice showed significantly greater social isolation-induced territorial aggressive behavior than control mice. Additionally, socially-isolated DE-exposed mice expressed significantly higher concentrations of serum testosterone levels than control mice. Neurochemical analysis revealed that dopamine levels in the prefrontal cortex and nucleus accumbens were higher in socially isolated DE-exposed mice. Serotonin levels in the nucleus accumbens, amygdala, and hypothalamus were also lower in the socially isolated DE-exposed mice than in control mice. Thus, even at low doses, prenatal exposure to DE increased aggression and serum testosterone levels, and caused neurochemical changes in male socially isolated mice. These results may have serious implications for pregnant women living in regions with high levels of traffic-related air pollution. PMID:26919122

Continuous exposure to a novel stressor based on water aversion induces abnormal circadian locomotor rhythms and sleep-wake cycles in mice.

PubMed

Miyazaki, Koyomi; Itoh, Nanako; Ohyama, Sumika; Kadota, Koji; Oishi, Katsutaka

2013-01-01

Psychological stressors prominently affect diurnal rhythms, including locomotor activity, sleep, blood pressure, and body temperature, in humans. Here, we found that a novel continuous stress imposed by the perpetual avoidance of water on a wheel (PAWW) affected several physiological diurnal rhythms in mice. One week of PAWW stress decayed robust circadian locomotor rhythmicity, while locomotor activity was evident even during the light period when the mice are normally asleep. Daytime activity was significantly upregulated, whereas nighttime activity was downregulated, resulting in a low amplitude of activity. Total daily activity gradually decreased with increasing exposure to PAWW stress. The mice could be exposed to PAWW stress for over 3 weeks without adaptation. Furthermore, continuous PAWW stress enhanced food intake, but decreased body weight and plasma leptin levels, indicating that sleep loss and PAWW stress altered the energy balance in these mice. The diurnal rhythm of corticosterone levels was not severely affected. The body temperature rhythm was diurnal in the stressed mice, but significantly dysregulated during the dark period. Plasma catecholamines were elevated in the stressed mice. Continuous PAWW stress reduced the duration of daytime sleep, especially during the first half of the light period, and increased nighttime sleepiness. Continuous PAWW stress also simultaneously obscured sleep/wake and locomotor activity rhythms compared with control mice. These sleep architecture phenotypes under stress are similar to those of patients with insomnia. The stressed mice could be entrained to the light/dark cycle, and when they were transferred to constant darkness, they exhibited a free-running circadian rhythm with a timing of activity onset predicted by the phase of their entrained rhythms. Circadian gene expression in the liver and muscle was unaltered, indicating that the peripheral clocks in these tissues remained intact.

Benzene inhalation effects upon tetanus antitoxin. Responses and leukemogenesis in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stoner, R D; Drew, R T; Bernstein, D M

1980-01-01

The effects of inhaled benzene on primary and secondary antibody responses and the incidence of leukemia in mice are reported. Young adult mice were given 5, 12, or 22 exposures to 400 ppM benzene for 6 hrs/day 5 days/week. After the exposure periods, the mice were immunized with absorbed tetanus toxoid (APTT) and/or fluid tetanus toxid (FTT). Exposure to benzene increasingly suppressed primary antibody responses to both antigens. Secondary antibody responses to FTT were nearly normal in animals given 10, 15, or 20 exposures to 400 ppM benzene. Other groups of mice were exposed to either 200 ppM or 50more » ppM benzene. Primary antibody responses elicited with FTT and/or APTT were nearly normal in all mice exposed to 50 ppM benzene and in mice exposed to 200 ppM benzene for 5 days. However, 10 and 20 exposures to 200 ppM benzene inhibited antibody production. The effects of chronically inhaled 300 ppM benzene on the time of onset and incidence of leukemia in 400 7-month-old female HRS/J mice were also studied. Two genotypes were used; the (hr/hr) hairless mice are leukemia-prone, whereas the (hr/+) haired mice are more resistant to leukemia. The exposure continued for a period of 6 months. Lymphoid, myeloid, and mixed (lymphoid and myeloid) leukemias were observed. Ninety percent of the (hr/hr) mice exposed to benzene died from leukemia as compared with 91% for the (hr/hr) air control group. Eighty-five percent of the (hr/+) mice exposed to benzene died from leukemia as compared with 81% for the (hr/+) air control group. Exposures to 300 ppM benzene did not alter the time of onset or the incidence of leukemia commonly expected in HRS/J mice.« less

Whole DNA methylome profiling in mice exposed to secondhand smoke.

PubMed

Tommasi, Stella; Zheng, Albert; Yoon, Jae-In; Li, Arthur Xuejun; Wu, Xiwei; Besaratinia, Ahmad

2012-11-01

Aberration of DNA methylation is a prime epigenetic mechanism of carcinogenesis. Aberrant DNA methylation occurs frequently in lung cancer, with exposure to secondhand smoke (SHS) being an established risk factor. The causal role of SHS in the genesis of lung cancer, however, remains elusive. To investigate whether SHS can cause aberrant DNA methylation in vivo, we have constructed the whole DNA methylome in mice exposed to SHS for a duration of 4 mo, both after the termination of exposure and at ensuing intervals post-exposure (up to 10 mo). Our genome-wide and gene-specific profiling of DNA methylation in the lung of SHS-exposed mice revealed that all groups of SHS-exposed mice and controls share a similar pattern of DNA methylation. Furthermore, the methylation status of major repetitive DNA elements, including long-interspersed nuclear elements (LINE L1), intracisternal A particle long-terminal repeat retrotransposons (IAP-LTR), and short-interspersed nuclear elements (SINE B1), in the lung of all groups of SHS-exposed mice and controls remains comparable. The absence of locus-specific gain of DNA methylation and global loss of DNA methylation in the lung of SHS-exposed mice within a timeframe that precedes neoplastic-lesion formation underscore the challenges of lung cancer biomarker development. Identifying the initiating events that cause aberrant DNA methylation in lung carcinogenesis may help improve future strategies for prevention, early detection and treatment of this highly lethal disease.

Antioxidant Diet Protects Against Emphysema, but Increases Mortality in Cigarette Smoke-Exposed Mice

PubMed Central

Nyunoya, Toru; March, Thomas H.; Tesfaigzi, Yohannes; Seagrave, JeanClare

2012-01-01

Oxidative stress plays an important role in cigarette smoke-induced lung inflammation and emphysema. We produced an enriched diet by adding freeze-dried fruits and vegetables and additional supplements to the 8604 Teklad Rodent Diet, a standard rodent diet. In this study, we examined the effects of the antioxidant-enriched diet on cigarette smoke-induced lung inflammation and emphysema. CH3/HeN mice were fed either a regular diet or an antioxidant diet. These mice were exposed to filtered air, a low concentration of cigarette smoke (total particulate matter: 100 mg/m3) or a high concentration of cigarette smoke (total particulate matter: 250mg/m3) for 6 hours/day, 5 days/week for total 16 weeks. Surprisingly, increased mortality (53%) was observed in the high concentration of cigarette smoke-exposed mice fed the antioxidant diet compared to the high concentration of cigarette smoke-exposed mice that were fed a regular diet (13%). The necropsy analysis revealed nasal passage obstruction due to mucous plugging in cigarette smoke-exposed mice on the antioxidant diet. However, the antioxidant diet significantly reduced neutrophilic inflammation and emphysema in the high concentration of cigarette smoke-exposed mice as compared to the regular diet /high concentration of cigarette smoke controls. The antioxidant capacity in the bronchoalveolar fluid or oxidative damage to the lung tissue was not affected by the antioxidant diet. Pro-MMP-2, MMP-2, and MMP-9 activity did not correlate with the protective effects of AOD on cigarette smoke-induced emphysema. These data suggest that the antioxidant diet reduced cigarette smoke -induced inflammation and emphysema, but increased mortality in the obligate nose-breathing mice. PMID:21834692

Early gestational exposure to moderate concentrations of ethanol alters adult behaviour in C57BL/6J mice.

PubMed

Sanchez Vega, Michelle C; Chong, Suyinn; Burne, Thomas H J

2013-09-01

Alcohol consumption during pregnancy has deleterious effects on the developing foetus ranging from subtle physical deficits to severe behavioural abnormalities and is encompassed under a broad umbrella term, foetal alcohol spectrum disorders (FASD). High levels of exposure show distinct effects, whereas the consequences of moderate exposures have been less well studied. The aim of this study was to examine the effects of a moderate dose ethanol exposure using an ad libitum drinking procedure during the first eight days of gestation in mice on the behavioural phenotype of adult offspring. Adult female C57Bl/6J mice were mated and exposed to either 10% (v/v) ethanol or water for the first 8 days of gestation (GD 0-8), and then offered water for the rest of gestation. Early developmental milestone achievement was assessed in offspring at postnatal days (P) 7, 14 and 21. Adult offspring underwent a comprehensive battery of behavioural tests to examine a range of behavioural domains including locomotion, exploration, anxiety, social behaviour, learned helplessness, sensorimotor gating, and nociception, as well as spatial memory in a water maze. Ethanol-exposed mice had similar postnatal developmental trajectories to water-exposed mice. However, the ethanol-exposed mice showed increased hyperlocomotion at P 14, 21 and 70 (p<0.05). Increased exploration and heightened motivation were also observed in adult mice. Furthermore, ethanol-exposed mice showed a significant improvement in memory in the water maze. The main findings were that mice had persistent and long lasting alterations in behaviour, including hyperactivity and enhanced spatial memory. These data suggest that even moderate dose ethanol exposure in early gestation has long term consequences on brain function and behaviour in mice. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Effects of day-length variations on emotional responses towards unfamiliarity in Swiss mice.

PubMed

Kopp, C; Misslin, R; Vogel, E; Rettori, M C; Delagrange, P; Guardiola-Lemaitre, B

1997-11-01

Pineal melatonin secretion occurs at night in all vertebrates and the duration of its secretion is negatively correlated with day length. As an anxiolytic activity of melatonin has been shown in rats and mice, this study examined possible changes of emotional reactivity in response to day length variations in Swiss mice. Three groups of mice were observed in a free-exploratory test: a group submitted to a short-day exposure (6:18 h light-dark cycle) for 2 weeks, a group submitted to a long-day exposure (18:6 h light-dark cycle) for 2 weeks and a control group which was maintained in housing 12:12 h light-dark cycle. The short-day exposed group of mice exhibited significantly fewer attempts to enter into the unfamiliar enclosure, spent significantly more time in it and presented significantly more rears than controls whereas the long-day exposed group of mice made more attempts than controls. These results suggest a decreased emotional level in short-day exposed mice and an increased level in long-day exposed mice. This could be interpreted as confirming the idea of anxiolytic-like properties of melatonin; however, the specific role of this hormone in the changes of anxiety related to day length must be assessed by further measures of potential variations of circulating melatonin.

ALTERATION OF CIRCULATING ANTIBODY RESPONSE OF MICE EXPOSED TO 9-GHZ PULSED MICROWAVES

EPA Science Inventory

A significant increase was observed in the circulating antibody titers of mice exposed to 9-GHz pulsed microwaves at an average power density of 10 mW/sq. cm., two hours per day for five days compared with sham-irradiated animals. The mice were previously immunized with type III ...

Emergence of delayed behavioral effects in offspring mice exposed to low levels of mercury vapor during the lactation period.

PubMed

Yoshida, Minoru; Watanabe, Chiho; Honda, Akiko; Satoh, Masahiko; Yasutake, Akira

2013-02-01

This study examined the emergence of delayed behavioral effects in offspring mice exposed to low levels of mercury vapor (Hg(0)) during the lactation period. Female offspring of mice were repeatedly exposed to Hg(0) at 0.057 mg/m(3), similar to the current threshold value (TLV), for 24 hr until the 20(th) day postpartum. The behavioral effects were evaluated with locomotor activity in the open field (OPF), learning activity in the passive avoidance response (PA) and spatial learning ability in the Morris water maze (MM) at the ages of 3 and 15 months. Hg(0)-exposed mice did not differ from controls in the three behavioral measurements at 3 months of age, and no neurobehavioral effects were observed. On the other hand, the mice exhibited significantly more central locomotion in the OPF task when tested at 15 months of age, but no abnormality in other behavioral performance. Immediately after postnatal exposure, the brain mercury concentration of offspring was about 150 times that of the control, in which the concentrations were approximately 0.4 µg/g. The results indicate that mice exposed to Hg(0) at concentrations around TLV during the developing period resulted in the emergence of delayed behavioral effects at a later stage in life.

Altered expressions of fibroblast growth factor receptors and alveolarization in neonatal mice exposed to 85% oxygen.

PubMed

Park, Min Soo; Rieger-Fackeldey, Esther; Schanbacher, Brandon L; Cook, Angela C; Bauer, John A; Rogers, Lynette K; Hansen, Thomas N; Welty, Stephen E; Smith, Charles V

2007-12-01

In the present study, we tested the hypothesis that exposure of newborn mice to sublethal hyperoxia would alter lung development and expressions of fibroblast growth factor receptors (FGFRs)-3 and FGFR-4. Newborn FVB mice were exposed to 85% O2 or maintained in room air for up to 14 d. No animal mortality was observed, and body weight gains were not affected by hyperoxia. At postnatal d 7 and 14 (P7, P14), lungs of mice exposed to 85% O2 showed fewer alveolar secondary crests and larger alveoli or terminal air spaces than did mice in room air. In pups kept in room air, lung levels of FGFR-3 and FGFR-4 mRNA were greater at P3 than at P1, but similar increases were not observed in hyperoxic mice. Immunoreactivity of FGFR-3 and FGFR-4 was lower in lungs of hyperoxic mice than in controls at P14. In pups kept in room air, lung fibroblast growth factor (FGF)-7 mRNA levels were greater at P14 than at P1, but similar changes were not observed in hyperoxic mice. The temporally and spatially specific alterations in the expressions of FGFR-3, FGFR-4, and FGF-7 in the mice exposed to hyperoxia may contribute to aberrant lung development.

Acute and chronic in vivo effects of exposure to nicotine and propylene glycol from an E-cigarette on mucociliary clearance in a murine model

PubMed Central

Laube, Beth L.; Afshar-Mohajer, Nima; Koehler, Kirsten; Chen, Gang; Lazarus, Philip; Collaco, Joseph M.; McGrath-Morrow, Sharon A.

2017-01-01

Objective To determine the effect of an acute (1 week) and chronic (3 weeks) exposure to E-cigarette (E-cig) emissions on mucociliary clearance (MCC) in murine lungs. Methods C57BL/6 male mice (age 10.5 ±2.4 weeks) were exposed for 20min/day to E-cigarette aerosol generated by a Joyetech 510-T® E-cig containing either 0% nicotine (N)/propylene glycol (PG) for 1 week (n = 6), or 3 weeks (n = 9), or 2.4% N/PG for one week (n = 6), or 3 weeks (n = 9), followed by measurement of MCC. Control mice (n = 15) were not exposed to PG alone, or N/PG. MCC was assessed by gamma camera following aspiration of 99mtechnetium aerosol and was expressed as the amount of radioactivity removed from both lungs over 6 hours (MCC6hrs). Venous blood was assayed for cotinine levels in control mice and in mice exposed for 3-weeks to PG alone and N/PG. Results MCC6hrs in control mice and in mice acutely exposed to PG alone and N/PG was similar, averaging (±1 standard deviation) 8.6±5.2%, 7.5±2.8% and 11.2±5.9%, respectively. In contrast, chronic exposure to PG alone stimulated MCC6hrs (17.2 ±8.0)% and this stimulation was significantly blunted following chronic exposure to N/PG (8.7 ±4.6)% (p < .05). Serum cotinine levels were <0.5ng/ml in control mice and in mice exposed to PG alone, whereas, N/PG exposed mice averaged 14.6 ± 12.0 ng/ml. Conclusions In this murine model, a chronic, daily, 20 min-exposure to N/PG, but not an acute exposure, slowed MCC, compared to exposure to PG alone and led to systemic absorption of nicotine. PMID:28651446

Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE-/- mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srivastava, Sanjay, E-mail: sanjay@louisville.ed; Center for Environmental Genomics and Integrative Biology, University of Louisville, Louisville, KY 40202; Vladykovskaya, Elena N.

2009-11-15

Exposure to arsenic-contaminated water has been shown to be associated with cardiovascular disease, especially atherosclerosis. We examined the effect of arsenic exposure on atherosclerotic lesion formation, lesion composition and nature in ApoE-/- mice. Early post-natal exposure (3-week-old mice exposed to 49 ppm arsenic as NaAsO{sub 2} in drinking water for 7 weeks) increased the atherosclerotic lesion formation by 3- to 5-fold in the aortic valve and the aortic arch, without affecting plasma cholesterol. Exposure to arsenic for 13 weeks (3-week-old mice exposed to 1, 4.9 and 49 ppm arsenic as NaAsO{sub 2} in drinking water) increased the lesion formation andmore » macrophage accumulation in a dose-dependent manner. Temporal studies showed that continuous arsenic exposure significantly exacerbated the lesion formation throughout the aortic tree at 16 and 36 weeks of age. Withdrawal of arsenic for 12 weeks after an initial exposure for 21 weeks (to 3-week-old mice) significantly decreased lesion formation as compared with mice continuously exposed to arsenic. Similarly, adult exposure to 49 ppm arsenic for 24 weeks, starting at 12 weeks of age increased lesion formation by 2- to 3.6-fold in the aortic valve, the aortic arch and the abdominal aorta. Lesions of arsenic-exposed mice displayed a 1.8-fold increase in macrophage accumulation whereas smooth muscle cell and T-lymphocyte contents were not changed. Expression of pro-inflammatory chemokine MCP-1 and cytokine IL-6 and markers of oxidative stress, protein-HNE and protein-MDA adducts were markedly increased in lesions of arsenic-exposed mice. Plasma concentrations of MCP-1, IL-6 and MDA were also significantly elevated in arsenic-exposed mice. These data suggest that arsenic exposure increases oxidative stress, inflammation and atherosclerotic lesion formation.« less

Effects of a fire alarm strobe light on fecal corticosterone metabolite concentrations in mice.

PubMed

Godfrey, Denice; Silverman, Jerald

2009-02-01

The type and location of fire alarms are important considerations in animal facility design. The Guide for the Care and Use of Laboratory Animals recommends minimizing animal exposure to such alarms. Nevertheless, it is often necessary to maintain fire alarms within animal housing or procedural areas. The authors exposed male mice to the flashing strobe light component of a standard fire alarm and evaluated mouse fecal corticosterone concentration, which is known to be an indicator of stress. Mice were exposed to the strobe light for 5 min during either the light or the dark phase of the light:dark cycle. The authors collected fecal samples every 6 h for 24 h before exposing mice to the alarm and every 6 h for 24 h after exposure. Fecal samples taken before exposure (baseline samples) showed a normal circadian pattern of corticosterone metabolite excretion. In fecal samples taken after mice were exposed to the fire alarm, metabolite concentrations did not significantly differ from baseline concentrations over time.

Whole DNA methylome profiling in mice exposed to secondhand smoke

PubMed Central

Tommasi, Stella; Zheng, Albert; Yoon, Jae-In; Li, Arthur Xuejun; Wu, Xiwei; Besaratinia, Ahmad

2012-01-01

Aberration of DNA methylation is a prime epigenetic mechanism of carcinogenesis. Aberrant DNA methylation occurs frequently in lung cancer, with exposure to secondhand smoke (SHS) being an established risk factor. The causal role of SHS in the genesis of lung cancer, however, remains elusive. To investigate whether SHS can cause aberrant DNA methylation in vivo, we have constructed the whole DNA methylome in mice exposed to SHS for a duration of 4 mo, both after the termination of exposure and at ensuing intervals post-exposure (up to 10 mo). Our genome-wide and gene-specific profiling of DNA methylation in the lung of SHS-exposed mice revealed that all groups of SHS-exposed mice and controls share a similar pattern of DNA methylation. Furthermore, the methylation status of major repetitive DNA elements, including long-interspersed nuclear elements (LINE L1), intracisternal A particle long-terminal repeat retrotransposons (IAP-LTR), and short-interspersed nuclear elements (SINE B1), in the lung of all groups of SHS-exposed mice and controls remains comparable. The absence of locus-specific gain of DNA methylation and global loss of DNA methylation in the lung of SHS-exposed mice within a timeframe that precedes neoplastic-lesion formation underscore the challenges of lung cancer biomarker development. Identifying the initiating events that cause aberrant DNA methylation in lung carcinogenesis may help improve future strategies for prevention, early detection and treatment of this highly lethal disease. PMID:23051858

Exposure of mice to secondhand smoke elicits both transient and long-lasting transcriptional changes in cancer-related functional networks.

PubMed

Tommasi, Stella; Zheng, Albert; Besaratinia, Ahmad

2015-05-15

Secondhand smoke (SHS) has long been linked to lung cancer and other diseases in nonsmokers. Yet, the underlying mechanisms of SHS carcinogenicity in nonsmokers remain to be elucidated. We investigated the immediate and long-lasting effects of SHS exposure on gene expression in mice in vivo. We exposed mice whole body to SHS for 5 h/day, 5 days/week for 4 months in exposure chambers of a microprocessor-controlled smoking machine. Subsequently, we performed microarray gene expression profiling, genome-wide, to construct the pulmonary transcriptome of SHS-exposed mice, immediately after discontinuation of exposure (T0) and following 1-month (T1) and 7-month (T2) recoveries in clean air. Sub-chronic exposure of mice to SHS elicited a robust transcriptomic response, including both reversible and irreversible changes in gene expression. There were 674 differentially expressed transcripts immediately after treatment (T0), of which the majority were involved in xenobiotic metabolism, signaling, and innate immune response. Reduced, yet, substantial numbers of differentially expressed transcripts were detectable in mice after cessation of SHS-exposure (254 transcripts at T1 and 30 transcripts at T2). Top biofunctional networks disrupted in SHS-exposed mice, even after termination of exposure, were implicated in cancer, respiratory disease, and inflammatory disease. Our data show that exposure of mice to SHS induces both transient and long-lasting changes in gene expression, which impact cancer-related functional networks. The pattern of transcriptional changes in SHS-exposed mice may provide clues on the underlying mechanisms of lung tumorigenesis in nonsmokers. Our findings underscore the importance of eliminating SHS from environments where nonsmokers are unavoidably exposed to this carcinogen. © 2014 UICC.

Experimental ultraviolet photocarcinogenesis: wavelength interactions and time-dose relationships.

PubMed

Forbes, P D; Davies, R E; Urbach, F

1978-12-01

Tumors were induced in the skin of SKH hairless mice by exposure to fluorescent FS sun lamps or to a long-arc xenon solar simulator. Tumores developed about equally well with varying amounts of UV-A radiation (lambda greater than 320 nm) given simultaneously. In contrast, incremental changes in the UV-B region (lambda less than 320 nm) led to substantial increases in carcinogenic effectiveness. A tumor-"initiating" dose of UV-B (4-10 wk of daily FS lamp exposures) was rendered less effective by subsequent exposures of the mice to UV-A (6 hr/day, F-40 T12BL lamps). The mechanism for this effect is not known. Most tumors induced by a short course (10 wk) of FS lamp exposure grew slowly or regressed, whereas mice exposed for a longer period (30 wk) developed more tumors, and many of those that appeared early grew aggressively. Effects of daily dose fractionation were less clear, and the subject requires further study. These and other variables are being tested in a program designed to yield useful information on the effects of changing spectrum, dose, and dose delivery rates on sunlight-induced cancer.

Analysis of PFOA in Dosed CD-1 Mice Part 2: Disposition of PFOA in Tissues and fluids from pregnant and lactating mice and their pups

EPA Science Inventory

Previous studies in mice with multiple gestational exposures to perfluorooctanoic acid (PFOA) demonstrate numerous dose dependent growth and developmental effects which appeared to worsen if offspring exposed in utero nursed from PFOA-exposed dams. To evaluate the disposition of ...

Histopathological and Ultrastructural Studies of Liver Tissue from TCDD-Exposed Beach Mice (Peromyscus polionotus).

DTIC Science & Technology

1980-03-01

TQuantitative ultrastructural studies were conducted on liver tissue f ran beach Lj mice, Per~ ascus polionotus, exposed to the toxin 2,3, 7f8...weights per se was not attempted since the ages of the beach mice were not known and the animals could only be classified by sex and treatment. The

Regulatory T cells and IL10 suppress pulmonary host defense during early-life exposure to radical containing combustion derived ultrafine particulate matter.

PubMed

Jaligama, Sridhar; Saravia, Jordy; You, Dahui; Yadav, Nikki; Lee, Greg I; Shrestha, Bishwas; Cormier, Stephania A

2017-01-13

Exposure to elevated levels of particulate matter (PM) is associated with increased risk of morbidity and mortality due to respiratory tract viral infections in infants. Recent identification of environmentally persistent free radicals (EPFRs) in the PM from a variety of combustion sources suggests its role in the enhancement of disease severity of lower respiratory tract infections (LRTI). Our previous studies demonstrated that acute exposure to EPFRs induces pulmonary immunosuppression allowing for enhanced influenza disease severity. Here, we determine the mechanism of EPFR-induced immunosuppression and its impact on the immune response towards influenza infection. Neonatal mice (3 days old) were acutely exposed to DCB (combustion derived PM with chemisorbed EPFR) for seven consecutive days. Four days post-exposure (dpe), mice were infected with influenza virus. Pulmonary T cell phenotypes including regulatory T cells (Tregs) were analyzed by flow cytometry. The role of IL10 in EPFR-induced exacerbation of influenza disease severity was determined by administering recombinant IL10 (rIL10) to wild type mice or by using IL10 deficient (IL10 -/- ) neonatal mice. Mice were assessed for morbidity by measuring percent weight change and pulmonary viral load. Neonatal mice exposed to EPFRs had a significant increase in pulmonary Tregs and the immunosuppressive cytokine IL10 following influenza infection, which coincided with decreased protective T cell responses to influenza infection at 6 dpi. Depletion of Tregs in EPFR-exposed neonatal mice resulted in increased protective, adaptive T cell responses, whereas adoptive transfer of Tregs from EPFR-exposed neonates to air-exposed neonatal mice suppressed adaptive T cell responses towards influenza infection. Further, treatment with rIL10 could recapitulate EPFR-induced exacerbation of morbidity and pulmonary viral load compared to air exposed and influenza infected mice, whereas, EPFR-exposed IL10 -/- neonates exhibited significant reductions in morbidity, pulmonary viral load and adaptive T cell responses following influenza infection. Neonatal exposure to EPFRs induced Tregs and IL10 resulting in suppressed adaptive T cell responses and enhanced influenza disease severity in neonatal mice. Depletion of Tregs increased adaptive T cell responses and deficiency of IL10 reduced morbidity and conferred enhanced protection against influenza virus.

Impact of Oral Fidaxomicin Administration on the Intestinal Microbiota and Susceptibility to Clostridium difficile Colonization in Mice.

PubMed

Ajami, N J; Cope, J L; Wong, M C; Petrosino, J F; Chesnel, L

2018-05-01

Clostridium difficile infection (CDI), a common cause of hospital-acquired infections, typically occurs after disruption of the normal gut microbiome by broad-spectrum antibiotics. Fidaxomicin is a narrow-spectrum antibiotic that demonstrates a reduced impact on the normal gut microbiota and is approved for the treatment of CDI. To further explore the benefits of this property, we used a murine model to examine the effects of fidaxomicin versus vancomycin on gut microbiota and susceptibility to C. difficile colonization while tracking microbiota recovery over time. Mice were exposed to fidaxomicin or vancomycin by oral gavage for 3 days and subsequently challenged with C. difficile spores at predetermined time points up to 21 days postexposure to antibiotics. Fecal samples were subsequently collected for analysis. Twenty-four hours postchallenge, mice were euthanized and the colon contents harvested. The microbiota was characterized using 16S rRNA gene sequencing. All fidaxomicin-exposed mice (except for one at day 8) were resistant to C. difficile colonization. However, 9 of 15 vancomycin-exposed mice were susceptible to C. difficile colonization until day 12. All vancomycin-exposed mice recovered colonization resistance by day 16. Bacterial diversity was similar prior to antibiotic exposure in both arms and decreased substantially after exposure. A shift in taxonomic structure and composition occurred after both exposures; however, the shift was greater in vancomycin-exposed than in fidaxomicin-exposed mice. In summary, compared with vancomycin, fidaxomicin exposure had less impact on microbiota composition, promoted faster microbial recovery, and had less impact on the loss of C. difficile colonization resistance. Copyright © 2018 American Society for Microbiology.

Effects of Long Term Exposure of 900-1800 MHz Radiation Emitted from 2G Mobile Phone on Mice Hippocampus- A Histomorphometric Study.

PubMed

Mugunthan, Narayanaperumal; Shanmugasamy, Kathirvelu; Anbalagan, Jayaram; Rajanarayanan, Swamynathan; Meenachi, Swamynathan

2016-08-01

The advancement in the telecommunications technology with multi-functional added features in mobile phone, attracts more users of all age group. It is alarming to note that, the mobile phone use has increased amongst children and they are exposed to potentially harmful radiofrequency radiation in their lifetime. To investigate the long term exposure of 900 to 1800 MHz radiations emitted from 2G mobile phone in mice hippocampus at histomorphometric level. With due approval from institutional animal ethics committee, 36 mice were exposed to 2G mobile phone radiation, 48 minutes per day for a period of 30-180 days. The control group was kept under similar conditions without 2G exposure. Mice were sacrificed and the brain was removed from the first month to six months period. Brain was removed from the cranial cavity and hippocampus region was dissected out carefully and processed for routine histological study. Random serial sections were analysed under microscope for histomorphometric changes. For statistical analysis, independent t-test was used for comparing control and 2G exposed groups. The mean density of neurons in the hippocampus regions CA1, CA2 and DGDB from first to sixth month was significantly lower in the 2G exposed groups; however, in CA3 and DGVB, the 2G exposed mice showed significantly higher density of neurons. The mean nuclear diameter of neurons in the hippocampus region of CA1, CA2, CA3, DGDB and DGVB from first to sixth months showed lower nuclear diameter in 2G exposed mice. The long term exposure to 900-1800 MHz frequency radiations emitted from 2G mobile phone could cause significantly reduced neuron density and decreased nuclear diameter in the hippocampus neurons of mice.

Toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. I. Acute exposure and recovery studies.

PubMed Central

Bucher, J R; Gupta, B N; Adkins, B; Thompson, M; Jameson, C W; Thigpen, J E; Schwetz, B A

1987-01-01

Male and female F344/N rats and B6C3F1 mice were exposed to lethal and sublethal concentrations of methyl isocyanate by inhalation. Mortality, clinical signs, body and organ weights, and changes in clinical pathology and hematology were monitored immediately after 2-hr exposures and during the ensuing 3 months. Additional studies investigated the possible involvement of cyanide in the toxicity of methyl isocyanate. During exposures, signs of restlessness, lacrimation, and a reddish discharge from the nose and mouth were evident in rats and mice. Following exposures, rats and mice were dyspneic and weak. Deaths of rats and mice exposed to lethal concentrations (20 to 30 ppm) began within 15-18 hr, with males more prone to early death than females. A second wave of deaths occurred after 8 to 10 days, affecting primarily female rats and mice exposed to 20 to 30 ppm of methyl isocyanate, and male and female rats exposed to 10 ppm. Most deaths occurred during the first month following the exposures and were preceded by periods of severe respiratory distress. Body weights decreased in proportion to dose early, but then weight gain resumed in survivors at control rates. The only organ with a consistent, dose-related weight change was the lung, which was heavier throughout the studies in animals exposed to high concentrations of methyl isocyanate. No significant clinical pathology, or hematologic changes were observed in exposed rats. Blood and brain cholinesterase were not inhibited. Studies attempting to measure cyanide in the blood of methyl isocyanate-exposed rats, and attempting to affect lethality with a cyanide antidote (sodium nitrite and sodium thiosulfate) gave negative results.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3622444

Particulate matter triggers depressive-like response associated with modulation of inflammatory cytokine homeostasis and brain-derived neurotrophic factor signaling pathway in mice.

PubMed

Liu, Xuemei; Qian, Xin; Xing, Jing; Wang, Jinhua; Sun, Yixuan; Wang, Qin'geng; Li, Huiming

2018-04-23

Particulate matter (PM) exposure may contribute to depressive-like response in mice. However, few studies have evaluated the adaptive impacts of long-term PM exposure on depressive-like response associated with systemic inflammation and brain-derived neurotrophic factor (BDNF) signaling pathway. We studied the association among depressive-like behaviors, mRNA levels of pro- and anti-inflammatory cytokines, and the expression of BDNF signaling pathway in mice by long-term PM exposure. C57BL/6 male mice were exposed to ambient air alongside control mice breathing air filtered through a high-efficiency air PM (HEPA) filter. Depressive-like behaviors were assessed together with pro-inflammatory, anti-inflammatory cytokine mRNA levels and the modulation of BDNF pathway in hippocampus and olfactory-bulb of mice exposed to PM for 4, 8, and 12 weeks. Exposure to HEPA filtered air for 4 weeks may exert antidepressant like effects in mice. Pro-inflammatory cytokines were up-regulated while the expression of BDNF, its high-affinity receptor tropomyosin-related kinase B (TrkB), and the transcription factor cAMP-response-element binding protein (CREB) were down-regulated in ambient air mice. However, after 8 weeks, there was no significant difference in the rate of depressive-like behaviors between the two groups. After 12 weeks, mice exposed to ambient air again had a higher rate of depressive-like behaviors, significant up-regulation of pro-inflammatory cytokines, down-regulation of interleukin-10 (IL-10), BDNF, TrkB, and CREB than HEPA mice. Ultrafine PM in brain tissues of mice exposed to ambient air was observed. Our results suggest continuous high-level PM exposure alters the depressive-like response in mice and induces a damage-repair-imbalance reaction.

Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains

PubMed Central

Mahawong, Phitsanu; Sinclair, Adriane; Li, Yi; Schlomer, Bruce; Rodriguez, Esequiel; Max, Ferretti M.; Liu, Baomei; Baskin, Laurence S.; Cunha, Gerald R.

2014-01-01

Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5 to 120 days postnatal to evaluate ExG malformations. Of 23 adult (≥60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18 to 100% in prenatally DES-exposed CD-1 males and 31 to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation. PMID:25449352

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

PubMed Central

Karkhanis, Anushree N.; Huggins, Kimberly N.; Rose, Jamie H.; Jones, Sara R.

2016-01-01

Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade. KORs are located on presynaptic dopamine terminals in the nucleus accumbens (NAc) and inhibit release, an effect which has been linked to negative affective behaviors. Previous reports show an upregulation in KOR function following extended CIE exposure; however it is not clear whether there is a direct link between KOR upregulation and dopamine downregulation during withdrawal from CIE. This study aimed to examine the effects of KOR modulation on dopamine responses to ethanol of behaving mice exposed to air or ethanol vapor in a repeated intermittent pattern. First, we showed that KORs have a greater response to an agonist after moderate CIE compared to air exposed mice using ex vivo fast scan cyclic voltammetry. Second, using in vivo microdialysis, we showed that, in contrast to the expected increase in extracellular levels of dopamine following an acute ethanol challenge in air exposed mice, CIE exposed mice exhibited a robust decrease in dopamine levels. Third, we showed that blockade of KORs reversed the aberrant inhibitory dopamine response to ethanol in CIE exposed mice while not affecting the air exposed mice demonstrating that inhibition of KORs “rescued” dopamine responses in CIE exposed mice. Taken together, these findings indicate that augmentation of dynorphin/KOR system activity drives the reduction in stimulated (electrical and ethanol) dopamine release in the NAc. Thus, blockade of KORs is a promising avenue for developing pharmacotherapies for alcoholism. PMID:27450094

Inhibition of pan neurotrophin receptor p75 attenuates diesel particulate-induced enhancement of allergic airway responses in C57/B16J mice.

PubMed

Farraj, Aimen K; Haykal-Coates, Najwa; Ledbetter, Allen D; Evansky, Paul A; Gavett, Stephen H

2006-06-01

Recent investigations have linked neurotrophins, including nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF), to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance in allergic mice. Diesel exhaust particle (DEP) exposure has been linked to asthma exacerbation in many cities with vehicular traffic congestion. We tested the hypothesis that DEP-induced enhancement of the hallmark features of allergic airway disease in a murine model is dependent on the function of the pan neurotrophin receptor p75. Ovalbumin (OVA)-sensitized C57B1/6J mice were intranasally instilled with an antibody against the p75 receptor or saline alone 1 h before OVA challenge. The mice were then exposed nose-only to the PM2.5 fraction of SRM2975 DEP or air alone for 5 h beginning 1 h after OVA challenge. Two days later, air-exposed OVA-allergic mice developed a small but insignificant increase in methacholine-induced airflow obstruction relative to air-exposed, vehicle-sensitized mice. DEP-exposed OVA-allergic mice had a significantly greater degree of airway obstruction than all other groups. Instillation of anti-p75 significantly attenuated the DEP-induced increase in airway obstruction in OVA-allergic mice to levels similar to non-sensitized mice. The DEP-induced exacerbation of allergic airway responses may, in part, be mediated by neurotrophins.

Autism-relevant social abnormalities in mice exposed perinatally to extremely low frequency electromagnetic fields.

PubMed

Alsaeed, Ibrahim; Al-Somali, Faisal; Sakhnini, Lama; Aljarallah, Omar S; Hamdan, Rayan M M; Bubishate, Saleh A; Sarfaraz, Ziyab Khan; Kamal, Amer

2014-10-01

The incidence of autism spectrum disorders (ASD) has been rising, but the causes of ASD remain largely unidentified. Collective data have implicated the increased human exposure to electromagnetic fields (EMF) in the increasing incidence of ASD. There are established biological effects of extremely low-frequency (ELF) EMF, but the relation to ASD is not investigated enough. In this study we examined the effects of perinatal exposure to ELF EMF on some ASD-relevant behavioral parameters in mice. The EMF was delivered via a Helmholtz coil pair. Male BALB/C mice were used and divided into exposed and control groups (n=8 and n=9, respectively). Tests were used to assess sociability, preference for social novelty, locomotion, anxiety, exploratory behavior, motor coordination, and olfaction. The examined mice were all males and exposed to EMF during the last week of gestation and for 7 days after delivery. The exposed mice demonstrated a lack of normal sociability and preference for social novelty while maintaining normal anxiety-like behavior, locomotion, motor coordination, and olfaction. Exposed mice also demonstrated decreased exploratory activity. We concluded that these results are supportive of the hypothesis of a causal link between exposure to ELF-EMF and ASD; however, replications of the study with further tests are recommended. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Inflammation and emphysema in cigarette smoke-exposed mice when instilled with poly (I:C) or infected with influenza A or respiratory syncytial viruses

USDA-ARS?s Scientific Manuscript database

Background: The length of time for cigarette smoke (CS) exposure to cause emphysema in mice is drastically reduced when CS exposure is combined with viral infection. However, the extent of inflammatory responses and lung pathologies of mice exposed to CS and infected with influenza A virus (IAV), re...

Automated measurement of pulmonary emphysema and small airway remodeling in cigarette smoke-exposed mice.

PubMed

Laucho-Contreras, Maria E; Taylor, Katherine L; Mahadeva, Ravi; Boukedes, Steve S; Owen, Caroline A

2015-01-16

COPD is projected to be the third most common cause of mortality world-wide by 2020((1)). Animal models of COPD are used to identify molecules that contribute to the disease process and to test the efficacy of novel therapies for COPD. Researchers use a number of models of COPD employing different species including rodents, guinea-pigs, rabbits, and dogs((2)). However, the most widely-used model is that in which mice are exposed to cigarette smoke. Mice are an especially useful species in which to model COPD because their genome can readily be manipulated to generate animals that are either deficient in, or over-express individual proteins. Studies of gene-targeted mice that have been exposed to cigarette smoke have provided valuable information about the contributions of individual molecules to different lung pathologies in COPD((3-5)). Most studies have focused on pathways involved in emphysema development which contributes to the airflow obstruction that is characteristic of COPD. However, small airway fibrosis also contributes significantly to airflow obstruction in human COPD patients((6)), but much less is known about the pathogenesis of this lesion in smoke-exposed animals. To address this knowledge gap, this protocol quantifies both emphysema development and small airway fibrosis in smoke-exposed mice. This protocol exposes mice to CS using a whole-body exposure technique, then measures respiratory mechanics in the mice, inflates the lungs of mice to a standard pressure, and fixes the lungs in formalin. The researcher then stains the lung sections with either Gill's stain to measure the mean alveolar chord length (as a readout of emphysema severity) or Masson's trichrome stain to measure deposition of extracellular matrix (ECM) proteins around small airways (as a readout of small airway fibrosis). Studies of the effects of molecular pathways on both of these lung pathologies will lead to a better understanding of the pathogenesis of COPD.

Ozone-Induced Nasal Type 2 Immunity in Mice Is Dependent on Innate Lymphoid Cells.

PubMed

Kumagai, Kazuyoshi; Lewandowski, Ryan; Jackson-Humbles, Daven N; Li, Ning; Van Dyken, Steven J; Wagner, James G; Harkema, Jack R

2016-06-01

Epidemiological studies suggest that elevated ambient concentrations of ozone are associated with activation of eosinophils in the nasal airways of atopic and nonatopic children. Mice repeatedly exposed to ozone develop eosinophilic rhinitis and type 2 immune responses. In this study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced eosinophilic rhinitis by using lymphoid-sufficient C57BL/6 mice, Rag2(-/-) mice that are devoid of T cells and B cells, and Rag2(-/-)Il2rg(-/-) mice that are depleted of all lymphoid cells including ILCs. The animals were exposed to 0 or 0.8 ppm ozone for 9 consecutive weekdays (4 h/d). Mice were killed 24 hours after exposure, and nasal tissues were selected for histopathology and gene expression analysis. ILC-sufficient C57BL/6 and Rag2(-/-) mice exposed to ozone developed marked eosinophilic rhinitis and epithelial remodeling (e.g., epithelial hyperplasia and mucous cell metaplasia). Chitinase-like proteins and alarmins (IL-33, IL-25, and thymic stromal lymphopoietin) were also increased morphometrically in the nasal epithelium of ozone-exposed C57BL/6 and Rag2(-/-) mice. Ozone exposure elicited increased expression of Il4, Il5, Il13, St2, eotaxin, MCP-2, Gob5, Arg1, Fizz1, and Ym2 mRNA in C57BL/6 and Rag2(-/-) mice. In contrast, ozone-exposed ILC-deficient Rag2(-/-)Il2rg(-/-) mice had no nasal lesions or overexpression of Th2- or ILC2-related transcripts. These results indicate that ozone-induced eosinophilic rhinitis, nasal epithelial remodeling, and type 2 immune activation are dependent on ILCs. To the best of our knowledge, this is the first study to demonstrate that ILCs play an important role in the nasal pathology induced by repeated ozone exposure.

Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates later-life Notch1-mediated T cell development and leukemogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahrenhoerster, Lori S.; Leuthner, Tess C.; Tate, Everett R.

2015-03-01

Over half of T cell acute lymphoblastic leukemia (T-ALL) patients have activating mutations in the Notch gene. Moreover, the contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen that mediates its toxicity through the aryl hydrocarbon receptor (AHR), and crosstalk between activated AHR and Notch signaling pathways has previously been observed. Given the importance of Notch signaling in thymocyte development and T-ALL disease progression, we hypothesized that the activated AHR potentiates disease initiation and progression in an in vivo model of Notch1-induced thymoma. This hypothesis was tested utilizing adult and developmental exposure paradigms to TCDD in mice expressing a constitutively activemore » Notch1 transgene (Notch{sup ICN-TG}). Following exposure of adult Notch{sup ICN-TG} mice to a single high dose of TCDD, we observed a significant increase in the efficiency of CD8 thymocyte generation. We next exposed pregnant mice to 3 μg/kg of TCDD throughout gestation and lactation to elucidate effects of developmental AHR activation on later-life T cell development and T-ALL-like thymoma susceptibility induced by Notch1. We found that the vehicle-exposed Notch{sup ICN-TG} offspring have a peripheral T cell pool heavily biased toward the CD4 lineage, while TCDD-exposed Notch{sup ICN-TG} offspring were biased toward the CD8 lineage. Furthermore, while the vehicle-exposed NotchICN-TG mice showed increased splenomegaly and B to T cell ratios indicative of disease, mice developmentally exposed to TCDD were largely protected from disease. These studies support a model where developmental AHR activation attenuates later-life Notch1-dependent impacts on thymocyte development and disease progression. - Highlights: • Adult mice exposed to 30 μg/kg TCDD have higher efficiency of CD8 thymocyte generation. • Mice carrying a constitutively active Notch transgene were exposed to 3 μg/kg TCDD throughout development. • Progression of Notch-induced thymoma was different in offspring exposed to TCDD developmentally. • Developmental AHR activation attenuates later-life Notch1-dependent impacts on T cell differentiation.« less

Simultaneous, But Not Consecutive, Combination With Folinate Salts Potentiates 5-Fluorouracil Antitumor Activity In Vitro and In Vivo.

PubMed

Di Paolo, Antonello; Orlandi, Paola; Di Desidero, Teresa; Danesi, Romano; Bocci, Guido

2017-08-07

The combination of folinate salts to 5-fluoruracil (5-FU)-based schedules is an established clinical routine in the landscape of colorectal cancer treatment. The aim of this study was to investigate the pharmacological differences between the sequential administration of folinate salts (1 h before, as in clinical routine) followed by 5-FU and the simultaneous administration of both drugs. Proliferation and apoptotic assays were performed on human colon cancer cells exposed to 5-FU, calcium (CaLV), or disodium (NaLV) levofolinate or their simultaneous and sequential combination for 24 and 72 h. TYMS and SLC19A1 gene expression was performed with real-time PCR. In vivo experiments were performed in xenografted nude mice, which were treated with 5-FU escalating doses and CaLV or NaLV alone or in simultaneous and sequential combination. The simultaneous combination of folinate salts and 5-FU was synergistic (NaLV) or additive (CaLV) in a 24-h treatment in both cell lines. In contrast, the sequential combination of both folinate salts and 5-FU was antagonistic at 24 and 72 h. The simultaneous combination of 5-FU and NaLV or CaLV inhibited TYMS gene expression at 24 h, whereas the sequential combination reduced SLC19A1 gene expression. In vivo experiments confirmed the enhanced antitumor activity of the 5-FU + NaLV simultaneous combination with a good toxicity profile, whereas the sequential combination with CaLV failed to potentiate 5-FU activity. In conclusion, only the simultaneous, but not the consecutive, in vitro and in vivo combination of 5-FU and both folinate salt formulations potentiated the antiproliferative effects of the drugs.

Vascular Hyperpermeability Response in Animals Systemically Exposed to Arsenic.

PubMed

Chen, Shih-Chieh; Chang, Chao-Yuah; Lin, Ming-Lu

2018-01-01

The mechanisms underlying cardiovascular diseases induced by chronic exposure to arsenic remain unclarified. The objectives of this study were to investigate whether increased vascular leakage is induced by inflammatory mustard oil in mice systemically exposed to various doses of arsenic and whether an increased vascular leakage response is still present in arsenic-fed mice after arsenic discontinuation for 2 or 6 months. ICR mice were fed water or various doses of sodium arsenite (10, 15, or 20 mg/kg/day; 5 days/week) for 8 weeks. In separate experiments, the mice were treated with sodium arsenite (20 mg/kg) for 2 or 8 weeks, followed by arsenic discontinuation for 2 or 6 months. Vascular permeability to inflammatory mustard oil was quantified using Evans blue (EB) techniques. Both arsenic-exposed and water-fed (control) mice displayed similar basal levels of EB leakage in the ears brushed with mineral oil, a vehicle of mustard oil. The levels of EB leakage induced by mustard oil in the arsenic groups fed with sodium arsenite (10 or 15 mg/kg) were similar to those of water-fed mice. However, increased levels of EB leakage in response to mustard oil stimulation were significantly higher in mice treated with sodium arsenite (20 mg/kg; high dose) than in arsenic-fed (10 or 15 mg/kg; low and middle doses) or control mice. After arsenic discontinuation for 2 or 6 months, mustard oil-induced vascular EB leakage in arsenic-fed (20 mg/kg) mice was similar to that in control mice. Dramatic increases in mustard oil-induced vascular leakage were only present in mice systemically exposed to the high arsenic dose, indicating the synergistic effects of the high arsenic dose and mustard oil.

Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain.

PubMed

Lomazzo, Ermelinda; Bindila, Laura; Remmers, Floor; Lerner, Raissa; Schwitter, Claudia; Hoheisel, Ulrich; Lutz, Beat

2015-01-01

The occurrence of chronic stress, depression, and anxiety can increase nociception in humans and may facilitate the transition from localized to chronic widespread pain. The mechanisms underlying chronic widespread pain are still unknown, hindering the development of effective pharmacological therapies. Here, we exposed C57BL/6J mice to chronic unpredictable stress (CUS) to investigate how persistent stress affects nociception. Next, mice were treated with multiple intramuscular nerve growth factor (NGF) injections, which induced chronic widespread nociception. Thus, combination of CUS and NGF served as a model where psychophysiological impairment coexists with long-lasting hyperalgesia. We found that CUS increased anxiety- and depression-like behavior and enhanced basal nociception in mice. When co-applied with repeated NGF injections, CUS elicited a sustained long-lasting widespread hyperalgesia. In order to evaluate a potential therapeutic strategy for the treatment of chronic pain associated with stress, we hypothesized that the endocannabinoid system (ECS) may represent a target signaling system. We found that URB597, an inhibitor of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), and JZL184, an inhibitor of the 2-arachidonoyl glycerol-degrading enzyme monoacylglycerol lipase (MAGL), increased eCB levels in the brain and periphery and were both effective in reducing CUS-induced anxiety measured by the light-dark test and CUS-induced thermal hyperalgesia. Remarkably, the long-lasting widespread hyperalgesia induced by combining CUS and NGF was effectively reduced by URB597, but not by JZL184. Simultaneous inhibition of FAAH and MAGL did not improve the overall therapeutic response. Therefore, our findings indicate that enhancement of anandamide signaling with URB597 is a promising pharmacological approach for the alleviation of chronic widespread nociception in stress-exposed mice, and thus, it could represent a potential treatment strategy for chronic pain associated with neuropsychiatric disorders in humans.

Cisplatin-Induced Renal Injury is Independently Mediated by OCT2 and p53

PubMed Central

Sprowl, Sprowl; Lancaster, Cynthia S.; Pabla, Navjotsingh; Hermann, Edwin; Kosloske, Ashley M.; Gibson, Alice A.; Li, Lie; Zeeh, Dorothea; Schlatter, Eberhard; Janke, Laura J.; Ciarimboli, Giuliano; Sparreboom, Alex

2014-01-01

Purpose Tubular secretion of cisplatin is abolished in mice deficient for the organic cation transporters Oct1 and Oct2 [Oct1/2(−/−) mice], and these animals are protected from severe cisplatin-induced kidney damage. Since tubular necrosis is not completely absent in Oct1/2(−/−) mice, we hypothesized that alternate pathways are involved in the observed injury. Experimental Design Studies were done in wildtype, Oct1/2(−/−), or p53-deficient animals, all on an FVB background, receiving i.p. cisplatin at 15 mg/kg. The cisplatin metabolites were analyzed using mass spectrometry, and gene expression was assessed using Affymetrix microarrays and RT-PCR arrays. Results KEGG pathway analyses on kidneys from mice exposed to cisplatin revealed that most significantly altered genes were associated with the p53 signaling network, including Cdnk1a and Mdm2, in both wildtype (P=2.40×10–11) and Oct1/2(−/−) mice (P=1.92×10-8). This was confirmed by demonstrating that homozygosity for a p53-null allele partially reduced renal tubular damage, while loss of p53 in Oct1/2(−/−) mice [p53(−/−)/Oct1/2(−/−)] completely abolished nephrotoxicity. We found that pifithrin-α, an inhibitor of p53-dependent transcriptional activation, inhibits Oct2 and can mimic the lack of nephrotoxicity observed in p53(−/−)/Oct1/2(−/−) mice. Conclusions These findings indicate that (i) the p53 pathway plays a crucial role in the kidney in response to cisplatin treatment and (ii) clinical exploration of OCT2 inhibitors may not lead to complete nephroprotection unless the p53 pathway is simultaneously antagonized. PMID:24916697

Chronic cocaine exposure in adolescence: Effects on spatial discrimination reversal, delay discounting, and performance on fixed-ratio schedules in mice.

PubMed

Pope, Derek A; Boomhower, Steven R; Hutsell, Blake A; Teixeira, Kathryn M; Newland, M Christopher

2016-04-01

Adolescence is marked by the continued development of the neural pathways that support choice and decision-making, particularly those involving dopamine signaling. Cocaine exposure during adolescence may interfere with this development and manifest as increased perseveration and delay discounting in adulthood, behavioral processes that are related to drug addiction. Adolescent mice were exposed to 30mg/kg/day of cocaine (n=11) or saline vehicle (n=10) for 14days and behavior was assessed in adulthood. In Experiment 1, performance on a spatial-discrimination-reversal procedure was evaluated. In the first two sessions following the first reversal, cocaine-exposed mice produced more preservative errors relative to controls. In Experiment 2, cocaine-exposed mice displayed steeper delay discounting than saline-exposed mice, effects that were reversed by acute cocaine administration. Experiment 3 examined responding maintained by a range of fixed-ratio schedules of reinforcement. An analysis based on a theoretical framework called Mathematical Principles of Reinforcement (MPR) was applied to response-rate functions of individual mice. According to MPR, differences in response-rate functions in adulthood were due to a steepening of the delay-of-reinforcement gradient, disrupted motoric capacity (lower maximum response rates), and enhanced reinforcer efficacy for the adolescent cocaine- compared with saline-exposed mice. Overall, these experiments suggest that chronic exposure to cocaine during adolescence may impair different features of 'executive functions' in adulthood, and these may be related to distortions in the impact of reinforcing events. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute and chronic in vivo effects of exposure to nicotine and propylene glycol from an E-cigarette on mucociliary clearance in a murine model.

PubMed

Laube, Beth L; Afshar-Mohajer, Nima; Koehler, Kirsten; Chen, Gang; Lazarus, Philip; Collaco, Joseph M; McGrath-Morrow, Sharon A

2017-04-01

To determine the effect of an acute (1 week) and chronic (3 weeks) exposure to E-cigarette (E-cig) emissions on mucociliary clearance (MCC) in murine lungs. C57BL/6 male mice (age 10.5 ± 2.4 weeks) were exposed for 20 min/day to E-cigarette aerosol generated by a Joyetech 510-T ® E-cig containing either 0% nicotine (N)/propylene glycol (PG) for 1 week (n = 6), or 3 weeks (n = 9), or 2.4% N/PG for one week (n = 6), or 3 weeks (n = 9), followed by measurement of MCC. Control mice (n = 15) were not exposed to PG alone, or N/PG. MCC was assessed by gamma camera following aspiration of 99m technetium aerosol and was expressed as the amount of radioactivity removed from both lungs over 6 hours (MCC6hrs). Venous blood was assayed for cotinine levels in control mice and in mice exposed for 3-weeks to PG alone and N/PG. MCC6hrs in control mice and in mice acutely exposed to PG alone and N/PG was similar, averaging (±1 standard deviation) 8.6 ± 5.2%, 7.5 ± 2.8% and 11.2 ± 5.9%, respectively. In contrast, chronic exposure to PG alone stimulated MCC6hrs (17.2 ± 8.0)% and this stimulation was significantly blunted following chronic exposure to N/PG (8.7 ± 4.6)% (p < .05). Serum cotinine levels were <0.5 ng/ml in control mice and in mice exposed to PG alone, whereas, N/PG exposed mice averaged 14.6 ± 12.0 ng/ml. In this murine model, a chronic, daily, 20 min-exposure to N/PG, but not an acute exposure, slowed MCC, compared to exposure to PG alone and led to systemic absorption of nicotine.

Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cai Ping; Koenig, Rolf; Boor, Paul J.

2008-04-01

Trichloroethene (TCE) exacerbates the development of autoimmune responses in autoimmune-prone MRL +/+ mice. Although TCE-mediated autoimmune responses are associated with an increase in serum immunoglobulins and autoantibodies, the underlying mechanism of autoimmunity is not known. To determine the progression of TCE-mediated immunotoxicity, female MRL +/+ mice were chronically exposed to TCE through the drinking water (0.5 mg/ml of TCE) for various periods of time. Serum concentrations of antinuclear antibodies increased after 36 and 48 weeks of TCE exposure. Histopathological analyses showed lymphocyte infiltration in the livers of MRL +/+ mice exposed to TCE for 36 or 48 weeks. Lymphocyte infiltrationmore » was also apparent in the pancreas, lungs, and kidneys of mice exposed to TCE for 48 weeks. Immunoglobulin deposits in kidney glomeruli were found after 48 weeks of exposure to TCE. Our results suggest that chronic exposure to TCE promotes inflammation in the liver, pancreas, lungs, and kidneys, which may lead to SLE-like disease in MRL +/+ mice.« less

Soy Biodiesel Emissions Have Reduced Inflammatory Effects ...

EPA Pesticide Factsheets

Toxicity of exhaust from combustion of petroleum diesel (BO), soy-based biodiesel (B100), or a 20% biodiesel/80% petrodiesel mix (B20) was compared in healthy and house dust mite (HDM)-allergic mice. Fuel emissions were diluted to target fine particulate matter (PM2.5) conrentrations of 50, 150, or 500 µg/m(3). Studies in healthy mice showed greater levels of neutrophils and MIP-2 in bronchoaeolar lavage (BAL) fluid 2 h after a single 4-h exposure to BO compared with mice exposed to B20 or B100. No consistent differences in BAL cells and biochemistry, or hematological parameters, were observed after 5 d or 4 weeks of exposure to any of the emissions. Air-exposed HDM-allergc mice had significantly increased responsiveness to methacholine aerosol challenge compared with non-allergic mice. Exposure to any of the emissions for 4 weeks did not further increase responsiveness in either non-allergic or HDM­ allergic mice, and few parameters of allergic inflammation in BAL fluid were altered. Lung and nasal pathology were not significantly different among BO-, B20-, or B100-exposed groups. In HDM-allergic mice, exposure to BO, but not B20 or B100, significantly increased resting peribronchiolar lymph node cell proliferation and production of TH2 cytokines (IL-4, IL-5, and IL-13) and IL-17 in comparison with air-exposed allergic mice. These results suggest that diesel exhaust at a relatively high concentration (500 µg/m(3)) can induce inflammation acutely in healthy m

Iron is associated with the development of hypoxia-induced pulmonary vascular remodeling in mice.

PubMed

Naito, Yoshiro; Hosokawa, Manami; Sawada, Hisashi; Oboshi, Makiko; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Eguchi, Akiyo; Nishimura, Koichi; Soyama, Yuko; Hirotani, Shinichi; Mano, Toshiaki; Ishihara, Masaharu; Masuyama, Tohru

2016-12-01

Several recent observations provide the association of iron deficiency with pulmonary hypertension (PH) in human and animal studies. However, it remains completely unknown whether PH leads to iron deficiency or iron deficiency enhances the development of PH. In addition, it is obscure whether iron is associated with the development of pulmonary vascular remodeling in PH. In this study, we investigate the impacts of dietary iron restriction on the development of hypoxia-induced pulmonary vascular remodeling in mice. Eight- to ten-week-old male C57BL/6J mice were exposed to chronic hypoxia for 4 weeks. Mice exposed to hypoxia were randomly divided into two groups and were given a normal diet or an iron-restricted diet. Mice maintained in room air served as normoxic controls. Chronic hypoxia induced pulmonary vascular remodeling, while iron restriction led a modest attenuation of this change. In addition, chronic hypoxia exhibited increased RV systolic pressure, which was attenuated by iron restriction. Moreover, the increase in RV cardiomyocyte cross-sectional area and RV interstitial fibrosis was observed in mice exposed to chronic hypoxia. In contrast, iron restriction suppressed these changes. Consistent with these changes, RV weight to left ventricular + interventricular septum weight ratio was increased in mice exposed to chronic hypoxia, while this increment was inhibited by iron restriction. Taken together, these results suggest that iron is associated with the development of hypoxia-induced pulmonary vascular remodeling in mice.

In utero arsenic exposure induces early onset of atherosclerosis in ApoE−/− mice

PubMed Central

Srivastava, Sanjay; D’Souza, Stanley E.; Sen, Utpal; States, J. Christopher

2007-01-01

Consumption of arsenic contaminated drinking water has been linked to higher rates of coronary disease, stroke, and peripheral arterial disease. Recent evidence suggests that early life exposures may play a significant role in the onset of chronic adult diseases. To investigate the potential for in utero exposure to accelerate the onset of cardiovascular disease we exposed pregnant ApoE-knockout (ApoE−/−) mice to arsenic in their drinking water and examined the aortic trees of their male offspring for evidence of early disease 10 and 16 weeks after birth. Mice were maintained on normal chow after weaning. ApoE−/− mice are a commonly used model for atherogenesis and spontaneously develop atherosclerotic disease. Mice exposed to arsenic in utero showed a >2-fold increase in lesion formation in the aortic roots as well as the aortic arch compared to control mice at both 10 and 16 weeks of age. The mice exposed to arsenic also had a 20 – 40% decrease in total triglycerides, but no change in total cholesterol, phospholipids and total abundance of VLDL or HDL particles. Subfractionation of VLDL particles showed a decrease in large VLDL particles. In addition, the arsenic exposed mice showed a vasorelaxation defect in response to acetylcholine suggesting disturbance of endothelial cell signalling. These results indicate that in utero arsenic exposure induces an early onset of atherosclerosis in ApoE−/− mice without a hyperlipidemic diet and support the hypothesis that in utero arsenic exposure may be atherogenic in humans. PMID:17317095

The effect of methylmercury exposure on behavior and cerebellar granule cell physiology in aged mice.

PubMed

Bellum, Sairam; Thuett, Kerry A; Bawa, Bhupinder; Abbott, Louise C

2013-09-01

Epidemiology studies have clearly documented that the central nervous system is highly susceptible to methylmercury toxicity, and exposure to this neurotoxicant in humans primarily results from consumption of contaminated fish. While the effects of methylmercury exposure have been studied in great detail, comparatively little is known about the effects of moderate to low dose methylmercury toxicity in the aging central nervous system. We examined the toxic effects of a moderate dose of methylmercury on the aging mouse cerebellum. Male and female C57BL/6 mice at 16-20 months of age were exposed to methylmercury by feeding a total dose of 5.0 mg kg(-1) body weight and assessed using four behavioral tests. Methylmercury-treated aged mice performed significantly worse in open field, footprint analysis and the vertical pole test compared with age-matched control mice. Isolated cerebellar granule cells from methylmercury-treated aged mice exhibited higher levels of reactive oxygen species and reduced mitochondrial membrane potentials, but no differences in basal intracellular calcium ion levels compared with age-matched control mice. When aged mice were exposed to a moderate dose of methylmercury, they exhibited a similar degree of impairment when compared with young adult mice exposed to the same moderate dose of methylmercury, as reported in earlier studies from this laboratory. Thus, at least in mice, exposure of the aged brain to moderate concentrations methylmercury does not pose greater risk compared with the young adult brain exposed to similar concentrations of methylmercury. Copyright © 2012 John Wiley & Sons, Ltd.

Effects of acute social stress on the conditioned place preference induced by MDMA in adolescent and adult mice.

PubMed

García-Pardo, Maria P; Rodríguez-Arias, Marta; Maldonado, Concepcion; Manzanedo, Carmen; Miñarro, Jose; Aguilar, Maria A

2014-09-01

Exposure to social defeat stress increases the rewarding effects of psychostimulants in animal models, but its effect on 3,4-methylenedioxymethylamphetamine (MDMA) reward has received little attention. In the present study, we evaluated the influence of social defeat on the rewarding effects of MDMA in adolescent [postnatal day (PND) 29-40] and adult (PND 50-61) male mice using the conditioned place preference paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1.25 or 10 mg/kg of MDMA. The effects of social defeat on corticosterone levels and the motor or the anxiogenic effects of MDMA were also evaluated. Mice exposed to social defeat during adulthood did not show conditioned place preference after conditioning with either dose of MDMA. Conversely, social defeat did not affect the anxiogenic and motor effects of MDMA. Adult mice exposed to social defeat showed higher levels of corticosterone than their controls and adolescent mice. Social stress did not induce behavioural effects in adolescent mice. Our results show that stress induced by social defeat decreases the sensitivity of adult mice to the rewarding effects of MDMA.

NTP toxicity studies of sodium dichromate dihydrate (CAS No. 7789-12-0) administered in drinking water to male and female F344/N rats and B6C3F1 mice and male BALB/c and am3-C57BL/6 mice.

PubMed

Bucher, John R

2007-01-01

Sodium dichromate dihydrate is one of a number of inorganic compounds containing hexavalent chromium (CR VI) found in drinking water supplies as a contaminant resulting from various industrial processes including electroplating operations, leather tanning, and textile manufacturing. Because of the lack of adequate experimental data on the toxicity and carcinogenicity of hexavalent chromium ingested orally, and because hexavalent chromium has been found in human drinking water supplies, the California Congressional delegation and the California Environmental Protection Agency nominated hexavalent chromium to the NTP for study. In study 1, male and female F344/N rats and B6C3F1 mice were exposed to sodium dichromate dihydrate (greater than 99% pure) in drinking water for 3 months. In study 2, sodium dichromate dihydrate was administered in drinking water to male B6C3F1, BALB/c, and am3-C57BL/6 mice for 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. In study 1, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were given drinking water containing 0, 62.5, 125, 250, 500, or 1,000 mg sodium dichromate dihydrate/L for 3 months (equivalent to average daily doses of approximately 5, 10, 17, 32, or 60 mg sodium dichromate dihydrate/kg body weight to rats and 9, 15, 26, 45, or 80 mg/kg to mice). On a molecular weight basis, these doses are equivalent to approximately 1.7, 3.5, 5.9, 11.2, and 20.9 mg hexavalent chromium/kg body weight per day to rats and 3.1, 5.2, 9.1, 15.7, and 27.9 mg/kg per day to mice. Additional groups of 10 rats per sex were exposed to the same concentrations of sodium dichromate dihydrate for 4 weeks. All rats and mice survived to the end of the study. Reduced body weights occurred in 500 and 1,000 mg/L male rats, 1,000 mg/L female rats, and in male and female mice exposed to 125 mg/L or greater. Water consumption by male and female rats exposed to 250 mg/L or greater and male and female mice exposed to 125 mg/L or greater was generally less than that by the control groups, and decreases in urine volume and increases in urine specific gravity in rats were related to reduced water consumption. Exposure to sodium dichromate dihydrate caused a microcytic hypochromic anemia in rats and mice, but the severity was less in mice. Serum cholesterol and triglyceride concentrations were decreased in rats. Increased bile acid concentrations in exposed groups of rats may have been due to altered hepatic function. The incidences of histiocytic cellular infiltration were generally significantly increased in the duodenum of rats and mice, the liver of female rats, and the mesenteric lymph node of mice exposed to 125 mg/L or greater. Significantly increased nonneoplastic lesions (focal ulceration, regenerative epithelial hyperplasia, and squamous epithelial metaplasia) occurred in the glandular stomach of male and female rats exposed to 1,000 mg/L. Incidences of epithelial hyperplasia of the duodenum were significantly increased in all exposed groups of mice. In study 2, sodium dichromate dihydrate was administered in drinking water to groups of 10 male B6C3F1, 10 male BALB/c, and five male am3-C57BL/6 mice for 3 months at exposure concentrations of 0, 62.5, 125, or 250 mg/L (equivalent to average daily doses of approximately 8, 15, or 25 mg/kg sodium dichromate dihydrate or 2.8, 5.2, or 8.7 mg/kg chromium to B6C3F1, BALB/c, and am3-C57BL/6 mice). All mice in study 2 survived until study termination. Mean body weights of 125 and 250 mg/L B6C3F1 and BALB/c mice and all exposed groups of am3-C57BL/6 mice were less than those of the control groups. Mice exposed to 250 mg/L consumed less water than the control groups. Exposure concentration-related decreases in mean red cell volumes and mean red cell hemoglobin values were observed in all three mouse strains. Erythrocyte counts were increased in exposed B6C3F1 and BALB/c mice but not in am3-C57BL/6 mice. Changes in organ weights were generally consistent with reduced body weights in exposed groups in all mouse strains. No biologically significant differences in reproductive parameters were observed in any strain. Histiocytic cellular infiltration and epithelial hyperplasia of the duodenum occurred in most mice exposed to 125 or 250 mg/L, and the incidences of these lesions were increased in the 62.5 mg/L group compared to controls. Secretory depletion was present in the pancreas of most mice exposed to 125 or 250 mg/L. The incidences of glycogen depletion of the liver were significantly increased in male B6C3F1 mice exposed to 125 or 250 mg/L and in all exposed groups of male am3-C57BL/6 mice. The incidence of histiocytic cellular infiltration in the mesenteric lymph node was significantly increased in the 250 mg/L group of male am3-C57BL/6 mice. Sodium dichromate dihydrate was mutagenic in S. typhimurium strains TA100 and TA98 and in E. coli strain WP2 uvrA pKM101 with and without induced rat liver S9 enzymes. The results of four micronucleus tests conducted in the three strains of mice from studies 1 and 2 were mixed. In study 1, no significant increases were seen in micronucleated normochromatic erythrocytes in peripheral blood samples from male or female B6C3F1 mice; there was a decrease in the percentage of polychromatic erythrocytes among total erythrocytes (an indication of bone marrow toxicity), but the changes were small and not well correlated with exposure concentrations. In study 2, a significant exposure concentration-related increase (P<0.001) in micronucleated normochromatic erythrocytes was seen in am3-C57BL/6 male mice. An equivocal increase in micronucleated erythrocytes was noted in male B6C3F1 mice, based on a small increase in micronucleated normochromatic erythrocytes that did not reach statistical significance. No increase in micronucleated normochromatic erythrocytes was observed in male BALB/c mice. No significant effect of sodium dichromate dihydrate exposure on the percentage of polychromatic erythrocytes was observed in any of the three micronucleus tests conducted in study 2. In summary, administration of sodium dichromate dihydrate in the drinking water to F344/N rats and B6C3F1 mice resulted in focal ulceration, hyperplasia, and metaplasia in the glandular stomach at the limiting ridge in rats in the 1,000 mg/L group and evidence of increased histiocytic infiltration in the liver (female), duodenum of the small intestine, and/or pancreatic lymph nodes at concentrations as low as 62.5 mg/L, the lowest concentration studied. In addition, a microcytic, hypochromic anemia occurred at all exposure concentrations and was considered evidence of a toxic response resulting from absorption of Cr VI following oral ingestion in rats. A similar, but less severe, anemia was evident in mice receiving drinking water containing sodium dichromate dihydrate; histiocytic infiltration was noted in the duodenum of all three strains studied (B6C3F1, BALB/c, and am3-C57BL/6) at all concentrations employed, in the mesenteric lymph nodes at 125 mg/L or greater in the B6C3F1 strain, and at 250 mg/L in the am3-C57BL/6 strain. There was no consistent evidence of hepatocyte injury in mice in any of the strains tested. Variations in glycogen content were considered more likely related to diminished food intake than to the toxicity of sodium dichromate dihydrate. Synonyms: Chromic acid; dichromic acid; disodium salt, dihydrate; disodium dichromate dihydrate; chromium VI.

Metabolic changes and DNA hypomethylation in cerebellum are associated with behavioral alterations in mice exposed to trichloroethylene postnatally

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blossom, Sarah J., E-mail: blossomsarah@uams.edu; Cooney, Craig A.; Melnyk, Stepan B.

2013-06-15

Previous studies demonstrated that low-level postnatal and early life exposure to the environmental contaminant, trichloroethylene (TCE), in the drinking water of MRL +/+ mice altered glutathione redox homeostasis and increased biomarkers of oxidative stress indicating a more oxidized state. Plasma metabolites along the interrelated transmethylation pathway were also altered indicating impaired methylation capacity. Here we extend these findings to further characterize the impact of TCE exposure in mice exposed to water only or two doses of TCE in the drinking water (0, 2, and 28 mg/kg/day) postnatally from birth until 6 weeks of age on redox homeostasis and biomarkers ofmore » oxidative stress in the cerebellum. In addition, pathway intermediates involved in methyl metabolism and global DNA methylation patterns were examined in cerebellar tissue. Because the cerebellum is functionally important for coordinating motor activity, including exploratory and social approach behaviors, these parameters were evaluated in the present study. Mice exposed to 28 mg/kg/day TCE exhibited increased locomotor activity over time as compared with control mice. In the novel object exploration test, these mice were more likely to enter the zone with the novel object as compared to control mice. Similar results were obtained in a second test when an unfamiliar mouse was introduced into the testing arena. The results show for the first time that postnatal exposure to TCE causes key metabolic changes in the cerebellum that may contribute to global DNA methylation deficits and behavioral alterations in TCE-exposed mice. - Highlights: • We exposed male mice to low-level trichloroethylene from postnatal days 1 through 42. • This exposure altered redox potential and increased oxidative stress in cerebellum. • This exposure altered metabolites important in cellular methylation in cerebellum. • This exposure promoted DNA hypomethylation in cerebellum. • This exposure enhanced locomotor activity and exploratory behavior.« less

Soy biodiesel emissions have reduced inflammatory effects compared to diesel emissions in healthy and allergic mice.

PubMed

Gavett, Stephen H; Wood, Charles E; Williams, Marc A; Cyphert, Jaime M; Boykin, Elizabeth H; Daniels, Mary J; Copeland, Lisa B; King, Charly; Krantz, Todd Q; Richards, Judy H; Andrews, Debora L; Jaskot, Richard H; Gilmour, M Ian

2015-01-01

Toxicity of exhaust from combustion of petroleum diesel (B0), soy-based biodiesel (B100), or a 20% biodiesel/80% petrodiesel mix (B20) was compared in healthy and house dust mite (HDM)-allergic mice. Fuel emissions were diluted to target fine particulate matter (PM(2.5)) concentrations of 50, 150, or 500 μg/m(3). Studies in healthy mice showed greater levels of neutrophils and MIP-2 in bronchoalveolar lavage (BAL) fluid 2 h after a single 4-h exposure to B0 compared with mice exposed to B20 or B100. No consistent differences in BAL cells and biochemistry, or hematological parameters, were observed after 5 d or 4 weeks of exposure to any of the emissions. Air-exposed HDM-allergic mice had significantly increased responsiveness to methacholine aerosol challenge compared with non-allergic mice. Exposure to any of the emissions for 4 weeks did not further increase responsiveness in either non-allergic or HDM-allergic mice, and few parameters of allergic inflammation in BAL fluid were altered. Lung and nasal pathology were not significantly different among B0-, B20-, or B100-exposed groups. In HDM-allergic mice, exposure to B0, but not B20 or B100, significantly increased resting peribronchiolar lymph node cell proliferation and production of T(H)2 cytokines (IL-4, IL-5, and IL-13) and IL-17 in comparison with air-exposed allergic mice. These results suggest that diesel exhaust at a relatively high concentration (500 μg/m(3)) can induce inflammation acutely in healthy mice and exacerbate some components of allergic responses, while comparable concentrations of B20 or B100 soy biodiesel fuels did not elicit responses different from those caused by air exposure alone.

Severe and protracted sleep disruptions in mouse model of post-traumatic stress disorder.

PubMed

Sharma, Rishi; Sahota, Pradeep; Thakkar, Mahesh M

2018-03-01

Increasing evidences suggest that the predator threat model is a valid animal model of post-traumatic stress disorder (PTSD). However, sleep has never been examined in this model. Since sleep disturbances, including insomnia and excessive daytime sleepiness, are severe and protracted symptoms of PTSD, we hypothesized that mice exposed to predator odor trauma (POT) will display contextual fear conditioning along with severe and protracted sleep disruptions. Adult male C57BL/6J mice, instrumented with wire electrodes (to record hippocampal local field potentials [LFP] and nuchal muscle [electromyogram, EMG] activity), were exposed to contextual conditioning using soiled cat litter as unconditional stimulus (US). On day 1, fear memory acquisition (FMA) training was performed by exposing mice to contextual cage (conditional stimulus; CS) for 30 min followed by exposure to CS + US for 90 min. On day 5, fear memory recall (FMR) testing was performed by exposing mice to CS (without US) for 120 min. LFP and EMG were recorded continuously for 5 days. Mice exposed to POT displayed as follows: (1) hyperarousal coupled with electrophysiological indicators of memory acquisition and retrieval (increased hippocampal θ and γ power) during FMA and FMR; (2) increased nonrapid eye movement (NREM) δ and rapid eye movement θ power during sleep post FMA, indicating memory consolidation; (3) protracted sleep disturbances as evident by increased wakefulness, reduced NREM sleep and NREM δ power, increased NREM β power during light (sleep) period, and increased sleep during dark (active) period. Based on these results, we suggest that mice exposed to POT display severe and protracted sleep disturbances mimicking sleep disturbance observed in human PTSD.

Differential Mouse Pulmonary Dose and Time Course Responses to Titanium Dioxide Nanospheres and Nanobelts

PubMed Central

Porter, Dale W.

2013-01-01

Three anatase titanium dioxide (TiO2) nanoparticles (NPs) were prepared; nanospheres (NSs), short nanobelts (NB1), and long nanobelts (NB2). These NPs were used to investigate the effect of NP shape and length on lung toxicity. Mice were exposed (0–30 µg per mouse) by pharyngeal aspiration and pulmonary toxicity was assessed over a 112-day time course. Whole lung lavage data indicated that NB1- and NB2-exposed mice, but not NS-exposed mice, had significant dose- and time-dependent pulmonary inflammation and damage. Histopathological analyses at 112 days postexposure determined no interstitial fibrosis in any NS-exposed mice, an increased incidence in 30 µg NB1-exposed mice, and significant interstitial fibrosis in 30 µg NB2-exposed mice. At 112 days postexposure, lung burden of NS was decreased by 96.4% and NB2 by 80.5% from initial deposition levels. At 112 days postexposure, enhanced dark field microscopy determined that alveolar macro- phages were the dominant deposition site, but a fraction of NB1 and NB2 was observed in the alveolar interstitial spaces. For the 30 µg exposure groups at 112 days postexposure, confocal micro- scopy and immunofluorescent staining demonstrated that retained NB2 but not NS were present in the interstitium subjacent to the terminal bronchiole near the normal location of the smallest lymphatic capillaries in the lung. These lymphatic capillaries play a critical role in particle clearance, and the accumulation of NB2, but not NS, suggests possible impaired lymphatic clearance by the high aspect ratio particles. In summary, our data indicate that TiO2 NP shape alters pulmonary responses, with severity of responses being ranked as NS < NB1 < NB2. PMID:22956629

Triggering Receptor Expressed on Myeloid Cells 2 Deficiency Alters Acute Macrophage Distribution and Improves Recovery after Traumatic Brain Injury.

PubMed

Saber, Maha; Kokiko-Cochran, Olga; Puntambekar, Shweta S; Lathia, Justin D; Lamb, Bruce T

2017-01-15

Traumatic brain injury (TBI) affects 1.7 million persons annually in the United States (Centers for Disease Control and Prevention). There is increasing evidence that persons exposed to TBI have increased risk of the development of multiple neurodegenerative conditions, including Alzheimer disease (AD). TBI triggers a strong neuroinflammatory response characterized by astrogliosis, activation of microglia, and infiltration of peripheral monocytes. Recent evidence suggests that alterations in innate immunity promote neurodegeneration. This includes genetic studies demonstrating that mutations in triggering receptor expressed on myeloid cells 2 (TREM2) is associated with a higher risk for not only AD but also multiple neurodegenerative diseases. To examine whether TREM2 deficiency affects pathological outcomes of TBI, Trem2 knockout (Trem2 -/- ) and C57BL/6J (B6) mice were given a lateral fluid percussion injury (FPI) and sacrificed at 3 and 120 days post-injury (DPI) to look at both acute and chronic consequences of TREM2 deficiency. Notably, at 3 DPI, B6 mice exposed to TBI exhibited increased expression of TREM2 in the brain. Further, Trem2 -/- mice exposed to TBI exhibited enhanced macrophage activation near the lesion, but significantly less macrophage activation away from the lesion when compared with B6 mice exposed to TBI. In addition, at 120 DPI, Trem2 -/- mice exposed to TBI demonstrated reduced hippocampal atrophy and rescue of TBI-induced behavioral changes when compared with B6 mice exposed to TBI. Taken together, this study suggests that TREM2 deficiency influences both acute and chronic responses to TBI, leading to an altered macrophage response at early time points, and improved pathological and functional outcomes at later time points.

[Modification of radiation damage to biological objects by lasers].

PubMed

Voskanian, K Sh; Vorozhzova, S V; Abrosimova, A N; Mitsyn, G V; Gaevskiĭ, V N

2012-01-01

A series of experiments had the purpose to study effects of gamma-rays 60Co (5 Gy) and the combined effects of laser 650 nm (1 mJ/cm2) and gamma-rays 60Co (5 Gy) on survivability, body mass, integument and mitotic index of marrow cells (MC) of young mice C57BL/6. Laser was applied to the mouse hairy back only. Ten months of gamma-irradiation brought death to 50% of mice; the combined irradiation killed only 30%. Starting on month six after gamma-irradiation, body mass was less in comparison with mice exposed to the combined irradiation. In addition, all mice lost body mass sharply before death. All gamma-irradiated mice were touched with grey over the period of 30 days; in 40 days, 10 of 20 mice had incipient local radiation alopecia on the back that passed fully within next month. However, all mice developed radiation ulcers on the fourth month since irradiation. Two mice formed also neck tumors. In 5 months tails fell off in 2 mice. Some grey streaks appeared on mice exposed to the combined irradiation 3 months later only; three mice remained black throughout the follow-up. Alopecia was found in three survivors in 5 months after irradiation. Mitotic activity of marrow cells obtained from mice on day 15 since exposure to lasing and combined irradiation was higher in comparison with cells from intact mice. In a year, the MC mitotic index was higher in mice exposed to the combined irradiation as compared with the gamma-irradiated mice.

Long-Term Effects of Neonatal Methamphetamine Exposure on Cognitive Function in Adolescent Mice

PubMed Central

Siegel, Jessica A.; Park, Byung S.; Raber, Jacob

2011-01-01

Exposure to methamphetamine during brain development impairs cognition in children and adult rodents. In mice, these impairments are greater in females than males. Adult female, but not male, mice show impairments in novel location recognition following methamphetamine exposure during brain development. In contrast to adulthood, little is known about the potential effects of methamphetamine exposure on cognition in adolescent mice. As adolescence is an important time of development and is relatively understudied, the aim of the current study was to examine potential long-term effects of neonatal methamphetamine exposure on behavior and cognition during adolescence. Male and female mice were exposed to methamphetamine (5 mg/kg) or saline once a day from postnatal day 11-20, the period of rodent hippocampal development. Behavioral and cognitive function was assessed during adolescence beginning on postnatal day 30. During the injection period, methamphetamine-exposed mice gained less weight on average compared to saline-exposed mice. In both male and female mice, methamphetamine exposure significantly impaired novel object recognition and there was a trend towards impaired novel location recognition. Anxiety-like behavior, sensorimotor gating, and contextual and cued fear conditioning were not affected by methamphetamine exposure. Thus, neonatal methamphetamine exposure affects cognition in adolescence and unlike in adulthood equally affects male and female mice. PMID:21238498

Consequences of low or moderate prenatal ethanol exposures during gastrulation or neurulation for open field activity and emotionality in mice.

PubMed

Schambra, Uta B; Nunley, Kevin; Harrison, Theresa A; Lewis, C Nicole

In a previous study we used a mouse model for ethanol exposure during gastrulation or neurulation to investigate the effects of modest and occasional human drinking during the 3rd or 4th week of pregnancy (Schambra et al., 2015). Pregnant C57Bl/6J mice were treated by gavage during gastrulation on gestational day (GD) 7 or neurulation on GD8 with 2 doses 4h apart of either 2.4 or 2.9g ethanol/kg body weight, resulting in peak blood ethanol concentrations (BECs) of 104 and 177mg/dl, respectively. We found that mice exposed to the low dose on either day were significantly delayed in their neonatal sensorimotor development. In the present study, we tested the same cohort of mice in an open field as juveniles on postnatal day (PD) 23-25 and as young adults on PD65-67 for prenatal ethanol effects on exploration and emotionality with measures of activity, rearing, grooming and defecation. We evaluated the effects of dose, sex, day of treatment and day of birth by multiple regression analyses. We found that, compared to the respective gavage controls, juvenile mice that had been prenatally exposed to the low BEC on either GD7 or GD8 were significantly hypoactive on the first 2 test days, reared significantly more on the last 2 test days, and groomed and defecated significantly more on all 3 test days. Only mice that had been treated on GD7 remained hypoactive as adults. Juvenile mice prenatally exposed to the moderate BEC on GD7 groomed significantly more, while those exposed on GD8 reared and defecated significantly more. Sex differences were highly significant in adult control mice, with control males less active and more emotional than females. Similar, but smaller, sex differences were also evident in adults exposed to ethanol prenatally. Persistence into later life of a deleterious effect of premature birth (i.e., birth on GD19 rather than GD20) on weight and behavior was not consistently supported by these data. Importantly, mice shown previously to be delayed in sensorimotor development as neonates, in the present study demonstrated hypoactivity and increased emotionality in open field behaviors as juveniles, and those mice exposed during gastrulation remained hypoactive as adults. Thus, we propose that the delayed motor development, hypoactivity and emotionality we observed in mice exposed to a low BEC during gastrulation or neurulation may relate to an attention deficit-activity disorder in humans, possibly the inattentive subtype, or Sluggish Cognitive Tempo (SCT). We further discuss concerns about occasional light or moderate alcohol consumption during the 3rd or 4th week of human pregnancy. Copyright © 2016 Elsevier Inc. All rights reserved.

Disposition of Perfluorooctanoic Acid (PFOA) in Pregnant and Lactating CD-1 Mice and Their Pups

EPA Science Inventory

Previous studies in mice prenatally-exposed to PFOA demonstrate growth and developmental effects, including impaired body weight gain and mammary gland development, delayed eye opening, and increased mortality. Those dose dependent effects appeared to worsen if offspring exposed ...

CYTOGENETIC ANALYSES OF MICE EXPOSED TO DICHLOROMETHANE

EPA Science Inventory

Chromosome damage was studied in female B6C3F1 mice exposed to dichloromethane (DCM) by subcutaneous or inhalation treatments. o increase in either the frequencies of sister chromatid exchanges (SCEs) or chromosome aberrations (CAs) in bone marrow cells was observed after a singl...

Effects of Long Term Exposure of 900-1800 MHz Radiation Emitted from 2G Mobile Phone on Mice Hippocampus- A Histomorphometric Study

PubMed Central

Shanmugasamy, Kathirvelu; Anbalagan, Jayaram; Rajanarayanan, Swamynathan; Meenachi, Swamynathan

2016-01-01

Introduction The advancement in the telecommunications technology with multi-functional added features in mobile phone, attracts more users of all age group. It is alarming to note that, the mobile phone use has increased amongst children and they are exposed to potentially harmful radiofrequency radiation in their lifetime. Aim To investigate the long term exposure of 900 to 1800 MHz radiations emitted from 2G mobile phone in mice hippocampus at histomorphometric level. Materials and Methods With due approval from institutional animal ethics committee, 36 mice were exposed to 2G mobile phone radiation, 48 minutes per day for a period of 30-180 days. The control group was kept under similar conditions without 2G exposure. Mice were sacrificed and the brain was removed from the first month to six months period. Brain was removed from the cranial cavity and hippocampus region was dissected out carefully and processed for routine histological study. Random serial sections were analysed under microscope for histomorphometric changes. For statistical analysis, independent t-test was used for comparing control and 2G exposed groups. Results The mean density of neurons in the hippocampus regions CA1, CA2 and DGDB from first to sixth month was significantly lower in the 2G exposed groups; however, in CA3 and DGVB, the 2G exposed mice showed significantly higher density of neurons. The mean nuclear diameter of neurons in the hippocampus region of CA1, CA2, CA3, DGDB and DGVB from first to sixth months showed lower nuclear diameter in 2G exposed mice. Conclusion The long term exposure to 900-1800 MHz frequency radiations emitted from 2G mobile phone could cause significantly reduced neuron density and decreased nuclear diameter in the hippocampus neurons of mice. PMID:27656427

[Modeling of mixed infection by tick-borne encephalitis and Powassan viruses in mice].

PubMed

Khozinskaia, G A; Pogodina, V V

1982-01-01

Simultaneous inoculation of mice with tick-borne and Powassan viruses was shown, depending on experimental conditions, to result either in stimulation of infection or its unchanged course as compared with monoinfection and inoculation with the viruses at 2--3-week intervals in cross protection of mice against the superinfecting virus. Simultaneous inoculation of mice with the two viruses was accompanied by their multiplication in the blood and brains of mice and formation of antihemagglutinating antibodies to each of them. In the virus population in the brains of mice there was either formation of a mixture of two viruses or their phenotypic mixing. In cross protection, multiplication of the superinfecting virus in the blood and brain of mice was slightly inhibited, the antihemagglutinating antibody to a second virus either did not form or appeared in low titres.

Toxicology and Carcinogenesis Studies of Furfuryl Alcohol (CAS No. 98-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

PubMed

1999-02-01

Furfuryl alcohol-based resins are used as binding agents in foundry sand and as corrosion inhibitors in mortar, grout, and cement. Because of their heat resistance, furan resins are used in the manufacture of fiberglass-reinforced plastic equipment. Furfuryl alcohol was selected for evaluation because of the absence of data on its carcinogenic potential and its large production volume, widespread use in manufacturing, and ubiquitous presence in consumer goods. Male and female F344/N rats and B6C3F1 mice were exposed to furfuryl alcohol (greater than 98% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female rats exposed to 250 ppm died by day 2 of the study, and one male rat exposed to 125 ppm died on day 5. Final mean body weights of male and female rats exposed to 125 ppm were significantly less than those of the chamber control groups. Male rats exposed to 31, 63, or 125 ppm and female rats exposed to 125 ppm gained less weight than the chamber control groups. Clinical findings included dyspnea, hypoactivity, and nasal and ocular discharge in males and females exposed to 63, 125, or 250 ppm. All exposed animals developed lesions in the nasal respiratory epithelium and olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female mice exposed to 250 ppm died by day 4 of the study, and one female mouse exposed to 125 ppm died on day 14. Mean body weights of male and female mice exposed to 63 or 125 ppm were significantly less than those of the chamber control groups. All exposed animals except one 16 ppm male developed lesions in the nasal respiratory epithelium and/or olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to furfuryl alcohol at concentrations of 0, 2, 4, 8, 16, or 32 ppm, 6 hours per day, 5 days per week for 14 weeks. All rats survived to the end of the study. The mean body weight gain of females exposed to 32 ppm was less than that of the chamber control group. Exposure-related increases in the incidences of squamous metaplasia of the respiratory and transitional epithelium, goblet cell hyperplasia of the respiratory epithelium, and hypertrophy of the respiratory epithelium lining the nasopharyngeal duct were observed in the nose of male and female rats. The incidences of degeneration, hyperplasia, metaplasia, and surface exudate of the olfactory epithelium generally increased with increasing exposure concentration in males and females. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to furfuryl alcohol at concentrations of 0, 2, 4, 8, 16, or 32 ppm, 6 hours per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Heart weights of 32 ppm males were significantly less than those of the chamber controls. Exposure-related histologic changes included degeneration, metaplasia, and chronic inflammation of the olfactory epithelium; hyaline droplets of the respiratory epithelium; and squamous metaplasia of the submucosal gland of the cuboidal epithelium in males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 105 weeks, at concentrations of 0, 2, 8, or 32 ppm. Survival and Body Weights All male rats exposed to 32 ppm died by week 99; survival of all other exposed groups of male and femald female rats was similar to that of the chamber control groups. Mean body weights of 32 ppm males were less than those of the chamber control group beginning at week 19. Pathology Findings All groups of exposed male and female rats had significantly increased incidences of nonneoplastic histologic changes of the nose compared to the chamber control groups. An adenoma of the lateral wall of the nose was observed in one 2 ppm male and one 8 ppm female, an adenoma of the respiratory epithelium was observed in one 8 ppm male and one 32 ppm female, one carcinoma of the respiratory epithelium was observed in a 32 ppm male, and squamous cell carcinomas of the nose were observed in three 32 ppm males. Renal tubule adenomas were present in one chamber control male, one 2 ppm male, two 8 ppm males, and two 32 ppm females. One 2 ppm female had a renal tubule carcinoma. Additional histologic sections from the kidney revealed the presence of additional hyperplasias in all groups of males and females; one additional renal tubule adenoma was observed in each of the chamber control, 2 ppm, and 8 ppm male groups, and four additional adenomas were observed in 32 ppm males. In females, two additional adenomas were found in the 8 ppm group, one adenoma in the 32 ppm group, and one carcinoma in the 2 ppm group. The severities of nephropathy relative to the chamber controls were increased in 32 ppm males and females. Males exposed to 32 ppm had extrarenal signs indicative of marked nephropathy including parathyroid gland hyperplasia and fibrous osteodystrophy. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 105 weeks, at concentrations of 0, 2, 8, or 32 ppm. Survival, Body Weights, and Clinical Findings Survival of exposed males and females was similar to that of the chamber control groups. Mean body weights of exposed males were generally similar to those of the chamber control group throughout the study. Mean body weights of exposed females were less than those of the chamber control group during year 2 of the study. Female mice exposed to 32 ppm developed focal corneal opacities. Pathology Findings The incidences of renal tubule neoplasms were increased in 32 ppm male mice compared to the chamber control group and exceeded the historical control range for inhalation studies. Step sectioning revealed the presence of additional hyperplasias in the chamber control and exposed groups and one adenoma in 32 ppm males. The severity of nephropathy increased with increasing exposure concentration in male mice. The incidence of renal tubule degeneration in male mice exposed to 32 ppm was significantly greater than in the chamber control group. Incidences of a variety of nonneoplastic lesions of the nose were significantly greater in all exposed groups of male and female mice than in the chamber control groups. The incidence of degeneration of the cornea was significantly greater in 32 ppm female mice compared to the chamber control group. GENETIC TOXICOLOGY: Furfuryl alcohol was not mutagenic in Salmonella typhimurium strain TA98, TA100, TA1535, or TA1537, with or without S9. It did induce sister chromatid exchanges in cultured Chinese hamster ovary cells in the absence of S9, but not in the presence of S9. No induction of chromosomal aberrations was noted in cultured Chinese hamster ovary cells treated with furfuryl alcohol in the absence of S9, but in the presence of S9 an equivocal result was obtained. In vivo, no induction of sister chromatid exchanges, chromosomal aberrations, or micronuclei was noted in bone marrow cells of male mice after treatment with furfuryl alcohol. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of furfuryl alcohol in male F344/N rats based on increased incidences of combined neoplasms of the nose. There was equivocal evidence of carcinogenic activity of furfuryl alcohol in female F344/N rats based on marginally increased incidences of neoplasms of the nose and renal tubule neoplasms. There was some evidence of carcinogenic activity of furfuryl alcohol in male B6C3F1 mice based on increased inci dences of renal tubule neoplasms. There was no evidence of carcinogenic activity of furfuryl alcohol in female B6C3F1 mice exposed to 2, 8, or 32 ppm. Exposure of male and female rats and male mice to furfuryl alcohol was associated with increased incidences of nonneoplastic lesions of the nose and increased severities of nephropathy. Exposure of female mice to furfuryl alcohol was associated with increased incidences of nonneoplastic lesions of the nose and corneal degeneration. Synonyms: 2-Furancarbinol; 2-furanmethanol, furfuralcohol, a-furylcarbinol; 2-hydroxymethylfuran

Mucus secretion by single tracheal submucosal glands from normal and cystic fibrosis transmembrane conductance regulator knockout mice

PubMed Central

Ianowski, Juan P; Choi, Jae Young; Wine, Jeffrey J; Hanrahan, John W

2007-01-01

Submucosal glands line the cartilaginous airways and produce most of the antimicrobial mucus that keeps the airways sterile. The glands are defective in cystic fibrosis (CF), but how this impacts airway health remains uncertain. Although most CF mouse strains exhibit mild airway defects, those with the C57Bl/6 genetic background have increased airway pathology and susceptibility to Pseudomonas. Thus, they offer the possibility of studying whether, and if so how, abnormal submucosal gland function contributes to CF airway disease. We used optical methods to study fluid secretion by individual glands in tracheas from normal, wild-type (WT) mice and from cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice (Cftrm1UNC/Cftrm1UNC; CF mice). Glands from WT mice qualitatively resembled those in humans by responding to carbachol and vasoactive intestinal peptide (VIP), although the relative rates of VIP- and forskolin-stimulated secretion were much lower in mice than in large mammals. The pharmacology of mouse gland secretion was also similar to that in humans; adding bumetanide or replacement of HCO3− by Hepes reduced the carbachol response by ∼50%, and this inhibition increased to 80% when both manoeuvres were performed simultaneously. It is important to note that glands from CFTR knockout mice responded to carbachol but did not secrete when exposed to VIP or forskolin, as has been shown previously for glands from CF patients. Tracheal glands from WT and CF mice both had robust secretory responses to electrical field stimulation that were blocked by tetrodotoxin. It is interesting that local irritation of the mucosa using chili pepper oil elicited secretion from WT glands but did not stimulate glands from CF mice. These results clarify the mechanisms of murine submucosal gland secretion and reveal a novel defect in local regulation of glands lacking CFTR which may also compromise airway defence in CF patients. PMID:17204498

Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gustafsson, Åsa, E-mail: asa.gustafsson@foi.se; Dept of Public Health and Clinical Medicine, Umeå University; Bergström, Ulrika

The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 andmore » 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials. - Highlights: • Hematite NPs induce differential responses in airways of healthy and allergic mice. • Hematite induced an airway inflammation in healthy mice. • Hematite induced cellular reduction in the alveolus and lymph nodes of allergic mice. • Cell death is possible due to extensive pro-oxidative environment in allergic mice. • It is important to include sensitive individuals when valuing health effects of NPs.« less

Neurotoxicity of low bisphenol A (BPA) exposure for young male mice: Implications for children exposed to environmental levels of BPA.

PubMed

Zhou, Yuanxiu; Wang, Zhouyu; Xia, Minghan; Zhuang, Siyi; Gong, Xiaobing; Pan, Jianwen; Li, Chuhua; Fan, Ruifang; Pang, Qihua; Lu, Shaoyou

2017-10-01

To investigate the neuron toxicities of low-dose exposure to bisphenol A (BPA) in children, mice were used as an animal model. We examined brain cell damage and the effects of learning and memory ability after BPA exposure in male mice (4 weeks of age) that were divided into four groups and chronically received different BPA treatments for 8 weeks. The comet assay and hippocampal neuron counting were used to detect the brain cell damage. The Y-maze test was applied to test alterations in learning and memory ability. Long term potentiation induction by BPA exposure was performed to study the potential mechanism of performance. The percentages of tail DNA, tail length and tail moment in brain cells increased with increasing BPA exposure concentrations. Significant differences in DNA damage were observed among the groups, including between the low-dose and control groups. In the Y-maze test, the other three groups qualified for the learned standard one day earlier than the high-exposed group. Furthermore, the ratio of qualified mice in the high-exposed group was always the lowest among the groups, indicating that high BPA treatment significantly altered the spatial memory performance of mice. Different BPA treatments exerted different effects on the neuron numbers of different regions in the hippocampus. In the CA1 region, the high-exposed group had a significant decrease in neuron numbers. A non-monotonic relationship was observed between the exposure concentrations and neuron quantity in the CA3 region. The hippocampal slices in the control and medium-exposed groups generated long-term potentiation after induction by theta burst stimulation, but the low-exposed group did not. A significant difference was observed between the control and low-exposed groups. In conclusion, chronic exposure to a low level of BPA had adverse effects on brain cells and altered the learning and memory ability of adolescent mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Critical role of aldehydes in cigarette smoke-induced acute airway inflammation

PubMed Central

2013-01-01

Background Cigarette smoking (CS) is the most important risk factor for COPD, which is associated with neutrophilic airway inflammation. We hypothesize, that highly reactive aldehydes are critical for CS-induced neutrophilic airway inflammation. Methods BALB/c mice were exposed to CS, water filtered CS (WF-CS) or air for 5 days. Levels of total particulate matter (TPM) and aldehydes in CS and WF-CS were measured. Six hours after the last exposure, inflammatory cells and cytokine levels were measured in lung tissue and bronchoalveolar lavage fluid (BALF). Furthermore, Beas-2b bronchial epithelial cells were exposed to CS extract (CSE) or WF-CS extract (WF-CSE) in the absence or presence of the aldehyde acrolein and IL-8 production was measured after 24 hrs. Results Compared to CS, in WF-CS strongly decreased (CS; 271.1 ± 41.5 μM, WF-CS; 58.5 ± 8.2 μM) levels of aldehydes were present whereas levels of TPM were only slightly reduced (CS; 20.78 ± 0.59 mg, WF-CS; 16.38 ± 0.36 mg). The numbers of mononuclear cells in BALF (p<0.01) and lung tissue (p<0.01) were significantly increased in the CS- and WF-CS-exposed mice compared to air control mice. Interestingly, the numbers of neutrophils (p<0.001) in BALF and neutrophils and eosinophils (p<0.05) in lung tissue were significantly increased in the CS-exposed but not in WF-CS-exposed mice as compared to air control mice. Levels of the neutrophil and eosinophil chemoattractants KC, MCP-1, MIP-1α and IL-5 were all significantly increased in lung tissue from CS-exposed mice compared to both WF-CS-exposed and air control mice. Interestingly, depletion of aldehydes in WF-CS extract significantly reduced IL-8 production in Beas-2b as compared to CSE, which could be restored by the aldehyde acrolein. Conclusion Aldehydes present in CS play a critical role in inflammatory cytokine production and neutrophilic- but not mononuclear airway inflammation. PMID:23594194

Inflammation and emphysema in cigarette smoke-exposed mice when instilled with poly (I:C) or infected with influenza A or respiratory syncytial viruses.

PubMed

Mebratu, Yohannes A; Smith, Kevin R; Agga, Getahun E; Tesfaigzi, Yohannes

2016-07-01

The length of time for cigarette smoke (CS) exposure to cause emphysema in mice is drastically reduced when CS exposure is combined with viral infection. However, the extent of inflammatory responses and lung pathologies of mice exposed to CS and infected with influenza A virus (IAV), respiratory syncytial virus (RSV), or treated with the viral derivative dsRNA (polyinosine-polycytidylic acid [poly (I:C)] have not been compared. Mice were exposed to CS or filtered air for 4 weeks and received a single dose of vehicle, AV, or RSV infection and extent of inflammation and emphysema was evaluated 14 d later. In another set of experiments, mice were instilled with poly (I:C) twice a week during the third and fourth weeks of CS exposure and immediately analyzed for extent of inflammation and lung pathologies. In CS-exposed mice, inflammation was characterized mainly by macrophages, lymphocytes, and neutrophils after IAV infection, mainly by lymphocytes, and neutrophils after RSV infection, and mainly by lymphocytes and neutrophils after poly (I:C) instillations. Despite increased inflammation, extent of emphysema by poly (I:C) was very mild; but was robust and similar for both IAV and RSV infections with enhanced MMP-12 mRNA expression and TUNEL positivity. Both IAV and RSV infections increased the levels of IL-17, IL-1β, IL-12b, IL-18, IL-23a, Ccl-2, Ccl-7 mRNAs in the lungs of CS-exposed mice with IAV causing more increases than RSV. CS-induced inflammatory responses and extent of emphysematous changes differ depending on the type of viral infection. These animal models may be useful to study the mechanisms by which different viruses exacerbate CS-induced inflammation and emphysema.

The effects of electronic cigarette emissions on systemic cotinine levels, weight and postnatal lung growth in neonatal mice.

PubMed

McGrath-Morrow, Sharon A; Hayashi, Madoka; Aherrera, Angela; Lopez, Armando; Malinina, Alla; Collaco, Joseph M; Neptune, Enid; Klein, Jonathan D; Winickoff, Jonathan P; Breysse, Patrick; Lazarus, Philip; Chen, Gang

2015-01-01

Electronic cigarette (E-cigarettes) emissions present a potentially new hazard to neonates through inhalation, dermal and oral contact. Exposure to nicotine containing E-cigarettes may cause significant systemic absorption in neonates due to the potential for multi-route exposure. Systemic absorption of nicotine and constituents of E-cigarette emissions may adversely impact weight and lung development in the neonate. To address these questions we exposed neonatal mice to E-cigarette emissions and measured systemic cotinine levels and alveolar lung growth. Neonatal mice were exposed to E-cigarettes for the first 10 days of life. E-cigarette cartridges contained either 1.8% nicotine in propylene glycol (PG) or PG vehicle alone. Daily weights, plasma and urine cotinine levels and lung growth using the alveolar mean linear intercept (MLI) method were measured at 10 days of life and compared to room air controls. Mice exposed to 1.8% nicotine/PG had a 13.3% decrease in total body weight compared to room air controls. Plasma cotinine levels were found to be elevated in neonatal mice exposed to 1.8% nicotine/PG E-cigarettes (mean 62.34± 3.3 ng/ml). After adjusting for sex and weight, the nicotine exposed mice were found to have modestly impaired lung growth by MLI compared to room air control mice (p<.054 trial 1; p<.006 trial 2). These studies indicate that exposure to E-cigarette emissions during the neonatal period can adversely impact weight gain. In addition exposure to nicotine containing E-cigarettes can cause detectable levels of systemic cotinine, diminished alveolar cell proliferation and a modest impairment in postnatal lung growth.

Effects of methimepip and JNJ-5207852 in Wistar rats exposed to an open-field with and without object and in Balb/c mice exposed to a radial-arm maze.

PubMed

Abuhamdah, Rushdie M A; van Rensburg, Ruan; Lethbridge, Natasha L; Ennaceur, Abdel; Chazot, Paul L

2012-01-01

The role of the histamine H(3) receptor (H(3)R) in anxiety is controversial, due to limitations in drug selectivity and limited validity of behavioral tests used in previous studies. In the present report, we describe two experiments. In the first one, Wistar rats were treated with an H(3)R agonist (methimepip), and exposed to an open-field. In the second one, Balb/c mice were treated with H(3)R agonist (methimepip) or antagonist (JNJ-5207852), and exposed to an open space 3D maze which is a modified version of the radial-arm maze. C57BL/6J saline treated mice were included for comparisons. When exposed to an empty open field, Wistar rats spent more time in the outer area and made very low number of brief crossings in the central area. However, when an object occupied the central area, rats crossed frequently into and spent a long time in the central area. Administration of a range of different doses of methimepip (selective H(3)R agonist) reduced the entries into the central area with a novel object, indicating enhanced avoidance response. In the 3D maze, both Balb/c and C57BL/6J saline-treated mice crossed frequently onto the bridges that radiate from the central platform but only C57BL/6J mice crossed onto the arms which extend the bridges. This suggests that Balb/c mice are more anxious than C57BL/6J mice. Neither methimepip nor JNJ-5207852 (selective H(3)R antagonist/inverse agonist) induced entry into the arms of the maze, indicative of lack of anxiolytic effects.

Studies on delayed systemic effects of ultraviolet B radiation on the induction of contact hypersensitivity, 3. Dendritic cells from secondary lymphoid organs are deficient in interleukin-12 production and capacity to promote activation and differentiation of T helper type 1 cells.

PubMed

Kitazawa, T; Streilein, J W

2000-02-01

Ultraviolet-B radiation (UVR) of mouse skin promotes both local and systemic immune aberrations that are thought to be important in the pathogenesis of cutaneous malignancies. Acute, low-dose UVR regimens inhibit the induction of contact hypersensitivity (CH) in genetically susceptible mice by TNF-alpha-dependent mechanisms. In addition, these regimens also promote the development of tolerance when hapten is applied to the UVR-exposed site at the completion of the radiation treatment protocol. A third immune abnormality is also observed in mice exposed to acute, low-dose UVR. This abnormality, which develops within 48-72 hr of the completion of the UVR regimen, has been described among antigen-presenting cells within secondary lymphoid organs, including lymph nodes that do not drain the site of irradiation. Dendritic cells (DCs) from lymph nodes and spleens of mice exposed to UVR lack the capacity to induce CH if they are derivatized with hapten and injected intracutaneously into naive mice. The DC defect is related to the production of and systemic dissemination of interleukin-10 (IL-10) by keratinocytes within the epidermis of the UVR-exposed skin. We have now examined the nature of the functional aberration that exists among DCs within the secondary lymphoid organs of UVR-exposed mice by examining the capacity of DCs to express co-stimulatory molecules, and their ability to activate ovalbumin (OVA) -specific DO11.10 T-cell receptor transgenic T cells in vitro. Our results indicate that DCs from UVR-exposed mice produced insufficient amounts of IL-12. When pulsed with OVA, these cells were capable of inducing proliferation among DO11.10 T cells in vitro, but the responding cells produced neither IFN-gamma nor IL-10 and IL-4. A similar antigen-presenting cell defect was generated in mice treated with a subcutaneous injection of IL-10. We conclude that acute, low-dose UVR creates an IL-10-dependent functional deficit in DCs in secondary lymphoid organs, and that this defect robs UVR-exposed mice of the capacity to develop CH when hapten is painted epicutaneously.

COSMIC RADIATION AND TUBERCULOSIS. IV. INFLUENCE OF COSMIC RADIATION ON TUBERCULOSIS AT HIGH ALTITUDE (3,130 M) AND AT SEA-LEVEL

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ong, S.G.

1964-01-01

At high altitude (3,130 m) tuberculous mice exposed to cosmic radiation under 10 cm of lead showed significantly greater mean survival time and a significantly greater number of survivors than tuberculous mice exposed to direct cosmic radiation. Tuberculous mice exposed to cosmic radiation at high altitude under 10 cm of lead showed a significantly greater mean survival time than tuberculous mice kept at sea level, exposed to direct cosmic radiation, and to cosmic radiation under 1, 2, and 10 cm of lead. The correlation analysis shows that a decreas in lung lesions is associated with an increase in survival time.more » The decrease in lung lesions is associated with an enlargement of the spleen. At high altitude the female showed a significantly greater number of survivors than the male. At sea level no significant difference was observed. On the average the female showed a significantly greater number of survivors. The beneficial effect of daylight with ultraviolet light on tuberculous mice was manifested in a lower maximum of mortality and in a significant decrease of lung and spleen lesions. (auth)« less

Static and ELF magnetic fields enhance the in vivo anti-tumor efficacy of cis-platin against lewis lung carcinoma, but not of cyclophosphamide against B16 melanotic melanoma.

PubMed

Tofani, S; Barone, D; Berardelli, M; Berno, E; Cintorino, M; Foglia, L; Ossola, P; Ronchetto, F; Toso, E; Eandi, M

2003-07-01

Previous works showed that exposure to static and extremely low frequency (ELF) magnetic fields (MF) over 3 mT slows down the growth kinetics of human tumors engrafted s.c. in immunodeficient mice, reducing their metastatizing power and prolonging mouse survival. In the experiments reported here, immunocompetent mice bearing murine Lewis Lung carcinomas (LLCs) or B16 melanotic melanomas were exposed to MF and treated respectively with two commonly used anti-cancer drugs: cis-diamminedichloroplatinum (cis-platin) and N,N-bis (2-chloroethyl)tetra-hydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide (cyclophosphamide). The experiment endpoint was survival time. The survival time of mice treated with cis-platin (3mg/kg i.p.) and exposed to MF was significantly (P<0.01) longer than that of mice treated only with cis-platin or only exposed to MF, superimposing that of mice treated with 10mg/kg i.p. of the drug, showing that MF act synergically with the pharmacological treatment. On the contrary, when mice treated with cyclophosphamide (50mg/kg i.p.) were exposed to MF no synergic effects were observed, the survival curve being exactly the same as that of mice treated with the drug alone. No clinical signs or toxicity were seen in any of the mice exposed to MF alone or along with cis-platin or cyclophosphamide treatment, compared to mice given only the two known drugs.A possible explanation for the synergic effect of MF being found in mice treated with cis-platin could be that the platinum ion stimulates radical production and that MF enhance active oxygen production bringing about changes in tumor cell membrane permeability, influencing positively the drug uptake. Alternatively, or in addition to this, it has been demonstrated that the rate of conversion of cis-platin to reactive species able to bind to DNA, is increased by localized production of free radicals by MF.

Influenza Virus-Induced Lung Inflammation Was Modulated by Cigarette Smoke Exposure in Mice

PubMed Central

Han, Yan; Ling, Man To; Mao, Huawei; Zheng, Jian; Liu, Ming; Lam, Kwok Tai; Liu, Yuan; Tu, Wenwei; Lau, Yu-Lung

2014-01-01

Although smokers have increased susceptibility and severity of seasonal influenza virus infection, there is no report about the risk of 2009 pandemic H1N1 (pdmH1N1) or avian H9N2 (H9N2/G1) virus infection in smokers. In our study, we used mouse model to investigate the effect of cigarette smoke on pdmH1N1 or H9N2 virus infection. Mice were exposed to cigarette smoke for 21 days and then infected with pdmH1N1 or H9N2 virus. Control mice were exposed to air in parallel. We found that cigarette smoke exposure alone significantly upregulated the lung inflammation. Such prior cigarette smoke exposure significantly reduced the disease severity of subsequent pdmH1N1 or H9N2 virus infection. For pdmH1N1 infection, cigarette smoke exposed mice had significantly lower mortality than the control mice, possibly due to the significantly decreased production of inflammatory cytokines and chemokines. Similarly, after H9N2 infection, cigarette smoke exposed mice displayed significantly less weight loss, which might be attributed to lower cytokines and chemokines production, less macrophages, neutrophils, CD4+ and CD8+ T cells infiltration and reduced lung damage compared to the control mice. To further investigate the underlying mechanism, we used nicotine to mimic the effect of cigarette smoke both in vitro and in vivo. Pre-treating the primary human macrophages with nicotine for 72 h significantly decreased their expression of cytokines and chemokines after pdmH1N1 or H9N2 infection. The mice subcutaneously and continuously treated with nicotine displayed significantly less weight loss and lower inflammatory response than the control mice upon pdmH1N1 or H9N2 infection. Moreover, α7 nicotinic acetylcholine receptor knockout mice had more body weight loss than wild-type mice after cigarette smoke exposure and H9N2 infection. Our study provided the first evidence that the pathogenicity of both pdmH1N1 and H9N2 viruses was alleviated in cigarette smoke exposed mice, which might partially be attributed to the immunosuppressive effect of nicotine. PMID:24465940

Mononuclear cells, mast cells and mucous cells as part of the delayed hypersensitivity response to aerosolized antigen in mice.

PubMed Central

Enander, I; Ahlstedt, S; Nygren, H

1984-01-01

Mice (BALB/c) exposed to picryl chloride (PiCl) on their shaved abdomen and untreated animals were after 7 days exposed to daily aerosolized trinitrophenylated dog serum albumin (TNP-DSA). Mice exposed to PiCl tended to respond earlier and more strongly with both delayed hypersensitivity (DH) and IgG antibodies in serum and bronchial washings than did mice exposed to aerosol only. Picryl chloride sensitization resulted in spontaneously proliferating axillary lymph node cells, which could not be further stimulated with antigen or mitogen. Histological examination of lung tissue of aerosol-sensitized animals revealed an increase in mononuclear cells and mast cells around bronchioli and mucous cells, particularly in those animals exposed for prolonged periods and sensitized with PiCl prior to aerosol. Sensitization of mice with aerosolized TNP-DSA administrated in two 2- and 1-week periods with a 4-week interval responded with DH and IgG antibody in a dose dependent fashion irrespective of presensitization with PiCl. In bronchial washings IgG antibodies were found particularly after two 2-week periods of exposure. The cells taken from the axillary or brachial lymph nodes showed spontaneous proliferation. Culture of the cells to achieve mast cell maturation resulted in no or very low numbers of mast cells in the lymph nodes. PMID:6706375

Early Exposure to Intermediate-Frequency Magnetic Fields Alters Brain Biomarkers without Histopathological Changes in Adult Mice

PubMed Central

Win-Shwe, Tin-Tin; Ohtani, Shin; Ushiyama, Akira; Kunugita, Naoki

2015-01-01

Recently we have reported that intermediate-frequency magnetic field (IF-MF) exposure transiently altered the mRNA expression levels of memory function-related genes in the hippocampi of adult male mice. However, the effects of IF-MF exposure during brain development on neurological biomarkers have not yet been clarified. In the present study, we investigated the effect of IF-MF exposure during development on neurological and immunological markers in the mouse hippocampus in 3- and 7-week-old male mice. Pregnant C57BL/6J mice were exposed to IF-MF (21 kHz, 3.8 mT) for one hour per day from organogenesis period day 7 to 17. At adolescence, some IF-MF-exposed mice were further divided into exposure, recovery, and sham-exposure groups. The adolescent-exposure groups were exposed again to IF-MF from postnatal day 27 to 48. The expression of mRNA in the hippocampi was examined using a real-time RT-PCR method, and microglia activation was examined by immunohistochemical analysis. The expression levels of NR1 and NR2B as well as transcription factors (CaMKIV, CREB1), inflammatory mediators (COX2, IL-1 β,TNF-α), and the oxidative stress marker heme-oxygenase (HO)-1 were significantly increased in the IF-MF-exposed mice, compared with the control group, in the 7-week-old mice, but not in the 3-week-old mice. Microglia activation was not different between the control and other groups. This study provides the first evidence that early exposure to IF-MF reversibly affects the NMDA receptor, its related signaling pathways, and inflammatory mediators in the hippocampus of young adult mice; these changes are transient and recover after termination of exposure without histopathological changes. PMID:25913185

Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke.

PubMed

Conklin, Daniel J; Haberzettl, Petra; Prough, Russell A; Bhatnagar, Aruni

2009-05-01

Exposure to tobacco smoke impairs endothelium-dependent arterial dilation. Reactive constituents of cigarette smoke are metabolized and detoxified by glutathione-S-transferases (GSTs). Although polymorphisms in GST genes are associated with the risk of cancer in smokers, the role of these enzymes in regulating the cardiovascular effects of smoking has not been studied. The P isoform of GST (GSTP), which catalyzes the conjugation of electrophilic molecules in cigarette smoke such as acrolein, was expressed in high abundance in the mouse lung and aorta. Exposure to tobacco smoke for 3 days (5 h/day) decreased total plasma protein. These changes were exaggerated in GSTP(-/-) mice. Aortic rings isolated from tobacco smoke-exposed GSTP(-/-) mice showed greater attenuation of ACh-evoked relaxation than those from GSTP(+/+) mice. The lung, plasma, and aorta of mice exposed to tobacco smoke or acrolein (for 5 h) accumulated more acrolein-adducted proteins than those tissues of mice exposed to air, indicating that exposure to tobacco smoke results in the systemic delivery of acrolein. Relative to GSTP(+/+) mice, modification of some proteins by acrolein was increased in the aorta of GSTP(-/-) mice. Aortic rings prepared from GSTP(-/-) mice that inhaled acrolein (1 ppm, 5 h/day for 3 days) or those exposed to acrolein in an organ bath showed diminished ACh-induced arterial relaxation more strongly than GSTP(+/+) mice. Acrolein-induced endothelial dysfunction was prevented by pretreatment of the aorta with N-acetylcysteine. These results indicate that GSTP protects against the endothelial dysfunction induced by tobacco smoke exposure and that this protection may be related to the detoxification of acrolein or other related cigarette smoke constituents.

Molecular mechanisms mediating a deficit in recall of fear extinction in adult mice exposed to cocaine in utero.

PubMed

Kabir, Zeeba D; Katzman, Aaron C; Kosofsky, Barry E

2013-01-01

Prenatal cocaine exposure has been shown to alter cognitive processes of exposed individuals, presumed to be a result of long-lasting molecular alterations in the brain. In adult prenatal cocaine exposed (PCOC) mice we have identified a deficit in recall of fear extinction, a behavior that is dependent on the medial prefrontal cortex (mPFC) and the hippocampus. While we observed no change in the constitutive expression of brain derived neurotrophic factor (BDNF) protein and mRNA in the mPFC and hippocampus of adult PCOC mice, we observed blunted BDNF signaling in the mPFC of adult PCOC mice after fear extinction compared to the control animals. Specifically, during the consolidation phase of the extinction memory, we observed a decrease in BDNF protein and it's phospho-TrkB receptor expression. Interestingly, at this same time point there was a significant increase in total Bdnf mRNA levels in the mPFC of PCOC mice as compared with controls. In the Bdnf gene, we identified decreased constitutive binding of the transcription factors, MeCP2 and P-CREB at the promoters of Bdnf exons I and IV in the mPFC of PCOC mice, that unlike control mice remained unchanged when measured during the behavior. Finally, bilateral infusion of recombinant BDNF protein into the infralimbic subdivision of the mPFC during the consolidation phase of the extinction memory rescued the behavioral deficit in PCOC mice. In conclusion, these findings extend our knowledge of the neurobiologic impact of prenatal cocaine exposure on the mPFC of mice, which may lead to improved clinical recognition and treatment of exposed individuals.

[Effects of nano-selenium on cognition performance of mice exposed in 1800 MHz radiofrequency fields].

PubMed

Qin, Fenju; Yuan, Hongxia; Nie, Jihua; Cao, Yi; Tong, Jian

2014-01-01

To study the effects of nano-selenium (NSe) on cognition performance of mice exposed to 1800 MHz radiofrequency fields (RF). Male mice were randomly divided into four groups, control and nano-Se low, middle and high dose groups (L, M, H). Each group was sub-divided into three groups, RF 0 min, RF 30 min and RF 120 min. Nano-se solution (2, 4 and 8 microg/ml) were administered to mice of L, M, H groups by intra-gastric injection respectively, 0.5 ml/d for 50 days, the conctral group were administered with distilled water. At the 21st day, the mice in RF subgroup were exposed to 208 microW/cm2 1800 MHz radiofrequency fields (0, 30 and 120 min/d respectively) for 30 days. The cognitive ability of the mice were tested with Y-maze. Further, the levels of MDA, GABA, Glu, Ach and the activities of CAT and GSH-Px in cerebra were measured. Significant impairments in learning and memory (P < 0.05) were observed in the RF 120 min group, and with reduction of the Ach level and the activities of CAT and GSH-Px and increase of the content of GABA, Glu and MDA in cerebrum. NSe enhanced cognitive performance of RF mice, decreased GABA, Glu and MDA levels, increased Ach levels, GSH-Px and CAT activities. NSe could improve cognitive impairments of mice exposed to RF, the mechanism of which might involve the increasing antioxidation, decreasing free radical content and the changes of cerebra neurotransmitters.

Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles.

PubMed

Gustafsson, Åsa; Bergström, Ulrika; Ågren, Lina; Österlund, Lars; Sandström, Thomas; Bucht, Anders

2015-10-01

The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials. Copyright © 2015 Elsevier Inc. All rights reserved.

Uridine homeostatic disorder leads to DNA damage and tumorigenesis.

PubMed

Cao, Zhe; Ma, Jun; Chen, Xinchun; Zhou, Boping; Cai, Chuan; Huang, Dan; Zhang, Xuewen; Cao, Deliang

2016-03-28

Uridine is a natural nucleoside precursor of uridine monophosphate in organisms and thus is considered to be safe and is used in a wide range of clinical settings. The far-reaching effects of pharmacological uridine have long been neglected. Here, we report that the homeostatic disorder of uridine is carcinogenic. Targeted disruption (-/-) of murine uridine phosphorylase (UPase) disrupted the homeostasis of uridine and increased spontaneous tumorigenesis by more than 3-fold. Multiple tumors (e.g., lymphoma, hepatoma and lung adenoma) occurred simultaneously in some UPase deficient mice, but not in wild-type mice raised under the same conditions. In the tissue from UPase -/- mice, the 2'-deoxyuridine,5'-triphosphate (dUTP) levels and uracil DNA were increased and p53 was activated with an increased phospho-Ser18 p53 level. Exposing cell lines (e.g., MCF-7, RKO, HCT-8 and NCI-H460) to uridine (10 or 30 µM) led to uracil DNA damage and p53 activation, which in turn triggered the DNA damage response. In these cells, phospho-ATM, phospho-CHK2, and phospho-γH2AX were increased by uridine. These data suggest that uridine homeostatic disorder leads to uracil DNA damage and that pharmacological uridine may be carcinogenic. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Memory Deficit Recovery after Chronic Vanadium Exposure in Mice

PubMed Central

Folarin, Oluwabusayo; Olopade, Funmilayo; Onwuka, Silas; Olopade, James

2016-01-01

Vanadium is a transitional metal with an ability to generate reactive oxygen species in the biological system. This work was designed to assess memory deficits in mice chronically exposed to vanadium. A total of 132 male BALB/c mice (4 weeks old) were used for the experiment and were divided into three major groups of vanadium treated, matched controls, and animals exposed to vanadium for three months and thereafter vanadium was withdrawn. Animals were tested using Morris water maze and forelimb grip test at 3, 6, 9, and 12 months of age. The results showed that animals across the groups showed no difference in learning but had significant loss in memory abilities after 3 months of vanadium exposure and this trend continued in all vanadium-exposed groups relative to the controls. Animals exposed to vanadium for three months recovered significantly only 9 months after vanadium withdrawal. There was no significant difference in latency to fall in the forelimb grip test between vanadium-exposed groups and the controls in all age groups. In conclusion, we have shown that chronic administration of vanadium in mice leads to memory deficit which is reversible but only after a long period of vanadium withdrawal. PMID:26962395

Memory Deficit Recovery after Chronic Vanadium Exposure in Mice.

PubMed

Folarin, Oluwabusayo; Olopade, Funmilayo; Onwuka, Silas; Olopade, James

2016-01-01

Vanadium is a transitional metal with an ability to generate reactive oxygen species in the biological system. This work was designed to assess memory deficits in mice chronically exposed to vanadium. A total of 132 male BALB/c mice (4 weeks old) were used for the experiment and were divided into three major groups of vanadium treated, matched controls, and animals exposed to vanadium for three months and thereafter vanadium was withdrawn. Animals were tested using Morris water maze and forelimb grip test at 3, 6, 9, and 12 months of age. The results showed that animals across the groups showed no difference in learning but had significant loss in memory abilities after 3 months of vanadium exposure and this trend continued in all vanadium-exposed groups relative to the controls. Animals exposed to vanadium for three months recovered significantly only 9 months after vanadium withdrawal. There was no significant difference in latency to fall in the forelimb grip test between vanadium-exposed groups and the controls in all age groups. In conclusion, we have shown that chronic administration of vanadium in mice leads to memory deficit which is reversible but only after a long period of vanadium withdrawal.

Mechanisms involved in the blood-testis barrier increased permeability induced by EMP.

PubMed

Wang, Xiao-Wu; Ding, Gui-Rong; Shi, Chang-Hong; Zeng, Li-Hua; Liu, Jun-Ye; Li, Jing; Zhao, Tao; Chen, Yong-Bin; Guo, Guo-Zhen

2010-09-30

The blood-testis barrier (BTB) plays an important role in male reproductive system. Lots of environmental stimulations can increase the permeability of BTB and then result in antisperm antibody (AsAb) generation, which is a key step in male immune infertility. Here we reported the results of male mice exposed to electromagnetic pulse (EMP) by measuring the expression of tight-junction-associated proteins (ZO-1 and Occludin), vimentin microfilaments, and transforming growth factor-beta (TGF-beta3) as well as AsAb level in serum. Male BALB/c mice were sham exposed or exposed to EMP at two different intensities (200kV/m and 400kV/m) for 200 pulses. The testes were collected at different time points after EMP exposure. Immunofluorescence histocytochemistry, western blotting, laser confocal microscopy and RT-PCR were used in this study. Compared with sham group, the expression of ZO-1 and TGF-beta3 significantly decreased accompanied with unevenly stained vimentin microfilaments and increased serum AsAb levels in EMP-exposed mice. These results suggest a potential BTB injury and immune infertility in male mice exposed to a certain intensity of EMP. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Neural Tube Defects In Mice Exposed To Tap Water

PubMed Central

Mallela, Murali K; Werre, Stephen R; Hrubec, Terry C

2010-01-01

In May of 2006 we suddenly began to observe neural tube defects (NTDs) in embryos of untreated control mice. We hypothesized the mice were being exposed unknowingly to a teratogenic agent and investigated the cause. Our results suggested that NTDs were not resulting from bedding material, feed, strain or source of the mice. Additionally, mice were negative for routine and comprehensive screens of pathogens. To further test whether the NTDs resulted from infectious or genetic cause localized to our facility, we obtained three strains of timed pregnant mice from commercial suppliers located in 4 different states. All strains and sources of mice arrived in our laboratory with NTDs, implying that commercially available mice were possibly exposed to a teratogen prior to purchase. Our investigation eventually concluded that exposure to tap water was causing the NTDs. The incidence of NTDs was greatest in purchased mice provided tap water and lowest in purchased mice provided distilled deionized water (DDI). Providing mice DDI water for two generations (F2-DDI) eliminated the NTDs. When F2-DDI mice were provided tap water from three different urban areas prior to breeding, their offspring again developed NTDs. Increased length of exposure to tap water significantly increased the incidence of NTDs. These results indicate that a contaminant in municipal tap water is likely causing NTDs in mice. The unknown teratogen appears to have a wide geographic distribution but has not yet been identified. Water analysis is currently underway to identify candidate contaminants that might be responsible for the malformations. PMID:20549630

Transmission probabilities of mouse parvovirus 1 to sentinel mice chronically exposed to serial dilutions of contaminated bedding.

PubMed

Besselsen, David G; Myers, Erin L; Franklin, Craig L; Korte, Scott W; Wagner, April M; Henderson, Kenneth S; Weigler, Benjamin J

2008-04-01

Intermittent serodetection of mouse parvovirus (MPV) infections in animal facilities occurs frequently when soiled bedding sentinel mouse monitoring systems are used. We evaluated induction of seroconversion in naïve single-caged weanling ICR mice (n = 10 per group) maintained on 5-fold serially diluted contaminated bedding obtained from SCID mice persistently shedding MPV1e. Soiled bedding from the infected SCID mice was collected, diluted, and redistributed weekly to cages housing ICR mice to represent chronic exposure to MPV at varying prevalence in a research colony. Sera was collected every other week for 12 wk and evaluated for reactivity to MPV nonstructural and capsid antigens by multiplex fluorescent immunoassay. Mice were euthanized after seroconversion, and DNA extracted from lymph node and spleen was evaluated by quantitative PCR. Cumulative incidence of MPV infection for each of the 7 soiled bedding dilution groups (range, 1:5 to 1:78125 [v/v]) was 100%, 100%, 90%, 20%, 70%, 60%, and 20%, respectively. Most seropositive mice (78%) converted within the first 2 to 3 wk of soiled bedding exposure, correlating to viral exposure when mice were 4 to 7 wk of age. Viral DNA was detected in lymphoid tissues collected from all mice that were seropositive to VP2 capsid antigen, whereas viral DNA was not detected in lymphoid tissue of seronegative mice. These data indicate seroconversion occurs consistently in young mice exposed to high doses of virus equivalent to fecal MPV loads observed in acutely infected mice, whereas seroconversion is inconsistent in mice chronically exposed to lower doses of virus.

Dissociation of spontaneous seizures and brainstem seizure thresholds in mice exposed to eight flurothyl-induced generalized seizures.

PubMed

Kadiyala, Sridhar B; Ferland, Russell J

2017-03-01

C57BL/6J mice exposed to eight flurothyl-induced generalized clonic seizures exhibit a change in seizure phenotype following a 28-day incubation period and subsequent flurothyl rechallenge. Mice now develop a complex seizure semiology originating in the forebrain and propagating into the brainstem seizure network (a forebrain→brainstem seizure). In contrast, this phenotype change does not occur in seizure-sensitive DBA/2J mice. The underlying mechanism(s) was the focus of these studies. DBA2/J mice were exposed to eight flurothyl-induced seizures (1/day) followed by 24-hour video-electroencephalographic recordings for 28-days. Forebrain and brainstem seizure thresholds were determined in C57BL/6J and DBA/2J mice following one or eight flurothyl-induced seizures, or after eight flurothyl-induced seizures, a 28-day incubation period, and final flurothyl rechallenge. Similar to C57BL/6J mice, DBA2/J mice expressed spontaneous seizures. However, unlike C57BL/6J mice, DBA2/J mice continued to have spontaneous seizures without remission. Because DBA2/J mice do not express forebrain→brainstem seizures following flurothyl rechallenge after a 28-day incubation period, this indicated that spontaneous seizures were not sufficient for the evolution of forebrain→brainstem seizures. Therefore, we determined whether brainstem seizure thresholds were changing during this repeated-flurothyl model and whether this could account for the expression of forebrain→brainstem seizures. Brainstem seizure thresholds were not different between C57BL/6J and DBA/2J mice on day one or on the last induction seizure trial (day eight). However, brainstem seizure thresholds did differ significantly on flurothyl rechallenge (day 28) with DBA/2J mice showing no lowering of their brainstem seizure thresholds. These results demonstrated that DBA/2J mice exposed to the repeated-flurothyl model develop spontaneous seizures without evidence of seizure remission and provide a new model of epileptogenesis. Moreover, these findings indicated that the transition of forebrain ictal discharge into the brainstem seizure network occurs due to changes in brainstem seizure thresholds that are independent of spontaneous seizure expression.

Effects of Fetal Exposure to Asian Sand Dust on Development and Reproduction in Male Offspring.

PubMed

Yoshida, Seiichi; Ichinose, Takamichi; Arashidani, Keiichi; He, Miao; Takano, Hirohisa; Shibamoto, Takayuki

2016-11-23

In recent experimental studies, we reported the aggravating effects of Asian sand dust (ASD) on male reproduction in mice. However, the effects of fetal ASD exposure on male reproduction have not been investigated. The present study investigated the effects of fetal ASD exposure on reproduction in male offspring. Using pregnant CD-1 mice, ASD was administered intratracheally on days 7 and 14 of gestation, and the reproduction of male offspring was determined at 5, 10, and 15 weeks after birth. The secondary sex ratio was significantly lower in the fetal ASD-exposed mice than in the controls. Histologic examination showed partial vacuolation of seminiferous tubules in immature mice. Moreover, daily sperm production (DSP) was significantly less in the fetal ASD-exposed mice than in the controls. DSP in the fetal ASD-exposed mice was approximately 10% less than the controls at both 5 and 10 weeks. However, both the histologic changes and the DSP decrease were reversed as the mice matured. These findings suggest that ASD exposure affects both the fetal development and the reproduction of male offspring. In the future, it will be necessary to clarify the onset mechanisms of ASD-induced male fetus death and male reproductive disorders.

Urban air pollution targets the dorsal vagal complex and dark chocolate offers neuroprotection.

PubMed

Villarreal-Calderon, Rafael; Torres-Jardón, Ricardo; Palacios-Moreno, Juan; Osnaya, Norma; Pérez-Guillé, Beatriz; Maronpot, Robert R; Reed, William; Zhu, Hongtu; Calderón-Garcidueñas, Lilian

2010-12-01

Mexico City (MC) residents exposed to fine particulate matter and endotoxin exhibit inflammation of the olfactory bulb, substantia nigra, and vagus nerve. The goal of this study was to model these endpoints in mice and examine the neuroprotective effects of chocolate. Mice exposed to MC air received no treatment or oral dark chocolate and were compared to clean-air mice either untreated or treated intraperitoneally with endotoxin. Cyclooxygenase-2 (COX-2), interleukin 1 beta (IL-1β), and CD14 messenger RNA (mRNA) were quantified after 4, 8, and 16 months of exposure in target brain regions. After 16 months of exposure, the dorsal vagal complex (DVC) exhibited significant inflammation in endotoxin-treated and MC mice (COX-2 and IL-1β P<.001). Mexico City mice had olfactory bulb upregulation of CD14 (P=.002) and significant DVC imbalance in genes for antioxidant defenses, apoptosis, and neurodegeneration. These findings demonstrate sustained DVC inflammation in mice exposed to MC air, which is mitigated by chocolate administration. © The Author(s) 2010

Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bardullas, U.; Limon-Pacheco, J.H.; Giordano, M.

2009-09-01

Arsenic (As) is a toxic metalloid widely present in the environment. Human exposure to As has been associated with the development of skin and internal organ cancers and cardiovascular disorders, among other diseases. A few studies report decreases in intelligence quotient (IQ), and sensory and motor alterations after chronic As exposure in humans. On the other hand, studies of rodents exposed to high doses of As have found alterations in locomotor activity, brain neurochemistry, behavioral tasks, and oxidative stress. In the present study both male and female C57Bl/6J mice were exposed to environmentally relevant doses of As such as 0.05,more » 0.5, 5.0, or 50 mg As/L of drinking water for 4 months, and locomotor activity was assessed every month. Male mice presented hyperactivity in the group exposed to 0.5 mg As/L and hypoactivity in the group exposed to 50 mg As/L after 4 months of As exposure, whereas female mice exposed to 0.05, 0.5, and 5.0 mg As/L exhibited hyperactivity in every monthly test during As exposure. Furthermore, striatal and hypothalamic dopamine content was decreased only in female mice. Also decreases in tyrosine hydroxylase (TH) and cytosolic thioredoxin (Trx-1) mRNA expression in striatum and nucleus accumbens were observed in male and female mice, respectively. These results indicate that chronic As exposure leads to gender-dependent alterations in dopaminergic markers and spontaneous locomotor activity, and down-regulation of the antioxidant capacity of the brain.« less

Inhalation exposure study of titanium dioxide nanoparticles with a primary particle size of 2 to 5 nm.

PubMed

Grassian, Vicki H; O'shaughnessy, Patrick T; Adamcakova-Dodd, Andrea; Pettibone, John M; Thorne, Peter S

2007-03-01

Nanotechnology offers great promise in many industrial applications. However, little is known about the health effects of manufactured nanoparticles, the building blocks of nanomaterials. Titanium dioxide (TiO(2)) nanoparticles with a primary size of 2-5 nm have not been studied previously in inhalation exposure models and represent some of the smallest manufactured nanoparticles. The purpose of this study was to assess the toxicity of these nanoparticles using a murine model of lung inflammation and injury. The properties of TiO(2) nanoparticles as well as the characteristics of aerosols of these particles were evaluated. Mice were exposed to TiO(2) nanoparticles in a whole-body exposure chamber acutely (4 hr) or subacutely (4 hr/day for 10 days). Toxicity in exposed mice was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase (LDH) activity and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Lungs were also evaluated for histopathologic changes Mice exposed acutely to 0.77 or 7.22 mg/m(3) nanoparticles demonstrated minimal lung toxicity or inflammation. Mice exposed subacutely (8.88 mg/m(3)) and necropsied immediately and at week 1 or 2 postexposure had higher counts of total cells and alveolar macrophages in the BAL fluid compared with sentinels. However, mice recovered by week 3 postexposure. Other indicators were negative. Mice subacutely exposed to 2-5 nm TiO(2) nanoparticles showed a significant but moderate inflammatory response among animals at week 0, 1, or 2 after exposure that resolved by week 3 postexposure.

Lung development and the host response to influenza A virus are altered by different doses of neonatal oxygen in mice

PubMed Central

Buczynski, Bradley W.; Yee, Min; Paige Lawrence, B.

2012-01-01

Oxygen exposure in preterm infants has been associated with altered lung development and increased risk for respiratory viral infections later in life. Although the dose of oxygen sufficient to exert these changes in humans remains unknown, adult mice exposed to 100% oxygen between postnatal days 1–4 exhibit alveolar simplification and increased sensitivity to influenza virus infection. Additionally, two nonlinear thresholds of neonatal oxygen exposures were previously identified that promote modest (between 40% and 60% oxygen) and severe (between 80% and 100% oxygen) changes in lung development. Here, we investigate whether these two thresholds correlate with the severity of lung disease following respiratory viral infection. Adult mice exposed to 100% oxygen at birth, and to a lesser extent 80% oxygen, demonstrated enhanced body weight loss, persistent inflammation, and fibrosis following infection compared with infected siblings exposed to room air at birth. In contrast, the host response to infection was indistinguishable between mice exposed to room air and 40% or 60% oxygen. Interestingly, levels of monocyte chemoattractant protein (MCP)-1 were equivalently elevated in infected mice that had been exposed to 80% or 100% oxygen as neonates. However, reducing levels of MCP-1 using heterozygous Mcp-1 mice did not affect oxygen-dependent changes in the response to infection. Thus lung development and the host response to respiratory viral infection are disrupted by different doses of oxygen. Our findings suggest that measuring lung function alone may not be sufficient to identify individuals born prematurely who have increased risk for respiratory viral infection. PMID:22408042

NTP Toxicology and Carcinogenesis Studies of EMODIN (CAS NO. 518-82-1) Feed Studies in F344/N Rats and B6C3F1 Mice.

PubMed

2001-06-01

Emodin is a naturally occurring anthraquinone present in the roots and bark of numerous plants of the genus Rhamnus. Extracts from the roots, bark, and/or dried leaves of buckthorn, senna, cascara, aloe, frangula, and rhubarb have been used as laxatives since ancient times and currently are widely used in the preparation of herbal laxative preparations. Anthraquinone glycosides are poorly absorbed from the gastrointestinal tract but are cleaved by gut bacteria to produce aglycones (such as emodin) that are more readily absorbed and are responsible for the purgative properties of these preparations. There is extensive exposure to emodin and other anthraquinones resulting from the use of herb-based stimulant laxatives. Reports that 1,8-dihydroxyanthraquinone, a commonly used laxative ingredient, caused tumors in the gastrointestinal tract of rats raised the possibility of an association between colorectal cancer and the use of laxatives containing anthraquinones. Because emodin is a hydroxyanthraquinone structurally similar to 1,8-dihydroxyanthraquinone, is present in herbal laxatives, and was reported to be mutagenic in bacteria, it was considered a potential carcinogen and was selected for in-depth evaluation. Male and female F344/N rats and B6C3F1 mice were exposed to emodin (at least 94% pure) in feed for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female rats were fed diets containing 0, 600, 2,000, 5,500, 17,000, or 50,000 ppm emodin (equivalent to average daily doses of approximately 50, 170, 480, 1,400, or 3,700 mg emodin/kg body weight to males and 50, 160, 460, 1,250, or 2,000 mg/kg to females) for 15 (males) or 16 (females) days. Three female rats died before the end of the study. Mean body weights of males and females exposed to 5,500 ppm or greater were significantly less than those of the controls. Feed consumption by males and females receiving 17,000 or 50,000 ppm was decreased throughout the study. Macroscopic lesions were present in the kidney of rats exposed to 17,000 or 50,000 ppm. 16-DAY STUDY IN MICE: Groups of five male and five female mice were fed diets containing 0, 600, 2,000, 5,500, 17,000, or 50,000 ppm emodin (equivalent to average daily doses of approximately 120, 400, 1,200, or 3,800 mg/kg to males and 140, 530, 1,600, or 5,000 mg/kg to females; 50,000 ppm equivalents were not calculated due to high mortality) for 15 (males) or 16 (females) days. All mice exposed to 50,000 ppm died before the end of the study. Mice in the 17,000 ppm groups lost weight during the study. Feed consumption by 5,500 ppm females was greater than that by the controls throughout the study. Macroscopic lesions were present in the gallbladder and kidney of mice exposed to 17,000 ppm. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 312.5, 625, 1,250, 2,500, or 5,000 ppm emodin (equivalent to average daily doses of approximately 20, 40, 80, 170, or 300 mg/kg to males and females) for 14 weeks. Mean body weights of males exposed to 2,500 ppm or greater and females exposed to 1,250 ppm or greater were significantly less than those of the controls. During the first week of the study, feed consumption by males exposed to 2,500 or 5,000 ppm and females exposed to 5,000 ppm was less than that by the controls. Feed consumption by these groups was similar to that by the controls for the remainder of the study. In rats exposed to 2,500 or 5,000 ppm, there were increases in platelet counts in males and females and segmented neutrophil counts in females. Total serum protein and albumin concentrations were decreased in females exposed to 2,500 or 5,000 ppm. Relative kidney weights of rats exposed to 1,250 ppm or greater and relative lung weights of rats exposed to 625 ppm or greater were significantly increased compared to the control groups. Relative liver weights were incree increased in females exposed to 625 ppm or greater. The estrous cycle length wassignificantly increased in females exposed to 1,250 or 5,000 ppm. All male rats exposed to 1,250 ppm or greater and all exposed female rats had pigment in the renal tubules; and the severity of pigmentation generally increased with increasing exposure concentration. The incidences of hyaline droplets in the cortical epithelial cytoplasm were increased in all groups of exposed males and in females exposed to 312.5, 625, or 1,250 ppm. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 312.5, 625, 1,250, 2,500, or 5,000 ppm emodin (equivalent to average daily doses of approxi mately 50, 100, 190, 400, or 800 mg/kg to males and 60, 130, 240, 500, or 1,100 mg/kg to females) for 14 weeks. All mice survived to the end of the study. Mean body weights of males exposed to 2,500 or 5,000 ppm were significantly less than those of the controls. Feed consumption by exposed groups was generally similar to that by the controls. Relative kidney weights of male mice exposed to 1,250 ppm or greater, relative lung weights of males exposed to 625 ppm or greater, and relative liver weights of female mice exposed to 625 ppm or greater were increased. The incidences and severities of nephropathy were increased in males and females exposed to 1,250 ppm or greater. The incidences of renal tubule pigmentation were significantly increased in males exposed to 625 ppm or greater and in females exposed to 1,250 ppm or greater. 2-YEAR STUDY IN RATS: Groups of 65 male and 65 female rats were fed diets containing 0, 280, 830, or 2,500 ppm emodin (equivalent to average daily doses of approximately 110, 320, or 1,000 mg/kg to males and 120, 370, or 1,100 mg/kg to females) for 105 weeks. Ten male and ten female rats from each group were necropsied at 6 months. Blood samples from five male and five female rats in each group were evaluated at 3, 6, and 12 months for plasma emodin concentrations; these rats were necropsied at 12 months. Survival, Body Weights, and Feed Consumption: Survival of exposed males and females was similar to that of the controls. The mean body weights of rats in the 2,500 ppm groups were less than those of the controls beginning at week 2 of the study. Feed consumption by exposed groups was similar to that by the controls throughout the study. Pathology Findings: Three Zymbal's gland carcinomas were observed in female rats exposed to 2,500 ppm. This incidence exceeded the range observed for current historical controls and was considered an equivocal finding. At the 6- and 12-month interim evaluations and at 2 years, emodin-related increases in the incidences of renal tubule hyaline droplets occurred in all exposed groups. The incidences of renal tubule pigmentation were significantly increased in all exposed groups of males at 2 years. There were negative trends in the incidences of mononuclear cell leukemia in male and female rats, and the incidences in the 2,500 ppm groups were significantly decreased. In females exposed to 2,500 ppm, the incidence was below the historical control range; the incidence in males exposed to 2,500 ppm was at the lower end of the historical control range. 2-YEAR STUDY IN MICE: Groups of 60 male mice were fed diets containing 0, 160, 312, or 625 ppm emodin (equivalent to average daily doses of approximately 15, 35, or 70 mg/kg) for 105 weeks. Groups of 60 female mice were fed diets containing 0, 312, 625, or 1,250 ppm emodin (equivalent to average daily doses of approximately 30, 60, or 120 mg/kg) for 105 weeks. Ten male and ten female mice from each group were necropsied at 12 months. Survival, Body Weights, and Feed Consumption Survival and mean body weights of exposed males and females were similar to those of the controls. No differences in feed consumption were noted between exposed and control groups. Pathology Findings: Low incidences of renal tubule adenoma and carcinoma occurred in exposed male mice; these incidences included one carcinoma each in the 312 and 625 ppm groups. Renal tubule neoplasms are rare in male mice, and their presence in these groups suggested a possible association with emodin exposure. At the 12-month interim evaluation, the severity of nephropathy was slightly increased in males exposed to 625 ppm. Also at 12 months, the severity of nephropathy increased from minimal in the lower exposure groups to mild in females exposed to 1,250 ppm; the incidence in this group was significantly increased compared to the control group. At 2 years, the severities of nephropathy were slightly increased in males exposed to 625 ppm and females exposed to 1,250 ppm. The incidences of nephropathy were significantly increased in all exposed groups of females. At the 12-month interim evaluation, the incidences of renal tubule pigmentation were significantly increased in all exposed groups of males and in females exposed to 625 or 1,250 ppm. The severities increased with increasing exposure concentration. At 2 years, the incidences of renal tubule pigmentation were significantly increased in all exposed groups; severities increased with increasing exposure concentration. GENETIC TOXICOLOGY: Emodin was mutagenic in Salmonella typhimurium strain TA100 in the presence of S9 activation; no mutagenicity was detected in strain TA98, with or without S9. Chromosomal aberrations were induced in cultured Chinese hamster ovary cells treated with emodin, with and without S9. Three separate in vivo micronucleus tests were performed with emodin. A male rat bone marrow micronucleus test, with emodin administered by three intraperitoneal injections, gave negative results. Results of acute-exposure (intraperitoneal injection) micronucleus tests in bone marrow and peripheral blood erythrocytes of male and female mice were negative. In a peripheral blood micronucleus test on mice from the 14-week study, negative results were seen in male mice, but a weakly positive response was observed in similarly exposed females. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of emodin in male F344/N rats exposed to 280, 830, or 2,500 ppm. There was equivocal evidence of carcinogenic activity of emodin in female F344/N rats based on a marginal increase in the incidence of Zymbal's gland carcinoma. There was equivocal evidence of carcinogenic activity of emodin in male B6C3F1 mice based on a low incidence of uncommon renal tubule neoplasms. There was no evidence of carcinogenic activity of emodin in female B6C3F1 mice exposed to 312, 625, or 1,250 ppm. Exposure of rats to emodin resulted in increased incidences of renal tubule hyaline droplets and pigmentation in males, increased incidences of renal tubule hyaline droplets in females, and increased severities of renal tubule pigmentation in males and females. Emodin exposure resulted in increased incidences of renal tubule pigmentation in male and female mice and increased incidences of nephropathy in female mice. Incidences of mononuclear cell leukemia decreased in male and female rats exposed to 2,500 ppm. Synonyms: Archin; C.I. 75440; C.I. Natural Green 2; C.I. Natural Yellow 14; emodol; frangulic acid; frangula emodin; 6-methyl- 1,3,8-trihydroxyanthraquinone; Persian Berry Lake; rheum emodin; schuttgelb; 1,3,8-trihydroxy-6-methyl-9,10- anthracenedione; 1,3,8-trihydroxy-6-methylanthraquinone; 4,5,7-trihydroxy-2-methylanthraquinone.

Chronic consumption of distilled sugarcane spirit induces anxiolytic-like effects in mice.

PubMed

Sena, Maria Clecia P; Nunes, Fabíola C; Salvadori, Mirian G S Stiebbe; Carvalho, Cleyton Charles D; Morais, Liana Clebia S L; Braga, Valdir A

2011-01-01

Chronic ethanol consumption is a major public health problem throughout the world. We investigated the anxiolytic-like effects and the possible ever injury induced by the chronic consumption of ethanol or sugarcane spirit in mice. Adult mice were exposed to a two-bottle free-choice paradigm for 6 weeks. The mice in Group A (n = 16) had access to sugarcane spirit + distilled water, the mice in Group B (n = 15) had access to ethanol + distilled water, and the mice in Group C (control, n = 14) had access to distilled water + distilled water. The ethanol content in the beverages offered to Groups A and B was 2% for the first week, 5% for the second week and 10% for the remaining four weeks. At the end of the experimental period, the mice were evaluated using the elevated-plus maze and the hole-board test to assess their anxiety-related behaviors. We also determined the serum aspartate aminotransferase and alanine aminotransferase levels. In the elevated-plus maze, the time spent in the open arms was increased in the mice exposed to chronic ethanol (32 ± 8 vs. 7 ± 2 s, n = 9) or sugarcane spirit (36 ± 9 vs. 7 ± 2 s, n = 9) compared to the controls. In the hole-board test, the mice exposed to ethanol or sugarcane spirit displayed increases in their head-dipping frequency (16 ± 1 for the control group, 27 ± 2 for the ethanol group, and 31 ± 3 for the sugarcane-spirit group; n = 9 for each group). In addition, the mice exposed to sugarcane spirit displayed an increase in the aspartate aminotransferase / alanine aminotransferase ratio compared to the ethanol group (1.29 ± 0.17 for the control group and 2.67 ± 0.17 for the sugarcane spirit group; n = 8 for each group). The chronic consumption of sugarcane-spirit produces liver injury and anxiolytic-like effects and the possible liver injury in mice.

Prenatal Exposure to Paint Thinner Alters Postnatal Development and Behavior in Mice

PubMed Central

Malloul, Hanaa; Mahdani, Ferdaousse M.; Bennis, Mohammed; Ba-M’hamed, Saadia

2017-01-01

Occupational exposure and sniffing of volatile organic solvents continue to be a worldwide health problem, raising the risk for teratogenic sequelae of maternal inhalant abuse. Real life exposures usually involve simultaneous exposures to multiple solvents, and almost all the abused solvents contain a mixture of two or more different volatile compounds. However, several studies examined the teratogenicity due to industrial exposure to a single volatile solvent but investigating the teratogenic potential of complex chemical mixture such as thinner remains unexplored. This study was undertaken to evaluate developmental neurotoxicity of paint thinner using a mouse model. Mated female mice (N = 21) were, therefore, exposed to repeated and brief inhalation episodes of 0, 300 or 600 ppm of thinner during the entire period of pregnancy. Females weigh was recorded and their standard fertility and reproductive parameters were assessed. After birth postnatal day 1 (PND1), offspring (N = 88) length and body weight were measured in a daily basis. At PND5, the pups were assessed for their postnatal growth, physical maturation, reflex development, neuromotor abilities, sensory function, activity level, anxiety, depression, learning and memory functions. At adulthood, structural changes of the hippocampus were examined by estimating the total volume of the dentate gyrus. Except one case of thinner induced abortion at the higher dose, our results showed that the prenatal exposure to the solvent did not cause any maternal toxicity or decrease in the viability of the offspring. Therefore, a lower birth weight, decrease in the litter size and delayed reflexes ontogeny were registered in prenatally exposed offspring to both 300 ppm and 600 ppm of thinner. In addition, prenatally exposure to thinner resulted in increased anxiolytic- and depression-like behaviors. In contrast, impaired learning and memory functions and decreased hippocampal dentate gyrus volume were revealed only in the prenatally treated offspring by 600 ppm of thinner. Based on these results, we can conclude that prenatally exposure to paint thinner causes a long-lasting developmental neurotoxicity and alters a wide range of behavioral functions in mice. This shows the risk that mothers who abuse thinner paint expose their offspring. PMID:28959195

EARLY GENE EXPRESSION CHANGES IN THE LIVERS OF MICE EXPOSED TO DICHLOROACETIC ACID

EPA Science Inventory

EARLY GENE EXPRESSION CHANGES IN THE LIVERS OF MICE EXPOSED TO DICHLOROACETIC ACID

Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have shown that DCA induces liver tumors in rodents when administered in drinking wate...

Proteomic Profiling of Bladders from Mice Exposed with Sodium Arsenite

EPA Science Inventory

Arsenic, an environmental contaminant, has been linked with cancer of the bladder in humans. To study the mode of action of arsenic, female CH3 mice were exposed to 85 ppm sodium arsenite in their drinking water for 30 days. Following the exposure a comparative proteomic analysis...

SIX1 oncoprotein is necessary for abnormal uterine basal cell development in mice exposed neonatally to DES.

EPA Science Inventory

Exposing female mice on neonatal days 1-5 to the synthetic estrogen diethylstilbestrol (DES) results in high incidence of uterine carcinoma. However, the biological mechanisms driving DES-induced carcinogenesis remain unclear. We previously showed that the sine oculis homeobox ho...

SIX1 Oncoprotein Promotes Abnormal Uterine Basal Cell Development in Mice Exposed Neonatally to Diethylstilbestrol

EPA Science Inventory

In a classical model of latent hormonal carcinogenesis, exposing mice on neonatal days 1-5 to the synthetic estrogen diethylstilbestrol (DES; 1 mg/kg/day) results in high incidence of uterine carcinoma. However, the biological mechanisms driving DES-induced carcinogenesis remain ...

SIX1 oncoprotein is necessary for abnormal uterine basal cell development in mice exposed neonatally to DES

EPA Science Inventory

In a classical model of latent hormonal carcinogenesis, exposing female mice on neonatal days 1-5 to the synthetic estrogen diethylstilbestrol (DES; 1 mg/kg/day) results in high incidence of uterine carcinoma. However, the biological mechanisms driving DES-induced carcinogenesis ...

EARLY GENE EXPRESSION CHANGES IN THE LIVERS OF MICE EXPOSED TO DICHOLORACETC ACID

EPA Science Inventory

EARLY GENE EXPRESSION CHANGES IN THE LIVERS OF MICE EXPOSED TO DICHLOROACETIC ACID

Dichloroacetic acid COCA) is a major by-product ofwater disinfection by cWorination. Several
studies have shown that DCA induces liver tumors in rodents when administered in drinkmg wate...

Effect of parsley (Petroselinum crispum, Apiaceae) juice against cadmium neurotoxicity in albino mice (Mus musculus).

PubMed

Maodaa, Saleh N; Allam, Ahmed A; Ajarem, Jamaan; Abdel-Maksoud, Mostafa A; Al-Basher, Gadah I; Wang, Zun Yao

2016-02-04

Parsley was employed as an experimental probe to prevent the behavioral, biochemical and morphological changes in the brain tissue of the albino mice following chronic cadmium (Cd) administration. Non-anesthetized adult male mice were given parsley juice (Petroselinum crispum, Apiaceae) daily by gastric intubation at doses of 10 and 20 g/kg/day. The animals were divided into six groups: Group A, mice were exposed to saline; Groups B and C, were given low and high doses of parsley juice, respectively; Group D, mice were exposed to Cd; Groups E and F, were exposed to Cd and concomitantly given low and high doses of parsley, respectively. Cd intoxication can cause behavioral abnormalities, biochemical and histopathological disturbances in treated mice. Parsley juice has significantly improved the Cd-associated behavioral changes, reduced the elevation of lipid peroxidation and normalized the Cd effect on reduced glutathione and peroxidase activities in the brain of treated mice. Histological data have supported these foundations whereas Cd treatment has induced neuronal degeneration, chromatolysis and pyknosis in the cerebrum, cerebellum and medulla oblongata. The low dose (5 g/kg/day) of parsley exhibited beneficial effects in reducing the deleterious changes associated with Cd treatment on the behavior, neurotransmitters level, oxidative stress and brain neurons of the Cd-treated mice.

Intake of high-fat diet stimulates the risk of ultraviolet radiation-induced skin tumors and malignant progression of papillomas to carcinoma in SKH-1 hairless mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vaid, Mudit; Singh, Tripti; Prasad, Ram

Previously, we showed that administration of a high-fat diet (HF-diet) to C57BL/6 mice exacerbates their response to short-term UVB radiation-induced inflammation in the skin. To explore the effects of an HF-diet on UVB-induced tumorigenesis, we have used the SKH-1 hairless mouse model in which the mice are exposed to UVB radiation (180 mJ/cm{sup 2}) three times a week for 24 weeks. The development of UVB-induced skin tumors was rapid and the tumor multiplicity and tumor size were significantly higher (P < 0.01–0.005) in the mice fed an HF-diet than the mice fed a control-diet (C-diet). Moreover, the malignant progression ofmore » UVB-induced papillomas to carcinomas was higher in HF-diet-fed mice. On analysis of tumors and tumor-uninvolved skin samples from the tumor-bearing mice, we found that administration of an HF-diet significantly enhanced the levels of UVB-induced expression of cyclooxygenase-2 (COX-2), prostaglandin E{sub 2} (P < 0.01), and PGE{sub 2} receptors, and activation of NF-κB in the UVB-exposed skin as well as in tumors. In addition the HF-diet enhanced the expression of proinflammatory cytokines, including tumor necrosis factor-α (P < 0.01), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.05) in the UVB-exposed skin as well as in tumors. Western blot analysis revealed that HF-diet enhanced the levels of epidermal cell proliferation, phosphatidylinositol 3-kinase and phosphorylation of Akt at Ser{sup 473} in UVB-exposed skin and skin tumors. Collectively, these data demonstrate that the regular consumption of an HF-diet increases the risk of photocarcinogenesis in mice and that this is associated with enhanced expression of inflammatory mediators in the UVB-exposed skin and tumors. - Highlights: • Consumption of high-fat diet increases UVB-induced skin tumor development in mice. • Intake of high-fat diet stimulates progression of UV-induced papilloma to carcinoma. • Intake of high-fat diet enhances inflammation in UV-exposed skin • Regular consumption of low-fat diet may inhibit the risk of photocarcinogenesis.« less

In vitro and in vivo antimutagenic effects of DIG, a herbal preparation of Berberis vulgaris, Taraxacum officinale and Arctium lappa, against mitomycin C.

PubMed

Di Giorgio, C; Boyer, L; De Meo, M; Laurant, C; Elias, R; Ollivier, E

2015-07-01

DIG, a liquid herbal preparation made from a mixture of diluted mother tinctures of Berberis vulgaris, Taraxacum officinale and Arctium lappa, was assessed for its antimutagenic properties against mitomycin C. The micronucleus assay on Chinese hamster ovary (CHO)-K1 cells was used to evaluate the in vitro anticlastogenic activity of DIG compared to those of separately diluted mother tinctures. The micronucleus assay was performed on mouse erythrocytes and the comet assay was performed on mouse liver, kidney, lung, brain and testicles to assess the protective effects of DIG (0.2 and 2 % at libitum) against an intraperitoneal injection of mitomycin C (1 mg Kg(-1)) in mice. DIG exerted a powerful anticlastogenic activity, under both pretreatment and simultaneous treatment conditions as assessed by the micronucleus assay in CHO-K1 cells. Its protective activity was greater than that observed for each mother tincture. DIG reduced micronuclei levels in mouse erythrocytes and suppressed >80 % of DNA strand breaks in the liver, kidney, lung, brain and testicles of mice exposed to mitomycin C.

NTP toxicology and carcinogenesis studies of decalin (CAS No. 91-17-8) in F344/N rats and B6C3F(1) mice and a toxicology study of decalin in male NBR rats (inhalation studies).

PubMed

2005-01-01

Decalin is used as an industrial solvent for naphthalene, fats, resins, oils, and waxes. It is also used as a substitute for turpentine in lacquers, paints, and varnishes; as a solvent and stabilizer for shoe polishes and floor waxes; and as a constituent of motor fuels and lubricants. Other applications include use as a paint thinner and remover, a patent fuel in stoves, a high-density fuel in submarine-launched cruise missile systems, and in stain removal and cleaning machinery. Decalin was nominated for study by the National Cancer Institute because of its chemical structure, its potential for consumer exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were exposed to decalin (greater than 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. Groups of male NBR rats were exposed to decalin for 2 weeks. Male NBR rats do not produce alpha2u-globulin; the NBR rats were included to study the relationship of alpha2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDIES IN RATS: Groups of five male and five female F344/N rats and five male NBR rats were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber controls. Renal toxicity studies were performed in male F344/N and NBR rats. The numbers of labeled cells and the labeling indices in the left kidney of 200 and 400 ppm F344/N male rats were significantly greater than those in the chamber controls. The alpha2u-globulin/soluble protein ratios were significantly increased in all exposed groups of F344/N rats. Liver weights of male F344/N and NBR rats exposed to 100 ppm or greater were significantly increased, as were those of all exposed groups of females. Kidney weights of male F344/N rats exposed to 50 ppm or greater were significantly increased. Exposure-related hyaline droplet accumulation, degeneration and regeneration of renal cortical tubules, and granular casts occurred in the kidney of exposed F344/N male rats. 2-WEEK STUDIES IN MICE: Groups of five male and five female B6C3F(1) mice were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 17 days. All mice survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber control groups. Liver weights of 200 and 400 ppm males and females and 100 ppm females were significantly increased. 3-MONTH STUDY IN RATS: Groups of 25 male and 20 female F344/N rats were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 2 (five male renal toxicity rats), 6 (10 male and 10 female clinical pathology rats), or 14 (10 core study rats) weeks. All rats survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber control groups. Urinalysis results indicated that decalin exposure caused increases in urine glucose and protein concentrations and enzyme activities that were consistent with the renal lesions observed microscopically. Renal toxicity studies were performed on rats sacrificed at 2 and 6 weeks and at the end of the study. In kidney tissue examined for cell proliferation, the numbers of PCNA-labeled cells and labeling indices were generally significantly greater than those of the chamber controls in exposed groups of rats at all three time points. Concentrations of alpha2u-globulin in the kidney as well as the alpha2u-globulin/soluble protein ratios were significantly increased at week 2 in all exposed groups and in the 200 and 400 ppm groups at week 6 and at the end of the study. Absolute and/or relative kidney and liver weights of male rats exposed to 50 ppm or greater were increased. Incidences of renal tubule regeneration and granular casts in the medulla of the kidney in exposed male rats were increased, and the severities of hyaline droplets generally increased with increasing exposure concentration. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female B6C3F(1) mice were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 14 weeks. All mice survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber control groups. Liver weights of 200 and 400 ppm males and females were significantly increased. There was a significant exposure concentration-related decrease in the absolute spermatid head count and a significant decrease in absolute head count of the 400 ppm group compared to the chamber controls. Incidences of centrilobular cytomegaly of the liver were increased in exposed male mice. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 25, 50 (male rats only), 100, or 400 ppm (female rats only) decalin vapor 6 hours per day, 5 days per week for 105 weeks. A group of 20 male rats was exposed to 400 ppm. Survival of exposed groups was similar to that of the chamber control groups. Mean body weights of 400 ppm males were slightly less than those of the chamber controls during the second year of the study. Incidences of renal tubule adenoma and adenoma or carcinoma (combined) and of benign or malignant pheochromocytoma (combined) of the adrenal medulla in 100 and 400 ppm males were significantly increased. There was a significant association between nephropathy severity and adrenal pheochromocytoma incidence. Nonneoplastic lesions related to decalin exposure occurred in the kidney of male rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F(1) mice were exposed to 0, 25, 100, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 105 weeks. Survival of exposed mice was similar to that of the chamber controls. Mean body weights of exposed groups were generally similar to those of the chamber control groups throughout the study. Increased incidences of hepatocellular neoplasms occurred in 25 and 400 ppm female mice, and the incidences of centrilobular hypertrophy, necrosis, syncytial alteration, and erythrophagocytosis of the liver in 400 ppm males were significantly increased. The incidences of uterine stromal polyp and stromal polyp or stromal sarcoma (combined) occurred with positive trends in female mice. The rate of metabolism of decalin was the same for males and females in rats and mice. Also in rats and mice, decalin metabolism was saturated at less than 400 ppm. Increased labeling indices in male rats were likely due to changes related to alpha2u-globulin. Decalin was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535, with or without induced hamster or rat liver S9 enzymes. A small but significant increase in the frequency of micronucleated normochromatic erythrocytes was noted in male mice exposed to decalin for 3 months; however, no induction of micronuclei was observed in female mice. Under the conditions of these studies, there was clear evidence of carcinogenic activity of decalin in male F344/N rats based on increased incidences of renal tubule neoplasms. The increased incidences of benign or malignant pheochromocytoma (combined) of the adrenal medulla in male rats were also considered to be exposure related. There was no evidence of carcinogenic activity of decalin in female F344/N rats exposed to 25, 100, or 400 ppm. There was no evidence of carcinogenic activity of decalin in male B6C3F(1) mice exposed to 25, 100, or 400 ppm. There was equivocal evidence of carcinogenic activity of decalin in female B6C3F(1) mice based on marginally increased incidences of hepatocellular and uterine neoplasms. Exposure of male rats to decalin resulted in nonneoplastic lesions of the kidney characteristic of alpha2u-globulin accumulation. Nonneoplastic lesions of the liver were observed in male mice exposed to decalin.

Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells.

PubMed

Li, Diandian; Hu, Jun; Wang, Tao; Zhang, Xue; Liu, Lian; Wang, Hao; Wu, Yanqiu; Xu, Dan; Wen, Fuqiang

2016-11-22

Cigarette smoke (CS) is a major risk of chronic obstructive pulmonary disease (COPD), contributing to airway inflammation. Our previous study revealed that silymarin had an anti-inflammatory effect in CS-exposed mice. In this study, we attempt to further elucidate the molecular mechanisms of silymarin in CS extract (CSE)-induced inflammation using human bronchial epithelial cells. Silymarin significantly suppressed autophagy activation and the activity of ERK/p38 mitogen-activated protein kinase (MAPK) pathway in Beas-2B cells. We also observed that inhibiting the activity of ERK with specific inhibitor U0126 led to reduced autophagic level, while knockdown of autophagic gene Beclin-1 and Atg5 decreased the levels of ERK and p38 phosphorylation. Moreover, silymarin attenuated CSE-induced upregulation of inflammatory cytokines TNF-α, IL-6 and IL-8 which could also be dampened by ERK/p38 MAPK inhibitors and siRNAs for Beclin-1 and Atg5. Finally, we validated decreased levels of both autophagy and inflammatory cytokines (TNF-α and KC) in CS-exposed mice after silymarin treatment. The present research has demonstrated that CSE-induced autophagy in bronchial epithelia, in synergism with ERK MAPK pathway, may initiate and exaggerate airway inflammation. Silymarin could attenuate inflammatory responses through intervening in the crosstalk between autophagy and ERK MAPK pathway, and might be an ideal agent treating inflammatory pulmonary diseases.

Proteomic CNS profile of delayed cognitive impairment in mice exposed to Gulf War agents.

PubMed

Abdullah, Laila; Crynen, Gogce; Reed, Jon; Bishop, Alex; Phillips, John; Ferguson, Scott; Mouzon, Benoit; Mullan, Myles; Mathura, Venkatarajan; Mullan, Michael; Ait-Ghezala, Ghania; Crawford, Fiona

2011-12-01

Gulf War Illness (GWI) is a chronic multisymptom condition with a central nervous system (CNS) component, for which there is no treatment available. It is now believed that the combined exposure to Gulf War (GW) agents, including pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), was a key contributor to the etiology of GWI. In this study, a proteomic approach was used to characterize the biomolecular disturbances that accompany neurobehavioral and neuropathological changes associated with combined exposure to PB and PER. Mice acutely exposed to PB and PER over 10 days showed an increase in anxiety-like behavior, psychomotor problems and delayed cognitive impairment compared to control mice that received vehicle only. Proteomic analysis showed changes in proteins associated with lipid metabolism and molecular transport in the brains of GW agent-exposed mice compared to controls. Proteins associated with the endocrine and immune systems were also altered, and dysfunction of these systems is a prominent feature of GWI. The presence of astrogliosis in the GW agent-exposed mice compared to control mice further suggests an immune system imbalance, as is observed in GWI. These studies provide a broad perspective of the molecular disturbances driving the late pathology of this complex illness. Evaluation of the potential role of these biological functions in GWI will be useful in identifying molecular pathways that can be targeted for the development of novel therapeutics against GWI.

[Study of genome instability using DNA fingerprinting of the offspring of male mice subjected to chronic low dose gamma irradiation].

PubMed

Bezlepkin, V G; Vasil'eva, G V; Lomaeva, M G; Sirota, N P; Gaziev, A I

2000-01-01

By a polymerase chain reaction with an arbitrary primer (AP-PCR), the possibility of transmission of genome instability to somatic cells of the offspring (F1 generation) from male parents of mice exposed to chronic low-level gamma-radiation was studied. Male BALB/c mice 15 days after exposure to 10-50 cGy were mated with unirradiated females. Biopsies were taken from tale tips of two month-old offspring mice and DNA was isolated. The primer in the AP-PCR was a 20-mer oligonucleotide flanking the microsatellite locus Atp1b2 on chromosome 11 of the mouse. A comparative analysis of individual fingerprints of AP-PCR products on DNA-templates from the offspring of irradiated and unirradiated male mice revealed an increased variability of microsatellite-associated sequences in the genome of the offspring of the males exposed to 25 and 50 cGy. The DNA-fingerprints of the offspring of male mice exposed to chronic irradiation with the doses 10 and 25 cGy 15 days before fertilization (at the post-meiotic stage of spermatogenesis) showed an increased frequency of "non-parent bands". The results of the study point to the possibility of transmission to the offspring somatic cells of changes increasing genome instability from male parents exposed to chronic low-level radiation prior to fertilization.

Exposure to nicotine increases nicotinic acetylcholine receptor density in the reward pathway and binge ethanol consumption in C57BL/6J adolescent female mice.

PubMed

Locker, Alicia R; Marks, Michael J; Kamens, Helen M; Klein, Laura Cousino

2016-05-01

Nearly 80% of adult smokers begin smoking during adolescence. Binge alcohol consumption is also common during adolescence. Past studies report that nicotine and ethanol activate dopamine neurons in the reward pathway and may increase synaptic levels of dopamine in the nucleus accumbens through nicotinic acetylcholine receptor (nAChR) stimulation. Activation of the reward pathway during adolescence through drug use may produce neural alterations affecting subsequent drug consumption. Consequently, the effect of nicotine exposure on binge alcohol consumption was examined along with an assessment of the neurobiological underpinnings that drive adolescent use of these drugs. Adolescent C57BL/6J mice (postnatal days 35-44) were exposed to either water or nicotine (200μg/ml) for ten days. On the final four days, ethanol intake was examined using the drinking-in-the-dark paradigm. Nicotine-exposed mice consumed significantly more ethanol and displayed higher blood ethanol concentrations than did control mice. Autoradiographic analysis of nAChR density revealed higher epibatidine binding in frontal cortical regions in mice exposed to nicotine and ethanol compared to mice exposed to ethanol only. These data show that nicotine exposure during adolescence increases subsequent binge ethanol consumption, and may affect the number of nAChRs in regions of the brain reward pathway, specifically the frontal cortex. Published by Elsevier Inc.

Toxicology and carcinogenesis studies of diethylamine (CAS No. 109-89-7) in F344/N rats and B6C3F1 mice (inhalation studies).

PubMed

2011-10-01

Diethylamine is used mainly as a chemical intermediate to produce the corrosion inhibitor N,N-diethylethanolamine and a lesser amount is used to produce pesticides and insect repellants and in rubber processing. Diethylamine was nominated for study by the National Institute of Environmental Health Sciences based upon its high production volume and ubiquitous natural occurrence in trace amounts and because of the lack of chronic toxicity and carcinogenicity data on the chemical. Male and female F344/N rats and B6C3F1 mice were exposed to diethylamine (approximately 99.9% pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in bacterial mutagenicity tester strains and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to diethylamine vapor at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 16 days. All rats survived to the end of the study. The mean body weights of 250 and 500 ppm males and females and 125 ppm males were significantly less than those of the chamber controls. Clinical findings included lethargy, nasal/eye discharge, abnormal breathing, thinness, eye abnormalities, and discolored urine. The thymus weights of males exposed to 125 ppm or greater and females exposed to 500 ppm were significantly less than those of the chamber controls. Focal eye lesions were noted at necropsy in four males and three females exposed to 500 ppm and one male exposed to 250 ppm. Crusty noses were observed in most 500 ppm males and females and in two 250 ppm males. Suppurative inflammation, necrosis of the turbinates (except in one 125 ppm female), and squamous metaplasia of the respiratory epithelium of the nose were present in all rats exposed to 125 ppm or greater. Ulcer of the respiratory epithelium and atrophy of the olfactory epithelium occurred in all rats exposed to 250 or 500 ppm, and ulcer of the nasopharyngeal duct was present in all 500 ppm rats. Suppurative inflammation of the cornea was present in most rats exposed to 500 ppm. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to diethylamine vapor at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 17 days. Two males and three females exposed to 500 ppm died during the first week of the study. The mean body weights of males and females exposed to 125 ppm or greater were significantly less than those of the chamber controls. Males and females exposed to 250 or 500 ppm lost weight during the study. Lethargy, abnormal breathing, and thinness were observed in most mice exposed to 250 or 500 ppm. Eye irritation and discharge, nasal discharge, and low fecal and urine output were noted in 500 ppm mice. Thymus weights of 250 and 500 ppm males and 125 ppm or greater females were significantly less than those of the chamber controls. Suppurative inflammation of the nose occurred in all males exposed to 250 or 500 ppm and all females exposed to 125 ppm or greater, and most males exposed to 125 ppm. Turbinate necrosis occurred in all exposed mice except one 31 ppm female. Squamous metaplasia of the respiratory epithelium and olfactory epithelial atrophy were seen in mice exposed to 125 ppm or greater. In the lung, the incidence of minimal chronic active inflammation of mainstem bronchi was significantly increased in 500 ppm males. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to diethylamine vapor at concentrations of 0, 8, 16, 32, 62, or 125 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All rats survived to the end of the study. Mean body weights of all exposed groups were similar to those of the chamber control groups. There were significant exposure concentration-related decreases in sperm motility in 32, 62, and 125 ppm males; there were no significant differences in the lengths of estrous cycles between chamber control and exposed groups of females. Exposure-related nasal lesions were seen primarily in rats exposed to 62 or 125 ppm. These lesions included turbinate necrosis, suppurative inflammation, respiratory epithelial hyperplasia, squamous metaplasia of the respiratory epithelium, and olfactory epithelial atrophy. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to diethylamine vapor at concentrations of 0, 8, 16, 32, 62, or 125 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. The mean body weights of 125 ppm males and females were significantly less than those of the chamber controls. There were significant exposure concentration-related decreases in sperm motility in males exposed to 32, 62, or 125 ppm; the estrous cycle of 125 ppm females was significantly longer than that of the chamber controls but only by half a day. Histopathologic changes were noted primarily in the nasal cavity and involved both the respiratory and olfactory epithelium of males and females principally in the 62 or 125 ppm groups. These lesions included suppurative inflammation, squamous metaplasia of the respiratory epithelium, olfactory epithelial atrophy, and necrosis of the turbinates. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to diethylamine vapor at concentrations of 0, 31, 62.5, or 125 ppm, 6 hours plus T90 (15 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups of rats was similar to that of the chamber control groups. Mean body weights of males and females exposed to 125 ppm were less than those of the chamber controls after week 57. Increased incidences of eye abnormality occurred in exposed males and females. A spectrum of nonneoplastic lesions was observed in the respiratory and olfactory epithelium of the nose in exposed rats. The lesions included suppurative inflammation, ulceration of the respiratory epithelium, hyaline droplet accumulation in the glands of the respiratory epithelium, necrosis of the turbinates, squamous metaplasia of the respiratory epithelium, hyperplasia of the respiratory epithelium, atrophy of the olfactory epithelium, hyaline droplet accumulation in the respiratory and olfactory epithelium, basal cell hyperplasia of the olfactory epithelium, respiratory metaplasia of the olfactory epithelium, and goblet cell hyperplasia. The incidence of chronic inflammation of the pleura was significantly increased in 125 ppm females. The incidences of histiocytic cellular infiltration of the alveolus of the lung were significantly increased in all exposed groups of females and the incidence of chronic inflammation was significantly increased in 125 ppm females. In 125 ppm males, the incidence of suppurative inflammation of the cornea was significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to diethylamine vapor at concentrations of 0, 16, 31, or 62.5 ppm, 6 hours plus T90 (15 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups of mice was similar to that of the chamber control groups. Mean body weights of males and females were similar to those of the chamber controls. Eye abnormality was observed in greater incidence in exposed groups of males than in the chamber controls, and torso/ventral ulcer/abscess was observed in six 62.5 ppm males compared to none in the chamber controls. A similar spectrum of nonneoplastic lesions was seen in the nose of exposed mice as was seen in rats. Diethylamine was not mutagenic in either of two independent bacterial mutagenicity assays, each conducted with and without exogenous metabolic activation enzymes. Bacterial strains tested included Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli strain WP2 uvrA/pKM101. In addition to the negative results in the two bacterial assays, no significant increases in the frequencies of micronucleated erythrocytes were seen in peripheral blood of male or female B6C3F1 mice from the 3-month study. Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of diethylamine in male or female F344/N rats exposed to 31, 62.5, or 125 ppm. There was no evidence of carcinogenic activity of diethylamine in male or female B6C3F1 mice exposed to 16, 31, or 62.5 ppm. Exposure to diethylamine resulted in increased incidences of nonneoplastic lesions of the nose in male and female rats and mice, of the cornea in male rats, and of the pleura and lung in female rats.

Early postnatal exposure to ultrafine particulate matter air pollution: persistent ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice.

PubMed

Allen, Joshua L; Liu, Xiufang; Pelkowski, Sean; Palmer, Brian; Conrad, Katherine; Oberdörster, Günter; Weston, Douglas; Mayer-Pröschel, Margot; Cory-Slechta, Deborah A

2014-09-01

Air pollution has been associated with adverse neurological and behavioral health effects in children and adults. Recent studies link air pollutant exposure to adverse neurodevelopmental outcomes, including increased risk for autism, cognitive decline, ischemic stroke, schizophrenia, and depression. We sought to investigate the mechanism(s) by which exposure to ultrafine concentrated ambient particles (CAPs) adversely influences central nervous system (CNS) development. We exposed C57BL6/J mice to ultrafine (< 100 nm) CAPs using the Harvard University Concentrated Ambient Particle System or to filtered air on postnatal days (PNDs) 4-7 and 10-13, and the animals were euthanized either 24 hr or 40 days after cessation of exposure. Another group of males was exposed at PND270, and lateral ventricle area, glial activation, CNS cytokines, and monoamine and amino acid neurotransmitters were quantified. We observed ventriculomegaly (i.e., lateral ventricle dilation) preferentially in male mice exposed to CAPs, and it persisted through young adulthood. In addition, CAPs-exposed males generally showed decreases in developmentally important CNS cytokines, whereas in CAPs-exposed females, we observed a neuroinflammatory response as indicated by increases in CNS cytokines. We also saw changes in CNS neurotransmitters and glial activation across multiple brain regions in a sex-dependent manner and increased hippocampal glutamate in CAPs-exposed males. We observed brain region- and sex-dependent alterations in cytokines and neurotransmitters in both male and female CAPs-exposed mice. Lateral ventricle dilation (i.e., ventriculomegaly) was observed only in CAPs-exposed male mice. Ventriculomegaly is a neuropathology that has been associated with poor neurodevelopmental outcome, autism, and schizophrenia. Our findings suggest alteration of developmentally important neurochemicals and lateral ventricle dilation may be mechanistically related to observations linking ambient air pollutant exposure and adverse neurological/neurodevelopmental outcomes in humans.

Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone.

PubMed

Kumagai, Kazuyoshi; Lewandowski, Ryan P; Jackson-Humbles, Daven N; Buglak, Nicholas; Li, Ning; White, Kaylin; Van Dyken, Steven J; Wagner, James G; Harkema, Jack R

2017-08-01

Exposure to elevated levels of ambient ozone in photochemical smog is associated with eosinophilic airway inflammation and nonatopic asthma in children. In the present study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced nonatopic asthma by using lymphoid cell-sufficient C57BL/6 mice, ILC-sufficient Rag2 -/- mice (devoid of T and B cells), and ILC-deficient Rag2 -/- Il2rg -/- mice (depleted of all lymphoid cells including ILCs). Mice were exposed to 0 or 0.8 parts per million ozone for 1 day or 9 consecutive weekdays (4 hr/day). A single exposure to ozone caused neutrophilic inflammation, airway epithelial injury, and reparative DNA synthesis in all strains of mice, irrespective of the presence or absence of ILCs. In contrast, 9-day exposures induced eosinophilic inflammation and mucous cell metaplasia only in the lungs of ILC-sufficient mice. Repeated ozone exposures also elicited increased messenger RNA expression of transcripts associated with type 2 immunity and airway mucus production in ILC-sufficient mice. ILC-deficient mice repeatedly exposed to ozone had no pulmonary pathology or increased gene expression related to type 2 immunity. These results suggest a new paradigm for the biologic mechanisms underlying the development of a phenotype of childhood nonatopic asthma that has been linked to ambient ozone exposures.

Immunological effects of reduced mucosal integrity in the early life of BALB/c mice.

PubMed

Bendtsen, Katja Maria; Hansen, Camilla Hartmann Friis; Krych, Łukasz; Skovgaard, Kerstin; Kot, Witold; Vogensen, Finn Kvist; Hansen, Axel Kornerup

2017-01-01

Certain stimuli at the gut barrier may be necessary in early life to establish a proper balance of immune tolerance. We evaluated a compromised barrier in juvenile mice in relation to microbiota and local and systemic immunity. BALB/c mice were treated with a low dose of dextran sulfate sodium (DSS) with or without ampicillin and lipopolysaccharide (LPS) to clarify the importance of microbial antigens and interaction between microbial-associated patterns and toll-like receptors. The barrier breach resulted in increased plasma LPS, which was highest in mice treated simultaneously with ampicillin. Adding LPS in the food reduced its levels in plasma. Regulatory T cells were acutely increased in mesenteric lymph nodes (MLN) and spleen during DSS treatment regardless of simultaneous ampicillin treatment. In contrast, NK T and NK cells decreased in MLN and in spleen. This acute DSS effect was reflected in fold changes of haptoglobin and Il1a in colon, and this was also more pronounced in mice simultaneously treated with ampicillin. On day 1 post-treatment, major upregulations of Ifng, Foxp3, Il1b, Il2, and Il6 genes in colon were only observed in the mice simultaneously treated with ampicillin. A two-fold upregulation of colonic Foxp3 and Il1a was evident 25 days post-treatment. DSS skewed the microbiota in favor of Gram negative phyla. Therefore, increased permeability induced tolerogenic immunity independent of microbiota, and this was enhanced by LPS stimulation.

Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication.

PubMed

Dunn, Emily N; Ferrara-Bowens, Teresa M; Chachich, Mark E; Honnold, Cary L; Rothwell, Cristin C; Hoard-Fruchey, Heidi M; Lesyna, Catherine A; Johnson, Erik A; Cerasoli, Douglas M; McDonough, John H; Cadieux, C Linn

2018-06-07

Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure. No expression differences were detected between Es1 KO and WT mice in more than 34 000 mouse genes tested. There was a significant difference between Es1 KO and WT mice in MLD values, as the MLD for GD-exposed WT mice was significantly higher than the MLD for GD-exposed Es1 KO mice. Behavioral assessments of Es1 KO and WT mice included an open field test, a zero maze, a Barnes maze, and a sucrose preference test (SPT). While sex differences were observed in various measures of these tests, overall, Es1 KO mice behaved similarly to WT mice. The two genotypes also showed virtually identical neuropathological changes following GD exposure. Es1 KO mice appear to have an enhanced susceptibility to GD toxicity while retaining all other behavioral and physiological responses to this nerve agent, making the Es1 KO mouse a more human-like model for nerve agent research.

Editor's Highlight: Complete Attenuation of Mouse Lung Cell Proliferation and Tumorigenicity in CYP2F2 Knockout and CYP2F1 Humanized Mice Exposed to Inhaled Styrene for up to 2 Years Supports a Lack of Human Relevance.

PubMed

Cruzan, George; Bus, James S; Banton, Marcy I; Sarang, Satinder S; Waites, Robbie; Layko, Debra B; Raymond, James; Dodd, Darol; Andersen, Melvin E

2017-10-01

Styrene is a mouse-specific lung carcinogen, and short-term mode of action studies have demonstrated that cytotoxicity and/or cell proliferation, and genomic changes are dependent on CYP2F2 metabolism. The current study examined histopathology, cell proliferation, and genomic changes in CD-1, C57BL/6 (WT), CYP2F2(-/-) (KO), and CYP2F2(-/-) (CYP2F1, 2B6, 2A13-transgene) (TG; humanized) mice following exposure for up to 104 weeks to 0- or 120-ppm styrene vapor. Five mice per treatment group were sacrificed at 1, 26, 52, and 78 weeks. Additional 50 mice per treatment group were followed until death or 104 weeks of exposure. Cytotoxicity was present in the terminal bronchioles of some CD-1 and WT mice exposed to styrene, but not in KO or TG mice. Hyperplasia in the terminal bronchioles was present in CD-1 and WT mice exposed to styrene, but not in KO or TG mice. Increased cell proliferation, measured by KI-67 staining, occurred in CD-1 and WT mice exposed to styrene for 1 week, but not after 26, 52, or 78 weeks, nor in KO or TG mice. Styrene increased the incidence of bronchioloalveolar adenomas and carcinomas in CD-1 mice. No increase in lung tumors was found in WT despite clear evidence of lung toxicity, or, KO or TG mice. The absence of preneoplastic lesions and tumorigenicity in KO and TG mice indicates that mouse-specific CYP2F2 metabolism is responsible for both the short-term and chronic toxicity and tumorigenicity of styrene, and activation of styrene by CYP2F2 is a rodent MOA that is neither quantitatively or qualitatively relevant to humans. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effects of environmental enrichment on the amyotrophic lateral sclerosis mouse model.

PubMed

Sorrells, A D; Corcoran-Gomez, K; Eckert, K A; Fahey, A G; Hoots, B L; Charleston, L B; Charleston, J S; Roberts, C R; Markowitz, H

2009-04-01

The manner in which an animal's environment is furnished may have significant implications for animal welfare as well as research outcomes. We evaluated four different housing conditions to determine the effects of what has been considered standard rodent enrichment and the exercise opportunities those environments allow on disease progression in the amyotrophic lateral sclerosis mouse model. Forty-eight copper/zinc superoxide dismutase mice (strain: B6SJL-TgN [SOD1-G931]1Gur) (SOD1) and 48 control (C) (strain: B6SJL-TgN[SOD1]2Gur) male mice were randomly assigned to four different conditions where 12 SOD1 and 12 C animals were allotted to each condition (n = 96). Conditions tested the effects of standard housing, a forced exercise regime, access to a mouse house and opportunity for ad libitum exercise on a running wheel. In addition to the daily all-occurrence behavioural sampling, mice were weighed and tested twice per week on gait and Rotor-Rod performance until the mice reached the age of 150 days (C) or met the criteria for our humane endpoint (SOD1). The SOD1 mice exposed to the forced exercise regime and wheel access did better in average lifespan and Rotor-Rod performance, than SOD1 mice exposed to the standard cage and mouse house conditions. In SOD1 mice, stride length remained longest throughout the progression of the disease in mice exposed to the forced exercise regime compared with other SOD1 conditions. Within the control group, mice in the standard cage and forced exercise regime conditions performed significantly less than the mice with the mouse house and wheels on the Rotor-Rod. Alpha motor neuron counts were highest in mice with wheels and in mice exposed to forced exercise regime in both mouse strains. All SOD1 mice had significantly lower alpha neuron counts than controls (P < 0.05). These data show that different enrichment strategies affect behaviour and disease progression in a transgenic mouse model, and may have implications for the effects of these strategies on experimental outcomes.

Simultaneous vs. Successive Bilingualism among Preschool-Aged Children: A Study of Four-Year-Old Korean-English Bilinguals in the USA

ERIC Educational Resources Information Center

Kim, Ah-Young; Park, Anne; Lust, Barbara

2018-01-01

The current study compares simultaneous vs. successive bilingualism through a mixed-method research design with four four-year-old Korean-English bilingual children who were born and raised in the USA. Two simultaneous bilinguals were exposed to Korean and English from birth, whereas two successive bilinguals were exposed to Korean from birth, but…

Alpha-tocopherol succinate- and AMD3100-mobilized progenitors mitigate radiation combined injury in mice.

PubMed

Singh, Vijay K; Wise, Stephen Y; Fatanmi, Oluseyi O; Beattie, Lindsay A; Ducey, Elizabeth J; Seed, Thomas M

2014-01-01

The purpose of this study was to elucidate the role of alpha-tocopherol succinate (TS)- and AMD3100-mobilized progenitors in mitigating combined injury associated with acute radiation exposure in combination with secondary physical wounding. CD2F1 mice were exposed to high doses of cobalt-60 gamma-radiation and then transfused intravenously with 5 million peripheral blood mononuclear cells (PBMCs) from TS- and AMD3100-injected mice after irradiation. Within 1 h after irradiation, mice were exposed to secondary wounding. Mice were observed for 30 d after irradiation and cytokine analysis was conducted by multiplex Luminex assay at various time-points after irradiation and wounding. Our results initially demonstrated that transfusion of TS-mobilized progenitors from normal mice enhanced survival of acutely irradiated mice exposed 24 h prior to transfusion to supralethal doses (11.5-12.5 Gy) of (60)Co gamma-radiation. Subsequently, comparable transfusions of TS-mobilized progenitors were shown to significantly mitigate severe combined injuries in acutely irradiated mice. TS administered 24 h before irradiation was able to protect mice against combined injury as well. Cytokine results demonstrated that wounding modulates irradiation-induced cytokines. This study further supports the conclusion that the infusion of TS-mobilized progenitor-containing PBMCs acts as a bridging therapy in radiation-combined-injury mice. We suggest that this novel bridging therapeutic approach involving the infusion of TS-mobilized hematopoietic progenitors following acute radiation exposure or combined injury might be applicable to humans.

Exercise differentially affects metabolic functions and white adipose tissue in female letrozole- and dihydrotestosterone-induced mouse models of polycystic ovary syndrome.

PubMed

Marcondes, Rodrigo R; Maliqueo, Manuel; Fornes, Romina; Benrick, Anna; Hu, Min; Ivarsson, Niklas; Carlström, Mattias; Cushman, Samuel W; Stenkula, Karin G; Maciel, Gustavo A R; Stener-Victorin, Elisabet

2017-06-15

Here we hypothesized that exercise in dihydrotestosterone (DHT) or letrozole (LET)-induced polycystic ovary syndrome mouse models improves impaired insulin and glucose metabolism, adipose tissue morphology, and expression of genes related to adipogenesis, lipid metabolism, Notch pathway and browning in inguinal and mesenteric fat. DHT-exposed mice had increased body weight, increased number of large mesenteric adipocytes. LET-exposed mice displayed increased body weight and fat mass, decreased insulin sensitivity, increased frequency of small adipocytes and increased expression of genes related to lipolysis in mesenteric fat. In both models, exercise decreased fat mass and inguinal and mesenteric adipose tissue expression of Notch pathway genes, and restored altered mesenteric adipocytes morphology. In conclusion, exercise restored mesenteric adipocytes morphology in DHT- and LET-exposed mice, and insulin sensitivity and mesenteric expression of lipolysis-related genes in LET-exposed mice. Benefits could be explained by downregulation of Notch, and modulation of browning and lipolysis pathways in the adipose tissue. Copyright © 2017 Elsevier B.V. All rights reserved.

Low-tar and high-tar cigarettes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holt, P.G.; Chalmer, J.E.; Roberts, L.M.

Mice were exposed for 7 to 8 minutes on weekdays to fresh smoke from high-tar (HT) or low-tar (LT) cigarettes for varying periods of up to 36 weeks. Mice exposed to HT cigarettes exhibited more marked alterations in humoral immune responsiveness, hematological profiles, and pulmonary pathologic findings than those exposed to LT cigarettes. However, cell-mediated immune responsiveness to both bacterial and tumor-specific antigens was depressed similarly in animals exposed to HT or LT cigarettes. Furthermore, the growth rates of subcutaneously established tumors were enhanced similarly in the two groups, with respect to those in control animals.

Identification of the key molecules involved in chronic copper exposure-aggravated memory impairment in transgenic mice of Alzheimer's disease using proteomic analysis.

PubMed

Yu, Jun; Luo, Xiaobin; Xu, Hua; Ma, Quan; Yuan, Jianhui; Li, Xuling; Chang, Raymond Chuen-Chung; Qu, Zhongsen; Huang, Xinfeng; Zhuang, Zhixiong; Liu, Jianjun; Yang, Xifei

2015-01-01

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by a progressive impairment of cognitive functions including spatial learning and memory. Excess copper exposure accelerates the development of AD; however, the potential mechanisms by which copper exacerbates the symptoms of AD remain unknown. In this study, we explored the effects of chronic copper exposure on cognitive function by treating 6 month-old triple AD transgenic (3xTg-AD) mice with 250 ppm copper sulfate in drinking water for 6 months, and identified several potential key molecules involved in the effects of chronic copper exposure on memory by proteomic analysis. The behavioral test showed that chronic copper exposure aggravated memory impairment of 3xTg-AD mice. Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry revealed a total of 44 differentially expressed proteins (18 upregulated and 26 down-regulated) in hippocampus between the wild-type (WT) mice and non-exposed 3xTg-AD mice. A total of 40 differentially expressed proteins were revealed (20 upregulated and 20 down-regulated) in hippocampus between copper exposed and non-exposed 3xTg-AD mice. Among these differentially expressed proteins, complexin-1 and complexin-2, two memory associated proteins, were significantly decreased in hippocampus of 3xTg-AD mice compared with the WT mice. Furthermore, the expression of these two proteins was further down-regulated in 3xTg-AD mice when exposed to copper. The abnormal expression of complexin-1 and complexin-2 identified by proteomic analysis was verified by western blot analysis. Taken together, our data showed that chronic copper exposure accelerated memory impairment and altered the expression of proteins in hippocampus in 3xTg-AD mice. The functional analysis on the differentially expressed proteins suggested that complexin-1 and complexin-2 may be the key molecules involved in chronic copper exposure-aggravated memory impairment in AD.

Reproductive toxicity to male mice of nose only exposure to water- pipe smoke.

PubMed

Ali, Badreldin H; Adham, Sirin A; Al Balushi, Khalid A; Shalaby, Asem; Waly, Mostafa I; Manoj, Priyadarsin; Beegam, Sumaya; Yuvaraju, Priya; Nemmar, Abderrahim

2015-01-01

Water-pipe smoking (WPS) is popular in the Middle East and is starting to gain popularity in several Western countries as well. It is widely and erroneously perceived to be less harmful than other forms of tobacco use. The reproductive adverse effects of cigarette smoking have been studied before with conflicting results, but data on the possible adverse reproductive effects of WPS are lacking. Here, we assessed the effects of nose-only exposure to mainstream WPS generated by commercially available honey-flavored "moasel" tobacco in mice. The duration of the session was 30 min/day for one month. Control mice were exposed to air. Twenty-four h after the last exposure, mice were killed and the testes and plasma removed for analysis. In testicular homogenates total protein, alkaline phosphatase activity, several indices of oxidative damage and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) were quantified. The plasma concentrations of leptin, testosterone, estrogen and luteinizing hormone (LH) were also measured. Histological analysis of testes and lungs was also conducted. WPS caused statistically significant decreases in the plasma concentrations of leptin, testosterone, and LH, and in the concentrations of total protein and the antioxidant indices measured. A statistically non-significant decrease in VEGFR2 protein in the WPS--exposed mice compared to the control mice was also found. The body and testicular weights of mice exposed to WPS, as well as their testicular alkaline phosphatase activity and light microscopic histology, and plasma estrogen concentration were all not significantly affected by WPS. Further studies on the functional implications of these findings in mice exposed to WPS for longer durations are warranted.

Age- and gender-dependent impairments of neurobehaviors in mice whose mothers were exposed to lipopolysaccharide during pregnancy.

PubMed

Wang, Hua; Meng, Xiu-Hong; Ning, Huan; Zhao, Xian-Feng; Wang, Qun; Liu, Ping; Zhang, Heng; Zhang, Cheng; Chen, Gui-Hai; Xu, De-Xiang

2010-02-01

Lipopolysaccharide (LPS)-induced intrauterine infection has been associated with neurodevelopmental injury in rodents. The purpose of the present study was to analyze the dynamic changes of neurobehaviors in mice whose mothers were exposed to LPS during pregnancy. The pregnant mice were intraperitoneally (i.p.) injected with LPS (8 microg/kg) daily from gestational day (gd) 8 to gd 15. A battery of neurobehavioral tasks was performed in mice at postnatal day (PND) 70, 200, 400 and 600. Results showed that the spatial learning and memory ability, determined by radial six-arm water maze (RAWM), were obviously impaired in two hundred-day-old female mice and four hundred-day-old male mice whose mothers were exposed to LPS during pregnancy. Open field test showed that the number of squares crossed and peripheral time, a marker of anxiety and exploration activity, were markedly increased in two hundred-day-old female mice following prenatal LPS exposure. In addition, prenatal LPS exposure significantly shortened the latency to the first grid crossing in six hundred-day-old female offspring. Moreover, sensorimotor impairment in the beam walking was observed in two hundred-day-old female mice whose mothers were exposed to LPS during pregnancy. Species-typical behavior examination showed that prenatal LPS exposure markedly increased weight burrowed in seventy-day-old male offspring and six hundred-day-old female offspring. Correspondingly, prenatal LPS exposure significantly reduced weight hoarded in two hundred-day-old female offspring. Taken together, these results suggest that prenatal LPS exposure induces neurobehavioral impairments at adulthood in an age- and gender-dependent manner. 2009 Elsevier Ireland Ltd. All rights reserved.

Volatile Organic Compounds Enhance Allergic Airway Inflammation in an Experimental Mouse Model

PubMed Central

Bönisch, Ulrike; Böhme, Alexander; Kohajda, Tibor; Mögel, Iljana; Schütze, Nicole; von Bergen, Martin; Simon, Jan C.; Lehmann, Irina; Polte, Tobias

2012-01-01

Background Epidemiological studies suggest an association between exposure to volatile organic compounds (VOCs) and adverse allergic and respiratory symptoms. However, whether VOCs exhibit a causal role as adjuvants in asthma development remains unclear. Methods To investigate the effect of VOC exposure on the development of allergic airway inflammation Balb/c mice were exposed to VOCs emitted by new polyvinylchloride (PVC) flooring, sensitized with ovalbumin (OVA) and characterized in acute and chronic murine asthma models. Furthermore, prevalent evaporated VOCs were analyzed and mice were exposed to selected single VOCs. Results Exposure of mice to PVC flooring increased eosinophilic lung inflammation and OVA-specific IgE serum levels compared to un-exposed control mice. The increased inflammation was associated with elevated levels of Th2-cytokines. Long-term exposure to PVC flooring exacerbated chronic airway inflammation. VOCs with the highest concentrations emitted by new PVC flooring were N-methyl-2-pyrrolidone (NMP) and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB). Exposure to NMP or TXIB also increased the allergic immune response in OVA-sensitized mice. In vitro or in vivo exposure to NMP or TXIB reduced IL-12 production in maturing dendritic cells (DCs) and enhanced airway inflammation after adoptive DC transfer into Balb/c mice. At higher concentrations both VOCs induced oxidative stress demonstrated by increased isoprostane and glutathione-S-transferase-pi1 protein levels in the lung of non-sensitized mice. Treatment of PVC flooring-exposed mice with N-acetylcysteine prevented the VOC-induced increase of airway inflammation. Conclusions Our results demonstrate that exposure to VOCs may increase the allergic immune response by interfering with DC function and by inducing oxidative stress and has therefore to be considerate as risk factor for the development of allergic diseases. PMID:22802943

Volatile organic compounds enhance allergic airway inflammation in an experimental mouse model.

PubMed

Bönisch, Ulrike; Böhme, Alexander; Kohajda, Tibor; Mögel, Iljana; Schütze, Nicole; von Bergen, Martin; Simon, Jan C; Lehmann, Irina; Polte, Tobias

2012-01-01

Epidemiological studies suggest an association between exposure to volatile organic compounds (VOCs) and adverse allergic and respiratory symptoms. However, whether VOCs exhibit a causal role as adjuvants in asthma development remains unclear. To investigate the effect of VOC exposure on the development of allergic airway inflammation Balb/c mice were exposed to VOCs emitted by new polyvinylchloride (PVC) flooring, sensitized with ovalbumin (OVA) and characterized in acute and chronic murine asthma models. Furthermore, prevalent evaporated VOCs were analyzed and mice were exposed to selected single VOCs. Exposure of mice to PVC flooring increased eosinophilic lung inflammation and OVA-specific IgE serum levels compared to un-exposed control mice. The increased inflammation was associated with elevated levels of Th2-cytokines. Long-term exposure to PVC flooring exacerbated chronic airway inflammation. VOCs with the highest concentrations emitted by new PVC flooring were N-methyl-2-pyrrolidone (NMP) and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB). Exposure to NMP or TXIB also increased the allergic immune response in OVA-sensitized mice. In vitro or in vivo exposure to NMP or TXIB reduced IL-12 production in maturing dendritic cells (DCs) and enhanced airway inflammation after adoptive DC transfer into Balb/c mice. At higher concentrations both VOCs induced oxidative stress demonstrated by increased isoprostane and glutathione-S-transferase-pi1 protein levels in the lung of non-sensitized mice. Treatment of PVC flooring-exposed mice with N-acetylcysteine prevented the VOC-induced increase of airway inflammation. Our results demonstrate that exposure to VOCs may increase the allergic immune response by interfering with DC function and by inducing oxidative stress and has therefore to be considerate as risk factor for the development of allergic diseases.

Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin.

PubMed

Knippenberg, Sarah; Ueberberg, Bianca; Maus, Regina; Bohling, Jennifer; Ding, Nadine; Tort Tarres, Meritxell; Hoymann, Heinz-Gerd; Jonigk, Danny; Izykowski, Nicole; Paton, James C; Ogunniyi, Abiodun D; Lindig, Sandro; Bauer, Michael; Welte, Tobias; Seeger, Werner; Guenther, Andreas; Sisson, Thomas H; Gauldie, Jack; Kolb, Martin; Maus, Ulrich A

2015-07-01

Respiratory tract infections are common in patients suffering from pulmonary fibrosis. The interplay between bacterial infection and fibrosis is characterised poorly. To assess the effect of Gram-positive bacterial infection on fibrosis exacerbation in mice. Fibrosis progression in response to Streptococcus pneumoniae was examined in two different mouse models of pulmonary fibrosis. We demonstrate that wild-type mice exposed to adenoviral vector delivery of active transforming growth factor-β1 (TGFß1) or diphteria toxin (DT) treatment of transgenic mice expressing the DT receptor (DTR) under control of the surfactant protein C (SPC) promoter (SPC-DTR) to induce pulmonary fibrosis developed progressive fibrosis following infection with Spn, without exhibiting impaired lung protective immunity against Spn. Antibiotic treatment abolished infection-induced fibrosis progression. The cytotoxin pneumolysin (Ply) of Spn caused this phenomenon in a TLR4-independent manner, as Spn lacking Ply (SpnΔply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGFβ1-exposed Ply-challenged TLR4 KO mice. Increased apoptotic cell death of alveolar epithelial cells along with an attenuated intrapulmonary release of antifibrogenic prostaglandin E2 was found to underlie progressive fibrogenesis in Ply-challenged AdTGFβ1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGFβ1-exposed mice. Our data unravel a novel mechanism by which infection with Spn through Ply release induces progression of established lung fibrosis, which can be attenuated by protein-based vaccination of mice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

A Model of Medical Countermeasures for Vesicant Exposure

DTIC Science & Technology

2015-10-01

measured protease activity that was collected from mouse ear exposures (Powers J. C., 1999) instead of via in vitro human keratinocyte exposure. The...to mice ears with and without treatment. This is a model study in the type of data that can best be used for the GVM, because it considers different...mice were exposed on their backs; however, for the Lomash et al. study the mice were exposed on their ears . This tends to be an issue when working

Welding fume exposure and associated inflammatory and hyperplastic changes in the lungs of tumor susceptible a/j mice.

PubMed

Solano-Lopez, Claudia; Zeidler-Erdely, Patti C; Hubbs, Ann F; Reynolds, Steven H; Roberts, Jenny R; Taylor, Michael D; Young, Shih-Houng; Castranova, Vincent; Antonini, James M

2006-01-01

It has been suggested that welding fume (WF) exposure increases lung cancer risk in welders. Epidemiology studies have failed to conclude that WF alone causes lung cancer and animal studies are lacking. We examined the course of inflammation, damage, and repair in the lungs of A/J mice, a lung tumor susceptible strain, caused by stainless steel WF. Mice were exposed by pharyngeal aspiration to 40 mg/kg of WF, silica, or saline. Bronchoalveolar lavage (BAL) was performed 24 hours, 1 and 16 weeks to assess lung injury and inflammation and histopathology was done 1, 8, 16, 24, and 48 weeks postexposure. Both exposures increased inflammatory cells, lactate dehydrogenase and albumin at 24 hr and 1 week. At 16 weeks, these parameters remained elevated in silica-exposed but not WF-exposed mice. Histopathologic evaluation at 1 week indicated that WF induced bronchiolar epithelial hyperplasia with associated cellular atypia, alveolar bronchiolo-alveolar hyperplasia (BAH) in peribronchiolar alveoli, and peribronchiolar lymphogranulomatous inflammation. Persistent changes included foci of histiocytic inflammation, fibrosis, atypical bronchiolar epithelial cells, and bronchiolar BAH. The principle changes in silica-exposed mice were histiocytic and suppurative inflammation, fibrosis, and alveolar BAH. Our findings that WF causes persistent bronchiolar and peribronchiolar epithelial changes, suggest a need for studies of bronchiolar changes after WF exposure.

NanoTIO(2) (UV-Titan) does not induce ESTR mutations in the germline of prenatally exposed female mice.

PubMed

Boisen, Anne Mette Zenner; Shipley, Thomas; Jackson, Petra; Hougaard, Karin Sørig; Wallin, Håkan; Yauk, Carole L; Vogel, Ulla

2012-06-01

Particulate air pollution has been linked to an increased risk of cardiovascular disease and cancer. Animal studies have shown that inhalation of air particulates induces mutations in the male germline. Expanded simple tandem repeat (ESTR) loci in mice are sensitive markers of mutagenic effects on male germ cells resulting from environmental exposures; however, female germ cells have received little attention. Oocytes may be vulnerable during stages of active cell division (e.g., during fetal development). Accordingly, an increase in germline ESTR mutations in female mice prenatally exposed to radiation has previously been reported. Here we investigate the effects of nanoparticles on the female germline. Since pulmonary exposure to nanosized titanium dioxide (nanoTiO(2)) produces a long-lasting inflammatory response in mice, it was chosen for the present study. Pregnant C57BL/6 mice were exposed by whole-body inhalation to the nanoTiO(2) UV-Titan L181 (~42.4 mg UV-Titan/m(3)) or filtered clean air on gestation days (GD) 8-18. Female C57BL/6 F1 offspring were raised to maturity and mated with unexposed CBA males. The F2 descendents were collected and ESTR germline mutation rates in this generation were estimated from full pedigrees (mother, father, offspring) of F1 female mice (192 UV-Titan-exposed F2 offspring and 164 F2 controls). ESTR mutation rates of 0.029 (maternal allele) and 0.047 (paternal allele) in UV-Titan-exposed F2 offspring were not statistically different from those of F2 controls: 0.037 (maternal allele) and 0.061 (paternal allele). We found no evidence for increased ESTR mutation rates in F1 females exposed in utero to UV-Titan nanoparticles from GD8-18 relative to control females.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sithu, Srinivas D.; Diabetes and Obesity Center, University of Louisville, Louisville, KY 40202; Srivastava, Sanjay

Acrolein is a common air pollutant that is present in high concentrations in wood, cotton, and tobacco smoke, automobile exhaust and industrial waste and emissions. Exposure to acrolein containing environmental pollutants such as tobacco smoke and automobile exhaust has been linked to the activation of the coagulation and hemostasis pathways and thereby to the predisposition of thrombotic events in human. To examine the effects of acrolein on platelets, adult male C57Bl/6 mice were subjected acute (5 ppm for 6 h) or sub-chronic (1 ppm, 6 h/day for 4 days) acrolein inhalation exposures. The acute exposure to acrolein did not causemore » pulmonary inflammation and oxidative stress, dyslipidemia or induce liver damage or muscle injury. Platelet GSH levels in acrolein-exposed mice were comparable to controls, but acrolein-exposure increased the abundance of protein-acrolein adducts in platelets. Platelets isolated from mice, exposed to both acute and sub-chronic acrolein levels, showed increased ADP-induced platelet aggregation. Exposure to acrolein also led to an increase in the indices of platelet activation such as the formation of platelet-leukocyte aggregates in the blood, plasma PF4 levels, and increased platelet-fibrinogen binding. The bleeding time was decreased in acrolein exposed mice. Plasma levels of PF4 were also increased in mice exposed to environmental tobacco smoke. Similar to inhalation exposure, acrolein feeding to mice also increased platelet activation and established a pro-thrombotic state in mice. Together, our data suggest that acrolein is an important contributing factor to the pro-thrombotic risk in human exposure to pollutants such as tobacco smoke or automobile exhaust, or through dietary consumption.« less

Oxidative damage induced by cigarette smoke exposure in mice: impact on lung tissue and diaphragm muscle*,**

PubMed Central

de Carlos, Samanta Portão; Dias, Alexandre Simões; Forgiarini, Luiz Alberto; Patricio, Patrícia Damiani; Graciano, Thaise; Nesi, Renata Tiscoski; Valença, Samuel; Chiappa, Adriana Meira Guntzel; Cipriano, Gerson; de Souza, Claudio Teodoro; Chiappa, Gaspar Rogério da Silva

2014-01-01

OBJECTIVE: To evaluate oxidative damage (lipid oxidation, protein oxidation, thiobarbituric acid-reactive substances [TBARS], and carbonylation) and inflammation (expression of phosphorylated AMP-activated protein kinase and mammalian target of rapamycin [p-AMPK and p-mTOR, respectively]) in the lung parenchyma and diaphragm muscles of male C57BL-6 mice exposed to cigarette smoke (CS) for 7, 15, 30, 45, or 60 days. METHODS: Thirty-six male C57BL-6 mice were divided into six groups (n = 6/group): a control group; and five groups exposed to CS for 7, 15, 30, 45, and 60 days, respectively. RESULTS: Compared with control mice, CS-exposed mice presented lower body weights at 30 days. In CS-exposed mice (compared with control mice), the greatest differences (increases) in TBARS levels were observed on day 7 in diaphragm-muscle, compared with day 45 in lung tissue; the greatest differences (increases) in carbonyl levels were observed on day 7 in both tissue types; and sulfhydryl levels were lower, in both tissue types, at all time points. In lung tissue and diaphragm muscle, p-AMPK expression exhibited behavior similar to that of TBARS. Expression of p-mTOR was higher than the control value on days 7 and 15 in lung tissue, as it was on day 45 in diaphragm muscle. CONCLUSION: Our data demonstrate that CS exposure produces oxidative damage, not only in lung tissue but also (primarily) in muscle tissue, having an additional effect on respiratory muscle, as is frequently observed in smokers with COPD. PMID:25210964

Exposure to Electronic Cigarettes Impairs Pulmonary Anti-Bacterial and Anti-Viral Defenses in a Mouse Model

PubMed Central

Sussan, Thomas E.; Gajghate, Sachin; Thimmulappa, Rajesh K.; Ma, Jinfang; Kim, Jung-Hyun; Sudini, Kuladeep; Consolini, Nicola; Cormier, Stephania A.; Lomnicki, Slawo; Hasan, Farhana; Pekosz, Andrew; Biswal, Shyam

2015-01-01

Electronic cigarettes (E-cigs) have experienced sharp increases in popularity over the past five years due to many factors, including aggressive marketing, increased restrictions on conventional cigarettes, and a perception that E-cigs are healthy alternatives to cigarettes. Despite this perception, studies on health effects in humans are extremely limited and in vivo animal models have not been generated. Presently, we determined that E-cig vapor contains 7x1011 free radicals per puff. To determine whether E-cig exposure impacts pulmonary responses in mice, we developed an inhalation chamber for E-cig exposure. Mice that were exposed to E-cig vapor contained serum cotinine concentrations that are comparable to human E-cig users. E-cig exposure for 2 weeks produced a significant increase in oxidative stress and moderate macrophage-mediated inflammation. Since, COPD patients are susceptible to bacterial and viral infections, we tested effects of E-cigs on immune response. Mice that were exposed to E-cig vapor showed significantly impaired pulmonary bacterial clearance, compared to air-exposed mice, following an intranasal infection with Streptococcus pneumonia. This defective bacterial clearance was partially due to reduced phagocytosis by alveolar macrophages from E-cig exposed mice. In response to Influenza A virus infection, E-cig exposed mice displayed increased lung viral titers and enhanced virus-induced illness and mortality. In summary, this study reports a murine model of E-cig exposure and demonstrates that E-cig exposure elicits impaired pulmonary anti-microbial defenses. Hence, E-cig exposure as an alternative to cigarette smoking must be rigorously tested in users for their effects on immune response and susceptibility to bacterial and viral infections. PMID:25651083

Connective Tissue Growth Factor Promotes Pulmonary Epithelial Cell Senescence and Is Associated with COPD Severity.

PubMed

Jang, Jun-Ho; Chand, Hitendra S; Bruse, Shannon; Doyle-Eisele, Melanie; Royer, Christopher; McDonald, Jacob; Qualls, Clifford; Klingelhutz, Aloysius J; Lin, Yong; Mallampalli, Rama; Tesfaigzi, Yohannes; Nyunoya, Toru

2017-04-01

The purpose of this study was to determine whether expression of connective tissue growth factor (CTGF) protein in chronic obstructive pulmonary disease (COPD) is consistent in humans and animal models of COPD and to investigate the role of this protein in lung epithelial cells. CTGF in lung epithelial cells of ex-smokers with COPD was compared with ex-smokers without COPD by immunofluorescence. A total of twenty C57Bl/6 mice and sixteen non-human primates (NHPs) were exposed to cigarette smoke (CS) for 4 weeks. Ten mice of these CS-exposed mice and eight of the CS-exposed NHPs were infected with H3N2 influenza A virus (IAV), while the remaining ten mice and eight NHPs were mock-infected with vehicle as control. Both mRNA and protein expression of CTGF in lung epithelial cells of mice and NHPs were determined. The effects of CTGF overexpression on cell proliferation, p16 protein, and senescence-associated β-galactosidase (SA-β-gal) activity were examined in cultured human bronchial epithelial cells (HBECs). In humans, CTGF expression increased with increasing COPD severity. We found that protein expression of CTGF was upregulated in lung epithelial cells in both mice and NHPs exposed to CS and infected with IAV compared to those exposed to CS only. When overexpressed in HBECs, CTGF accelerated cellular senescence accompanied by p16 accumulation. Both CTGF and p16 protein expression in lung epithelia are positively associated with the severity of COPD in ex-smokers. These findings show that CTGF is consistently expressed in epithelial cells of COPD lungs. By accelerating lung epithelial senescence, CTGF may block regeneration relative to epithelial cell loss and lead to emphysema.

Lung tumor production and tissue metal distribution after exposure to manual metal ARC-stainless steel welding fume in A/J and C57BL/6J mice.

PubMed

Zeidler-Erdely, Patti C; Battelli, Lori A; Salmen-Muniz, Rebecca; Li, Zheng; Erdely, Aaron; Kashon, Michael L; Simeonova, Petia P; Antonini, James M

2011-01-01

Stainless steel welding produces fumes that contain carcinogenic metals. Therefore, welders may be at risk for the development of lung cancer, but animal data are inadequate in this regard. Our main objective was to examine lung tumor production and histopathological alterations in lung-tumor-susceptible (A/J) and -resistant C57BL/6J (B6) mice exposed to manual metal arc-stainless steel (MMA-SS) welding fume. Male mice were exposed to vehicle or MMA-SS welding fume (20 mg/kg) by pharyngeal aspiration once per month for 4 mo. At 78 wk postexposure, gross tumor counts and histopathological changes were assessed and metal analysis was done on extrapulmonary tissue (aorta, heart, kidney, and liver). At 78 wk postexposure, gross lung tumor multiplicity and incidence were unremarkable in mice exposed to MMA-SS welding fume. Histopathology revealed that only the exposed A/J mice contained minimal amounts of MMA-SS welding fume in the lung and statistically increased lymphoid infiltrates and alveolar macrophages. A significant increase in tumor multiplicity in the A/J strain was observed at 78 wk. Metal analysis of extrapulmonary tissue showed that only the MMA-SS-exposed A/J mice had elevated levels of Cr, Cu, Mn, and Zn in kidney and Cr in liver. In conclusion, this study further supports that MMA-SS welding fume does not produce a significant tumorigenic response in an animal model, but may induce a chronic lung immune response. In addition, long-term extrapulmonary tissue alterations in metals in the susceptible A/J mouse suggest that the adverse effects of this fume might be cumulative.

Green tea diet decreases PCB 126-induced oxidative stress in mice by upregulating antioxidant enzymes

PubMed Central

Newsome, Bradley J; Petriello, Michael C; Han, Sung Gu; Murphy, Margaret O; Eske, Katryn E; Sunkara, Manjula; Morris, Andrew J; Hennig, Bernhard

2013-01-01

Superfund chemicals such as polychlorinated biphenyls pose a serious human health risk due to their environmental persistence and link to multiple diseases. Selective bioactive food components such as flavonoids have been shown to ameliorate PCB toxicity, but primarily in an in vitro setting. Here, we show that mice fed a green tea-enriched diet and subsequently exposed to environmentally relevant doses of coplanar PCB exhibit decreased overall oxidative stress primarily due to the upregulation of a battery of antioxidant enzymes. C57BL/6 mice were fed a low fat diet supplemented with green tea extract (GTE) for 12 weeks and exposed to 5 μmol PCB 126/kg mouse weight (1.63 mg/kg-day) on weeks 10, 11 and 12 (total body burden: 4.9 mg/kg). F2-Isoprostane and its metabolites, established markers of in vivo oxidative stress, measured in plasma via HPLC-MS/MS exhibited five-fold decreased levels in mice supplemented with GTE and subsequently exposed to PCB compared to animals on a control diet exposed to PCB. Livers were collected and harvested for both mRNA and protein analyses, and it was determined that many genes transcriptionally controlled by AhR and Nrf2 proteins were upregulated in PCB-exposed mice fed the green tea supplemented diet. An increased induction of genes such as SOD1, GSR, NQO1 and GST, key antioxidant enzymes, in these mice (green tea plus PCB) may explain the observed decrease in overall oxidative stress. A diet supplemented with green tea allows for an efficient antioxidant response in the presence of PCB 126 which supports the emerging paradigm that healthful nutrition may be able to bolster and buffer a physiological system against the toxicities of environmental pollutants. PMID:24378064

Erionite induces production of autoantibodies and IL-17 in C57BL/6 mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zebedeo, Christian Nash; Davis, Chad; Peña, Cecelia

Background: Erionite has similar chemical and physical properties to amphibole asbestos, which induces autoantibodies in mice. Current exposures are occurring in North Dakota due to the use of erionite-contaminated gravel. While erionite is known to cause mesothelioma and other diseases associated with asbestos, there is little known about its effects on the immune system. Objectives: We performed this study to determine whether erionite evokes autoimmune reactions in mice. Methods: Bone marrow derived macrophages (BMDM) were used to measure toxicity induced by erionite. Cytokine production by BMDM and splenocytes of C57BL/6 mice was examined by bead arrays and ELISA following exposuremore » to erionite, amphiboles and chrysotile. Wild type C57BL/6 mice were exposed to saline, erionite, amphibole asbestos (Libby 6-Mix) or chrysotile through intratracheal instillations at equal mass (60 μg/mouse). Seven months after exposure, sera were examined for anti-nuclear antibodies (ANA) and IL-17. Immunohistochemistry was used to detect immune complex deposition in the kidneys. Results: Erionite and tremolite caused increased cytokine production belonging to the T{sub H}17 profile including IL-17, IL-6, TGF-β, and TNF-α. The frequency of ANA was increased in mice treated with erionite or amphibole compared to saline-treated mice. IL-17 and TNF-α were elevated in the sera of mice treated with erionite. The frequency of immune complex deposition in the kidneys increased from 33% in saline-treated mice to 90% with erionite. Conclusions: These data demonstrate that both erionite and amphibole asbestos induce autoimmune responses in mice, suggesting a potential for adverse effects in exposed communities. - Highlights: • Erionite, a fibrous mineral, is a current public health concern in the western USA. • Erionite exposure induces antinuclear autoantibodies in exposed mice. • Erionite induces a clear Th17 cytokine response in vitro and in vivo. • These responses were distinct from responses caused by asbestos. • These data in mice suggest that exposed humans may be at risk for autoimmunity.« less

Pathology of Serially Sacrificed Female B6C3F1 Mice Continuously Exposed to Very Low-Dose-Rate Gamma Rays.

PubMed

Tanaka, I B; Komura, J; Tanaka, S

2017-03-01

We have previously reported on life span shortening as well as increased incidence rates in several neoplasms in B6C3F1 mice that were continuously exposed to 21 mGy/day of gamma rays for 400 days. To clarify whether the life shortening was due to early appearance of neoplasms (shortened latency) or increased promotion/progression, 8-week-old female specific-pathogen-free B6C3F1 mice were gamma-ray irradiated at a low dose rate of 20 mGy/day for 400 days. At 100 days postirradiation, 60-90 mice were sacrificed, and thereafter every 100 days alongside the age-matched nonirradiated controls, for 700 days. Additional groups were allowed to live out their natural life span. Pathological examination was performed on all mice to identify lesions, non-neoplastic and neoplastic, as well as to determine the cause of death. Body weights were significantly increased in irradiated mice from sacrifice days 200-500. Incidence rates for spontaneously occurring non-neoplastic lesions, such as adrenal subcapsular cell hyperplasia, fatty degeneration of the liver, atrophy and tubulostromal hyperplasia of the ovaries, were significantly increased in irradiated mice. Significantly increased incidence rates with no shortening of latency periods were observed in irradiated mice for malignant lymphomas, hepatocellular adenomas/carcinomas, bronchioloalveolar adenomas, harderian gland adenoma/adenocarcinoma. Shortened latencies with significantly increased incidence rates were observed for adrenal subcapsular cell adenomas and ovarian neoplasms (tubulostromal adenoma, granulosa cell tumors) in irradiated mice. Life span shortening in mice exposed to 20 mGy/day was mostly due to malignant lymphomas. Multiple primary neoplasms were significantly increased in mice exposed to 20 mGy/day from sacrifice days 400-700 and in the life span group. Our results confirm that continuous low-dose-rate gamma-ray irradiation of female B6C3F1 mice causes both cancer induction (shortened latency) and promotion/progression (early death), depending on the neoplasm's organ/tissue of origin.

Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice

PubMed Central

Rodriguez, Karina F.; Ungewitter, Erica K.; Crespo-Mejias, Yasmin; Liu, Chang; Nicol, Barbara; Kissling, Grace E.; Yao, Humphrey Hung-Chang

2015-01-01

Background Mice exposed to high levels of arsenic in utero have increased susceptibility to tumors such as hepatic and pulmonary carcinomas when they reach adulthood. However, the effects of in utero arsenic exposure on general physiological functions such as reproduction and metabolism remain unclear. Objectives We evaluated the effects of in utero exposure to inorganic arsenic at the U.S. Environmental Protection Agency (EPA) drinking water standard (10 ppb) and at tumor-inducing levels (42.5 ppm) on reproductive end points and metabolic parameters when the exposed females reached adulthood. Methods Pregnant CD-1 mice were exposed to sodium arsenite [none (control), 10 ppb, or 42.5 ppm] in drinking water from gestational day 10 to birth, the window of organ formation. At birth, exposed offspring were fostered to unexposed dams. We examined reproductive end points (age at vaginal opening, reproductive hormone levels, estrous cyclicity, and fertility) and metabolic parameters (body weight changes, hormone levels, body fat content, and glucose tolerance) in the exposed females when they reached adulthood. Results Arsenic-exposed females (10 ppb and 42.5 ppm) exhibited early onset of vaginal opening. Fertility was not affected when females were exposed to the 10-ppb dose. However, the number of litters per female was decreased in females exposed to 42.5 ppm of arsenic in utero. In both 10-ppb and 42.5-ppm groups, arsenic-exposed females had significantly greater body weight gain, body fat content, and glucose intolerance. Conclusion Our findings revealed unexpected effects of in utero exposure to arsenic: exposure to both a human-relevant low dose and a tumor-inducing level led to early onset of vaginal opening and to obesity in female CD-1 mice. Citation Rodriguez KF, Ungewitter EK, Crespo-Mejias Y, Liu C, Nicol B, Kissling GE, Yao HH. 2016. Effects of in utero exposure to arsenic during the second half of gestation on reproductive end points and metabolic parameters in female CD-1 mice. Environ Health Perspect 124:336–343; http://dx.doi.org/10.1289/ehp.1509703 PMID:26295903

Neurobehavioral changes in response to alterations in gene expression profiles in the brains of mice exposed to low and high levels of mercury vapor during postnatal development.

PubMed

Yoshida, Minoru; Honda, Akiko; Watanabe, Chiho; Satoh, Masahiko; Yasutake, Akira

2014-08-01

This study examined the relationship between neurobehavioral changes and alterations in gene expression profiles in the brains of mice exposed to different levels of Hg(0) during postnatal development. Neonatal mice were repeatedly exposed to mercury vapor (Hg(0)) at a concentration of 0.057 mg/m(3) (low level), which was close to the current threshold value (TLV), and 0.197 mg/m(3) (high level) for 24 hr until the 20(th) day postpartum. Behavioral responses were evaluated based on changes in locomotor activity in the open field test (OPF), learning ability in the passive avoidance response test (PA), and spatial learning ability in the Morris water maze (MM) at 12 weeks of age. No significant differences were observed in the three behavioral measurements between mice exposed to the low level of Hg(0) and control mice. On the other hand, total locomotive activity in mice exposed to the high level of Hg(0) was significantly decreased and central locomotion was reduced in the OPF task. Mercury concentrations were approximately 0.4 μg/g and 1.9 μg/g in the brains of mice exposed to the low and high levels of Hg(0), respectively. Genomic analysis revealed that the expression of 2 genes was up-regulated and 18 genes was down-regulated in the low-level exposure group, while the expression of 3 genes was up-regulated and 70 genes was down-regulated in the high-level exposure group. Similar alterations in the expression of seven genes, six down-regulated genes and one up-regulated gene, were observed in both groups. The results indicate that an increase in the number of altered genes in the brain may be involved in the emergence of neurobehavioral effects, which may be associated with the concentration of mercury in the brain. Moreover, some of the commonly altered genes following exposure to both concentrations of Hg(0) with and without neurobehavioral effects may be candidates as sensitive biomarker genes for assessing behavioral effects in the early stages of development.

Novel object recognition ability in female mice following exposure to nanoparticle-rich diesel exhaust

DOE Office of Scientific and Technical Information (OSTI.GOV)

Win-Shwe, Tin-Tin, E-mail: tin.tin.win.shwe@nies.go.jp; Fujimaki, Hidekazu; Fujitani, Yuji

2012-08-01

Recently, our laboratory reported that exposure to nanoparticle-rich diesel exhaust (NRDE) for 3 months impaired hippocampus-dependent spatial learning ability and up-regulated the expressions of memory function-related genes in the hippocampus of female mice. However, whether NRDE affects the hippocampus-dependent non-spatial learning ability and the mechanism of NRDE-induced neurotoxicity was unknown. Female BALB/c mice were exposed to clean air, middle-dose NRDE (M-NRDE, 47 μg/m{sup 3}), high-dose NRDE (H-NRDE, 129 μg/m{sup 3}), or filtered H-NRDE (F-DE) for 3 months. We then investigated the effect of NRDE exposure on non-spatial learning ability and the expression of genes related to glutamate neurotransmission using amore » novel object recognition test and a real-time RT-PCR analysis, respectively. We also examined microglia marker Iba1 immunoreactivity in the hippocampus using immunohistochemical analyses. Mice exposed to H-NRDE or F-DE could not discriminate between familiar and novel objects. The control and M-NRDE-exposed groups showed a significantly increased discrimination index, compared to the H-NRDE-exposed group. Although no significant changes in the expression levels of the NMDA receptor subunits were observed, the expression of glutamate transporter EAAT4 was decreased and that of glutamic acid decarboxylase GAD65 was increased in the hippocampus of H-NRDE-exposed mice, compared with the expression levels in control mice. We also found that microglia activation was prominent in the hippocampal area of the H-NRDE-exposed mice, compared with the other groups. These results indicated that exposure to NRDE for 3 months impaired the novel object recognition ability. The present study suggests that genes related to glutamate metabolism may be involved in the NRDE-induced neurotoxicity observed in the present mouse model. -- Highlights: ► The effects of nanoparticle-induced neurotoxicity remain unclear. ► We investigated the effect of exposure to nanoparticles on learning behavior. ► We found that exposure to nanoparticles impaired novel object recognition ability.« less

Effects of audiogenic hazard on fetal skeletal development in mice

NASA Astrophysics Data System (ADS)

Murata, M.; Kawade, F.; Kondo, M.; Takigawa, H.; Sakamoto, H.

1990-06-01

The effects of noise on fetal skeletal development in mice were examined. Pregnant ICR mice were exposed to a wide octave-band noise at 100 dB(C) for 6 hours a day in three ways: the first group was continuously exposed only on day 7 of pregnancy (group "N"); the second was exposed intermittently (15 min on/15 min off) only on day 7 of pregnancy (group "IN"); and the third was exposed to a continuous noise recurrently during days 7-12 of pregnancy (group "RN"). On day 18 of pregnancy, fetuses were removed and prepared as skeletons of cleared specimens stained with alizarin red S for examining skeletal development. Skeletal immaturity was observed in group "RN". The percentage of fetuses with skeletal malformations was significantly increased in group "N", as compared with the control. Significantly higher percentages of fetuses with variations in cervical vertebral arches were observed in groups "N" and "RN".

Stress conditioning in mice: alterations in immunity and tumor growth.

PubMed

Benaroya-Milshtein, Noa; Hollander, Nurit; Apter, Alan; Yaniv, Isaac; Pick, Chaim G

2011-05-01

The neuroendocrine and autonomic nervous systems are known regulators of brain-immune interaction. However, the functional significance of this interaction under stress is not fully understood. We investigated the effect of a stress paradigm by applying electric foot shock followed by three reminders, on behavior, immune parameters, and lymphoma tumor growth. Male C3H mice were divided into two groups: Group 1-exposed to electric foot shock followed by three reminders, and Group 2-untreated (controls). Sets of mice underwent the elevated plus maze, staircase, and hot plate tests. After foot shock, natural killer (NK) cell activity, and lymphocyte proliferation were measured. In addition, sets of mice were either vaccinated twice with B-cell lymphoma 38C-13 immunoglobulin for determination of anti-idiotype (Id) antibodies in sera, or inoculated with tumor cells and monitored for tumor development and survival time. Mice exposed to electric foot shock followed by the three reminders had higher NK cell activity, levels of anti-Id antibodies, and a higher proliferation rate of splenocytes in response to mitogens, than the control mice. The exposed mice also showed attenuated tumor growth. Thus, the stress paradigm inhibited tumor development and lead to some immune changes that were not accompanied by behavioral changes.

Accretion of biopsy specimens of vaginal adenosis from patients exposed in utero to diethylstilbestrol, when transplanted to athymic nude mice.

PubMed

Pienkowski, M M; Mann, L C; Rosloniec, E F; Welsch, C W

1979-03-01

Vaginal adenosis biopsy specimens from 10 patients exposed in utero to diethylstilbestrol were transplanted for 30 days into athymic (nude) mice. Almost all grafts were recovered, and they had morphologic features closely resembling those of the original biopsy specimens, i.e., cystic, complex, and simple occult glands covered mainly with an endocervical type of epithelium showing extensive squamous metaplasia. Autoradiographic analysis of these grafts after pulse administration of [3H]thymidine into the mice revealed extensive labeling of epithelial cells. These results imply that female athymic (nude) mice are compatible hosts for accretion of the human adenosis.

Ntp report on the toxicity studies of ethylbenzene in f344/n rats and b6c3f1 mice (inhalation studies). Report for 29 March-30 June 1988

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chan, P.

1992-03-01

Inhalation toxicology studies of ethylbenzene (99% pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to ethylbenzene vapor at chamber concentrations of 0 to 1000 ppm, 6 hours per day, 5 days per week for 13 weeks. No rats or mice died during the 13-week exposure. Body weight gains were slightly lower in the high dose groups of male and female rats, but the differences were not statistically significant. Absolute and relative kidney, liver, and lung weights were increased in the exposed rats, while weight increases occurred only in the livers of exposed mice.more » No changes were observed in the evaluation of sperm or vaginal cytology in rats or mice. Ethylbenzene was not mutagenic in Salmonella and did not induce chromosomal aberrations or sister chromatid exchanges in Chinese hamster ovary (CHO) cells in vitro, though it did induce trifluorothymidine resistance in mouse lymphoma cells at the highest concentration tested. Micronuclei assays in peripheral blood of mice were negative.« less

Arginase inhibition in airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bratt, Jennifer M.; Franzi, Lisa M.; Linderholm, Angela L.

Arginase1 and nitric oxide synthase2 (NOS2) utilize L-arginine as a substrate, with both enzymes expressed at high levels in the asthmatic lung. Inhibition of arginase in ovalbumin-exposed C57BL/6 mice with the transition state inhibitor N{sup o}mega-hydroxy-nor-L-arginine (nor-NOHA) significantly increased total L-arginine content in the airway compartment. We hypothesized that such an increase in L-arginine content would increase the amount of nitric oxide (NO) being produced in the airways and thereby decrease airway hyperreactivity and eosinophilic influx. We further hypothesized that despite arginase inhibition, NOS2 knockout (NOS2-/-) mice would be unable to up-regulate NO production in response to allergen exposure andmore » would demonstrate higher amounts of airway hyperreactivity and eosinophilia under conditions of arginase inhibition than C57BL/6 animals. We found that administration of nor-NOHA significantly decreased airway hyperreactivity and eosinophilic airway inflammation in ovalbumin-exposed C57BL/6 mice, but these parameters were unchanged in ovalbumin-exposed NOS2-/- mice. Arginase1 protein content was increased in mice exposed to ovalbumin, an effect that was reversed upon nor-NOHA treatment in C57BL/6 mice. Arginase1 protein content in the airway compartment directly correlated with the degree of airway hyperreactivity in all treatment groups. NOS2-/- mice had significantly greater arginase1 and arginase2 concentrations compared to their respective C57BL/6 groups, indicating that inhibition of arginase may be dependent upon NOS2 expression. Arginase1 and 2 content were not affected by nor-NOHA administration in the NOS2-/- mice. We conclude that L-arginine metabolism plays an important role in the development of airway hyperreactivity and eosinophilic airway inflammation. Inhibition of arginase early in the allergic inflammatory response decreases the severity of the chronic inflammatory phenotype. These effects appear to be attributable to NOS2, which is a major source of NO production in the inflamed airway, although arginase inhibition may also be affecting the turnover of arginine by the other NOS isoforms, NOS1 and NOS3. The increased L-arginine content in the airway compartment of mice treated with nor-NOHA may directly or indirectly, through NOS2, control arginase expression both in response to OVA exposure and at a basal level.« less

REPRODUCTIVE AND GENOMIC EFFECTS IN TESTES FROM MICE EXPOSED TO THE WATER DISINFECTANT BYPRODUCT BROMOCHLOROACETIC ACID

EPA Science Inventory

ABSTRACT

A byproduct of drinking water disinfection, bromochloroacetic acid (BCA), acts as a reproductive toxicant in rats. To determine if BCA produces similar reproductive toxicity in mice, juvenile and adult C57BL/6 males were exposed to 0, 8, 24, 72 or 216 mg/kg of BC...

Influence of dietary selenium on the disposition of arsenate in the female B6C3F{sub 1} mouse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kenyon, E.M.; Hughes, M.F.; Levander, O.A.

1997-06-27

Interactions between arsenic (As) and selenium (Se) at the metabolic level are multifaceted and complex. These interactions are of practical significance because populations in various parts of the world are simultaneously exposed to inorganic As in drinking water and Se mainly in the diet at varying levels. The primary goal of this study was to investigate whether differing dietary Se status would alter the profile of urinary metabolites or their time course for elimination after exposure to arsenate [As(V)]. Weanling female 86C3F, mice were maintained for 28 d on either a control diet of powdered rodent meal sufficient in Semore » (A 0.2 ppm) or Torula yeast-based (TYB) diets deficient (B, 0.02 ppm Se), sufficient (C, 0.2 ppm Se), or excessive (D, 2.0 ppm Se) in Se; mice then received by oral gavage 5 mg (As)/kg as sodium [{sup 73}As] arsenate. The time course for elimination of total arsenic and metabolites in urine was measured over a 48-h period, and total arsenic was determined in feces and tissues at 48 h. Mice on the Se excess diet excreted a significantly higher percentage of urinary As as inorganic As, with a significantly decreased ratio of organic to inorganic As compared to Se-sufficient mice, suggesting that As methylation was decreased. Mice on the Se-deficient diet appeared to eliminate As(V), arsenite, and dimethylarsinic acid (DMA) in urine more slowly than Se-sufficient mice; however, further studies are required to confirm this finding. Mice on the Se-sufficient meal diet (A) excreted significantly less (by percent) arsenate-derived radioactivity in urine and more in feces compared to mice on the Se-sufficient TYB diet (C), with total elimination being similar for both groups. This indicates that mice on the meal diet absorbed significantly less As(V) than mice on the TYB diet, and this may be due to more fiber or {open_quotes}bulk{close_quotes} in the meal diet. 35 refs., 6 figs., 6 tabs.« less

Social instigation and repeated aggressive confrontations in male Swiss mice: analysis of plasma corticosterone, CRF and BDNF levels in limbic brain areas.

PubMed

Fortes, Paula Madeira; Albrechet-Souza, Lucas; Vasconcelos, Mailton; Ascoli, Bruna Maria; Menegolla, Ana Paula; de Almeida, Rosa Maria M

2017-01-01

Agonistic behaviors help to ensure survival, provide advantage in competition, and communicate social status. The resident-intruder paradigm, an animal model based on male intraspecific confrontations, can be an ethologically relevant tool to investigate the neurobiology of aggressive behavior. To examine behavioral and neurobiological mechanisms of aggressive behavior in male Swiss mice exposed to repeated confrontations in the resident intruder paradigm. Behavioral analysis was performed in association with measurements of plasma corticosterone of mice repeatedly exposed to a potential rival nearby, but inaccessible (social instigation), or to 10 sessions of social instigation followed by direct aggressive encounters. Moreover, corticotropin-releasing factor (CRF) and brain-derived neurotrophic factor (BNDF) were measured in the brain of these animals. Control mice were exposed to neither social instigation nor aggressive confrontations. Mice exposed to aggressive confrontations exhibited a similar pattern of species-typical aggressive and non-aggressive behaviors on the first and the last session. Moreover, in contrast to social instigation only, repeated aggressive confrontations promoted an increase in plasma corticosterone. After 10 aggressive confrontation sessions, mice presented a non-significant trend toward reducing hippocampal levels of CRF, which inversely correlated with plasma corticosterone levels. Conversely, repeated sessions of social instigation or aggressive confrontation did not alter BDNF concentrations at the prefrontal cortex and hippocampus. Exposure to repeated episodes of aggressive encounters did not promote habituation over time. Additionally, CRF seems to be involved in physiological responses to social stressors.

NTP Toxicology and Carcinogenesis Studies of Nitromethane (CAS No. 75-52-5) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

PubMed

1997-02-01

Nitromethane is used as a rocket and engine fuel; as a synthesis intermediate for agricultural fumigants, biocides, and other products; as a solvent; and as an explosive in mining, oil-well drilling, and seismic exploration. It has been detected in air, in surface and drinking water, and in cigarette smoke. Nitromethane was studied because of the potential for widespread human exposure and because it is structurally related to the carcinogens 2-nitropropane and tetranitromethane. Male and female F344/N rats and B6C3F1 mice received nitromethane (purity 98% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood erythrocytes of mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived until the end of the study. The mean body weight gain of male rats in the 1,500 ppm group was slightly but significantly less than that of the controls; the final mean body weights and mean body weight gains of exposed females were similar to those of the controls. Clinical findings in all male and female rats in the 1,500 ppm groups included increased preening, rapid breathing, hyperactivity early in the study, and hypoactivity and loss of coordination in the hindlimbs near the end of the study. The relative liver weights of all exposed groups of male rats and the absolute and relative liver weights of females exposed to 375 ppm or greater were significantly greater than those of the controls. Minimal to mild degeneration of the olfactory epithelium was observed in the nose of males and females exposed to 375 ppm or greater. Sciatic nerve degeneration was present in all male and female rats exposed to 375 ppm or greater; rats exposed to 750 or 1,500 ppm also had reduced myelin around sciatic axons. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 16 days. All mice survived to the end of the study. The final mean body weights and weight gains of exposed males and females were similar to those of the controls. Clinical findings included hypoactivity and tachypnea in male and female mice in the 1,500 ppm groups. Absolute and relative liver weights of male mice in the 750 and 1,500 ppm groups and female mice in all exposed groups and the relative liver weight of males in the 375 ppm group were significantly greater than those of the controls. Degeneration of the olfactory epithelium of the nose was observed microscopically in all males and females exposed to 375 ppm or greater; this lesion was of minimal severity in males and minimal to mild severity in females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 13 weeks. All rats survived to the end of the study. The final mean body weight and weight gain of male rats in the 1,500 ppm group were significantly less than those of the controls. Clinical findings included hindlimb paralysis in rats in the 750 and 1,500 ppm groups. Inhalation exposure of rats to nitromethane resulted in an exposure concentration-dependent, microcytic, responsive anemia; anemia was most pronounced in males and females exposed to 375 ppm or greater. The presence of schistocytes, Heinz bodies, and spherocytes and increased mean cell hemoglobin concentration and methemoglobin concentration were evidence that a hemolytic process was occurring; this hemolytic process could have accounted, in part, for the anemia. Thrombocytosis accompanied the anemia and would be consistent with a reactive bone marrow or could have been due to the erroneous inclusion of small erythrocyte fragments as part of the platelet count. On day 23, transient decreases in serum triiodothyronine, thyroxine, and fr and free thyroxine were observed in male rats exposed to 375 ppm or greater and female rats exposed to 750 or 1,500 ppm. There was little or no pituitary response to the thyroid hormone decreases, as evidenced by the lack of significantly increased concentrations of thyroid-stimulating hormone in exposed rats. No biologically significant differences in organ weights were observed. The forelimb and hindlimb grip strengths of males in the 1,500 ppm group were significantly less than those of the controls. The hindlimb grip strengths of females in the 750 and 1,500 ppm groups were also significantly less than the control value. Minimal to mild hyperplasia of the bone marrow was observed microscopically in male rats in the 750 and 1,500 ppm groups and in females exposed to 188 ppm or greater. Nasal lesions in exposed males and females included olfactory epithelial degeneration in males and females exposed to 375 ppm or greater and in one female exposed to 188 ppm and respiratory epithelial hyaline droplets and goblet cell hyperplasia in males and females in the 750 and 1,500 ppm groups; the severity of nasal lesions in males and females was minimal to mild. Males and females exposed to 375 ppm or greater had minimal to mild degeneration of the sciatic nerve and the lumbar spinal cord. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weights and weight gains of exposed mice were generally similar to those of the controls. There were no treatment-related clinical findings. The absolute right kidney weights of all groups of exposed male mice except the 1,500 ppm group and of females exposed to 188 ppm or greater and the relative right kidney weights of all groups of exposed males and of females in the 750 and 1,500 ppm groups were significantly greater than those of the controls. The absolute liver weight of male mice in the 750 ppm group and the relative liver weights of males exposed to 375 ppm or greater were significantly greater than those of the controls. Olfactory epithelial degeneration and respiratory epithelial hyaline droplets were observed microscopically in all male and female mice exposed to 375 ppm or greater. Degeneration also occurred in females in the 188 ppm group, and hyaline droplets occurred in females in the 94 and 188 ppm groups. The average severity of the nasal lesions ranged from minimal to mild in males. In females, the average severity of olfactory epithelial degeneration ranged from minimal to mild and the severity of respiratory epithelial hyaline droplets ranged from minimal to moderate. All males and nine females in the 1,500 ppm groups also had minimal extramedullary hematopoiesis of the spleen. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 94, 188, or 375 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 103 weeks. Survival,Body Weights, and Clinical Findings: There were no significant differences in survival rates between exposed and control male or female rats. The mean body weight of females in the 375 ppm group was slightly greater than that of the control group; the mean body weights of exposed males were generally similar to the mean body weight of the controls throughout the study. Clinical findings were consistent with incidences of mammary gland neoplasms in females exposed to 188 or 375 ppm; no hindlimb paralysis, as occurred in rats in the 13-week study, was observed in male or female rats in the 2-year study. Pathology Findings: The incidences of mammary gland fibroadenoma and fibroadenoma, adenoma, or carcinoma (combined) in female rats in the 188 and 375 ppm groups were significantly greater than those in the controls. Additionally, the incidences of mammary gland carcinoma in the 375 ppm group were significantly greater than those in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 0, 188, 375, or 750 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 103 weeks. Survival,Body Weights, and ClinicalFindings The survival rate of females in the 750 ppm group was marginally greater than that of the controls. The mean body weights of exposed females were generally slightly greater than the mean body weights of the controls during the study but were generally similar to the mean body weight of the controls at the end of the study. The mean body weights of exposed males were similar to those of the controls throughout the study. Clinical findings included swelling around the eyes and exophthalmos in exposed males and females; these findings were coincident with harderian gland neoplasms. Pathology Findings: The incidences of harderian gland adenoma and adenoma or carcinoma (combined) in exposed mice increased with increasing exposure concentration and were significantly greater in males and females in the 375 and 750 ppm groups than those in the controls. The incidences of harderian gland carcinoma in males and females in the 375 and 750 ppm groups were also slightly greater than those in the controls. Female mice in the 188 and 750 ppm groups had significantly greater incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) than the controls. The incidences of liver eosinophilic focus increased with increasing exposure concentration, and the incidences in the 375 and 750 ppm groups were significantly greater than the control incidence. The incidences of alveolar/bronchiolar carcinoma in male mice in the 750 ppm group and female mice in the 375 ppm group were significantly greater than those in the controls. Females in the 750 ppm group also had a significantly greater incidence of alveolar/bronchiolar adenoma or carcinoma (combined) and a slightly greater incidence of alveolar/bronchiolar adenoma than the controls. Females in the 375 ppm group had a significantly greater incidence of cellular infiltration of histiocytes in the lung than the controls. The incidences of degeneration and metaplasia of the olfactory epithelium and hyaline degeneration of the respiratory epithelium were significantly greater in exposed male and female mice than those in the controls. Additionally, males in the 375 and 750 ppm groups had significantly greater incidences of inflammation of the nasolacrimal duct than did the controls. GENETIC TOXICOLOGY: Nitromethane was not mutagenic in any tests performed by the NTP. It did not induce mutations in Salmonella typhimurium, with or without S9 metabolic activation, and no induction of sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells exposed to nitromethane was noted with or without S9. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male and female mice at the end of the 13-week inhalation study of nitromethane. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of nitromethane in male F344/N rats exposed to 94, 188, or 375 ppm. There was clear evidence of carcinogenic activity of nitromethane in female F344/N rats based on increased incidences of mammary gland fibroadenomas and carcinomas. There was clear evidence of carcinogenic activity of nitromethane in male B6C3F1 mice based on increased incidences of harderian gland adenomas and carcinomas. There was clear evidence of carcin ogenic activity in female B6C3F1 mice, based on increased incidences of liver neoplasms (primarily adenomas) and harderian gland adenomas and carcinomas. Increased incidences of alveolar/bronchiolar adenomas and carcinomas in male and female mice exposed to nitromethane were also considered to be related to chemical administration. Exposure to nitromethane by inhalation for 2 years resulted in increased incidences of nasal lesions including degeneration and metaplasia of the olfactory epithelium and degeneration of the respiratory epithelium in male and female mice. Synonym: Nitrocarbol

Inhalation developmental toxicology studies: Teratology study of acetone in mice and rats: Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mast, T.J.; Evanoff, J.J.; Rommereim, R.L.

1988-11-01

Acetone, an aliphatic ketone, is a ubiquitous industrial solvent and chemical intermediate; consequently, the opportunity for human exposure is high. The potential for acetone to cause developmental toxicity was assessed in Sprague-Dawley rats exposed to 0, 440, 2200, or 11000 ppm, and in Swiss (CD-1) mice exposed to 0, 440, 2200, and 6600 ppm acetone vapors, 6 h/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and approx.32 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plugmore » or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 46 refs., 6 figs., 27 tabs.« less

Effects of adolescent nicotine exposure and withdrawal on intravenous cocaine self-administration during adulthood in male C57BL/6J mice.

PubMed

Dickson, Price E; Miller, Mellessa M; Rogers, Tiffany D; Blaha, Charles D; Mittleman, Guy

2014-01-01

Studies of adolescent drug use show (1) a pattern in which the use of tobacco precedes the use of other drugs and (2) a positive relationship between adolescent tobacco use and later drug use. These observations have led to the hypothesis that a causal relationship exists between early exposure to nicotine and the later use of hard drugs such as cocaine. Using male C57BL/6J mice, we tested the hypothesis that nicotine exposure in adolescence leads to increased intravenous self-administration (IVSA) of cocaine in adulthood. Using miniature osmotic pumps, we exposed mice and their littermate controls to nicotine (24 mg/kg/day) or vehicle, respectively, over the entire course of adolescence [postnatal days (P) 28-56]. Nicotine exposure was terminated on P56 and mice were not exposed to nicotine again during the experiment. On P73, mice were allowed to acquire cocaine IVSA (1.0 mg/kg/infusion) and a dose-response curve was generated (0.18, 0.32, 0.56, 1.0, 1.8 mg/kg/infusion). Lever pressing during extinction conditions was also evaluated. All mice rapidly learned to lever press for the combination of cocaine infusions and non-drug stimuli. Analysis of the dose-response curve revealed that adolescent nicotine-exposed mice self-administered significantly more (P < 0.05) cocaine than controls at all but the highest dose. No significant differences were observed between adolescent nicotine-exposed and control mice during the acquisition or extinction stages. These results indicate that adolescent nicotine exposure can increase cocaine IVSA in mice, which suggests the possibility of a causal link between adolescent tobacco use and later cocaine use in humans. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

No effects of GSM-modulated 900 MHz electromagnetic fields on survival rate and spontaneous development of lymphoma in female AKR/J mice

PubMed Central

Sommer, Angela M; Streckert, Joachim; Bitz, Andreas K; Hansen, Volkert W; Lerchl, Alexander

2004-01-01

Background Several reports indicated that non-thermal electromagnetic radiation such as from mobile phones and base stations may promote cancer. Therefore, it was investigated experimentally, whether 900 MHz electromagnetic field exposure influences lymphoma development in a mouse strain that is genetically predisposed to this disease. The AKR/J mice genome carries the AK-virus, which leads within one year to spontaneous development of thymic lymphoblastic lymphoma. Methods 320 unrestrained female mice were sham-exposed or exposed (each n = 160 animals) to GSM like 900 MHz electromagnetic fields for 24 hours per day, 7 days per week, at an average whole body specific absorption rate (SAR) value of 0.4 W/kg. Animals were visually checked daily and were weighed and palpated weekly. Starting with an age of 6 months, blood samples were taken monthly from the tail. Animals with signs of disease or with an age of about 46 weeks were sacrificed and a gross necropsy was performed. Results Electromagnetic field exposure had a significant effect on body weight gain, with higher values in exposed than in sham-exposed animals. However, survival rate and lymphoma incidence did not differ between exposed and sham-exposed mice. Conclusion These data do not support the hypothesis that exposure to 900 MHz electromagnetic fields is a significant risk factor for developing lymphoma in a genetically predisposed species, even at a relatively high exposure level. PMID:15538947

Long-term reduction in food allergy susceptibility in mice by combining breastfeeding-induced tolerance and TGF-β-enriched formula after weaning.

PubMed

Rekima, A; Macchiaverni, P; Turfkruyer, M; Holvoet, S; Dupuis, L; Baiz, N; Annesi-Maesano, I; Mercenier, A; Nutten, S; Verhasselt, V

2017-04-01

Oral tolerance induction in early life is a promising approach for food allergy prevention. Its success requires the identification of factors necessary for its persistence. We aimed to assess in mice duration of allergy prevention by breastfeeding-induced oral tolerance and whether oral TGF-β supplementation after weaning would prolong it. We quantified ovalbumin (OVA) and OVA-specific immunoglobulin levels by ELISA in milk from the EDEN birth cohort. As OVA-specific Ig was found in all samples, we assessed whether OVA-immunized mice exposed to OVA during lactation could prevent allergic diarrhoea in their 6- and 13-week-old progeny. In some experiments, a TGF-β-enriched formula was given after weaning. At 6 weeks, only 13% and 34% of mice breastfed by OVA-exposed mothers exhibited diarrhoea after six and seven OVA challenges vs. 44% and 72% in mice breastfed by naïve mothers (P = 0.02 and 0.01). Protection was associated with decreased levels of MMCP1 and OVA-specific IgE (P < 0.0001). At 13 weeks, although OVA-specific IgE remained low (P = 0.001), diarrhoea occurrence increased to 32% and 46% after six and seven OVA challenges in mice breastfed by OVA-exposed mothers. MMCP1 levels were not significantly inhibited. Supplementation with TGF-β after weaning induced a strong protection in 13-week-old mice breastfed by OVA-exposed mothers compared with mice breastfed by naive mothers (0%, 13% and 32% of diarrhoea at the fifth, sixth and seventh challenges vs. 17, 42 and 78%; P = 0.05, 0.0043 and 0.0017). MMCP1 levels decreased by half compared with control mice (P = 0.02). Prolonged protection was only observed in mice rendered tolerant by breastfeeding and was associated with an improved gut barrier. In mice, prevention of food allergy by breastfeeding-induced tolerance is of limited duration. Nutritional intervention by TGF-β supplementation after weaning could prolong beneficial effects of breast milk on food allergy prevention. © 2016 John Wiley & Sons Ltd.

Chronic consumption of distilled sugarcane spirit induces anxiolytic-like effects in mice

PubMed Central

Sena, Maria Clécia P; Nunes, Fabíola C; Stiebbe Salvadori, Mirian G S; Carvalho, Cleyton Charles D; Morais, Liana Clébia S L; Braga, Valdir A

2011-01-01

OBJECTIVE: Chronic ethanol consumption is a major public health problem throughout the world. We investigated the anxiolytic-like effects and the possible ever injury induced by the chronic consumption of ethanol or sugarcane spirit in mice. METHOD: Adult mice were exposed to a two-bottle free-choice paradigm for 6 weeks. The mice in Group A (n  =  16) had access to sugarcane spirit + distilled water, the mice in Group B (n  =  15) had access to ethanol + distilled water, and the mice in Group C (control, n  =  14) had access to distilled water + distilled water. The ethanol content in the beverages offered to Groups A and B was 2% for the first week, 5% for the second week and 10% for the remaining four weeks. At the end of the experimental period, the mice were evaluated using the elevated-plus maze and the hole-board test to assess their anxiety-related behaviors. We also determined the serum aspartate aminotransferase and alanine aminotransferase levels. RESULTS: In the elevated-plus maze, the time spent in the open arms was increased in the mice exposed to chronic ethanol (32 ± 8 vs. 7 ± 2 s, n  =  9) or sugarcane spirit (36 ± 9 vs. 7 ± 2 s, n  =  9) compared to the controls. In the hole-board test, the mice exposed to ethanol or sugarcane spirit displayed increases in their head-dipping frequency (16 ± 1 for the control group, 27 ± 2 for the ethanol group, and 31 ± 3 for the sugarcane-spirit group; n  =  9 for each group). In addition, the mice exposed to sugarcane spirit displayed an increase in the aspartate aminotransferase / alanine aminotransferase ratio compared to the ethanol group (1.29 ± 0.17 for the control group and 2.67 ± 0.17 for the sugarcane spirit group; n  =  8 for each group). CONCLUSION: The chronic consumption of sugarcane-spirit produces liver injury and anxiolytic-like effects and the possible liver injury in mice. PMID:21789394

Th1 Immune Response Induction by Biogenic Selenium Nanoparticles in Mice with Breast Cancer: Preliminary Vaccine Model

PubMed Central

Yazdi, Mohammad Hossein; Mahdavi, Mehdi; Faghfuri, Elnaz; Faramarzi, Mohammad Ali; Sepehrizadeh, Zargham; Hassan, Zuhair Mohammad; Gholami, Mehdi; Shahverdi, Ahmad Reza

2015-01-01

Background Tumor associated antigens can be viably used to enhance host immune response. Objectives The immunomodulatory effect of biogenic selenium nanoparticles (SeNPs) was compared between treated and untreated mice with crude antigens of 4T1 cells. Materials and Methods Female inbred BALB/c mice (60) were injected by cancinogenic 4T1 cells causing breast cancer. After 10 days, all tumor bearing mice were divided into 4 groups. Group 1 was daily provided oral PBS and injected by the same buffer after tumor induction and was considered as control. Group 2 received only 100 μg/day SeNPs as an oral supplement for 30 days. Group 3 was only injected with 4T1 cells crude antigens with nil supplementation of SeNPs. Group 4 animals were supplemented 100 μg/day SeNPs for 30 days and simultaneously injected with crude antigens of 4T1 cells. All antigens or PBS injections were introduced at 7, 14 and 28 days following tumor induction. Oral PBS and SeNPs supplementation initiated from the first day of tumor induction and continued up to 30 days. During tumor growth, animal weights and survival rates were monitored and at the end of the study the concentrations of different cytokines and DTH responses were measured. Results Data clearly showed that the levels of cellular immunomodulatory components (granzyme B, IL-12, IFN-γ, and IL-2) significantly increased (P < 0.05) in mice treated with both SeNPs and crude antigens of 4T1 cells in comparison to the other groups. In contrast, the levels of TGF-β in these mice decreased. Conclusions Although SeNPs showed a noticeable boosting effect for the immune response in mice bearing tumor exposed to crude antigens of 4T1 cells, further complementary studies seem to be inevitable. PMID:28959284

A brominated flame retardant, 2,2',4,4',5-pentabromodiphenyl ether: uptake, retention, and induction of neurobehavioral alterations in mice during a critical phase of neonatal brain development.

PubMed

Eriksson, P; Viberg, H; Jakobsson, E; Orn, U; Fredriksson, A

2002-05-01

Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame retardant additives. In a recent study, we have seen that neonatal exposure to some brominated flame retardants can cause permanent aberrations in spontaneous motor behavior that seem to worsen with age. In view of an increasing amount of PBDEs in mother's milk and in the environment, the present study was undertaken to investigate whether there is a critical and limited phase, during neonatal life, for induction of persistent neurotoxic effects of 2,2',4,4',5-pentaBDE (PBDE 99). Neonatal NMRI male mice were exposed on day 3, 10, or 19 to 8 mg 2,2',4,4',5-pentaBDE/kg body weight. Uptake and retention of 2,2',4,4',5-penta[(14)C]BDE were studied in the mouse brain after exposure to 1.5 M becquerel (Bq) 2,2',4,4',5-penta[(14)C]BDE /kg body weight (bw) on postnatal day 3, 10, or 19. Spontaneous motor behavior was observed in 4-month-old mice. Mice exposed to 2,2',4,4',5-pentaBDE on day 3 or 10 showed significantly impaired spontaneous motor behavior, whereas no effect was seen in mice exposed on day 19. Neonatal mice exposed to 2,2',4,4',5-penta[(14)C]BDE 99 on postnatal day 3, 10, or 19 were sacrificed 24 h or 7 days posttreatment. The amount of radioactivity, given as per mille ( per thousand) of total amount administered, was between 3.7 and 5.1 per thousand in the three different age categories at 24 h after administration. Seven days after the administration, 2,2',4,4',5-penta[(14)C]BDE or its metabolites could still be detected in the brain. The amount of radioactivity in the brain was not higher in mice exposed on day 3 or 10 when compared to exposure on day 19. Thus, the behavioral disturbances observed in adult mice following neonatal exposure to 2,2',4,4',5-pentaBDE are induced during a defined critical period of neonatal brain development.

The effects of electromagnetic pulses (EMP) on the bioactivity of insulin and a preliminary study of mechanism.

PubMed

Chen, Yong Bin; Li, Jing; Qi, Yuhong; Miao, Xia; Zhou, Yongchun; Ren, Dongqing; Guo, G Z

2010-01-01

To investigate the effects of electromagnetic pulse (EMP) exposure on the bioactivity of insulin and a preliminary mechanism for these effects. A tapered parallel plate Gigahertz Transverse Electromagnetic (GTEM) cell with a flared rectangular coaxial transmission line was used to expose the insulin solution to EMP. Concurrent sham-exposed insulin solutions were used as a control. The effect of EMP-exposed insulin on fasting blood glucose levels of type I diabetes model mice, the effect of EMP on binding affinity between insulin and its receptor and the effect of EMP on insulin's fluorescence intensity were detected, respectively. (i) After EMP exposure, compared with sham-exposed insulin, the bioactivity of insulin in decreasing fasting blood glucose levels in type I diabetes model mice was reduced significantly (p = 0.023). (ii) Compared with sham-exposed insulin group, the percentage fluorescein isothiocyannate (FITC) labelling of HL-7702 cells was significantly reduced in the EMP-exposed insulin group (22.7-13.8%, respectively). (iii) Compared with sham-exposed insulin, the fluorescence intensity was significantly reduced in EMP-exposed insulin (p < 0.001). EMP exposure significantly decreased the bioactivity of insulin to reduce the blood glucose levels in type I diabetic mice. This could be due to a decreased binding affinity between insulin and its receptor. This mechanism could involve an alteration of insulin's' conformation caused by EMP exposure.

Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells.

PubMed

Pihlaja, Rea; Takkinen, Jatta; Eskola, Olli; Vasara, Jenni; López-Picón, Francisco R; Haaparanta-Solin, Merja; Rinne, Juha O

2015-04-28

Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice. Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment. JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.

Technical Note: Partial body irradiation of mice using a customized PMMA apparatus and a clinical 3D planning/LINAC radiotherapy system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karagounis, Ilias V.; Koukourakis, Michael I., E-mail: targ@her.forthnet.gr, E-mail: mkoukour@med.duth.gr; Abatzoglou, Ioannis M., E-mail: abadzoglou@yahoo.gr

Purpose: In vivo radiobiology experiments involving partial body irradiation (PBI) of mice are of major importance because they allow for the evaluation of individual organ tolerance; overcoming current limitations of experiments using lower dose, whole body irradiation. In the current study, the authors characterize and validate an effective and efficient apparatus for multiple animal PBI, directed to the head, thorax, or abdomen of mice. Methods: The apparatus is made of polymethylmethacrylate and consists of a rectangular parallelepiped prism (40 cm × 16 cm × 8 cm), in which five holes were drilled to accomodate standard 60 ml syringes, each housingmore » an unanesthetized, fully immobilized mouse. Following CT-scanning and radiotherapy treatment planning, radiation fields were designed to irradiate the head, thorax, or abdomen of the animal. Thermoluminescent dosimeters (TLDs) were used to confirm the treatment planning dosimetry for primary beam and scattered radiation. Results: Mice are efficiently placed into 60 ml syringes and immobilized, without the use of anesthetics. Although partial rotational movement around the longitudinal axis and a minor 2 mm forward/backward movement are permitted, this does not compromise the irradiation of the chosen body area. TLDs confirmed the dose values predicted by the treatment planning dosimetry, both for primary beam and scattered radiation. Conclusions: The customized PMMA apparatus described and validated is cost-effective, convenient to use, and efficient in performing PBI without the use of anesthesia. The developed apparatus permits the isolated irradiation of the mouse head, thorax, and abdomen. Importantly, the apparatus allows the delivery of PBI to five mice, simultaneously, representing an efficient way to effectively expose a large number of animals to PBI through multiple daily fractions, simulating clinical radiotherapy treatment schedules.« less

Technical Note: Partial body irradiation of mice using a customized PMMA apparatus and a clinical 3D planning/LINAC radiotherapy system.

PubMed

Karagounis, Ilias V; Abatzoglou, Ioannis M; Koukourakis, Michael I

2016-05-01

In vivo radiobiology experiments involving partial body irradiation (PBI) of mice are of major importance because they allow for the evaluation of individual organ tolerance; overcoming current limitations of experiments using lower dose, whole body irradiation. In the current study, the authors characterize and validate an effective and efficient apparatus for multiple animal PBI, directed to the head, thorax, or abdomen of mice. The apparatus is made of polymethylmethacrylate and consists of a rectangular parallelepiped prism (40 cm × 16 cm × 8 cm), in which five holes were drilled to accomodate standard 60 ml syringes, each housing an unanesthetized, fully immobilized mouse. Following CT-scanning and radiotherapy treatment planning, radiation fields were designed to irradiate the head, thorax, or abdomen of the animal. Thermoluminescent dosimeters (TLDs) were used to confirm the treatment planning dosimetry for primary beam and scattered radiation. Mice are efficiently placed into 60 ml syringes and immobilized, without the use of anesthetics. Although partial rotational movement around the longitudinal axis and a minor 2 mm forward/backward movement are permitted, this does not compromise the irradiation of the chosen body area. TLDs confirmed the dose values predicted by the treatment planning dosimetry, both for primary beam and scattered radiation. The customized PMMA apparatus described and validated is cost-effective, convenient to use, and efficient in performing PBI without the use of anesthesia. The developed apparatus permits the isolated irradiation of the mouse head, thorax, and abdomen. Importantly, the apparatus allows the delivery of PBI to five mice, simultaneously, representing an efficient way to effectively expose a large number of animals to PBI through multiple daily fractions, simulating clinical radiotherapy treatment schedules.

Transforming growth factor alpha is a critical mediator of radiation lung injury.

PubMed

Chung, Eun Joo; Hudak, Kathryn; Horton, Jason A; White, Ayla; Scroggins, Bradley T; Vaswani, Shiva; Citrin, Deborah

2014-09-01

Radiation fibrosis of the lung is a late toxicity of thoracic irradiation. Epidermal growth factor (EGF) signaling has previously been implicated in radiation lung injury. We hypothesized that TGF-α, an EGF receptor ligand, plays a key role in radiation-induced fibrosis in lung. Mice deficient in transforming growth factor (TGF-α(-/-)) and control C57Bl/6J (C57-WT) mice were exposed to thoracic irradiation in 5 daily fractions of 6 Gy. Cohorts of mice were followed for survival (n ≥ 5 per group) and tissue collection (n = 3 per strain and time point). Collagen accumulation in irradiated lungs was assessed by Masson's trichrome staining and analysis of hydroxyproline content. Cytokine levels in lung tissue were assessed with ELISA. The effects of TGF-α on pneumocyte and fibroblast proliferation and collagen production were analyzed in vitro. Lysyl oxidase (LOX) expression and activity were measured in vitro and in vivo. Irradiated C57-WT mice had a median survival of 24.4 weeks compared to 48.2 weeks for irradiated TGF-α(-/-) mice (P = 0.001). At 20 weeks after irradiation, hydroxyproline content was markedly increased in C57-WT mice exposed to radiation compared to TGF-α(-/-) mice exposed to radiation or unirradiated C57-WT mice (63.0, 30.5 and 37.6 μg/lung, respectively, P = 0.01). C57-WT mice exposed to radiation had dense foci of subpleural fibrosis at 20 weeks after exposure, whereas the lungs of irradiated TGF-α (-/-) mice were largely devoid of fibrotic foci. Lung tissue concentrations of IL-1β, IL-4, TNF-α, TGF-β and EGF at multiple time points after irradiation were similar in C57-WT and TGF-α(-/-) mice. TGF-α in lung tissue of C57-WT mice rose rapidly after irradiation and remained elevated through 20 weeks. TGF-α(-/-) mice had lower basal LOX expression than C57-WT mice. Both LOX expression and LOX activity were increased after irradiation in all mice but to a lesser degree in TGF-α(-/-) mice. Treatment of NIH-3T3 fibroblasts with TGF-α resulted in increases in proliferation, collagen production and LOX activity. These studies identify TGF-α as a critical mediator of radiation-induced lung injury and a novel therapeutic target in this setting. Further, these data implicate TGF-α as a mediator of collagen maturation through a TGF-β independent activation of lysyl oxidase.

Attempted transmission of Ehrlichia risticii, causative agent of Potomac horse fever, by the ticks, Dermacentor variabilis, Rhipicephalus sanguineus, Ixodes scapularis and Amblyomma americanum.

PubMed

Hahn, N E; Fletcher, M; Rice, R M; Kocan, K M; Hansen, J W; Hair, J A; Barker, R W; Perry, B D

1990-01-01

Dermacentor variabilis, Rhipicephalus sanguineus, Amblyomma americanum, and Ixodes scapularis ticks were investigated for their ability to transmit Potomac horse fever. Larval and nymphal ticks were exposed to Ehrlichia risticii by feeding on mice inoculated with the organism. Molted exposed ticks were then allowed to feed on susceptible ponies or mice. No evidence of transmission, either clinically or by detection of antibodies to E. risticii in mice or ponies, was observed for any tick species examined.

Early life exposure to 2.45GHz WiFi-like signals: effects on development and maturation of the immune system.

PubMed

Sambucci, Manolo; Laudisi, Federica; Nasta, Francesca; Pinto, Rosanna; Lodato, Rossella; Lopresto, Vanni; Altavista, Pierluigi; Marino, Carmela; Pioli, Claudio

2011-12-01

The development of the immune system begins during embryogenesis, continues throughout fetal life, and completes its maturation during infancy. Exposure to immune-toxic compounds at levels producing limited/transient effects in adults, results in long-lasting or permanent immune deficits when it occurs during perinatal life. Potentially harmful radiofrequency (RF) exposure has been investigated mainly in adult animals or with cells from adult subjects, with most of the studies showing no effects. Is the developing immune system more susceptible to the effects of RF exposure? To address this question, newborn mice were exposed to WiFi signals at constant specific absorption rates (SAR) of 0.08 or 4 W/kg, 2h/day, 5 days/week, for 5 consecutive weeks, starting the day after birth. The experiments were performed with a blind procedure using sham-exposed groups as controls. No differences in body weight and development among the groups were found in mice of both sexes. For the immunological analyses, results on female and male newborn mice exposed during early post-natal life did not show any effects on all the investigated parameters with one exception: a reduced IFN-γ production in spleen cells from microwaves (MW)-exposed (SAR 4 W/kg) male (not in female) mice compared with sham-exposed mice. Altogether our findings do not support the hypothesis that early post-natal life exposure to WiFi signals induces detrimental effects on the developing immune system. Copyright © 2011 Elsevier Ltd. All rights reserved.

Exposure to Experimental Preeclampsia in Mice Enhances the Vascular Response to Future Injury

PubMed Central

Pruthi, Dafina; Khankin, Eliyahu V.; Blanton, Robert M.; Aronovitz, Mark; Burke, Suzanne D.; McCurley, Amy; Karumanchi, S. Ananth; Jaffe, Iris Z.

2015-01-01

Cardiovascular disease (CVD) remains the leading killer of women in developed nations. One gender-specific risk factor is preeclampsia (PE), a syndrome of hypertension and proteinuria that complicates 5% of pregnancies. Although PE resolves after delivery, exposed women are at increased long term risk of premature CVD and mortality. Preexisting CVD risk factors are associated with increased risk of developing PE but whether PE merely uncovers risk or contributes directly to future CVD remains a critical unanswered question. A mouse PE model was used to test the hypothesis that PE causes an enhanced vascular response to future vessel injury. A PE-like state was induced in pregnant CD1 mice by overexpressing soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating anti-angiogenic protein that induces hypertension and glomerular disease resembling human PE. Two months post-partum, sFlt-1 levels and blood pressure normalized and cardiac size and function by echocardiography and renal histology were indistinguishable in PE-exposed compared to control mice. Mice were then challenged with unilateral carotid injury. PE-exposed mice had significantly enhanced vascular remodeling with increased vascular smooth muscle cell proliferation (180% increase, P<0.01) and vessel fibrosis (216% increase, P<0.001) compared to control pregnancy. In the contralateral uninjured vessel, there was no difference in remodeling after exposure to PE. These data support a new model in which vessels exposed to PE retain a persistently enhanced vascular response to injury despite resolution of PE after delivery. This new paradigm may contribute to the substantially increased risk of CVD in woman exposed to PE. PMID:25712723

Response, thermal regulatory threshold and thermal breakdown threshold of restrained RF-exposed mice at 905 MHz

NASA Astrophysics Data System (ADS)

Ebert, S.; Eom, S. J.; Schuderer, J.; Apostel, U.; Tillmann, T.; Dasenbrock, C.; Kuster, N.

2005-11-01

The objective of this study was the determination of the thermal regulatory and the thermal breakdown thresholds for in-tube restrained B6C3F1 and NMRI mice exposed to radiofrequency electromagnetic fields at 905 MHz. Different levels of the whole-body averaged specific absorption rate (SAR = 0, 2, 5, 7.2, 10, 12.6 and 20 W kg-1) have been applied to the mice inside the 'Ferris Wheel' exposure setup at 22 ± 2 °C and 30-70% humidity. The thermal responses were assessed by measurement of the rectal temperature prior, during and after the 2 h exposure session. For B6C3F1 mice, the thermal response was examined for three different weight groups (20 g, 24 g, 29 g), both genders and for pregnant mice. Additionally, NMRI mice with a weight of 36 g were investigated for an interstrain comparison. The thermal regulatory threshold of in-tube restrained mice was found at SAR levels between 2 W kg-1 and 5 W kg-1, whereas the breakdown of regulation was determined at 10.1 ± 4.0 W kg-1(K = 2) for B6C3F1 mice and 7.7 ± 1.6 W kg-1(K = 2) for NMRI mice. Based on a simplified power balance equation, the thresholds show a clear dependence upon the metabolic rate and weight. NMRI mice were more sensitive to thermal stress and respond at lower SAR values with regulation and breakdown. The presented data suggest that the thermal breakdown for in-tube restrained mice, whole-body exposed to radiofrequency fields, may occur at SAR levels of 6 W kg-1(K = 2) at laboratory conditions.

Corneal NF-kappaB activity is necessary for the retention of transparency in the cornea of UV-B-exposed transgenic reporter mice.

PubMed

Alexander, George; Carlsen, Harald; Blomhoff, Rune

2006-04-01

To determine the dynamics of Nuclear Factor-kappaB (NF-kappaB) in murine corneal pathology and the role of NF-kappaB in maintaining corneal clarity after ultraviolet B radiation insult, transgenic mice containing NF-kappaB-luciferase reporter were exposed to LPS (bacterial lipopolysaccharide), TNF-alpha (Tumor Necrosis Factor-alpha) or 4 kJ m(-2) UV-B radiation. NF-kappaB decoy oligonucleotides were also administered in some of the UV-B experiments. Following various exposure times, the mice were sacrificed and whole eyes or corneal tissues were obtained. Whole eyes were examined for scattering using a point-source optical imaging technique. Tissue homogenates were examined for luciferase activity using a luminometer. TNF-alpha and LPS-injected NF-kappaB-luciferase transgenic mice demonstrated 3-10-fold increases in cornea NF-kappaB with peak activities at 4 and 6 hr post-injection, respectively. Mice exposed to 4 kJ m(-2) UV-B exhibited a 3-fold increase in NF-kappaB activity 4 hr post-exposure. The administration of NF-kappaB-decoy oligonucleotides to mice had the effect of reducing UV-B-induced NF-kappaB activity in the cornea and significantly increasing the amount of light scattering in UV-B exposed corneas 7 days post-UV-B exposure when compared to sham injected mice. These results indicate that NF-kappaB is activated in cornea in pathologies that involves increased plasma levels of LPS and TNF-alpha, as well as direct UV-B exposure, and suggest that NF-kappaB activation play an essential part in the corneal healing process.

A compromised liver alters polychlorinated biphenyl-mediated toxicity.

PubMed

Wahlang, Banrida; Perkins, Jordan T; Petriello, Michael C; Hoffman, Jessie B; Stromberg, Arnold J; Hennig, Bernhard

2017-04-01

Exposure to environmental toxicants namely polychlorinated biphenyls (PCBs) is correlated with multiple health disorders including liver and cardiovascular diseases. The liver is important for both xenobiotic and endobiotic metabolism. However, the responses of an injured liver to subsequent environmental insults has not been investigated. The current study aims to evaluate the role of a compromised liver in PCB-induced toxicity and define the implications on overall body homeostasis. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient diet (MCD) during the 12-week study. Mice were subsequently exposed to either PCB126 (4.9mg/kg) or the PCB mixture, Arcolor1260 (20mg/kg) and analyzed for inflammatory, calorimetry and metabolic parameters. Consistent with the literature, MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 showed observable wasting syndrome leading to mortality. PCB126 and Aroclor1260 exposure worsened hepatic fibrosis exhibited by the MCD groups. Interestingly, PCB126 but not Aroclor1260 induced steatosis and inflammation in CD-fed mice. Mice with liver injury and subsequently exposed to PCBs also manifested metabolic disturbances due to alterations in hepatic gene expression. Furthermore, PCB exposure in MCD-fed mice led to extra-hepatic toxicity such as upregulated circulating inflammatory biomarkers, implicating endothelial cell dysfunction. Taken together, these results indicate that environmental pollution can exacerbate toxicity caused by diet-induced liver injury which may be partially due to dysfunctional energy homeostasis. This is relevant to PCB-exposed human cohorts who suffer from alcohol or diet-induced fatty liver diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Blood and lung microRNAs as biomarkers of pulmonary tumorigenesis in cigarette smoke-exposed mice

PubMed Central

Izzotti, Alberto; Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta; Longobardi, Mariagrazia; Pulliero, Alessandra; Geretto, Marta; Micale, Rosanna T.; La Maestra, Sebastiano; Miller, Mark Steven; Steele, Vernon E.; De Flora, Silvio

2016-01-01

Cigarette smoke (CS) is known to dysregulate microRNA expression profiles in the lungs of mice, rats, and humans, thereby modulating several pathways involved in lung carcinogenesis and other CS-related diseases. We designed a study aimed at evaluating (a) the expression of 1135 microRNAs in the lung of Swiss H mice exposed to mainstream CS during the first 4 months of life and thereafter kept in filtered air for an additional 3.5 months, (b) the relationship between lung microRNA profiles and histopathological alterations in the lung, (c) intergender differences in microRNA expression, and (d) the comparison with microRNA profiles in blood serum. CS caused multiple histopathological alterations in the lung, which were almost absent in sham-exposed mice. An extensive microRNA dysregulation was detected in the lung of CS-exposed mice. Modulation of microRNA profiles was specifically related to the histopathological picture, no effect being detected in lung fragments with non-neoplastic lung diseases (emphysema or alveolar epithelial hyperplasia), whereas a close association occurred with the presence and multiplicity of preneoplastic lesions (microadenomas) and benign lung tumors (adenomas). Three microRNAs regulating estrogen and HER2-dependent mechanisms were modulated in the lung of adenoma-bearing female mice. Blood microRNAs were also modulated in mice affected by early neoplastic lesions. However, there was a poor association between lung microRNAs and circulating microRNAs, which can be ascribed to an impaired release of mature microRNAs from the damaged lung. Studies in progress are evaluating the feasibility of analyzing blood microRNAs as a molecular tool for lung cancer secondary prevention. PMID:27713172

Ultra-low dose of Mycobacterium tuberculosis aerosol creates partial infection in mice.

PubMed

Saini, Divey; Hopkins, Gregory W; Seay, Sarah A; Chen, Ching-Ju; Perley, Casey C; Click, Eva M; Frothingham, Richard

2012-03-01

A murine low dose (LD) aerosol model is commonly used to test tuberculosis vaccines. Doses of 50-400 CFU (24h lung CFU) infect 100% of exposed mice. The LD model measures progression from infection to disease based on organ CFU at defined time points. To mimic natural exposure, we exposed mice to an ultra-low dose (ULD) aerosol. We estimated the presented dose by sampling the aerosol. Female C57BL/6 mice were exposed to Mycobacterium tuberculosis H37Rv aerosol at 1.0, 1.1, 1.6, 5.4, and 11 CFU presented dose, infecting 27%, 36%, 36%, 100%, and 95% of mice, respectively. These data are compatible with a stochastic infection event (Poisson distribution, weighted R(2)=0.97) or with a dose-response relationship (sigmoid distribution, weighted R(2)=0.97). Based on the later assumption, the ID50 was 1.6CFU presented dose (95% confidence interval, 1.2-2.1). We compared organ CFU after ULD and LD aerosols (5.4 vs. 395CFU presented dose). Lung burden was 30-fold lower in the ULD model at 4 weeks (3.4 vs. 4.8 logs, p<0.001) and 18 weeks (≤3.6 vs. 5.0 logs, p=0.01). Mice exposed to ULD aerosols as compared to LD aerosols had greater within-group CFU variability. Exposure to ULD aerosols leads to infection in a subset of mice, and to persistently low organ CFU. The ULD aerosol model may resemble human pulmonary tuberculosis more closely than the standard LD model, and may be used to identify host or bacterial factors that modulate the initial infection event. Copyright © 2011 Elsevier Ltd. All rights reserved.

Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting

EPA Science Inventory

T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARa)-dependent and...

Protective Role of γδ T Cells in Cigarette Smoke and Influenza Infection

PubMed Central

Hong, M. J.; Gu, B. H.; Madison, M.; Landers, C.; Tung, H. Y.; Kim, M.; Yuan, X.; You, R.; MacHado, A. A.; Gilbert, B. E.; Soroosh, P.; Elloso, M.; Song, L.; Chen, M.; Corry, D. B.; Diehl, G.; Kheradmand, F.

2017-01-01

Airborne pathogens commonly trigger severe respiratory failure or death in smokers with lung disease. Cigarette smoking compromises the effectiveness of innate immunity against infections but the underlying mechanisms responsible for defective acquired immune responses in smokers remains less clear. We found that mice exposed to chronic cigarette smoke recovered poorly from primary Influenza A pneumonia with reduced type I and II interferons (IFNs) and viral-specific immunoglobulins, but recruited gamma delta (γδ) T cells to the lungs that predominantly expressed interleukin 17A (IL-17A). Il-17a-/- mice exposed to smoke and infected with Influenza A also recruited γδ T cells to the lungs, but in contrast to wild type mice, expressed increased IFNs, made protective influenza specific antibodies, and recovered from infection. Depletion of IL-17A with blocking antibodies significantly increased T-bet expression in γδ T cells and improved recovery from acute Influenza A infection in air, but not smoke exposed mice. In contrast, when exposed to smoke, γδ T cell deficient mice failed to mount an effective immune response to Influenza A and showed increased mortality. Our findings demonstrate a protective role for γδ T cells in smokers and suggest that smoke-induced increase in IL-17A inhibits the transcriptional programs required for their optimal anti-viral responses. PMID:29091081

The green tea modulates large intestinal microbiome and exo/endogenous metabolome altered through chronic UVB-exposure.

PubMed

Jung, Eun Sung; Park, Hye Min; Hyun, Seung Min; Shon, Jong Cheol; Singh, Digar; Liu, Kwang-Hyeon; Whon, Tae Woong; Bae, Jin-Woo; Hwang, Jae Sung; Lee, Choong Hwan

2017-01-01

The attenuating effects of green tea supplements (GTS) against the ultraviolet (UV) radiation induced skin damages are distinguished. However, the concomitant effects of GTS on the large intestinal microbiomes and associated metabolomes are largely unclear. Herein, we performed an integrated microbiome-metabolome analysis to uncover the esoteric links between gut microbiome and exo/endogenous metabolome maneuvered in the large intestine of UVB-exposed mice subjected to dietary GTS. In UVB-exposed mice groups (UVB), class Bacilli and order Bifidobacteriales were observed as discriminant taxa with decreased lysophospholipid levels compared to the unexposed mice groups subjected to normal diet (NOR). Conversely, in GTS fed UVB-exposed mice (U+GTS), the gut-microbiome diversity was greatly enhanced with enrichment in the classes, Clostridia and Erysipelotrichia, as well as genera, Allobaculum and Lachnoclostridium. Additionally, the gut endogenous metabolomes changed with an increase in amino acids, fatty acids, lipids, and bile acids contents coupled with a decrease in nucleobases and carbohydrate levels. The altered metabolomes exhibited high correlations with GTS enriched intestinal microflora. Intriguingly, the various conjugates of green tea catechins viz., sulfated, glucuronided, and methylated ones including their exogenous derivatives were detected from large intestinal contents and liver samples. Hence, we conjecture that the metabolic conversions for the molecular components in GTS strongly influenced the gut micro-environment in UVB-exposed mice groups, ergo modulate their gut-microbiome as well as exo/endogenous metabolomes.

Diphenyl ditelluride intoxication triggers histological changes in liver, kidney, and lung of mice.

PubMed

da Luz, Sônia Cristina Almeida; Daubermann, Melissa Falster; Thomé, Gustavo Roberto; Dos Santos, Matheus Mülling; Ramos, Angelica; Torres Salazar, Gerson; da Rocha, João Batista Teixeira; Barbosa, Nilda Vargas

2015-01-01

Tellurium compounds may be cytotoxic to different cells types. Thus, this work evaluated the effect of diphenyl ditelluride ((PhTe)2), an organotellurium commonly used in organic synthesis, on the morphology of liver, kidney, and lung. Adult mice were acutely (a subcutaneous single dose: 250 μmol/kg) or subchronically (one daily subcutaneous dose: 10 or 50 μmol/kg for 7 and 14 days) exposed to (PhTe)2. Afterwards, the histological analyses of liver, kidney, and lungs were performed. Liver histology revealed that the hepatocytes of mice subchronically exposed to (PhTe)2 presented cytoplasmic vacuolization, hydropic degeneration, and hyperchromatic nuclei. Subchronic exposure to 50 μmol/kg (PhTe)2 also caused hepatic necrosis. Microvesicular and macrovesicular steatosis were identified in liver of mice acutely exposed to (PhTe)2. Acute and subchronic intoxication with (PhTe)2 induced changes on epithelial cells of renal tubules, namely, loss of brush border and cytoplasmatic vacuolization. Atrophy and hypertrophy, cast proteinaceous formation, and acute tubular necrosis were also identified in renal tissue. Mice subchronically exposed to 50 μmol/kg (PhTe)2 developed intra-alveolar edema and alveolar wall congestion in some areas of lungs. Acute exposure to (PhTe)2 did not cause histological changes in lungs. Our data show that (PhTe)2 may be considered a histotoxic agent for liver, kidney, and lung.

Detection of Mouse Cough Based on Sound Monitoring and Respiratory Airflow Waveforms

PubMed Central

Chen, Liyan; Lai, Kefang; Lomask, Joseph Mark; Jiang, Bert; Zhong, Nanshan

2013-01-01

Detection for cough in mice has never yielded clearly audible sounds, so there is still a great deal of debates as to whether mice can cough in response to tussive stimuli. Here we introduce an approach for detection of mouse cough based on sound monitoring and airflow signals. 40 Female BALB/c mice were pretreated with normal saline, codeine, capasazepine or desensitized with capsaicin. Single mouse was put in a plethysmograph, exposed to aerosolized 100 µmol/L capsaicin for 3 min, followed by continuous observation for 3 min. Airflow signals of total 6 min were recorded and analyzed to detect coughs. Simultaneously, mouse cough sounds were sensed by a mini-microphone, monitored manually by an operator. When manual and automatic detection coincided, the cough was positively identified. Sound and sound waveforms were also recorded and filtered for further analysis. Body movements were observed by operator. Manual versus automated counts were compared. Seven types of airflow signals were identified by integrating manual and automated monitoring. Observation of mouse movements and analysis of sound waveforms alone did not produce meaningful data. Mouse cough numbers decreased significantly after all above drugs treatment. The Bland-Altman and consistency analysis between automatic and manual counts was 0.968 and 0.956. The study suggests that the mouse is able to present with cough, which could be detected by sound monitoring and respiratory airflow waveform changes. PMID:23555643

Preflight studies on tolerance of pocket mice to oxygen and heat. I - Physiological studies

NASA Technical Reports Server (NTRS)

Leon, H. A.; Suri, K.; Mctigue, M.; Smith, J.; Cooper, W.; Miquel, J.; Ashley, W. W.; Behnke, A. R., Jr.; Saunders, J. F.

1975-01-01

Tests were carried out on pocket mice to ascertain their tolerance to elevated oxygen pressures alone and to a combination of hyperoxia and heat in excess of that expected during the flight of the mice on Apollo XVII. The mice withstood oxygen partial pressures up to 12 psi at normal room temperature (24 C, 75 F) over a period of 7 days. A few mice previously exposed to increased PO2 died in the course of exposure to an oxygen pressure of 10 psi or 12 psi (517 mm or 620 mm Hg) for 13 d in ambient heat of 32 C (90 F). Supplemental vitamin E and physiological saline loading given prior to exposure had no apparent protective effect. The overall conclusion was that the pocket mice which were to go on Apollo XVII could readily survive the ambient atmosphere to which they would be exposed.

Prevention of psychological stress-induced immune suppression by aged garlic extract.

PubMed

Kyo, E; Uda, N; Ushijima, M; Kasuga, S; Itakura, Y

1999-11-01

We determined the effect of Aged Garlic Extract (AGE) on damage caused to immune function by a psychological stress using a communication box. After four days of a psychological stress, a decrease in spleen weight and spleen cells was observed in the psychological stress-exposed mice as compared normal mice (non-stress). AGE significantly prevented the decreases in spleen weight and cells. Additionally, AGE significantly prevented the reduction of hemolytic plaque-forming-cells in spleen cells and anti-SRBC antibody titer in serum caused by this psychological stress. Moreover, a reduction in NK activities was observed in the psychological stress-exposed mice as compared with normal mice (non-stress), whereas NK activities in the AGE administered mice were almost the same as normal mice (non-stress). These results indicate that psychological stress qualitatively and quantitatively impairs immune function, and that AGE is extremely useful for preventing psychologically-induced damage.

Acute social defeat stress increases the conditioned rewarding effects of cocaine in adult but not in adolescent mice.

PubMed

Montagud-Romero, S; Aguilar, M A; Maldonado, C; Manzanedo, C; Miñarro, J; Rodríguez-Arias, M

2015-08-01

Stressful experiences modify activity in areas of the brain involved in the rewarding effects of psychostimulants. In the present study we evaluated the influence of acute social defeat (ASD) on the conditioned rewarding effects of cocaine in adolescent (PND 29-32) and adult (PND 50-53) male mice in the conditioned place preference (CPP) paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1mg/kg or 25mg/kg of cocaine. The effects of social defeat on corticosterone levels were also evaluated. Adult mice exposed to ASD showed an increase in the conditioned reinforcing effects of cocaine. Only these mice developed cocaine-induced CPP with the subthreshold dose of cocaine, and they needed a higher number of extinction sessions for the 25mg/kg cocaine-induced CPP to be extinguished. In adolescent mice, on the other hand, ASD reduced the conditioned reinforcing effects of cocaine, since CPP was not produced with the lower dose of cocaine and was extinguished faster when they were conditioned with 25mg/kg. Adult mice exposed to social defeat displayed higher levels of corticosterone than their controls and adolescent mice. Our results confirm that the effect of social defeat stress on the acquisition and reinstatement of the CPP induced by cocaine varies depending on the age at which this stress is experienced. Copyright © 2015 Elsevier Inc. All rights reserved.

A novel platelet activating factor receptor antagonist reduces cell infiltration and expression of inflammatory mediators in mice exposed to desiccating conditions after PRK.

PubMed

Esquenazi, Salomon; He, Jiucheng; Li, Na; Bazan, Nicolas G; Esquenazi, Isi; Bazan, Haydee E P

2009-01-01

To study the contribution of a novel PAF receptor antagonist LAU-0901 in the modulation of the increased inflammatory response in mice exposed to dessicating conditions (DE) after PRK. Eighty 13-14 week old female Balb/C mice were used. They were divided into two groups: One group was treated with LAU-0901 topical drops. The other group was treated with vehicle. In each group ten mice served as controls and ten were placed in DE. The other twenty mice underwent bilateral PRK and were divided in two additional groups: ten mice remained under normal conditions (NC) and the other ten were exposed to DE. After 1 week all animals underwent in vivo confocal microscopy, immunostaining and western blotting analysis. Confocal microscopy showed an increased number of reflective structures in the corneal epithelium after PRK and exposure to DE in eyes treated with vehicle as compared to eyes treated with LAU-090). Significant decrease of COX-2 and Arginase I expression and reduced alpha SMA cells was observed after PRK and exposure to DE in eyes treated with LAU-0901. Exposure of mice to a DE after PRK increases the epithelial turnover rate. PAF is involved in the inflammatory cell infiltration and expression of inflammatory cytokines that follow PRK under DE.

Mice exposed to dim light at night exaggerate inflammatory responses to lipopolysaccharide.

PubMed

Fonken, Laura K; Weil, Zachary M; Nelson, Randy J

2013-11-01

The mammalian circadian system regulates many physiological functions including inflammatory responses. Appropriately timed light information is essential for maintaining circadian organization. Over the past ∼120 years, urbanization and the widespread adoption of electric lights have dramatically altered lighting environments. Exposure to light at night (LAN) is pervasive in modern society and disrupts core circadian clock mechanisms. Because microglia are the resident macrophages in the brain and macrophages contain intrinsic circadian clocks, we hypothesized that chronic exposure to LAN would alter microglia cytokine expression and sickness behavior following LPS administration. Exposure to 4 weeks of dim LAN elevated inflammatory responses in mice. Mice exposed to dimly lit, as compared to dark, nights exaggerated changes in body temperature and elevated microglia pro-inflammatory cytokine expression following LPS administration. Furthermore, dLAN mice had a prolonged sickness response following the LPS challenge. Mice exposed to dark or dimly lit nights had comparable sickness behavior directly following the LPS injection; however, dLAN mice showed greater reductions in locomotor activity, increased anorectic behavior, and increased weight loss than mice maintained in dark nights 24h post-LPS injection. Overall, these data suggest that chronic exposure to even very low levels of light pollution may alter inflammatory responses. These results may have important implications for humans and other urban dwelling species that commonly experience nighttime light exposure. Copyright © 2013 Elsevier Inc. All rights reserved.

Suspended animation-like state protects mice from lethal hypoxia.

PubMed

Blackstone, Eric; Roth, Mark B

2007-04-01

Joseph Priestley observed the high burn rate of candles in pure oxygen and wondered if people would "live out too fast" if we were in the same environment. We hypothesize that sulfide, a natural reducer of oxygen that is made in many cell types, acts as a buffer to prevent unrestricted oxygen consumption. To test this, we administered sulfide in the form of hydrogen sulfide (H2S) to mice (Mus musculus). As we have previously shown, H2S decreases the metabolic rate of mice by approximately 90% and induces a suspended animation-like state. Mice cannot survive for longer than 20 min when exposed to 5% oxygen. However, if mice are first put into a suspended animation-like state by a 20-min pretreatment with H2S and then are exposed to low oxygen, they can survive for more than 6.5 h in 5% oxygen with no apparent detrimental effects. In addition, if mice are exposed to a 20-min pretreatment with H2S followed by 1 h at 5% oxygen, they can then survive for several hours at oxygen tensions as low as 3%. We hypothesize that prior exposure to H2S reduces oxygen demand, therefore making it possible for the mice to survive with low oxygen supply. These results suggest that H2S may be useful to prevent damage associated with hypoxia.

RESISTANCE PRODUCED IN MICE BY EXPOSURE TO IRRADIATED SCHISTOSOMA MANSONI CERCARIAE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radke, M.G.; Sadun, E.H.

1963-04-01

Studies were undertaken to determine whether gamma irradiation of cercariae might provide a means of investigating some of the mechanisms involved in the acquired resistance to schistosomiasis. Control mice received 200 nonirradiated cercariae, and other groups received the same number of cercariae that had been exposed to 6 different doses of Co/sup 60/ gamma irradiation varying from 1000--20000 rep. Eight weeks later the worms recovered were counted. Doses of 4000 rep or higher completely inhibited the development of schistosomes. A few stunted and underdeveloped worms were found in some of the mice receiving cercariae irradiated at 2500 and 3000 rep.more » Some adult schistosomes were observed in the groups receiving 1500 and 2000 rep and eggs were found in the liver but not in the stools of some mice. However, all of the mice exposed to cercariae irradiated with 1000 rep had eggs in liver and stools. The worm burden decreased regularly with increasing dosages up to 3000 rep, beyond which no worms were found at necropsy. The decrease in the number of worms mice acquired was linear only when cercariae were exposed from 1000to 2000 rep, however, even beyond such dosages, it followed a straight line when the logarithm of irradiation dose was plotied. Acquired resistance to S. mansoni was observed in mice following a previous exposure to irradiated cercariae. (TCO)« less

Early chronic low-level lead exposure produces glomerular hypertrophy in young C57BL/6J mice☆

PubMed Central

Basgen, John M.; Sobin, Christina

2014-01-01

Early chronic lead exposure continues to pose serious health risks for children, particularly those living in lower socioeconomic environments. This study examined effects on developing glomeruli in young C57BL/6J mice exposed to low (30 ppm), higher (330 ppm) or no lead via dams’ drinking water from birth to sacrifice on post-natal day 28. Low-level lead exposed mice [BLL mean (SD); 3.19 (0.70) μg/dL] had an increase in glomerular volume but no change in podocyte number compared to control mice [0.03 (0.01) μg/dL]. Higher-level lead exposed mice [14.68 (2.74) μg/dL] had no change in either glomerular volume or podocyte number. The increase in glomerular volume was explained by increases in glomerular capillary and mesangial volumes with no change in podocyte volume. Early chronic lead exposure yielding very low blood lead levels alters glomerular development in pre-adolescent animals. PMID:24300173

Time- and dose-dependent effects of total-body ionizing radiation on muscle stem cells

PubMed Central

Masuda, Shinya; Hisamatsu, Tsubasa; Seko, Daiki; Urata, Yoshishige; Goto, Shinji; Li, Tao-Sheng; Ono, Yusuke

2015-01-01

Exposure to high levels of genotoxic stress, such as high-dose ionizing radiation, increases both cancer and noncancer risks. However, it remains debatable whether low-dose ionizing radiation reduces cellular function, or rather induces hormetic health benefits. Here, we investigated the effects of total-body γ-ray radiation on muscle stem cells, called satellite cells. Adult C57BL/6 mice were exposed to γ-radiation at low- to high-dose rates (low, 2 or 10 mGy/day; moderate, 50 mGy/day; high, 250 mGy/day) for 30 days. No hormetic responses in proliferation, differentiation, or self-renewal of satellite cells were observed in low-dose radiation-exposed mice at the acute phase. However, at the chronic phase, population expansion of satellite cell-derived progeny was slightly decreased in mice exposed to low-dose radiation. Taken together, low-dose ionizing irradiation may suppress satellite cell function, rather than induce hormetic health benefits, in skeletal muscle in adult mice. PMID:25869487

Voluntary exercise improves high-fat diet-induced leptin resistance independent of adiposity.

PubMed

Krawczewski Carhuatanta, Kimberly A; Demuro, Giovanna; Tschöp, Matthias H; Pfluger, Paul T; Benoit, Stephen C; Obici, Silvana

2011-07-01

The efficacy of exercise as primary prevention of obesity is the subject of intense investigation. Here, we show that voluntary exercise in a mouse strain susceptible to diet-induced obesity (C57B6J) decreases fat mass and increases energy expenditure. In addition, exercise attenuates obesity in mice fed a high-fat diet (HFD). Using FosB immunoreactivity as a marker of chronic neuronal activation, we found that exercise activates leptin receptor-positive neurons in the ventromedial hypothalamic nucleus, involved in homeostatic control of energy balance. FosB immunoreactivity in the ventromedial hypothalamic nucleus is decreased in sedentary mice exposed to HFD but is increased in exercised mice independent of adiposity. To determine whether the antiobesity effects of voluntary exercise improve central nervous system (CNS) leptin action, we measured the anorectic and weight reducing effects of intracerebroventricular (ICV) leptin in sedentary and exercised mice exposed to HFD (EH), as well as in sedentary mice that have been calorie restricted (SR) to match the fat mass of EH mice. ICV leptin was ineffective in lowering food intake and body weight (BW) in sedentary mice exposed to HFD mice. The anorectic potency of leptin was partially restored in EH and SR groups. However, ICV leptin significantly lowered BW in EH but not SR mice. Thus, exercise leads to the maintenance of a lower BW and leaner composition, as well as to improved CNS leptin action, independent of fat mass. These results support the notion that physical exercise directly influences the responsiveness of the CNS circuits involved in energy homeostasis by allowing the defense of a lowered BW.

Carnosic Acid, a Natural Diterpene, Attenuates Arsenic-Induced Hepatotoxicity via Reducing Oxidative Stress, MAPK Activation, and Apoptotic Cell Death Pathway

PubMed Central

Das, Sonjit; Joardar, Swarnalata; Dua, Tarun K.; Bhattacharjee, Niloy; Khanra, Ritu; Kalita, Jatin; Saha, Achintya; Ray, Supratim

2018-01-01

The present studies have been executed to explore the protective mechanism of carnosic acid (CA) against NaAsO2-induced hepatic injury. CA exhibited a concentration dependent (1–4 μM) increase in cell viability against NaAsO2 (12 μM) in murine hepatocytes. NaAsO2 treatment significantly enhanced the ROS-mediated oxidative stress in the hepatic cells both in in vitro and in vivo systems. Significant activation of MAPK, NF-κB, p53, and intrinsic and extrinsic apoptotic signaling was observed in NaAsO2-exposed hepatic cells. CA could significantly counteract with redox stress and ROS-mediated signaling and thereby attenuated NaAsO2-mediated hepatotoxicity. NaAsO2 (10 mg/kg) treatment caused significant increment in the As bioaccumulation, cytosolic ATP level, DNA fragmentation, and oxidation in the liver of experimental mice (n = 6). The serum biochemical and haematological parameters were significantly altered in the NaAsO2-exposed mice (n = 6). Simultaneous treatment with CA (10 and 20 mg/kg) could significantly reinstate the NaAsO2-mediated toxicological effects in the liver. Molecular docking and dynamics predicted the possible interaction patterns and the stability of interactions between CA and signal proteins. ADME prediction anticipated the drug-likeness characteristics of CA. Hence, there would be an option to employ CA as a new therapeutic agent against As-mediated toxic manifestations in future. PMID:29854073

In vitro and in vivo toxicity of urban and rural particulate matter from California

NASA Astrophysics Data System (ADS)

Mirowsky, Jaime E.; Jin, Lan; Thurston, George; Lighthall, David; Tyner, Tim; Horton, Lori; Galdanes, Karen; Chillrud, Steven; Ross, James; Pinkerton, Kent E.; Chen, Lung Chi; Lippmann, Morton; Gordon, Terry

2015-02-01

Particulate matter (PM) varies in chemical composition and mass concentration based on location, source, and particle size. This study sought to evaluate the in vitro and in vivo toxicity of coarse (PM10-2.5) and fine (PM2.5) PM samples collected at 5 diverse sites within California. Coarse and fine PM samples were collected simultaneously at 2 rural and 3 urban sites within California during the summer. A human pulmonary microvascular endothelial cell line (HPMEC-ST1.6R) was exposed to PM suspensions (50 μg/mL) and analyzed for reactive oxygen species (ROS) after 5 h of treatment. In addition, FVB/N mice were exposed by oropharyngeal aspiration to 50 μg PM, and lavage fluid was collected 24 h post-exposure and analyzed for total protein and %PMNs. Correlations between trace metal concentrations, endotoxin, and biological endpoints were calculated, and the effect of particle size range, locale (urban vs. rural), and location was determined. Absolute principal factor analysis was used to identify pollution sources of PM from elemental tracers of those sources. Ambient PM elicited an ROS and pro-inflammatory-related response in the cell and mouse models, respectively. These responses were dependent on particle size, locale, and location. Trace elements associated with soil and traffic markers were most strongly linked to the adverse effects in vitro and in vivo. Particle size, location, source, and composition of PM collected at 5 locations in California affected the ROS response in human pulmonary endothelial cells and the inflammatory response in mice.

A guanine-ethylthioethyl-glutathione adduct as a major DNA lesion in the skin and in organs of mice exposed to sulfur mustard.

PubMed

Batal, Mohamed; Rebelo-Moreira, Silvestre; Hamon, Nadège; Bayle, Pierre-Alain; Mouret, Stéphane; Cléry-Barraud, Cécile; Boudry, Isabelle; Douki, Thierry

2015-02-17

Sulfur mustard (SM) is an old chemical warfare but it remains a threat to both militaries and civilians. SM mainly targets skin, eyes and lungs and diffuses to internal organs. At the molecular level, SM is able to damage DNA through the formation of monoadducts and biadduct. Glutathione (GSH) is another critical target of SM in cells since it is part of the detoxification mechanism against alkylating agents. In the present work, we investigated whether SM could form covalent bonds simultaneously with a DNA base and the sulfhydryl group of GSH. The expected guanine adduct, S-[2-(N7-guanyl)-ethylthioethyl]-glutathione (N7Gua-ETE-GSH), was synthesized and detected in several tissues of SKH-1 mice exposed to 60mg/kg of SM in the dorsal-lumbar region. N7Gua-ETE-GSH was detected in all organs studied, except in the liver. The tissue exhibiting the highest levels of N7Gua-ETE-GSH was skin, followed by brain, lungs, kidneys and spleen. N7Gua-ETE-GSH was detected in skin, brain and lungs as long as two weeks after exposure. The persistence was less in other organs. The observation of the formation of N7Gua-ETE-GSH in vivo confirms the variety of damages induced by SM in DNA. It also provides another example of the formation of DNA adducts involving glutathione following in vivo exposure to bifunctional alkylating compounds. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury in mice.

PubMed

Savransky, Vladimir; Reinke, Christian; Jun, Jonathan; Bevans-Fonti, Shannon; Nanayakkara, Ashika; Li, Jianguo; Myers, Allen C; Torbenson, Michael S; Polotsky, Vsevolod Y

2009-02-01

Obstructive sleep apnoea (OSA) leads to chronic intermittent hypoxia (CIH) during sleep. Obstructive sleep apnoea has been associated with liver injury. Acetaminophen (APAP; known as paracetamol outside the USA) is one of the most commonly used drugs which has known hepatotoxicity. The goal of the present study was to examine whether CIH increases liver injury, hepatic oxidative stress and inflammation induced by chronic APAP treatment. Adult C57BL/6J mice were exposed to CIH or intermittent air (IA) for 4 weeks. Mice in both groups were treated with intraperitoneal injections of either APAP (200 mg kg(-1)) or normal saline daily. A combination of CIH and APAP caused liver injury, with marked increases in serum alanine aminotransferase, aspartate aminotransferase (AST), gamma-glutamyl transferase and total bilirubin levels, whereas CIH alone induced only elevation in serum AST levels. Acetaminophen alone did not affect serum levels of liver enzymes. Histopathology revealed hepatic necrosis and increased apoptosis in mice exposed to CIH and APAP, whereas the liver remained intact in all other groups. Mice exposed to CIH and APAP exhibited decreased hepatic glutathione in conjunction with a fivefold increase in nitrotyrosine levels, suggesting formation of toxic peroxynitrite in hepatocytes. Acetaminophen or CIH alone had no effect on either glutathione or nitrotyrosine. A combination of CIH and APAP caused marked increases in pro-inflammatory chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, which were not observed in mice exposed to CIH or APAP alone. We conclude that CIH and chronic APAP treatment lead to synergistic liver injury, which may have clinical implications for patients with OSA.

Neurobehavioral changes and alteration of gene expression in the brains of metallothionein-I/II null mice exposed to low levels of mercury vapor during postnatal development.

PubMed

Yoshida, Minoru; Honda, Masako; Watanabe, Chiho; Satoh, Masahiko; Yasutake, Akira

2011-10-01

This study examined the neurobehavioral changes and alteration in gene expression in the brains of metallothionein (MT)-I/II null mice exposed to low-levels of mercury vapor (Hg(0)) during postnatal development. MT-I/II null and wild-type mice were repeatedly exposed to Hg(0) at 0.030 mg/m(3) (range: 0.023-0.043 mg/m(3)), which was similar to the current threshold value (TLV), for 6 hr per day until the 20th day postpartum. The behavioral effects were evaluated with locomotor activity in the open field (OPF), learning ability in the passive avoidance response (PA) and spatial learning ability in the Morris water maze (MM) at 12 weeks of age. Hg(0)-exposed MT-I/II null mice showed a significant decrease in total locomotor activity in females, though learning ability and spatial learning ability were not affected. Immediately after Hg(0) exposure, mercury concentrations in the brain did not exceed 0.5 µg/g in any animals. Hg(0) exposure resulted in significant alterations in gene expression in the brains of both strains using DNA microarray analysis. The number of altered genes in MT-I/II null mice was higher than that in wild-type mice and calcium-calmodulin kinase II (Camk2a) involved in learning and memory in down-regulated genes was detected. These results provide useful information to elucidate the development of behavioral toxicity following low-level exposure to Hg(0).

Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver.

PubMed

Savransky, Vladimir; Bevans, Shannon; Nanayakkara, Ashika; Li, Jianguo; Smith, Philip L; Torbenson, Michael S; Polotsky, Vsevolod Y

2007-10-01

Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P < 0.01) and AST (637 +/- 37 U/l vs. 175 +/- 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1beta, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-alpha; and an increase in alpha1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.

Ajoene restored behavioral patterns and liver glutathione level in morphine treated C57BL6 mice.

PubMed

Yun, Jaesuk; Oliynyk, Sergiy; Lee, Yeonju; Kim, Jieun; Yun, Kyunghwa; Jeon, Raok; Ryu, Jae-Ha; Oh, Seikwan

2017-01-01

Oxidative stress exacerbates drug dependence induced by administration of opiate analgesics such as morphine-induced tolerance and physical dependence associated with the reduction in hepatic glutathione (GSH) level. Ajoene obtained from garlic (Allium sativum L.) has been reported for anti-tumorigenic, anti-oxidative and neuroprotective properties, however, little is known about its effect on morphine-induced dependence. Therefore, this study aimed at the effect of ajoene on physical and/or psychological dependence and liver GSH content in morphine-treated mice. Conditioned place preference (CPP) test and measurement of morphine withdrawal syndrome were performed in C57BL6 mice for behavioral experiments. Thereafter, mice were sacrificed for measurement of serum and liver GSH levels. Ajoene restored CPP and naloxone-precipitated jumping behavior in mice exposed to morphine. Moreover, the reduced level of liver GSH content in morphine treated mice was back to normal after ajoene administration. Taken together, ajoene improved behavioral patterns in mice exposed to morphine suggesting its potential therapeutic benefit against morphine-induced dependence.

Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression

PubMed Central

Saravia, Jordy; You, Dahui; Thevenot, Paul; Lee, Greg I.; Shrestha, Bishwas; Lomnicki, Slawo; Cormier, Stephania A.

2013-01-01

Elevated levels of combustion-derived particulate matter (CDPM) are a risk factor for the development of lung diseases such as asthma. Studies have shown that CDPM exacerbates asthma, inducing acute lung dysfunction and inflammation; however, the impact of CDPM exposure on early immunological responses to allergens remains unclear. To determine the effects of early-life CDPM exposure on allergic asthma development in infants, we exposed infant mice to CDPM and then induced a mouse model of asthma using house dust mite (HDM) allergen. Mice exposed to CDPM+HDM failed to develop a typical asthma phenotype including airway hyperresponsiveness, Th2-inflammation, Muc5ac expression, eosinophilia, and HDM-specific Ig compared to HDM-exposed mice. Although HDM-specific IgE was attenuated, total IgE was two-fold higher in CDPM+HDM mice compared to HDM-mice. We further demonstrate that CDPM exposure during early life induced an immunosuppressive environment in the lung, concurrent with increases in tolerogenic dendritic cells and Tregs, resulting in suppression of Th2 responses. Despite having early immunosuppression, these mice develop severe allergic inflammation when challenged with allergen as adults. These findings demonstrate a mechanism whereby CDPM exposure modulates adaptive immunity, inducing specific-antigen tolerance while amplifying total IgE, and leading to a predisposition to develop asthma upon rechallenge later in life. PMID:24172848

Toxicology and carcinogenesis studies of tetralin (CAS No. 119-64-2) in F344/N rats and B6C3F1 mice (inhalation studies).

PubMed

2011-04-01

Tetralin is used as an industrial solvent primarily for naphthalene, fats, resins, oils, and waxes; as a solvent and stabilizer for shoe polishes and floor waxes; as a solvent for pesticides, rubber, asphalt, and aromatic hydrocarbons (e.g., anthracene); as a dye solvent carrier in the textile industry; as a substitute for turpentine in lacquers, paints, and varnishes; in paint thinners and as a paint remover; in alkali-resistant lacquers for cleaning printing ink from rollers and type; as a constituent of motor fuels and lubricants; for the removal of naphthalene in gas distribution systems; and as an insecticide for clothes moths. Tetralin was nominated by the National Cancer Institute for carcinogenicity and disposition studies because of its structure, high production volume, and high potential for worker and consumer exposure. Male and female F344/N rats and B6C3F1 mice were exposed to tetralin (at least 97% pure) by inhalation for 2 weeks, 3 months, or 2 years; male NCI Black Reiter (NBR) rats were exposed to tetralin by inhalation for 2 weeks. Male NBR rats do not produce 2u-globulin; the NBR rats were included to study the relationship of 2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male (F344/N and NBR) and five female (F344/N) rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 12 exposures. All rats survived to the end of the studies. The final mean body weight of female rats exposed to 120 ppm and mean body weight gains of female rats exposed to 30 ppm or greater were significantly less than those of the chamber controls. Final mean body weights of exposed groups of male NBR rats and mean body weight gains of all exposed groups of male rats were significantly less than those of the chamber controls. Dark-stained urine was observed in all 120 ppm rats. Squinting, weeping, or matted fur around the eyes were noted in the majority of F344/N rats exposed to 120 ppm. The 2u-globulin concentrations in the kidney of male F344/N rats were significantly greater in all exposed groups than in the chamber control group. The absolute kidney weight of 60 ppm females and the relative kidney weights of male F344/N rats exposed to 30 ppm or greater and female rats exposed to 15 ppm or greater were significantly increased. The absolute liver weight of 120 ppm NBR male rats and the relative liver weights of male and female rats exposed to 60 or 120 ppm were significantly increased. In the nose, the incidences of mononuclear cell cellular infiltration were generally significantly increased in all exposed groups of rats, and incidences of olfactory epithelium degeneration and glandular hypertrophy occurred in all male F344/N rats exposed to 120 ppm. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 13 exposures. All mice survived to the end of the study. Mean body weights of male and female mice were similar to those of the chamber controls. Dark-stained urine was observed in most of the exposed mice. The absolute and relative liver weights of 60 and 120 ppm males and 30 and 120 ppm females and the relative liver weights of 60 ppm females were significantly greater than those of the chamber controls. In the nose, the incidences of olfactory epithelium atrophy were significantly increased in 60 and 120 ppm males and females. Glandular dilatation occurred in all 120 ppm females, and glandular hyperplasia occurred in all 120 ppm males and females. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. The same exposure concentrations were given to additional groups of 10 male and 10 female clinical pathology study rats for up to 6 weeks and five male renal toxicity rats for 2 weeks. All rats survived to the end of the study. During the first 4 weeks of exposure, dark-stained urine was observed in the catch pans of rats exposed to 30, 60, or 120 ppm. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. Tetralin increased urine aspartate aminotransferase and urine lactate dehydrogenase activities (males and females) and glucose/creatinine ratio (males), suggestive of renal injury. The absolute kidney weights of 60 and 120 ppm females and the relative kidney weights of males and females exposed to 15 ppm or greater were significantly greater than those of the chamber controls. Concentrations of 2u-globulin in the kidney of exposed male rats were generally greater than those of the chamber controls at all time points and greater at 6 and 14 weeks than at 2 weeks. There were significantly increased incidences of olfactory epithelium necrosis in rats exposed to 30 ppm or greater and of olfactory epithelium regeneration in 60 and 120 ppm rats. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of 120 ppm males were significantly less than those of the chamber controls. Dark-stained urine was observed in the catch pans of mice exposed to 30, 60, or 120 ppm during the first month of the study. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. The relative liver weights of 120 ppm males and 30 ppm or greater females were significantly greater than those of the chamber controls. Incidences of olfactory epithelium metaplasia in 60 and 120 ppm males and females, respiratory epithelium hyaline droplet accumulation in 120 ppm males and 60 and 120 ppm females, cytoplasmic eosinophilic granules within the transitional epithelium lining the urinary bladder in all exposed groups of males and females, and ovarian atrophy and uterine atrophy in 60 and 120 ppm females were significantly increased. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female rats were exposed to the same concentrations for 12 months. Survival of all exposed groups of rats was similar to that of the chamber controls. Mean body weights of 120 ppm females were 6% less than those of the chamber controls after week 29. Dark-stained urine was observed in all exposed groups of rats. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females. In the standard evaluation of the kidney, there were slightly increased incidences of cortical renal tubule adenoma in male rats. In the combined analysis of single and step sections, the incidence of cortical renal tubule adenoma was significantly increased in the 120 ppm group. In the combined analysis, there was also a significantly increased incidence of renal tubule hyperplasia in the 120 ppm group. In 120 ppm males in the standard evaluation, the severity of chronic nephropathy was increased and the incidence of transitional epithelial hyperplasia in the renal pelvis was significantly increased. Three hepatocellular adenomas occurred in 120 ppm females, and one hepatocellular carcinoma each was observed in the 60 and 120 ppm groups. The incidences of uterine stromal polyp and endometrium hyperplasia were significantly increased in 120 ppm females. Incidences of interstitial cell adenoma and germinal epithelium atrophy of the testis in 30 and 120 ppm males were significantly greater than those in the chamber controls. The incidences of olfactory epithelium degeneration, metaplasia, basal cell hyperplasia, suppurative inflammation, and mineralization (except 30 ppm females) in the nose were significantly increased in all exposed groups of rats. The incidences of glandular dilatation were significantly increased in 120 ppm males and all exposed groups of females. The incidences of respiratory epithelium chronic inflammation were significantly increased in males exposed to 60 or 120 ppm and all exposed groups of females. The incidences of lens cataract in 120 ppm females were significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female mice were exposed to the same concentrations for 12 months. Survival of 60 and 120 ppm female mice was significantly greater than that of the chamber controls. The mean body weights of all exposed groups of male and female mice were similar to those of the chamber controls by the end of the study. Dark-stained urine was observed in all exposed groups of male mice and in females exposed to 60 or 120 ppm. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females. The incidence of hemangiosarcoma of the spleen was increased in 120 ppm females and exceeded the historical control range for inhalation studies. The incidences of olfactory epithelium atrophy, respiratory metaplasia, glandular hyperplasia, and suppurative inflammation in exposed groups of mice were significantly greater than those in the chamber controls. Transitional epithelium cytoplasmic eosinophilic granules were present in the urinary bladder of all exposed mice. (ABSTRACT TRUNCATED)

Preflight studies on tolerance of pocket mice to oxygen and heat. IV - Observations on the brain

NASA Technical Reports Server (NTRS)

Bailey, O. T.; Ordy, J. M.; Haymaker, W.

1975-01-01

Experiments designed to ascertain the effects of oxygen at 8, 10, and 12 psi partial pressure on the brains of pocket mice (Perognathus longimembris) were carried out at room temperature (24 C, 75 F) and at 32 C (90 F). The animals exposed to 8-12 psi at 32 C had been in earlier KO2 oxygen tests. Five animals exposed either to 10 or 12 psi (517 mm or 620 mm Hg) O2 partial pressure at 32 C died during the course of the tests, possibly as a consequence of injury sustained by the earlier O2 partial pressure testing. Autopsy was not carried out. In the other 36 exposed animals, no pathological changes were observed in the brain. It is thus highly probable that oxygen pressures at the hyperbaric levels to which the pocket mice would be exposed during the Apollo XVII mission would not result in any lesions in the brain.

Effects of lead on the male mouse as investigated by in vitro fertilization and blastocyst culture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johansson, L.; Sjoeblom, P.; Wide, M.

1987-02-01

Long-term exposure of male mice to inorganic lead (lead chloride, 1 g/liter) in the drinking water reduces their fertility. The cause of this reduction, expressed as a decrease in the number of mated females showing inplantations, was investigated, using an in vivo fertilization method. It was found that spermatozoa from lead-exposed males had a significantly lower ability to fertilize mouse eggs than those from unexposed males. Preimplantation embryos, isolated from uterine horns of mice mated with lead-exposed males. Preimplantation embryos, isolated from uterine horns of mice mated with lead-exposed males, were examined. No morphologically abnormal embryos were found. However, whenmore » cultured in vitro over the implantation period, blastocysts of the group mated with lead-exposed males showed an increased frequency of delayed hatching from the zona pellucida or an inability to hatch. Among blastocysts from this group a decreased frequency of inner cell mass development was also found.« less

TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema.

PubMed

An, Chang Hyeok; Wang, Xiao Mei; Lam, Hilaire C; Ifedigbo, Emeka; Washko, George R; Ryter, Stefan W; Choi, Augustine M K

2012-11-01

Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ (Tlr4-mutated) mice and C57BL/10ScNJ (Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS.

TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema

PubMed Central

An, Chang Hyeok; Wang, Xiao Mei; Lam, Hilaire C.; Ifedigbo, Emeka; Washko, George R.; Ryter, Stefan W.

2012-01-01

Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ (Tlr4-mutated) mice and C57BL/10ScNJ (Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS. PMID:22983353

MORTALITY IN DIOXIN-EXPOSED MICE INFECTED WITH INFLUENZA: MITOCHONDRIAL TOXICITY (REYES-LIKE SYNDROME) VERSUS ENHANCED INFLAMMATION AS THE MODE OF ACTION

EPA Science Inventory

Abstract
Increased mortality following influenza A infection was reported in B6C3F1 mice exposed to a low (0.01 g/kg) dose of dioxin. However, mortality was not associated with increased viral load and antibody titers to the virus were not decreased at doses of TCDD 10 g/k...

DEVELOPMENTAL TOXICITY OF METHANOL: PATHOGENESIS IN CD-1 AND C57BL/6J MICE EXPOSED IN WHOLE EMBRYO CULTURE

EPA Science Inventory

BACKGROUND: Methanol causes axial skeleton and craniofacial defects in both CD-1 and C57BL/6J mice during gastrulation, but C57BL/6J embryos are more severely affected. We evaluated methanol-induced pathogenesis in CD-1 and C57BL/6J embryos exposed during gastrulation in whole em...

Down-regulation of vascular PPAR-γ contributes to endothelial dysfunction in high-fat diet-induced obese mice exposed to chronic intermittent hypoxia.

PubMed

Zhang, Yanan; Zhang, Chunlian; Li, Haiou; Hou, Jingdong

2017-10-14

Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is associated with endothelial dysfunction. The prevalence of OSA is linked to an epidemic of obesity. CIH has recently been reported to cause endothelial dysfunction in diet-induced obese animals by exaggerating oxidative stress and inflammation, but the underlying mechanism remains unclear. PPAR-γ, a ligand-inducible transcription factor that exerts anti-oxidant and anti-inflammatory effects, is down-regulated in the peripheral tissues in diet-induce obesity. We tested the hypothesis that down-regulation of vascular PPAR-γ in diet-induced obesity enhances inflammation and oxidative stress in response to CIH, resulting in endothelial dysfunction. Male C57BL/6 mice were fed either a high-fat diet (HFD) or a low-fat diet (LFD) and simultaneously exposed to CIH or intermittent air for 6 weeks. An additional HFD group received a combination of CIH and PPAR-γ agonist pioglitazone for 6 weeks. Endothelial-dependent vasodilation was impaired only in HFD group exposed to CIH, compared with other groups, but was restored by concomitant pioglitazone treatment. Molecular studies revealed that vascular PPAR-γ expression and activity were reduced in HFD groups, compared with LFD groups, but were reversed by pioglitazone treatment. In addition, CIH elevated vascular expression of NADPH oxidase 4 and dihydroethidium fluorescence, and increased expression of proinflammatory cytokines TNF-α and IL-1β in both LFD and HFD groups, but these increases was significantly greater in HFD group, along with decreased vascular eNOS activity. Pioglitazone treatment of HFD group prevented CIH-induced changes in above molecular markers. The results suggest that HFD-induced obesity down-regulates vascular PPAR-γ, which results in exaggerated oxidative stress and inflammation in response to CIH, contributing to endothelial dysfunction. This finding may provide new insights into the mechanisms by which OSA induces endothelial dysfunction and other cardiovascular disease in patients with obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of Proton and Combined Proton and (56)Fe Radiation on the Hippocampus.

PubMed

Raber, Jacob; Allen, Antiño R; Sharma, Sourabh; Allen, Barrett; Rosi, Susanna; Olsen, Reid H J; Davis, Matthew J; Eiwaz, Massarra; Fike, John R; Nelson, Gregory A

2016-01-01

The space radiation environment contains protons and (56)Fe, which could pose a significant hazard to space flight crews during and after missions. The space environment involves complex radiation exposures, thus, the effects of a dose of protons might be modulated by a dose of heavy-ion radiation. The brain, and particularly the hippocampus, may be susceptible to space radiation-induced changes. In this study, we first determined the dose-response effect of proton radiation (150 MeV) on hippocampus-dependent cognition 1 and 3 months after exposure. Based on those results, we subsequently exposed mice to protons alone (150 MeV, 0.1 Gy), (56)Fe alone (600 MeV/n, 0.5 Gy) or combined proton and (56)Fe radiations (protons first) with the two exposures separated by 24 h. At one month postirradiation, all animal groups showed novel object recognition. However, at three months postirradiation, mice exposed to either protons or combined proton and (56)Fe radiations showed impaired novel object recognition, which was not observed in mice irradiated with (56)Fe alone. The mechanisms in these impairments might involve inflammation. In mice irradiated with protons alone or (56)Fe alone three months earlier, there was a negative correlation between a measure of novel object recognition and the number of newly born activated microglia in the dentate gyrus. Next, cytokine and chemokine levels were assessed in the hippocampus. At one month after exposure the levels of IL-12 were higher in mice exposed to combined radiations compared with sham-irradiated mice, while the levels of IFN-γ were lower in mice exposed to (56)Fe radiation alone or combined radiations. In addition, IL-4 levels were lower in (56)Fe-irradiated mice compared with proton-irradiated mice and TNF-α levels were lower in proton-irradiated mice than in mice receiving combined radiations. At three months after exposure, macrophage-derived chemokine (MDC) and eotaxin levels were lower in mice receiving combined radiations. The levels of MDC and eotaxin correlated and the levels of MDC, but not eotaxin, correlated with the percentage of newly born activated microglia in the blades of the dentate gyrus. Finally, hippocampal IL-6 levels were higher in mice receiving combined radiations compared with mice receiving (56)Fe radiation alone. These data demonstrate the sensitivity of novel object recognition for detecting cognitive injury three months after exposure to proton radiation alone, and combined exposure to proton and (56)Fe radiations, and that newly-born activated microglia and inflammation might be involved in this injury.

RADIOPROTECTIVE PROPERTIES OF A SYNTHETIC PREPARATION OF OXYTOCIN (SYNTOCINON SANDOZ) IN THE CASE OF MICE (in French)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bacq, Z.M.; Beaumariage, M.L.

1960-05-01

Type-C/sub 57/ black mice are exposed to 650 r, after receiving injections of varying amounts of Syntocinon (oxytocin preparation). All uninjected control mice died within 16 days, but up to 85% of the mice protected by Syntocinon survived. (T.F.H.)

Hyperbaric pressure effects measured by growth of a transplantable tumor in the C3H/HeN mouse.

PubMed

Herndon, B L; Lally, J J

1984-09-01

Both hypobaric exposure at 0.5 atmospheres absolute (ATA) and hyperbaric pressure exposure at 3.5-8 ATA slowed transplantable tumor growth. These experiments detailed the hyperbaric pressure exposure. C3H/HeN-MTV+ mice, bearing the 16/C transplantable murine mammary adenocarcinoma and exposed to 18 days' treatment by a hyperbaric chamber at 3.5-8 ATA, had tumor weights that averaged 50-75% less than the tumor weights in mice caged at ambient ("sea level") pressure. A series of experiments was run to investigate this response to hyperbaric pressure exposure. After mice underwent continuous exposure to 3.5-8 ATA normoxic (normal oxygen) hyperbaric pressure with use of either argon or nitrogen inert gas, which began 3 days after tumor inoculation, tumors were removed at about 3 weeks' growth from these pressure-exposed mice and measured for growth by weighing. Final tumor weight in pressure-exposed experimental mice was significantly less than tumor weight in paired groups of tumor-bearing controls that received no hyperbaric pressure. Tumor weight was inversely related to pressure "dose," although the small pressure range produced an effect at all pressures used. The number of compression-decompression cycles to which the animals were subjected, however, was related positively to tumor weight at necropsy. Continued tumor growth in mice subjected to frequent pressure change (in conjunction with pressure exposure that otherwise limited tumor size) was unexplained by these experiments. The greatest difference between tumor weights in controls and pressure-exposed animals was seen with 2 weeks' continuous pressure exposure. A limited profile of blood tests was performed, and these reflected only minor, expected change in the pressure-exposed experimental animals. The data at hand did not suggest a mechanism by which chronic normoxic hyperbaric pressure limited tumor size.

Green tea diet decreases PCB 126-induced oxidative stress in mice by up-regulating antioxidant enzymes.

PubMed

Newsome, Bradley J; Petriello, Michael C; Han, Sung Gu; Murphy, Margaret O; Eske, Katryn E; Sunkara, Manjula; Morris, Andrew J; Hennig, Bernhard

2014-02-01

Superfund chemicals such as polychlorinated biphenyls pose a serious human health risk due to their environmental persistence and link to multiple diseases. Selective bioactive food components such as flavonoids have been shown to ameliorate PCB toxicity, but primarily in an in vitro setting. Here, we show that mice fed a green tea-enriched diet and subsequently exposed to environmentally relevant doses of coplanar PCB exhibit decreased overall oxidative stress primarily due to the up-regulation of a battery of antioxidant enzymes. C57BL/6 mice were fed a low-fat diet supplemented with green tea extract (GTE) for 12 weeks and exposed to 5 μmol PCB 126/kg mouse weight (1.63 mg/kg-day) on weeks 10, 11 and 12 (total body burden: 4.9 mg/kg). F2-isoprostane and its metabolites, established markers of in vivo oxidative stress, measured in plasma via HPLC-MS/MS exhibited fivefold decreased levels in mice supplemented with GTE and subsequently exposed to PCB compared to animals on a control diet exposed to PCB. Livers were collected and harvested for both messenger RNA and protein analyses, and it was determined that many genes transcriptionally controlled by aryl hydrocarbon receptor and nuclear factor (erythroid-derived 2)-like 2 proteins were up-regulated in PCB-exposed mice fed the green tea-supplemented diet. An increased induction of genes such as SOD1, GSR, NQO1 and GST, key antioxidant enzymes, in these mice (green tea plus PCB) may explain the observed decrease in overall oxidative stress. A diet supplemented with green tea allows for an efficient antioxidant response in the presence of PCB 126, which supports the emerging paradigm that healthful nutrition may be able to bolster and buffer a physiological system against the toxicities of environmental pollutants. Copyright © 2014 Elsevier Inc. All rights reserved.

Prenatal metformin exposure in mice programs the metabolic phenotype of the offspring during a high fat diet at adulthood.

PubMed

Salomäki, Henriikka; Vähätalo, Laura H; Laurila, Kirsti; Jäppinen, Norma T; Penttinen, Anna-Maija; Ailanen, Liisa; Ilyasizadeh, Juan; Pesonen, Ullamari; Koulu, Markku

2013-01-01

The antidiabetic drug metformin is currently used prior and during pregnancy for polycystic ovary syndrome, as well as during gestational diabetes mellitus. We investigated the effects of prenatal metformin exposure on the metabolic phenotype of the offspring during adulthood in mice. Metformin (300 mg/kg) or vehicle was administered orally to dams on regular diet from the embryonic day E0.5 to E17.5. Gene expression profiles in liver and brain were analysed from 4-day old offspring by microarray. Body weight development and several metabolic parameters of offspring were monitored both during regular diet (RD-phase) and high fat diet (HFD-phase). At the end of the study, two doses of metformin or vehicle were given acutely to mice at the age of 20 weeks, and Insig-1 and GLUT4 mRNA expressions in liver and fat tissue were analysed using qRT-PCR. Metformin exposed fetuses were lighter at E18.5. There was no effect of metformin on the maternal body weight development or food intake. Metformin exposed offspring gained more body weight and mesenteric fat during the HFD-phase. The male offspring also had impaired glucose tolerance and elevated fasting glucose during the HFD-phase. Moreover, the expression of GLUT4 mRNA was down-regulated in epididymal fat in male offspring prenatally exposed to metformin. Based on the microarray and subsequent qRT-PCR analyses, the expression of Insig-1 was changed in the liver of neonatal mice exposed to metformin prenatally. Furthermore, metformin up-regulated the expression of Insig-1 later in development. Gene set enrichment analysis based on preliminary microarray data identified several differentially enriched pathways both in control and metformin exposed mice. The present study shows that prenatal metformin exposure causes long-term programming effects on the metabolic phenotype during high fat diet in mice. This should be taken into consideration when using metformin as a therapeutic agent during pregnancy.

JP-8 jet fuel exposure suppresses the immune response to viral infections.

PubMed

Harris, D T; Sakiestewa, D; Titone, D; He, X; Hyde, J; Witten, M

2008-05-01

The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has reported that JP-8 exposure is immunosuppressive. Exposure of mice to JP-8 for 1A h/day resulted in immediate secretion of two immunosuppressive agents, namely, interleukin-10 and prostaglandin E2. Thus, it was of interest to determine if jet fuel exposure might alter the immune response to infectious agents. The Hong Kong influenza model was used for these studies. Mice were exposed to 1000A mg/m(3) JP-8 (1A h/day) for 7A days before influenza viral infection. Animals were infected intra-nasally with virus and followed in terms of overall survival as well as immune responses. All surviving animals were killed 14A days after viral infection. In the present study, JP-8 exposure increased the severity of the viral infection by suppressing the anti-viral immune responses. That is, exposure of mice to JP-8 for 1A h/day for 7A days before infection resulted in decreased immune cell viability after exposure and infection, a greater than fourfold decrease in immune proliferative responses to mitogens, as well as an overall loss of CD3(+), CD4(+), and CD8(+) T cells from the lymph nodes, but not the spleens, of infected animals. These changes resulted in decreased survival of the exposed and infected mice, with only 33% of animals surviving as compared with 50% of mice infected but not jet fuel-exposed (and 100% of mice exposed only to JP-8). Thus, short-term, low-concentration JP-8 jet fuel exposures have significant suppressive effects on the immune system which can result in increased severity of viral infections.

Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice

PubMed Central

Stephenson, Erin J.; Ragauskas, Alyse; Jaligama, Sridhar; Redd, JeAnna R.; Parvathareddy, Jyothi; Peloquin, Matthew J.; Saravia, Jordy; Han, Joan C.; Cormier, Stephania A.

2016-01-01

We have investigated the effects of in utero exposure to environmentally persistent free radicals (EPFRs) on growth, metabolism, energy utilization, and skeletal muscle mitochondria in a mouse model of diet-induced obesity. Pregnant mice were treated with laboratory-generated, combustion-derived particular matter (MCP230). The adult offspring were placed on a high-fat diet for 12 wk, after which we observed a 9.8% increase in their body weight. The increase in body size observed in the MCP230-exposed mice was not associated with increases in food intake but was associated with a reduction in physical activity and lower energy expenditure. The reduced energy expenditure in mice indirectly exposed to MCP230 was associated with reductions in skeletal muscle mitochondrial DNA copy number, lower mRNA levels of electron transport genes, and reduced citrate synthase activity. Upregulation of key genes involved in ameliorating oxidative stress was also observed in the muscle of MCP230-exposed mice. These findings suggest that gestational exposure to MCP230 leads to a reduction in energy expenditure at least in part through alterations to mitochondrial metabolism in the skeletal muscle. PMID:27117006

Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice.

PubMed

Stephenson, Erin J; Ragauskas, Alyse; Jaligama, Sridhar; Redd, JeAnna R; Parvathareddy, Jyothi; Peloquin, Matthew J; Saravia, Jordy; Han, Joan C; Cormier, Stephania A; Bridges, Dave

2016-06-01

We have investigated the effects of in utero exposure to environmentally persistent free radicals (EPFRs) on growth, metabolism, energy utilization, and skeletal muscle mitochondria in a mouse model of diet-induced obesity. Pregnant mice were treated with laboratory-generated, combustion-derived particular matter (MCP230). The adult offspring were placed on a high-fat diet for 12 wk, after which we observed a 9.8% increase in their body weight. The increase in body size observed in the MCP230-exposed mice was not associated with increases in food intake but was associated with a reduction in physical activity and lower energy expenditure. The reduced energy expenditure in mice indirectly exposed to MCP230 was associated with reductions in skeletal muscle mitochondrial DNA copy number, lower mRNA levels of electron transport genes, and reduced citrate synthase activity. Upregulation of key genes involved in ameliorating oxidative stress was also observed in the muscle of MCP230-exposed mice. These findings suggest that gestational exposure to MCP230 leads to a reduction in energy expenditure at least in part through alterations to mitochondrial metabolism in the skeletal muscle. Copyright © 2016 the American Physiological Society.

Exposure to experimental preeclampsia in mice enhances the vascular response to future injury.

PubMed

Pruthi, Dafina; Khankin, Eliyahu V; Blanton, Robert M; Aronovitz, Mark; Burke, Suzanne D; McCurley, Amy; Karumanchi, S Ananth; Jaffe, Iris Z

2015-04-01

Cardiovascular disease (CVD) remains the leading killer of women in developed nations. One sex-specific risk factor is preeclampsia, a syndrome of hypertension and proteinuria that complicates 5% of pregnancies. Although preeclampsia resolves after delivery, exposed women are at increased long-term risk of premature CVD and mortality. Pre-existing CVD risk factors are associated with increased risk of developing preeclampsia but whether preeclampsia merely uncovers risk or contributes directly to future CVD remains a critical unanswered question. A mouse preeclampsia model was used to test the hypothesis that preeclampsia causes an enhanced vascular response to future vessel injury. A preeclampsia-like state was induced in pregnant CD1 mice by overexpressing soluble fms-like tyrosine kinase-1, a circulating antiangiogenic protein that induces hypertension and glomerular disease resembling human preeclampsia. Two months postpartum, soluble fms-like tyrosine kinase-1 levels and blood pressure normalized and cardiac size and function by echocardiography and renal histology were indistinguishable in preeclampsia-exposed compared with control mice. Mice were then challenged with unilateral carotid injury. Preeclampsia-exposed mice had significantly enhanced vascular remodeling with increased vascular smooth muscle cell proliferation (180% increase; P<0.01) and vessel fibrosis (216% increase; P<0.001) compared with control pregnancy. In the contralateral uninjured vessel, there was no difference in remodeling after exposure to preeclampsia. These data support a new model in which vessels exposed to preeclampsia retain a persistently enhanced vascular response to injury despite resolution of preeclampsia after delivery. This new paradigm may contribute to the substantially increased risk of CVD in woman exposed to preeclampsia. © 2015 American Heart Association, Inc.

Early life exposure to a high fat diet promotes long-term changes in dietary preferences and central reward signaling.

PubMed

Teegarden, S L; Scott, A N; Bale, T L

2009-09-15

Overweight and obesity in the United States continues to grow at epidemic rates in large part due to the overconsumption of calorically-dense palatable foods. Identification of factors influencing long-term macronutrient preferences may elucidate points of prevention and behavioral modification. In our current study, we examined the adult macronutrient preferences of mice acutely exposed to a high fat diet during the third postnatal week. We hypothesized that the consumption of a high fat diet during early life would alter the programming of central pathways important in adult dietary preferences. As adults, the early-exposed mice displayed a significant preference for a diet high in fat compared to controls. This effect was not due to diet familiarity as mice exposed to a novel high carbohydrate diet during this same early period failed to show differences in macronutrient preferences as adults. The increased intake of high fat diet in early exposed mice was specific to dietary preferences as no changes were detected for total caloric intake or caloric efficiency. Mechanistically, mice exposed to a high fat diet during early life exhibited significant alterations in biochemical markers of dopamine signaling in the nucleus accumbens, including changes in levels of phospho-dopamine and cyclic AMP-regulated phosphoprotein, molecular weight 32 kDa (DARPP-32) threonine-75, DeltaFosB, and cyclin-dependent kinase 5. These results support our hypothesis that even brief early life exposure to calorically-dense palatable diets alters long-term programming of central mechanisms important in dietary preferences and reward. These changes may underlie the passive overconsumption of high fat foods contributing to the increasing body mass in the western world.

Source of biomass cooking fuel determines pulmonary response to household air pollution.

PubMed

Sussan, Thomas E; Ingole, Vijendra; Kim, Jung-Hyun; McCormick, Sarah; Negherbon, Jesse; Fallica, Jonathan; Akulian, Jason; Yarmus, Lonny; Feller-Kopman, David; Wills-Karp, Marsha; Horton, Maureen R; Breysse, Patrick N; Agrawal, Anurag; Juvekar, Sanjay; Salvi, Sundeep; Biswal, Shyam

2014-03-01

Approximately 3 billion people-half the worldwide population-are exposed to extremely high concentrations of household air pollution due to the burning of biomass fuels on inefficient cookstoves, accounting for 4 million annual deaths globally. Yet, our understanding of the pulmonary responses to household air pollution exposure and the underlying molecular and cellular events is limited. The two most prevalent biomass fuels in India are wood and cow dung, and typical 24-hour mean particulate matter (PM) concentrations in homes that use these fuels are 300 to 5,000 μg/m(3). We dissected the mechanisms of pulmonary responses in mice after acute or subchronic exposure to wood or cow dung PM collected from rural Indian homes during biomass cooking. Acute exposures resulted in robust proinflammatory cytokine production, neutrophilic inflammation, airway resistance, and hyperresponsiveness, all of which were significantly higher in mice exposed to PM from cow dung. On the contrary, subchronic exposures induced eosinophilic inflammation, PM-specific antibody responses, and alveolar destruction that was highest in wood PM-exposed mice. To understand the molecular pathways that trigger biomass PM-induced inflammation, we exposed Toll-like receptor (TLR)2-, TLR3-, TLR4-, TLR5-, and IL-1R-deficient mice to PM and found that IL-1R, TLR4, and TLR2 are the predominant receptors that elicit inflammatory responses via MyD88 in mice exposed to wood or cow dung PM. In conclusion, this study demonstrates that subchronic exposure to PM collected from households burning biomass fuel elicits a persistent pulmonary inflammation largely through activation of TLR and IL-1R pathways, which could increase the risk for chronic respiratory diseases.

JP-8 jet fuel exposure potentiates tumor development in two experimental model systems.

PubMed

Harris, D T; Sakiestewa, D; Titone, D; He, X; Hyde, J; Witten, M

2007-11-01

The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has reported that JP-8 exposure is immunosuppressive. Exposure of mice to JP-8 for 1 h/day resulted in immediate secretion of two immunosuppressive agents; namely, interleukin-10 (IL-10) and prostaglandin E2 (PGE2). Thus, it was of interest to determine if jet fuel exposure might promote tumor growth and metastasis. The syngeneic B16 tumor model was used for these studies. Animals were injected intravenously with tumor cells, and lung colonies were enumerated. Animals were also examined for metastatic spread of the tumor. Mice were either exposed to 1000 mg/m3 JP-8 (1 h/ day) for 7 days before tumor injection or were exposed to JP-8 at the time of tumor injection. All animals were killed 17 days after tumor injection. In the present study, JP8 exposure potentiated the growth and metastases of B16 tumors in an animal model. Exposure of mice to JP-8 for 1 h/day before tumor induction resulted in an approximately 8.7-fold increase in tumors, whereas those mice exposed to JP8 at the time of tumor induction had a 5.6-fold increase in tumor numbers. Thus, low concentration JP-8 jet fuel exposures have significant immune suppressive effects on the immune system that can result in increased tumor formation and metastases. We have now extended the observations to an experimental subcutaneous tumor model. JP8 exposure at the time of tumor induction in this model did not affect the growth of the tumor. However, JP8-exposed, tumor-bearing animals died at an accelerated rate as compared with air-exposed, tumor-bearing mice.

Toxicology and carcinogenesis studies of sodium nitrite (CAS NO. 7632-00-0) in F344/N rats and B6C3F1 mice (drinking water studies).

PubMed

2001-05-01

Sodium nitrite is used as a color fixative and preservative in meats and fish. It is also used in manufacturing diazo dyes, nitroso compounds, and other organic compounds; in dyeing and printing textile fabrics and bleaching fibers; in photography; as a laboratory reagent and a corrosion inhibitor; in metal coatings for phosphatizing and detinning; and in the manufacture of rubber chemicals. Sodium nitrite also has been used in human and veterinary medicine as a vasodilator, a bronchial dilator, an intestinal relaxant, and an antidote for cyanide poisoning. Sodium nitrite was nominated by the FDA for toxicity and carcinogenesis studies based on its widespread use in foods. Male and female F344/N rats and B6C3F1 mice were exposed to sodium nitrite (99% pure) in drinking water for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow, and mouse peripheral blood. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 375, 750, 1500, 3,000, or 5000 ppm sodium nitrite (equivalent to average daily doses of approximately 30, 55, 115, 200, or 310 mg sodium nitrite/kg body weight to males and 40, 80, 130, 225, or 345 mg/kg to females) in drinking water for 14 weeks. Clinical pathology study groups of 15 male and 15 female rats were exposed to the same concentrations for 70 or 71 days. One female exposed to 3000 ppm died before the end of the study. Body weights of males exposed to 3000 or 5000 ppm and females exposed to 5000 ppm were significantly less than those of the controls. Water consumption by 5000 ppm males and 3000 and 5000 ppm females was less than that by the controls at weeks 2 and 14. Clinical findings related to sodium nitrite exposure included brown discoloration in the eyes and cyanosis of the mouth, tongue, ears, and feet of males exposed to 3000 or 5000 ppm and of females exposed to 1500 ppm or greater. Reticulocyte counts were increased in males and females exposed to 3000 or 5000 ppm. The erythron was decreased on day 19 but increased by week 14 in males and females exposed to 5000 ppm. Methemoglobin concentrations were elevated in almost all exposed groups throughout the 14 week study; a no-observed-adverse-effect level was not achieved. The relative kidney and spleen weights of males and females exposed to 3000 or 5000 ppm were significantly greater than those of the controls. Sperm motility in 1500 and 5000 ppm males was significantly decreased. Increased erythropoietic activity in the bone marrow of exposed males and females was observed. The incidences of squamous cell hyperplasia of the forestomach in 5000 ppm males and females were significantly increased. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 375, 750, 1500, 3000, or 5000 ppm sodium nitrite (equivalent to average daily doses of approximately 90, 190, 345, 750, or 990 mg/kg to males and 120, 240, 445, 840, or 1230 mg/kg to females) in drinking water for 14 weeks. Body weights of males exposed to 5000 ppm were significantly less than those of the controls. Water consumption by males exposed to 1500 ppm or greater was slightly less than that by the controls at week 13. Relative spleen weights of 3000 and 5000 ppm males and absolute and relative heart, kidney, liver, and spleen weights of females exposed to 3000 or 5000 ppm were greater than those of the control groups. Sperm motility was decreased in 5000 ppm males, and the estrous cycles of 1500 and 5000 ppm females were significantly longer than in the controls. There were increased incidences of squamous cell hyperplasia of the forestomach in 5000 ppm males and females, extramedullary hematopoiesis of the spleen in 3000 and 5000 ppm males and 1500 ppm or greater females, and degeneration of the testis in 3000 and 5000 ppm males. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 750, 1500, or 3000 ppm sodium nitrite (equivalent to average daily doses of approximately 35, 70, or 130 mg/kg to males and 40, 8d 40, 80, or 150 mg/kg to females) in drinking water for 2 years. For toxicokinetic studies of plasma nitrite and blood methemoglobin, 10 male and 10 female special study rats were exposed to the same concentrations for 12 months. Survival of exposed groups was similar to that of the controls. Mean body weights of males and females exposed to 3000 ppm were less than those of the controls throughout the study. Water consumption by males and females exposed to 3000 ppm was less than that by the controls throughout the study, and that by the other exposed groups was generally less after week 14. The incidences of hyperplasia of the forestomach epithelium in males and females exposed to 3000 ppm were significantly greater than those in the control groups. The incidence of fibroadenoma of the mam mary gland was significantly increased in females exposed to 1500 ppm, and the incidences of multiple fibroadenoma were increased in 750 ppm and 1500 ppm females; however, these neoplasms occur with a high background incidence, and no increase was seen in the 3000 ppm group. The incidences of mononuclear cell leukemia were significantly decreased in males and females exposed to 1500 or 3000 ppm. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 750, 1500, or 3000 ppm sodium nitrite (equivalent to average daily doses of approximately 60, 120, or 220 mg/kg to males and 45, 90, or 165 mg/kg to females) in drinking water for 2 years. Survival of exposed groups was similar to that of the controls; mean body weights of 3000 ppm females were less than those of the controls throughout the study. Exposed groups generally consumed less water than the control groups. The incidences of squamous cell papilloma or carcinoma (combined) in the forestomach of female mice occurred with a positive trend. The incidence of hyperplasia of the glandular stomach epithelium was significantly greater in 3000 ppm males than in the controls. Sodium nitrite was mutagenic in Salmonella typhimurium strain TA100, with and without Aroclor 1254-induced hamster and rat liver S9 enzymes; no mutagenicity was observed in strain TA98. Results of acute bone marrow micronucleus tests with sodium nitrite in male rats and mice by intraperitoneal injection were negative. In addition, a peripheral blood micronucleus assay conducted with mice from the 14-week study gave negative results. Under the conditions of this 2-year drinking water study, there was no evidence of carcinogenic activity of sodium nitrite in male or female F344/N rats exposed to 750, 1500, or 3000 ppm. There was no evidence of carcinogenic activity of sodium nitrite in male B6C3F1 mice exposed to 750, 1500, or 3000 ppm. There was equivocal evidence of carcinogenic activity of sodium nitrite in female B6C3F1 mice based on the positive trend in the incidences of squamous cell papilloma or carcinoma (combined) of the forestomach. Exposure to sodium nitrite in drinking water resulted in increased incidences of epithelial hyperplasia in the forestomach of male and female rats and in the glandular stomach of male mice. Decreased incidences of mononuclear cell leukemia occurred in male and female rats.

Targeting L-Selectin to Improve Neurologic and Urologic Function After Spinal Cord Injury

DTIC Science & Technology

2014-10-01

doses of DFA, male C57BL/6 mice were subjected to a 2g weight dropped 7.5 cm onto the exposed spinal cord at the thoracic 9 vertebral level (mild...detect the absence of L-selectin on leukocytes 1 day post-SCI. Male C57BL/6 mice were subjected to a 2g weight dropped 7.5 cm onto the exposed spinal...subjected to a 2g weight dropped 7.5 cm onto the exposed spinal cord at the thoracic 9 vertebral level. DFA (40mg/kg) or vehicle was administered

Low frequency noise and whole-body vibration cause increased levels of sister chromatid exchange in splenocytes of exposed mice.

PubMed

Silva, M J; Dias, A; Barreta, A; Nogueira, P J; Castelo-Branco, N A A; Boavida, M G

2002-01-01

Chronic exposure to low frequency (LF) noise and whole-body vibration (WBV) induces both physiological and psychological alterations in man. Recently, we have shown that long-term occupational exposure to LF noise and WBV produces genotoxic effects in man expressed as an increase in sister chromatid exchange (SCE) levels in lymphocytes. The objectives of the present study were to investigate whether the observed effect could be reproduced in a murine model and, if so, which of the agents, LF noise alone or in combination with WBV, would be instrumental in the SCE induction. SCEs were analyzed in spleen lymphocytes of mice exposed to LF noise alone and in combination with WBV for 300 and 600 hr. An effect at the cell cycle kinetics level was also investigated. The results revealed significant increases in the mean SCE number per cell and in the proportion of cells with high frequency of SCEs (HFCs) in lymphocytes of mice submitted to combined noise and WBV over controls. No significant differences were found between single noise-exposed and control mice. A cell cycle delay was observed exclusively in the noise and WBV exposure groups. In conclusion, we demonstrated that, as in exposed workers, prolonged exposure to the combination of LF noise and WBV determines an increase in SCE level in mice while LF noise alone is not effective in SCE induction. Copyright 2002 Wiley-Liss, Inc.

Pivotal role of IL-6 in the hyperinflammatory responses to subacute ozone in adiponectin-deficient mice

PubMed Central

Kim, Hye Y.; Mathews, Joel A.; Verbout, Norah G.; Williams, Alison S.; Wurmbrand, Allison P.; Ninin, Fernanda M. C.; Neto, Felippe L.; Benedito, Leandro A. P.; Hug, Christopher; Umetsu, Dale T.; Shore, Stephanie A.

2013-01-01

Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24–72 h), neutrophilic inflammation and IL-6 are augmented in adiponectin-deficient (Adipo−/−) mice. The IL-17/granulocyte colony-stimulating factor (G-CSF) axis is required for this increased neutrophilia. We hypothesized that elevated IL-6 in Adipo−/− mice contributes to their augmented responses to ozone via effects on IL-17A expression. Therefore, we generated mice deficient in both adiponectin and IL-6 (Adipo−/−/IL-6−/−) and exposed them to ozone or air. In ozone-exposed mice, bronchoalveolar lavage (BAL) neutrophils, IL-6, and G-CSF, and pulmonary Il17a mRNA expression were greater in Adipo−/− vs. wild-type mice, but reduced in Adipo−/−/IL-6−/− vs. Adipo−/− mice. IL-17A+ F4/80+ cells and IL-17A+ γδ T cells were also reduced in Adipo−/−/IL-6−/− vs. Adipo−/− mice exposed to ozone. Only BAL neutrophils were reduced in IL-6−/− vs. wild-type mice. In wild-type mice, IL-6 was expressed in Gr-1+F4/80−CD11c− cells, whereas in Adipo−/− mice F4/80+CD11c+ cells also expressed IL-6, suggesting that IL-6 is regulated by adiponectin in these alveolar macrophages. Transcriptomic analysis identified serum amyloid A3 (Saa3), which promotes IL-17A expression, as the gene most differentially augmented by ozone in Adipo−/− vs. wild-type mice. After ozone, Saa3 mRNA expression was markedly greater in Adipo−/− vs. wild-type mice but reduced in Adipo−/−/IL-6−/− vs. Adipo−/− mice. In conclusion, our data support a pivotal role of IL-6 in the hyperinflammatory condition observed in Adipo−/− mice after ozone exposure and suggest that this role of IL-6 involves its ability to induce Saa3, IL-17A, and G-CSF. PMID:24381131

Reciprocal Translocation in Somatic and Germ Cells of Mice Chronically Exposed by Inhalation to Ethylene Oxide: Implication for Risk Assessment

EPA Science Inventory

Groups of male B6C3F1 mice were exposed by inhalation to 0, 25, 50, 100 or 200 ppm EO for up to 48 weeks (6 hours/day, 5 days/week). Animals were sacrificed at 6, 12, 24, and 48 weeks after the startt of the exposure for analyses of reciprocal translocations in peripheral blood ...

Thirty days of spaceflight does not alter murine calvariae structure despite increased Sost expression.

PubMed

Macaulay, Timothy R; Siamwala, Jamila H; Hargens, Alan R; Macias, Brandon R

2017-12-01

Previously our laboratory documented increases in calvaria bone volume and thickness in mice exposed to 15 days of spaceflight aboard the NASA Shuttle mission STS-131. However, the tissues were not processed for gene expression studies to determine what bone formation pathways might contribute to these structural adaptations. Therefore, this study was designed to investigate both the structural and molecular changes in mice calvariae after a longer duration of spaceflight. The primary purpose was to determine the calvaria bone volume and thickness of mice exposed to 30 days of spaceflight using micro-computed tomography for comparison with our previous findings. Because sclerostin, the secreted glycoprotein of the Sost gene, is a potent inhibitor of bone formation, our second aim was to quantify Sost mRNA expression using quantitative PCR. Calvariae were obtained from six mice aboard the Russian 30-day Bion-M1 biosatellite and seven ground controls. In mice exposed to 30 days of spaceflight, calvaria bone structure was not significantly different from that of their controls (bone volume was about 5% lower in spaceflight mice, p = 0.534). However, Sost mRNA expression was 16-fold (16.4 ± 0.4, p < 0.001) greater in the spaceflight group than that in the ground control group. Therefore, bone formation may have been suppressed in mice exposed to 30 days of spaceflight. Genetic responsiveness (e.g. sex or strain of animals) or in-flight environmental conditions other than microgravity (e.g. pCO 2 levels) may have elicited different bone adaptations in STS-131 and Bion-M1 mice. Although structural results were not significant, this study provides biochemical evidence that calvaria mechanotransduction pathways may be altered during spaceflight, which could reflect vascular and interstitial fluid adaptations in non-weight bearing bones. Future studies are warranted to elucidate the processes that mediate these effects and the factors responsible for discordant calvaria bone adaptations between STS-131 and Bion-M1 mice.

In Vivo Dual Fluorescence Imaging to Detect Joint Destruction.

PubMed

Cho, Hongsik; Bhatti, Fazal-Ur-Rehman; Lee, Sangmin; Brand, David D; Yi, Ae-Kyung; Hasty, Karen A

2016-10-01

Diagnosis of cartilage damage in early stages of arthritis is vital to impede the progression of disease. In this regard, considerable progress has been made in near-infrared fluorescence (NIRF) optical imaging technique. Arthritis can develop due to various mechanisms but one of the main contributors is the production of matrix metalloproteinases (MMPs), enzymes that can degrade components of the extracellular matrix. Especially, MMP-1 and MMP-13 have main roles in rheumatoid arthritis and osteoarthritis because they enhance collagen degradation in the process of arthritis. We present here a novel NIRF imaging strategy that can be used to determine the activity of MMPs and cartilage damage simultaneously by detection of exposed type II collagen in cartilage tissue. In this study, retro-orbital injection of mixed fluorescent dyes, MMPSense 750 FAST (MMP750) dye and Alexa Fluor 680 conjugated monoclonal mouse antibody immune-reactive to type II collagen, was administered in the arthritic mice. Both dyes were detected with different intensity according to degree of joint destruction in the animal. Thus, our dual fluorescence imaging method can be used to detect cartilage damage as well as MMP activity simultaneously in early stage arthritis. © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Characteristics of Vibration that Alter Cardiovascular Parameters in Mice

PubMed Central

Li, Yao; Rabey, Karyne N; Schmitt, Daniel; Norton, John N; Reynolds, Randall P

2015-01-01

We hypothesized that short-term exposure of mice to vibration within a frequency range thought to be near the resonant frequency range of mouse tissue and at an acceleration of 0 to 1 m/s2 would alter heart rate (HR) and mean arterial pressure (MAP). We used radiotelemetry to evaluate the cardiovascular response to vibration in C57BL/6 and CD1 male mice exposed to vertical vibration of various frequencies and accelerations. MAP was consistently increased above baseline values at an acceleration near 1 m/s2 and a frequency of 90 Hz in both strains, and HR was increased also in C57BL/6 mice. In addition, MAP increased at 80 Hz in individual mice of both strains. When both strains were analyzed together, mean MAP and HR were increased at 90 Hz at 1 m/s2, and HR was increased at 80 Hz at 1 m/s2. No consistent change in MAP or HR occurred when mice were exposed to frequencies below 80 Hz or above 90 Hz. The increase in MAP and HR occurred only when the mice had conscious awareness of the vibration, given that these changes did not occur when anesthetized mice were exposed to vibration. Tested vibration acceleration levels lower than 0.75 m/s2 did not increase MAP or HR at 80 or 90 Hz, suggesting that a relatively high level of vibration is necessary to increase these parameters. These data are important to establish the harmful frequencies and accelerations of environmental vibration that should be minimized or avoided in mouse facilities. PMID:26224436

Age and exposure to arsenic alter base excision repair transcript levels in mice.

PubMed

Osmond, Megan J; Kunz, Bernard A; Snow, Elizabeth T

2010-09-01

Arsenic (As) induces DNA-damaging reactive oxygen species. Most oxidative DNA damage is countered by base excision repair (BER), the capacity for which may be reduced in older animals. We examined whether age and consumption of As in lactational milk or drinking water influences BER gene transcript levels in mice. Lactating mothers and 24-week-old mice were exposed (24 h or 2 weeks) to As (2 or 50 p.p.m.) in drinking water. Lung tissue was harvested from adults, neonates (initially 1 week old) feeding from lactating mothers and untreated animals 1-26 weeks old. Transcripts encoding BER proteins were quantified. BER transcript levels decreased precipitously with age in untreated mice but increased in neonates whose mothers were exposed to 50 p.p.m. As for 24 h or 2 weeks. Treatment of 24-week-old mice with 2 or 50 p.p.m. As for 2 weeks decreased all transcript levels measured. Exposure to As attenuated the age-related transcript level decline for only one BER gene. We conclude that aging is associated with a rapid reduction of BER transcript levels in mice, which may contribute to decreased BER activity in older animals. Levels of As that can alter gene expression are transmitted to neonatal mice in lactational milk produced by mothers drinking water containing As, raising concerns about breastfeeding in countries having As-contaminated groundwater. Reduction of BER transcript levels in 24-week-old mice exposed to As for 2 weeks suggests As may potentiate sensitivity to itself in older animals.

Plasticity of lifelong calorie-restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age.

PubMed

Rusli, Fenni; Boekschoten, Mark V; Borelli, Vincenzo; Sun, Chen; Lute, Carolien; Menke, Aswin L; van den Heuvel, Joost; Salvioli, Stefano; Franceschi, Claudio; Müller, Michael; Steegenga, Wilma T

2018-04-01

Calorie restriction (CR) is a dietary regimen that supports healthy aging. In this study, we investigated the systemic and liver-specific responses caused by a diet switch to a medium-fat (MF) diet in 24-month-old lifelong, CR-exposed mice. This study aimed to increase the knowledge base on dietary alterations of gerontological relevance. Nine-week-old C57BL/6J mice were exposed either to a control, CR, or MF diet. At the age of 24 months, a subset of mice of the CR group was transferred to ad libitumMF feeding (CR-MF). The mice were sacrificed at the age of 28 months, and then, biochemical and molecular analyses were performed. Our results showed that, despite the long-term exposure to the CR regimen, mice in the CR-MF group displayed hyperphagia, rapid weight gain, and hepatic steatosis. However, no hepatic fibrosis/injury or alteration in CR-improved survival was observed in the diet switch group. The liver transcriptomic profile of CR-MF mice largely shifted to a profile similar to the MF-fed animals but leaving ~22% of the 1,578 differentially regulated genes between the CR and MF diet groups comparable with the expression of the lifelong CR group. Therefore, although the diet switch was performed at an old age, the CR-MF-exposed mice showed plasticity in coping with the challenge of a MF diet without developing severe liver pathologies. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Mitigative Effects of a Combination of Multiple Pharmaceutical Drugs on the Survival of Mice Exposed to Lethal Ionizing Radiation.

PubMed

Hirouchi, Tokuhisa; Ito, Koichi; Nakano, Manabu; Monzen, Satoru; Yoshino, Hironori; Chiba, Mitsuru; Hazawa, Masaharu; Nakano, Akira; Ishikawa, Junya; Yamaguchi, Masaru; Tanaka, Kimio; Kashiwakura, Ikuo

2015-01-01

It is important to establish an easy-to-use therapeutic protocol for the emergency medical care of patients involved in radiation accidents to reduce the radiation-related casualties. The present study aimed to establish an optimum therapeutic protocol using currently approved pharmaceutical drugs to increase the survival of victims exposed to lethal radiation. Different combinations of four drugs-recombinant human erythropoietin (EPO), granulocyte-colony stimulating factor (G-CSF), c-mpl receptor agonist romiplostim (RP) and nandrolone decanoate (ND)-were administered to mice within 2 h after exposure to a lethal 7 Gy dose of γ-irradiation. On day 30 after irradiation, the condition of the mice was analyzed using various hematological parameters, such as the number of peripheral blood cells, bone marrow cells, hematopoietic progenitor cells and the expression of cell surface antigens. Approximately 10% of the untreated irradiated control mice survived for 21 days, but all of the control mice died by day 30. The combined administration of G-CSF, EPO and RP for five days immediately after irradiation led to a complete survival of the irradiated mice until day 30. However, the treatment with G-CSF, EPO and RP with ND led to only 75% survival at day 30. The hematological analyses showed that the numbers of almost all of hematopoietic cells in the surviving mice treated with effective medications recovered to the levels of non-irradiated mice. The present findings show that the combination of G-CSF, EPO and RP may be a useful countermeasure for victims exposed to accidental lethal irradiation.

Dim light at night increases depressive-like responses in male C3H/HeNHsd mice.

PubMed

Fonken, Laura K; Nelson, Randy J

2013-04-15

Daily patterns of light exposure have become increasingly variable since the widespread adoption of electrical lighting during the 20th century. Seasonal fluctuations in light exposure, shift-work, and transmeridian travel are all associated with alterations in mood. These studies implicate fluctuations in environmental lighting in the development of depressive disorders. Here we argue that exposure to light at night (LAN) may be causally linked to depression. Male C3H/HeNHsd mice, which produce nocturnal melatonin, were housed in either a standard light/dark (LD) cycle or exposed to nightly dim (5 lux) LAN (dLAN). After four weeks in lighting conditions mice underwent behavioral testing and hippocampal tissue was collected at the termination of the study for qPCR. Here were report that mice exposed to dLAN increase depressive-like responses in both a sucrose anhedonia and forced swim test. In contrast to findings in diurnal grass rats, dLAN mice perform comparably to mice housed under dark nights in a hippocampus-dependent learning and memory task. TNFα and IL1β gene expression do not differ between groups, demonstrating that changes in these pro-inflammatory cytokines do not mediate dLAN induced depressive-like responses in mice. BDNF expression is reduced in the hippocampus of mice exposed to dLAN. These results indicate that low levels of LAN can alter mood in mice. This study along with previous work implicates LAN as a potential factor contributing to depression. Further understanding of the mechanisms through which LAN contributes to changes in mood is important for characterizing and treating depressive disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Circular swimming in mice after exposure to a high magnetic field.

PubMed

Houpt, Thomas A; Houpt, Charles E

2010-06-16

There is increasing evidence that exposure to high magnetic fields of 4T and above perturbs the vestibular system of rodents and humans. Performance in a swim test is a sensitive test of vestibular function. In order to determine the effect of magnet field exposure on swimming in mice, mice were exposed for 30 min within a 14.1T superconducting magnet and then tested at different times after exposure in a 2-min swim test. As previously observed in open field tests, mice swam in tight counter-clockwise circles when tested immediately after magnet exposure. The counter-clockwise orientation persisted throughout the 2-min swim test. The tendency to circle was transient, because no significant circling was observed when mice were tested at 3 min or later after magnet exposure. However, mice did show a decrease in total distance swum when tested between 3 and 40 min after magnet exposure. The decrease in swimming distance was accompanied by a pronounced postural change involving a counter-clockwise twist of the pelvis and hindlimbs that was particularly severe in the first 15s of the swim test. Finally, no persistent difference from sham-exposed mice was seen in the swimming of magnet-exposed mice when tested 60 min, 24h, or 96 h after magnet exposure. This suggests that there is no long-lasting effect of magnet exposure on the ability of mice to orient or swim. The transient deficits in swimming and posture seen shortly after magnet exposure are consistent with an acute perturbation of the vestibular system by the high magnetic field. (c) 2010 Elsevier Inc. All rights reserved.

Expression of the water channel protein, aquaporin-4, in mouse brains exposed to mobile telephone radiofrequency fields.

PubMed

Finnie, John W; Blumbergs, Peter C; Cai, Zhao; Manavis, Jim

2009-01-01

To determine whether exposure to mobile telephone radiofrequency (RF) fields, either acutely or long-term, produces up-regulation of the water channel protein, aquaporin-4 (AQP-4). Using a purpose-designed exposure system at 900 MHz, mice were given a single, far-field whole body exposure at a specific absorption rate of 4 W/kg for 60 minutes or a similar exposure on 5 successive days/week for 104 weeks. Control mice were sham-exposed or freely mobile in a cage to control for any stress caused by restraint in the exposure module. A positive control group was given a clostridial toxin known to cause microvascular endothelial injury, severe vasogenic oedema and upregulation of AQP-4. Brains were perfusion fixed with 4% paraformaldehyde, coronal sections cut from six levels, and immunostained for the principal water channel protein in brain, AQP-4. There was no increase in AQP-4 expression in brains exposed to mobile phone microwaves compared to control (sham exposed and freely moving caged mice) brains after short or protracted exposure, while AQP-4 was substantially upregulated in the brains of mice given the clostridial toxin. Brains exposed to mobile telephone RF fields for a short (60 minutes) or long (2 years) duration did not show any immunohistochemically detectable up-regulation of the water channel protein, AQP-4, suggesting that there was no significant increase in blood-brain barrier permeability

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

PubMed Central

Mi, Guiyun; Gao, Yunyun; Liu, Shuai; Ye, Enmao; Li, Yanyan; Jin, Xiao; Yang, Hongju; Yang, Zheng

2016-01-01

ABSTRACT The cuprizone (CPZ) model has been widely used for the studies of de-and remyelination. The CPZ-exposed mice show oligodendrocyte precursor cells (OPCs) increase and mature oligodendrocytes decrease, suggesting an imbalance between proliferation and differentiation of OPCs. In the first experiment of this study, we examined the expression of cell cycle related genes in brains of mice following CPZ administration for 5 weeks by means of microarray assay. In addition, we performed a double labeling of BrdU and Ki-67 to calculate cell cycle exit index in the mice. Our results showed that CPZ administration up-regulated the expression of 16 cell cycle related genes, but down-regulated the expression of only one in the prefrontal cortex (PFC) of mice compared to control group. The treatment inhibited potential precursor cells exit from cell cycle. In the second experiment, we evaluated effects of a CDK inhibitor flavopiridol (FLA) on CPZ-induced neuropathological changes and spatial working memory impairment in mice.FLA treatment for one week effectively attenuated the CPZ-induced increases in NG2 positive cells, microglia and astrocytes, alleviated the concurrent mature oligodendrocyte loss and myelin breakdown, and improved spatial working memory deficit in the CPZ-exposed mice. These results suggest that CPZ-induced neuropathological changes involve in dysregulation of cell cycle related genes. The therapeutic effects of FLA on CPZ-exposed mice may be related to its ability of cell cycle inhibition. PMID:27580304

Role of cytochrome P450 2E1 in protein nitration and ubiquitin-mediated degradation during acetaminophen toxicity.

PubMed

Abdelmegeed, Mohamed A; Moon, Kwan-Hoon; Chen, Chi; Gonzalez, Frank J; Song, Byoung-Joon

2010-01-01

It is well established that following a toxic dose of acetaminophen (APAP), nitrotyrosine protein adducts (3-NT), a hallmark of peroxynitrite production, were colocalized with necrotic hepatic centrilobular regions where cytochrome P450 2E1 (CYP2E1) is highly expressed, suggesting that 3-NT formation may be essential in APAP-mediated toxicity. This study was aimed at investigating the relationship between CYP2E1 and nitration (3-NT formation) followed by ubiquitin-mediated degradation of proteins in wild-type and Cyp2e1-null mice exposed to APAP (200 and 400mg/kg) for 4 and 24h. Markedly increased centrilobular liver necrosis and 3-NT formation were only observed in APAP-exposed wild-type mice in a dose- and time-dependent manner, confirming an important role for CYP2E1 in APAP biotransformation and toxicity. However, the pattern of 3-NT protein adducts, not accompanied by concurrent activation of nitric oxide synthase (NOS), was similar to that of protein ubiquitination. Immunoblot analysis further revealed that immunoprecipitated nitrated proteins were ubiquitinated in APAP-exposed wild-type mice, confirming the fact that nitrated proteins are more susceptible than the native proteins for ubiquitin-dependent degradation, resulting in shorter half-lives. For instance, cytosolic superoxide dismutase (SOD1) levels were clearly decreased and immunoprecipitated SOD1 was nitrated and ubiquitinated, likely leading to its accelerated degradation in APAP-exposed wild-type mice. These data suggest that CYP2E1 appears to play a key role in 3-NT formation, protein degradation, and liver damage, which is independent of NOS, and that decreased levels of many proteins in the wild-type mice (compared with Cyp2e1-null mice) likely contribute to APAP-related toxicity.

UV-blocking spectacle lens protects against UV-induced decline of visual performance.

PubMed

Liou, Jyh-Cheng; Teng, Mei-Ching; Tsai, Yun-Shan; Lin, En-Chieh; Chen, Bo-Yie

2015-01-01

Excessive exposure to sunlight may be a risk factor for ocular diseases and reduced visual performance. This study was designed to examine the ability of an ultraviolet (UV)-blocking spectacle lens to prevent visual acuity decline and ocular surface disorders in a mouse model of UVB-induced photokeratitis. Mice were divided into 4 groups (10 mice per group): (1) a blank control group (no exposure to UV radiation), (2) a UVB/no lens group (mice exposed to UVB rays, but without lens protection), (3) a UVB/UV400 group (mice exposed to UVB rays and protected using the CR-39™ spectacle lens [UV400 coating]), and (4) a UVB/photochromic group (mice exposed to UVB rays and protected using the CR-39™ spectacle lens [photochromic coating]). We investigated UVB-induced changes in visual acuity and in corneal smoothness, opacity, and lissamine green staining. We also evaluated the correlation between visual acuity decline and changes to the corneal surface parameters. Tissue sections were prepared and stained immunohistochemically to evaluate the structural integrity of the cornea and conjunctiva. In blank controls, the cornea remained undamaged, whereas in UVB-exposed mice, the corneal surface was disrupted; this disruption significantly correlated with a concomitant decline in visual acuity. Both the UVB/UV400 and UVB/photochromic groups had sharper visual acuity and a healthier corneal surface than the UVB/no lens group. Eyes in both protected groups also showed better corneal and conjunctival structural integrity than unprotected eyes. Furthermore, there were fewer apoptotic cells and less polymorphonuclear leukocyte infiltration in corneas protected by the spectacle lenses. The model established herein reliably determines the protective effect of UV-blocking ophthalmic biomaterials, because the in vivo protection against UV-induced ocular damage and visual acuity decline was easily defined.

Ethylene Oxide in Blood of Ethylene-Exposed B6C3F1 Mice, Fischer 344 Rats, and Humans

PubMed Central

Filser, Johannes Georg; Erbach, Eva; Faller, Thomas; Kreuzer, Paul Erich; Li, Qiang

2013-01-01

The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans). Both the compounds were determined by gas chromatography. At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (µmol × h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations ≤ 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET. PMID:24068676

The MAP kinase JNK2 mediates cigarette smoke-induced arterial thrombosis.

PubMed

Breitenstein, Alexander; Stämpfli, Simon F; Reiner, Martin F; Shi, Yi; Keller, Stephan; Akhmedov, Alexander; Schaub Clerigué, Ariane; Spescha, Remo D; Beer, Hans-Jürg; Lüscher, Thomas F; Tanner, Felix C; Camici, Giovanni G

2017-01-05

Despite public awareness of its deleterious effects, smoking remains a major cause of death. Indeed, it is a risk factor for atherothrombotic complications and in line with this, the introduction of smoking ban in public areas reduced smoking-associated cardiovascular complications. Nonetheless, smoking remains a major concern, and molecular mechanisms by which it causes cardiovascular disease are not known. Peripheral blood monocytes from healthy smokers displayed increased JNK2 and tissue factor (TF) gene expression compared to non-smokers (n=15, p<0.05). Similarly, human aortic endothelial cells exposed to cigarette smoke total particulate matter (CS-TPM) revealed increased TF expression mediated by JNK2 (n=4; p<0.05). Wild-type and JNK2 -/- mice were exposed to cigarette smoke for two weeks after which arterial thrombosis was investigated. Wild-type mice exposed to smoke displayed reduced time to thrombotic arterial occlusion (n=8; p<0.05) and increased tissue factor activity (n=7; p<0.05) as compared to wild-type controls (n=6), while JNK2 -/- mice exposed to smoke maintained an unaltered thrombotic potential (n=8; p=NS) and tissue factor activity (n=8) comparable to that of JNK2 -/- and wild-type controls (n=6; p=NS). Smoking caused an increased production of reactive oxygen species (ROS) in wild-type but not in JNK2 -/- mice (n=7; p<0.05 for wild-type mice and n=5-6; p=NS for JNK2 -/- mice). In conclusion, the MAP kinase JNK2 mediates cigarette smoke-induced TF activation, arterial thrombosis and ROS production. These results underscore a major role of JNK2 in smoke-mediated thrombus formation and may offer an attractive target to prevent smoke-related thrombosis in those subjects which do not manage quitting.

Rapid desensitization induces internalization of antigen-specific IgE on mouse mast cells.

PubMed

Oka, Tatsuya; Rios, Eon J; Tsai, Mindy; Kalesnikoff, Janet; Galli, Stephen J

2013-10-01

Rapid desensitization transiently prevents severe allergic reactions, allowing administration of life-saving therapies in previously sensitized patients. However, the mechanisms underlying successful rapid desensitization are not fully understood. We sought to investigate whether the mast cell (MC) is an important target of rapid desensitization in mice sensitized to exhibit IgE-dependent passive systemic anaphylaxis in vivo and to investigate the antigen specificity and underlying mechanisms of rapid desensitization in our mouse model. C57BL/6 mice (in vivo) or primary isolated C57BL/6 mouse peritoneal mast cells (PMCs; in vitro) were passively sensitized with antigen-specific anti-2,4-dinitrophenyl IgE, anti-ovalbumin IgE, or both. MCs were exposed over a short period of time to increasing amounts of antigen (2,4-dinitrophenyl-human serum albumin or ovalbumin) in the presence of extracellular calcium in vitro or by means of intravenous administration to sensitized mice in vivo before challenging the mice with or exposing the PMCs to optimal amounts of specific or irrelevant antigen. Rapidly exposing mice or PMCs to progressively increasing amounts of specific antigen inhibited the development of antigen-induced hypothermia in sensitized mice in vivo and inhibited antigen-induced PMC degranulation and prostaglandin D2 synthesis in vitro. Such MC hyporesponsiveness was induced antigen-specifically and was associated with a significant reduction in antigen-specific IgE levels on MC surfaces. Rapidly exposing MCs to progressively increasing amounts of antigen can both enhance the internalization of antigen-specific IgE on the MC surface and also desensitize these cells in an antigen-specific manner in vivo and in vitro. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Rapid desensitization induces internalization of antigen-specific IgE on mouse mast cells

PubMed Central

Oka, Tatsuya; Rios, Eon J.; Tsai, Mindy; Kalesnikoff, Janet; Galli, Stephen J.

2013-01-01

Background Rapid desensitization transiently prevents severe allergic reactions, allowing administration of life-saving therapies in previously sensitized patients. However, the mechanisms underlying successful rapid desensitization are not fully understood. Objectives We sought to investigate whether the mast cell (MC) is an important target of rapid desensitization in mice sensitized to exhibit IgE-dependent passive systemic anaphylaxis in vivo and to investigate the antigen specificity and underlying mechanisms of rapid desensitization in our mouse model. Methods C57BL/6 mice (in vivo) or primary isolated C57BL/6 mouse peritoneal mast cells (PMCs; in vitro) were passively sensitized with antigen-specific anti–2,4-dinitrophenyl IgE, anti-ovalbumin IgE, or both. MCs were exposed over a short period of time to increasing amounts of antigen (2,4-dinitrophenyl–human serum albumin or ovalbumin) in the presence of extracellular calcium in vitro or by means of intravenous administration to sensitized mice in vivo before challenging the mice with or exposing the PMCs to optimal amounts of specific or irrelevant antigen. Results Rapidly exposing mice or PMCs to progressively increasing amounts of specific antigen inhibited the development of antigen-induced hypothermia in sensitized mice in vivo and inhibited antigen-induced PMC degranulation and prostaglandin D2 synthesis in vitro. Such MC hyporesponsiveness was induced antigen-specifically and was associated with a significant reduction in antigen-specific IgE levels on MC surfaces. Conclusions Rapidly exposing MCs to progressively increasing amounts of antigen can both enhance the internalization of antigen-specific IgE on the MC surface and also desensitize these cells in an antigen-specific manner in vivo and in vitro. PMID:23810240

Hyperoxic exposure of immature mice increases the inflammatory response to subsequent rhinovirus infection: Association with danger signals

PubMed Central

Cui, Tracy X.; Maheshwer, Bhargavi; Hong, Jun Y.; Goldsmith, Adam M.; Bentley, J. Kelley; Popova, Antonia P.

2016-01-01

Infants with a history of prematurity and bronchopulmonary dysplasia (BPD) have a high risk of asthma and viral-induced exacerbations later in life. We hypothesized that hyperoxic exposure, a predisposing factor to BPD, modulates the innate immune response, producing an exaggerated pro-inflammatory reaction to viral infection. Two-to-3 day-old C57BL/6J mice were exposed to air or 75% oxygen for 14 days. Mice were infected intranasally with rhinovirus (RV) immediately after O2 exposure. Lung mRNA and protein expression, histology, dendritic cells (DCs) and airways responsiveness were assessed 1-12 days after infection. Tracheal aspirates from premature human infants were collected for mRNA detection. Hyperoxia increased lung IL-12 expression which persisted up to 12 days post-exposure. Hyperoxia-exposed RV-infected mice showed further increases in IL-12 and increased expression of IFN-γ, TNF-α, CCL2, CCL3 and CCL4, as well as increased airway inflammation and responsiveness. In RV-infected, air-exposed mice the response was not significant. Induced IL-12 expression in hyperoxia-exposed, RV-infected mice was associated with increased IL-12-producing CD103+ lung DCs. Hyperoxia also increased expression of Clec9a, a CD103+ DC-specific damaged cell-recognition molecule. Hyperoxia increased levels of ATP metabolites and expression of adenosine receptor A1, further evidence of cell damage and related signaling. In human preterm infants, tracheal aspirate Clec9a expression positively correlated with the level of prematurity. Hyperoxic exposure increases the activation of CD103+, Clec9a+ DCs, leading to increased inflammation and airway hyperresponsiveness upon RV infection. In premature infants, danger signal-induced DC activation may promote pro-inflammatory airway responses, thereby increasing respiratory morbidity. PMID:27183577

The growth and development of Schistosoma mansoni in mice exposed to sublethal doses of radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aitken, R.; Wilson, R.A.

1989-12-01

The maturation of Schistosoma mansoni was studied in mice exposed to various sublethal doses of radiation. Although the treatment of mice with 500 rads of radiation prior to infection did not alter parasite maturation, doses in excess of 500 rads led to a reduction in worm burden. This could not be attributed to a delay in the arrival of parasites in the hepatic portal system. Worms developing in mice treated with 800 rads commenced egg-laying about 1 wk later than worms in intact mice, and the rate of egg deposition appeared to be lower in irradiated hosts. The data demonstratemore » that exposure of C57BL/6 mice to doses of radiation in excess of 500 rads impairs their ability to carry infections of S. mansoni. The findings do not support the hypothesis that primary worm burdens in the mouse are controlled by a host immune response.« less

Methyl isobutyl ketone-induced hepatocellular carcinogenesis in B6C3F1 mice: A constitutive androstane receptor (CAR)-mediated mode of action.

PubMed

Hughes, B J; Thomas, J; Lynch, A M; Borghoff, S J; Green, S; Mensing, T; Sarang, S S; LeBaron, M J

2016-11-01

In a National Toxicology Program (NTP) chronic inhalation study with methyl isobutyl ketone (MIBK), increases in hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were observed in male and female B6C3F 1 mice at 1800 ppm. A DNA reactive Mode-of-Action (MOA) for this liver tumor response is not supported by the evidence as MIBK and its major metabolites lack genotoxicity in both in vitro and in vivo studies. Constitutive androstane receptor (CAR) nuclear receptor-mediated activation has been hypothesized as the MOA for MIBK-induced mouse liver tumorigenesis. To further investigate the MOA for MIBK-induced murine liver tumors, male and female B6C3F1, C57BL/6, and CAR/PXR Knockout (KO) mice were exposed to either 0 or 1800 ppm MIBK for 6 h/day, 5 days/week for a total of 10 days. On day 1, mice were implanted with osmotic mini-pumps containing 5-Bromo-2-deoxyuridine (BrdU) 1 h following exposure and humanely euthanized 1-3 h following the final exposure. B6C3F 1 and C57BL/6 mice had statistically significant increases in liver weights compared to controls that corresponded with hepatocellular hypertrophy and increased mitotic figures. Hepatocellular proliferation data indicated induction of S-phase DNA synthesis in B6C3F 1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to control, and no increase was observed in MIBK exposed CAR/PXR KO mice. Liver gene expression changes indicated a maximally-induced Cyp2b10 (CAR-associated) transcript and a slight increase in Cyp3a11(PXR-associated) transcript in B6C3F 1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to controls, but not in Cyp1a1 (AhR-associated) or Cyp4a10 (PPAR-α-associated) transcripts. CAR/PXR KO mice exposed to 1800 ppm MIBK showed no evidence of activation of AhR, CAR, PXR or PPAR-α nuclear receptors via their associated transcripts. MIBK induced hepatic effects are consistent with a phenobarbital-like MOA where the initiating events are activation of the CAR and PXR nuclear receptors and resultant hepatocellular proliferation leading to rodent liver tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

Dim Light at Night Increases Body Mass of Female Mice

PubMed Central

Aubrecht, Taryn G.; Jenkins, Richelle; Nelson, Randy J.

2016-01-01

During the past century the prevalence of light at night has increased in parallel with obesity rates. Dim light at night (dLAN) increases body mass in male mice. However, the effects of light at night on female body mass remain unspecified. Thus, female mice were exposed to a standard light/dark (LD; 16h light at ~150 lux/8h dark at ~0 lux) cycle or to light/dim light at night (dLAN; 16h light at ~150 lux/8h dim light at ~5 lux) cycles for six weeks. Females exposed to dLAN increased the rate of change in body mass compared to LD mice despite reduced total food intake during weeks five and six, suggesting that dLAN disrupted circadian rhythms resulting in deranged metabolism. PMID:25431079

[A survey of occupational health among polyether-exposed workers].

PubMed

Fu, Xu-ying; Yu, Bin; Zhang, Chun-ping; Zheng, Guan-hua; Bai, Lan; Zhang, Pan-pan

2013-06-01

To investigate the occupational health of the workers simultaneously exposed to acrylonitrile, epoxyethane, epoxypropane, and styrene. A questionnaire survey was conducted in 70 front-line workers simultaneously exposed to acrylonitrile, epoxyethane, epoxypropane, and styrene (exposure group) and 50 managers (control group) in a polyether manufacturer; in addition, air monitoring at workplace and occupational health examination were also performed. The obtained data were analyzed. The female workers in exposure group and the spouses of male workers in exposure group had significantly higher spontaneous abortion rates than their counterparts in control group (P < 0.01). The exposure group had a significantly higher abnormal rate of blood urea nitrogen than the control group (P < 0.01). The workers with different polyether-exposed working years had significantly higher mean levels of DNA damage than the control group (P < 0.01); the workers with not less than 5 and less than 20 polyether-exposed working years and those with not less than 20 polyether-exposed working years had significantly higher mean micronucleus rates than the control group (P < 0.01); there were no significant differences in overall chromosome aberration rate and mean level of DNA damage between each two groups of workers with different polyether-exposed working years (P > 0.05); the workers with not less than 5 and less than 20 polyether-exposed working years and workers with not less than 20 polyether-exposed working years had significantly higher mean micronucleus rates than those with less than 5 polyether-exposed working years (P < 0.01). Simultaneous exposure to acrylonitrile, epoxyethane, epoxypropane, and styrene causes occupational hazards among the workers in polyether manufacturer.

NTP Toxicology and Carcinogenesis Studies of Primidone (CAS No. 125-33-7) in F344/N Rats and B6C3F1 Mice (Feed Studies).

PubMed

2000-09-01

Primidone is used alone or with other anticonvulsants in the control of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsant therapy. Primidone was nominated by the National Cancer Institute for 2-year toxicology and carcinogenicity studies due to its human use as an anticonvulsant. Male and female F344/N rats and B6C3F1 mice received primidone (greater than 99% pure) in feed for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 14-DAY STUDY IN RATS: Five male and five female rats were exposed to 0, 1,250, 2,500, 5,000, 10,000 or 20,000 ppm primidone (equivalent to average daily doses of approximately 120, 240, 500, 970, or 1,100 mg primidone/kg body weight to males and 120, 240, 500, or 900 mg/kg to females) in feed for 14 days. All 20,000 ppm females died before the end of the study as did one 10,000 ppm male and two 20,000 ppm males. The mean body weights of 10,000 ppm males and females and 20,000 ppm males were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. Males and females in the 10,000 and 20,000 ppm groups were observed to have eye discharge, ataxia, and abnormal posture and were thin and lethargic. 14-DAY STUDY IN MICE: Five male and five female mice were exposed to 0, 625, 1,250, 2,500, 5,000 or 10,000 ppm primidone (equivalent to average daily doses of approximately 100, 200, 400, or 800 mg/kg body weight to males and 100, 250, 500, or 900 mg/kg to females) in feed for 14 days. All mice in the 10,000 ppm groups and one male and one female mouse in the 5,000 ppm groups died on day 3 of the study. The mean body weights of mice in the 625, 1,250, 2,500, and 5,000 ppm groups were similar to those of the controls. Feed consumption by all exposed mice was generally similar to that by the controls. Males and females in the 10,000 ppm groups were observed to have abnormal posture, ataxia, and lethargy. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 20, 40, 100, 200, or 400 mg/kg) in feed for 14 weeks. All rats survived to the end of the study. The mean body weights of male and female rats in the 2,500 and 5,000 ppm groups were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. A minimal to mild exposure-related thrombocytosis occurred on day 22 and at week 14 in all exposed groups of male rats and in females in the 1,300 ppm or greater groups. A minimal decrease in hemoglobin concentration occurred in 2,500 and 5,000 ppm male and female rats on day 22 and at week 14. The incidences of centrilobular hepatocyte hypertrophy in male rats exposed to 600 ppm or greater and in female rats exposed to 1,300 ppm or greater were significantly greater than those in the controls. The severity of chronic nephropathy in male rats exposed to 1,300 ppm or greater increased with increasing exposure concentration. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 50, 100, 200, 400, or 1,000 mg/kg to males and 60, 120, 220, 440, or 1,100 mg/kg to females) in feed for 14 weeks. Three male and two female mice in the 5,000 ppm group died during week 1 of the study. The final mean body weights of all exposed groups were similar to those of the controls. Feed consumption by male mice in the 5,000 ppm group was slightly greater than that by the controls; this may have been due to feed spillage. Male and female mice in the 5,000 ppm groups were ataxic and lethargic. Compared to controls, the estrous cycle lengths of females exposed to 1,300, 2,500, or 5,000 ppm were significantly longer. The liver weights of male and female mice exposed to 600 po 600 ppm or greater were significantly greater than those of the controls. The incidences of centrilobular hepatocyte hypertrophy in all exposed males and in females exposed to 600 ppm or greater and the incidences of cytoplasmic alteration of the adrenal gland and hematopoietic cell proliferation of the spleen in 2,500 and 5,000 ppm males and in 5,000 ppm females were significantly greater than in the controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 600, 1,300, or 2,500 ppm primidone (equivalent to average daily doses of approximately 25, 50, or 100 mg/kg) in feed for 2 years. Survival, Body Weights, and Feed Consumption Survival of the 1,300 and 2,500 ppm males was sig nificantly less than that of the controls. The mean body weights of males and females in the 2,500 ppm groups were less than those of the controls, beginning at week 29 for males and week 17 for females; the mean body weights of 1,300 ppm males and females were less than those of the controls during the second year of the study. Feed consumption by all exposed groups of rats was generally similar to that by the controls. Pathology Findings Male rats exposed to primidone had increased inci dences of thyroid gland follicular cell neoplasms (adenoma and/or carcinoma). All exposed groups of male rats had follicular cell adenomas or carcinomas (combined) at incidences above the historical control range, with the highest incidence in the 1,300 ppm group. Hepatocyte cytoplasmic vacuolation and centrilobular hypertrophy were associated with primidone exposure in male and female rats. These changes were more severe in females than in males and the incidences in all exposed groups of females were significantly greater than those in the controls. Females in the 2,500 ppm group had an increased incidence of hepatocellular eosinophilic foci. In 2,500 ppm males, the incidence of renal tubule hyperplasia was greater than that in the controls in the standard evaluation. Additional hyperplasias were found in the extended evaluation, and the incidences in exposed groups of males were significantly greater than that in the controls. In the extended evaluation, the incidence of renal tubule adenoma in 2,500 ppm males was significantly increased. The incidence of adenoma or carcinoma (combined) in 2,500 ppm males in the combined standard and extended evaluations were marginally increased over those in the controls. Male rats had an exposure-related increase in the severity of chronic nephropathy, which probably accounted for the reduced survival in the 1,300 and 2,500 ppm groups. The incidences of kidney cysts were increased in 1,300 and 2,500 ppm males. Hyperparathyroidism, secondary to the loss of renal function, was present in many exposed male rats. The incidences of parathyroid gland hyperplasia in all groups of exposed males were significantly greater than that in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to dietary levels of 0, 300, 600, or 1,300 ppm primidone (equivalent to average daily doses of approximately 30, 65, or 150 mg/kg to males and 25, 50, or 100 mg/kg to females) in feed for 2 years. Survival, Body Weights, Feed Consumption, and Clinical Findings Survival of the 1,300 ppm males was significantly less than that of the controls. During the second year of the study, the mean body weights of 1,300 ppm male and female mice were less than those of the controls. The final mean body weights of 600 ppm males and females were less than those of the controls. Feed consumption by all exposed groups of mice was similar to that by the controls. During the latter part of the study, a treatment-related increase in the number of animals with swelling of the abdominal area was observed; necropsy revealed that the swelling was due to liver nodules/masses. Pathology Findings The liver was a target organ in both male and female mice. The incidences and multiplicities of hepatocellular neoplasms (hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma) in all exposed groups of males and females (except hepatoblastoma in females) were significantly greater than those in the controls. The incidences of hepatocellular adenoma or carcinoma (combined) and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) in all exposed groups exceeded the historical control ranges in 2-year NTP studies. The incidences of centrilobular hepatocyte hypertrophy were increased in exposed groups of males and females, and the severities increased with increasing exposure concentration. The incidences of cytoplasmic vacuolization were increased in all exposed groups of females and in 300 ppm males. Incidences of eosinophilic focus in all exposed groups of females were significantly greater than those in the controls. Proliferative changes occurred in the thyroid gland in an exposure-related manner in male and female mice. Incidences of follicular cell hyperplasia were increased in all exposed groups of males and in 600 and 1,300 ppm females, but incidences of follicular cell adenomas were increased only in male mice. GENETIC TOXICOLOGY: Primidone was mutagenic in Salmonella typhimurium strain TA1535 in the absence of S9 activation only; no mutagenicity was detected in strain TA98, TA100, or TA1537, with or without S9. Primidone did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. The single in vivo study with primidone, a mouse bone marrow micronucleus test, also gave negative results. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of primidone in male F344/N rats based on a marginal increase in thyroid gland follicular cell neoplasms, primarily adenomas, and a marginal increase in renal tubule neoplasms. There was no evidence of carcinogenic activity of primidone in female F344/N rats exposed to 600, 1,300, or 2,500 ppm. There was clear evidence of carcinogenic activity of primidone in male B6C3F1 mice based on the increased incidences of hepatocellular neoplasms, and the increased incidence of thyroid gland follicular cell adenomas was also considered to be chemical related. There was clear evidence of carcinogenic activity of primidone in female B6C3F1 mice based on the increased incidences of hepatocellular neoplasms. Exposure of rats to primidone resulted in increased incidences of hepatocyte cytoplasmic vacuolization and centrilobular hypertrophy in males and females and eosinophilic foci in females. The increased severity of nephropathy and increased incidence of renal tubule hyperplasia in male rats were related to primidone exposure. Exposure of male mice to primidone resulted in hepatocyte centrilobular hypertrophy and thyroid gland follicular cell hyperplasia. Exposure of female mice to primidone resulted in hepatocyte centrilobular hypertrophy and cytoplasmic vacuolization, eosinophilic focus, and thyroid gland follicular cell hyperplasia. Synonyms: 5-Aethyl-5-phenyl-hexahydropyrimidin-4,6-dion; 2-deoxyphenobarbital; 2-desoxyphenobarbital; desoxyphenobarbitone; 5-ethyldihydro-5-phenyl-4,6 (1H,5H)-pyrimidinedione; 5-ethylhexahydro-4,6-dioxo-5-phenylphrimidine; 5-ethylhexahydro-5-phenylpyrimidine-4,6-dione; 5-ethyl-5-phenylhexahydropyrimidine-4,6-dione Trade names: Cyral; Hexadiona; Hexamidine; Lepimidin; Lepsiral; Majsolin; Midone; Milepsin; Misodine; Misolyne; Mizodin; Mizolin; Mylepsin; Mylepsinum; Mysedon; Mysoline; Prilepsin; Primacione; Primaclone; Primacone; Primakton; Primadon; Prysoline; Pyrimidone; ROE 101; Sertan

Disruption of NAD(P)H:quinone oxidoreductase 1 gene in mice leads to radiation induced myeloproliferative disease

PubMed Central

Iskander, Karim; Barrios, Roberto J.; Jaiswal, Anil K.

2008-01-01

NAD(P)H:quinone oxidoreductase1-null (NQO1-/-) mice exposed to 3 grays of γ-radiation demonstrated an increase in neutrophils, bone marrow hypercellularity, and enlarged lymph nodes and spleen. The spleen showed disrupted follicular structure, loss of red pulp, and granulocyte and megakarocyte invasion. Blood and histological analysis did not show any sign of infection in mice. These results suggested that exposure of NQO1-/- mice to γ-radiation led to myeloproliferative disease. Radiation-induced myeloproliferative disease was observed in 74% of NQO1-/- mice as compared to none in wild type mice. NQO1-/- mice exposed to γ-radiation also demonstrated tissues lymphoma (32%) and lung adenocarcinoma (84%). In contrast, only 11% wild type mice showed lymphoma and none showed lung adenocarcinoma. Exposure of NQO1-/- mice to γ-radiation resulted in reduced apoptosis in granulocytes and lack of induction of p53, p21, and Bax. NQO1-/- mice also demonstrated increased expression of myeloid differentiation factors C/EBPα and Pu.1. Intriguingly, exposure of NQO1-/- mice to γ-radiation failed to induce C/EBPα and Pu.1, as was observed in wild type mice. These results suggest that decreased p53/apoptosis and increased Pu.1 and C/EBPα led to myeloid hyperplasia in NQO1-/- mice. The lack of induction of apoptosis and differentiation contributed to radiation-induced myeloproliferative disease in NQO1-/- mice. PMID:18829548

Behavioral assessment of intermittent wheel running and individual housing in mice in the laboratory.

PubMed

Pham, Therese M; Brené, Stefan; Baumans, Vera

2005-01-01

Physical cage enrichment--exercise devices for rodents in the laboratory--often includes running wheels. This study compared responses of mice in enriched physical and social conditions and in standard social conditions to wheel running, individual housing, and open-field test. The study divided into 6 groups, 48 female BALB/c mice group housed in enriched and standard conditions. On alternate days, the study exposed 2 groups to individual running wheel cages. It intermittently separated from their cage mates and housed individually 2 groups with no running wheels; 2 control groups remained in enriched or standard condition cages. There were no significant differences between enriched and standard group housed mice in alternate days' wheel running. Over time, enriched, group housed mice ran less. Both groups responded similarly to individual housing. In open-field test, mice exposed to individual housing without running wheel moved more and faster than wheel running and home cage control mice. They have lower body weights than group housed and wheel running mice. Intermittent withdrawal of individual housing affects the animals more than other commodities. Wheel running normalizes some effects of intermittent separation from the enriched, social home cage.

In vivo simultaneous transcriptional activation of multiple genes in the brain using CRISPR-dCas9-activator transgenic mice.

PubMed

Zhou, Haibo; Liu, Junlai; Zhou, Changyang; Gao, Ni; Rao, Zhiping; Li, He; Hu, Xinde; Li, Changlin; Yao, Xuan; Shen, Xiaowen; Sun, Yidi; Wei, Yu; Liu, Fei; Ying, Wenqin; Zhang, Junming; Tang, Cheng; Zhang, Xu; Xu, Huatai; Shi, Linyu; Cheng, Leping; Huang, Pengyu; Yang, Hui

2018-03-01

Despite rapid progresses in the genome-editing field, in vivo simultaneous overexpression of multiple genes remains challenging. We generated a transgenic mouse using an improved dCas9 system that enables simultaneous and precise in vivo transcriptional activation of multiple genes and long noncoding RNAs in the nervous system. As proof of concept, we were able to use targeted activation of endogenous neurogenic genes in these transgenic mice to directly and efficiently convert astrocytes into functional neurons in vivo. This system provides a flexible and rapid screening platform for studying complex gene networks and gain-of-function phenotypes in the mammalian brain.

Promotion of allergic immune responses by intranasally-administrated nanosilica particles in mice

NASA Astrophysics Data System (ADS)

Yoshida, Tokuyuki; Yoshioka, Yasuo; Fujimura, Maho; Yamashita, Kohei; Higashisaka, Kazuma; Morishita, Yuki; Kayamuro, Hiroyuki; Nabeshi, Hiromi; Nagano, Kazuya; Abe, Yasuhiro; Kamada, Haruhiko; Tsunoda, Shin-Ichi; Itoh, Norio; Yoshikawa, Tomoaki; Tsutsumi, Yasuo

2011-12-01

With the increase in use of nanomaterials, there is growing concern regarding their potential health risks. However, few studies have assessed the role of the different physical characteristics of nanomaterials in allergic responses. Here, we examined whether intranasally administered silica particles of various sizes have the capacity to promote allergic immune responses in mice. We used nanosilica particles with diameters of 30 or 70 nm (nSP30 or nSP70, respectively), and conventional micro-sized silica particles with diameters of 300 or 1000 nm (nSP300 or mSP1000, respectively). Mice were intranasally exposed to ovalbumin (OVA) plus each silica particle, and the levels of OVA-specific antibodies (Abs) in the plasma were determined. Intranasal exposure to OVA plus smaller nanosilica particles tended to induce a higher level of OVA-specific immunoglobulin (Ig) E, IgG and IgG1 Abs than did exposure to OVA plus larger silica particles. Splenocytes from mice exposed to OVA plus nSP30 secreted higher levels of Th2-type cytokines than mice exposed to OVA alone. Taken together, these results indicate that nanosilica particles can induce allergen-specific Th2-type allergic immune responses in vivo. This study provides the foundations for the establishment of safe and effective forms of nanosilica particles.

Does vitamin E prevent tubal damage caused by smoking? A light microscopy and animal study.

PubMed

Duran, Muzeyyen; Ustunyurt, Emin; Kosus, Aydin; Kosus, Nermin; Turhan, Nilgun; Hızlı, Deniz; Sarac, Gulce Naz; Erdogan, Deniz

2014-04-01

To assess the histomorphological effects of smoking on the cilia of fallopian tubes in mice and the effect of vitamin E on the negative effects of smoke. Eighteen 12-14 week-old Swiss albino type female mice were randomly divided into three groups, each consisting of six mice: Group A: control group; Group B: mice exposed to cigarette smoke; Group C: mice exposed to cigarette smoke together with vitamin E. Groups B and C were exposed to cigarette smoke for 10 weeks. After 10 weeks, tubal excision was performed in all animals. Histopathologic examination of excised tubal tissue was conducted under light microscopy. The number of cilia was significantly lower in Group B. Although not statistically significant, the median number of cilia in Group C was measured to be higher than in Group B but lower than in Group A. Based on the results, it can be concluded that smoking decreases tubal cilia numbers. Supplementation by vitamin E may treat or at least help to slow down the decrease in number of cilia caused by smoking; therefore it could be used therapeutically in the treatment of smoking-related tubal damage. Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

Health, growth and reproductive success of mice exposed to environmentally relevant levels of Ra-226 via drinking water over multiple generations.

PubMed

Walsh, Stephanie; Satkunam, Meloja; Su, Ben; Festarini, Amy; Bugden, Michelle; Peery, Harry; Mothersill, Carmel; Stuart, Marilyne

2015-07-01

To assess health, growth and reproductive success of mammals exposed for multiple generations to levels of radium-226 known to occur in environments surrounding uranium mines and mills in Canada. The study consisted of a control group and four treatment groups each containing 40 mice (20 males and 20 females) of the CBA/CaJ strain that were continuously exposed to a range of radium-226 levels via drinking water. Breeding was at 8-10 weeks of age and the study was concluded after three breeding cycles. When compared to control mice, constant consumption of drinking water containing 0.012, 0.076, 0.78 and 8.0 Bq/l of radium-226 over four generations of mice did not demonstrably affect physical condition, weight, pregnancy rate, number of pups per litter, sex ratio and bodyweight gain of pups. Between generations, the observed differences in pregnancy rates that were noted in all groups, including controls, seemed to directly correlate with the weight and age of the females at breeding. Based on the endpoints measured on four generations of mice, there is no indication that the consumption of radium-226 via drinking water (at activity concentrations up to 8.0 Bq/l) affects health, growth and reproductive fitness.

Differential Immunotoxicity Induced by Two Different Windows of Developmental Trichloroethylene Exposure

PubMed Central

Gilbert, Kathleen M.; Woodruff, William; Blossom, Sarah J.

2014-01-01

Developmental exposure to environmental toxicants may induce immune system alterations that contribute to adult stage autoimmune disease. We have shown that continuous exposure of MRL+/+ mice to trichloroethylene (TCE) from gestational day (GD) 0 to postnatal day (PND) 49 alters several aspects of CD4+ T cell function. This window of exposure corresponds to conception-adolescence/young adulthood in humans. More narrowly defining the window of TCE developmental exposure causes immunotoxicity that would establish the stage at which avoidance and/or intervention would be most effective. The current study divided continuous TCE exposure into two separate windows, namely, gestation only (GD0 to birth (PND0)) and early-life only (PND0-PND49). The mice were examined for specific alterations in CD4+ T cell function at PND49. One potentially long-lasting effect of developmental exposure, alterations in retrotransposon expression indicative of epigenetic alterations, was found in peripheral CD4+ T cells from both sets of developmentally exposed mice. Interestingly, certain other effects, such as alterations in thymus cellularity, were only found in mice exposed to TCE during gestation. In contrast, expansion of memory/activation cell subset of peripheral CD4+ T cells were only found in mice exposed to TCE during early life. Different windows of developmental TCE exposure can have different functional consequences. PMID:24696780

Long-term effects of early adolescent methamphetamine exposure on depression-like behavior and the hypothalamic vasopressin system in mice.

PubMed

Joca, Lauren; Zuloaga, Damian G; Raber, Jacob; Siegel, Jessica A

2014-01-01

Methamphetamine (MA) has neurotoxic effects on the adult human brain that can lead to deficits in behavior and cognition. However, relatively little research has examined the behavioral or neurotoxic effects of MA in adolescents. The rising rates of adolescent MA use make it imperative that we understand the long-term effects of MA exposure on the adolescent brain and how these effects may differ from those seen in adults. In this study, the long-term effects of MA exposure during early adolescence on behavior and the vasopressin system in the paraventricular nucleus of the hypothalamus in late adolescent and adult male and female C57BL/6J mice were examined. MA exposure increased depression-like behavior in the Porsolt forced swim test in both late adolescent and adult male and female mice. Late adolescent male mice exposed to MA also showed a decrease in the number of vasopressin-immunoreactive neurons in the paraventricular nucleus compared to sex-matched saline-treated controls. Thus, similar to humans exposed to MA during adolescence, mice exposed to MA during adolescence show increased depression-like behavior later in life. These changes in behavior may be related to MA-induced alterations in vasopressin and the hypothalamic-pituitary-adrenal axis, especially in males. 2014 S. Karger AG, Basel

A simple cage-autonomous method for the maintenance of the barrier status of germ-free mice during experimentation.

PubMed

Hecht, G; Bar-Nathan, C; Milite, G; Alon, I; Moshe, Y; Greenfeld, L; Dotsenko, N; Suez, J; Levy, M; Thaiss, C A; Dafni, H; Elinav, E; Harmelin, A

2014-10-01

The use of germ-free (GF) isolators for microbiome-related research is exponentially increasing, yet limited by its cost, isolator size and potential for trans-contamination. As such, current isolator technology is highly limiting to researchers engaged in short period experiments involving multiple mouse strains and employing a variety of mono-inoculated microorganisms. In this study, we evaluate the use of positive pressure Isocages as a solution for short period studies (days to 2-3 weeks) of experimentation with GF mice at multiple simultaneous conditions. We demonstrate that this new Isocage technology is cost-effective and room-sparing, and enables maintenance of multiple simultaneous groups of GF mice. Using this technology, transferring GF mice from isolators to Isocage racks for experimentation, where they are kept under fully germ-free conditions, enables parallel inoculation with different bacterial strains and simultaneous experimentation with multiple research conditions. Altogether, the new GF Isocage technology enables the expansion of GF capabilities in a safe and cost-effective manner that can facilitate the growth, elaboration and flexibility of microbiome research. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Influenza virus infection in mice after exposure to coal dust and diesel engine emissions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hahon, N.; Booth, J.A.; Green, F.

1985-06-01

Influenza virus infection initiated after aerosol exposure of CD-1, white Swiss mice for durations of 1, 3, and 6 months to respirable particulates maintained at 2 mg/m3 of either coal dust (CD), diesel engine emissions (DEE), a combination of both (CD/DEE), or to filtered air (control) was studied. The course of infection in mice previously exposed for 1 month to various particulates did not differ appreciably among the four animal groups with respect to mortality, virus growth in lungs, interferon levels, or hemagglutinin antibody response. In mice exposed for 3 and 6 months to different particulates, the mortality response wasmore » similar among all animal groups. However, the percentage of animals showing lung consolidation was significantly higher in the 3-month groups exposed to DEE (96.5%) and CD/DEE (97%) than in the control (61.2%); in the 6-month groups, the percentages were twice that of the control for both DEE- and CD/DEE-exposed animals. Complementing these observations of both 3- and 6-month-exposed animals was the higher virus growth levels attained in the DEE and CD/DEE animals with concomitant depressed interferon levels which were the inverse of findings noted in the control group. Hemagglutinin-antibody levels in particulate-exposed animals, especially at the 6-month interval, were fourfold less than the control. Histopathologic examination of lungs revealed no qualitative differences in the inflammatory response at any one specified time interval of exposure to influenza virus among the control and particulate-exposed animal groups. However, there were differences in severity of reaction in relation to the particulate component of the exposures. Focal macular collections of pigment-laden macrophages were seen only in DEE and CD/DEE but not in CD animals after 3- and 6-month exposures.« less

Hyperoxia Inhibits T Cell Activation in Mice

NASA Astrophysics Data System (ADS)

Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

2013-02-01

Background: The immune response is blunted in mice and humans in spaceflight. The effects of hyperoxia in mice alter expression of some of the same immune response genes. If these two conditions are additive, there could be an increased risk of infection in long duration missions. Immunosuppression is seen in healthy astronauts who have flown in space; however little is known about the mechanisms that cause the reduced immunity in spaceflight. Here we examine the role of oxidative stress on mice exposed to periods of high O2 levels mimicking pre-breathing protocols and extravehicular activity (EVA). To prevent decompression sickness, astronauts are exposed to elevated oxygen (hyperoxia) before and during EVA activities. Spaceflight missions may entail up to 24 hours of EVA per crewmember per week to perform construction and maintenance tasks. The effectiveness and success of these missions depends on designing EVA systems and protocols that maximize human performance and efficiency while minimizing health and safety risks for crewmembers. To our knowledge, no studies have been conducted on the immune system under 100% oxygen exposures to determine the potential for immune compromise due to prolonged and repeated EVAs. Methods: Animals were exposed to hyperoxic or control conditions for 8 hours per day over a period of 3 days, initiated 4 hours into the dark cycle (12h dark/12h light), using animal environmental control cabinets and oxygen controller (Biospherix, Lacona, NY). Experimental mice were exposed to 98-100% oxygen as a model for pre-breathing and EVA conditions, while control mice were maintained in chambers supplied with compressed air. These are ground control studies where we use real-time RTPCR (qRTPCR) to measure gene expression of the early immune gene expression during bead activation of splenocytes of normoxic and hyperoxic mice. All procedures were reviewed and approved by the IACUC at Ames Research Center. After the last 8h of hyperoxic exposure, spleens were removed and the splenocytes were isolated and kept as individual biological samples. We have also examined transcription factors (JASPAR) and pathways of the immune system to help us understand the mechanism of regulation. Results: Our recent mouse immunology experiment aboard STS-131 suggests that the early T cell immune response was inhibited in animals that have been exposed to spaceflight, even 24 hours after return to earth. Moreover, recent experiments in hyperoxic mice show that many of the same genes involved in early T cell activation were altered. Specifically, expression of IL-2Rα, Cxcl2, TNFα, FGF2, LTA and BCL2 genes are dysregulated in mice exposed to hyperoxia. Conclusions: If these hyperoxia-induced changes of gene expression in early T cell activation are additive to the changes seen in the microgravity of spaceflight, there could be an increased infection risk to EVA astronauts, which should be addressed prior to conducting a Mars or other long-term mission.

Chronic Intermittent Hypoxia and Acetaminophen Induce Synergistic Liver Injury

PubMed Central

Savransky, Vladimir; Reinke, Christian; Jun, Jonathan; Bevans-Fonti, Shannon; Nanayakkara, Ashika; Li, Jianguo; Myers, Allen C.; Torbenson, Michael S.; Polotsky, Vsevolod Y.

2010-01-01

Obstructive sleep apnea (OSA) leads to chronic intermittent hypoxia (CIH) during sleep. OSA has been associated with liver injury. Acetaminophen (APAP) is one of the most commonly used drugs, which has known hepatotoxicity. The goal of the present study was to examine whether CIH increases liver injury, hepatic oxidative stress and inflammation induced by chronic APAP treatment. C57BL/6J mice were exposed to CIH or intermittent air (IA) for 4 weeks. Mice in both groups were treated with intraperitoneal injections of either APAP (200 mg/kg) or normal saline daily. A combination of CIH and APAP caused liver injury with marked increases in serum alanine aminotransferase, aspartate aminotransferase (AST), gamma glutamyl transferase and total bilirubin levels, whereas CIH alone induced only elevation in serum AST levels. APAP alone did not affect serum levels of liver enzymes. Histopathology revealed hepatic necrosis and increased apoptosis in mice exposed to CIH and APAP, whereas the liver remained intact in all other groups. Mice exposed to CIH and APAP exhibited decreased hepatic glutathione in conjunction with a five-fold increase in nitrotyrosine levels, suggesting formation of toxic peroxynitrite in hepatocytes. APAP or CIH alone had no effect on either glutathione or nitrotyrosine. A combination of CIH and APAP caused marked increases in pro-inflammatory chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, which were not observed in mice exposed to CIH or APAP alone. We conclude that CIH and chronic APAP treatment lead to synergistic liver injury, which may have clinical implications for patients with OSA. PMID:19028810

Supplementation of Korean Red Ginseng improves behavior deviations in animal models of autism

PubMed Central

Gonzales, Edson Luck T.; Jang, Jong-Hwa; Mabunga, Darine Froy N.; Kim, Ji-Woon; Ko, Mee Jung; Cho, Kyu Suk; Bahn, Geon Ho; Hong, Minha; Ryu, Jong Hoon; Kim, Hee Jin; Cheong, Jae Hoon; Shin, Chan Young

2016-01-01

Background Autism spectrum disorder (ASD) is heterogeneous neurodevelopmental disorders that primarily display social and communication impairments and restricted/repetitive behaviors. ASD prevalence has increased in recent years, yet very limited therapeutic targets and treatments are available to counteract the incapacitating disorder. Korean Red Ginseng (KRG) is a popular herbal plant in South Korea known for its wide range of therapeutic effects and nutritional benefits and has recently been gaining great scientific attention, particularly for its positive effects in the central nervous system. Objectives Thus, in this study, we investigated the therapeutic potential of KRG in alleviating the neurobehavioral deficits found in the valproic acid (VPA)-exposed mice models of ASD. Design Starting at 21 days old (P21), VPA-exposed mice were given daily oral administrations of KRG solution (100 or 200 mg/kg) until the termination of all experiments. From P28, mice behaviors were assessed in terms of social interaction capacity (P28–29), locomotor activity (P30), repetitive behaviors (P32), short-term spatial working memory (P34), motor coordination (P36), and seizure susceptibility (P38). Results VPA-exposed mice showed sociability and social novelty preference deficits, hyperactivity, increased repetitive behavior, impaired spatial working memory, slightly affected motor coordination, and high seizure susceptibility. Remarkably, long-term KRG treatment in both dosages normalized all the ASD-related behaviors in VPA-exposed mice, except motor coordination ability. Conclusion As a food and herbal supplement with various known benefits, KRG demonstrated its therapeutic potential in rescuing abnormal behaviors related to autism caused by prenatal environmental exposure to VPA. PMID:26837496

Differential neurotoxic effects of in utero and lactational exposure to hydroxylated polychlorinated biphenyl (OH-PCB 106) on spontaneous locomotor activity and motor coordination in young adult male mice.

PubMed

Haijima, Asahi; Lesmana, Ronny; Shimokawa, Noriaki; Amano, Izuki; Takatsuru, Yusuke; Koibuchi, Noriyuki

2017-01-01

We investigated whether in utero or lactational exposure to 4-hydroxy-2',3,3',4',5'-pentachlorobiphenyl (OH-PCB 106) affects spontaneous locomotor activity and motor coordination in young adult male mice. For in utero exposure, pregnant C57BL/6J mice received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from gestational day 10 to 18. For lactational exposure, the different groups of dams received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from postpartum day 3 to 13. At 6-7 weeks of age, the spontaneous locomotor activities of male offspring were evaluated for a 24-hr continuous session in a home cage and in an open field for 30-min. Motor coordination function on an accelerating rotarod was also measured. Mice exposed prenatally to OH-PCB 106 showed increased spontaneous locomotor activities during the dark phase in the home cage and during the first 10-min in the open field compared with control mice. Mice exposed lactationally to OH-PCB 106, however, did not show a time-dependent decrease in locomotor activity in the open field. Instead, their locomotor activity increased significantly during the second 10-min block. In addition, mice exposed lactationally to OH-PCB 106 displayed impairments in motor coordination in the rotarod test. These results suggest that perinatal exposure to OH-PCB 106 affects motor behaviors in young adult male mice. Depending on the period of exposure, OH-PCB 106 may have different effects on neurobehavioral development.

High-fat diet exacerbates inflammation and cell survival signals in the skin of ultraviolet B-irradiated C57BL/6 mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meeran, Syed M.; Singh, Tripti; Nagy, Tim R.

Inflammation induced by chronic exposure to ultraviolet (UV) radiation has been implicated in various skin diseases. We formulated the hypothesis that a high-fat diet may influence the UV-induced inflammatory responses in the skin. C57BL/6 mice were fed a high-fat diet or control diet and exposed to UVB radiation (120 mJ/cm{sup 2}) three times/week for 10 weeks. The mice were then sacrificed and skin and plasma samples collected for analysis of biomarkers of inflammatory responses using immunohistochemistry, western blotting, ELISA and real-time PCR. We found that the levels of inflammatory biomarkers were increased in the UVB-exposed skin of the mice fedmore » the high-fat diet than the UVB-exposed skin of the mice fed the control diet. The levels of inflammatory biomarkers of early responses to UVB exposure (e.g., myeloperoxidase, cyclooxygenase-2, prostaglandin-E{sub 2}), proinflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), and proliferating cell nuclear antigen and cell survival signals (phosphatidylinositol-3-kinase and p-Akt-Ser{sup 473}) were higher in high-fat-diet-fed mouse skin than control-diet-fed mouse skin. The plasma levels of insulin growth factor-1 were greater in the UVB-irradiated mice fed the high-fat diet than the UVB-irradiated mice fed the control diet, whereas the levels of plasma adiponectin were significantly lower. This pronounced exacerbation of the UVB-induced inflammatory responses in the skin of mice fed a high-fat diet suggests that high-fat diet may increase susceptibility to inflammation-associated skin diseases, including the risk of skin cancer.« less

Strain dependent effects of conditioned fear in adult C57Bl/6 and Balb/C mice following postnatal exposure to chlorpyrifos: relation to expression of brain acetylcholinesterase mRNA

PubMed Central

Oriel, Sarit; Kofman, Ora

2015-01-01

Following reports of emotional psychopathology in children and adults exposed to organophosphates, the effects of postnatal chlorpyrifos (CPF) on fear-conditioning and depression-like behaviors were tested in adult mice. Concomitant changes in expression of mRNA for synaptic and soluble splice variants of acetylcholinesterase (AChE) were examined in mouse pups and adults of the Balb/C and C57Bl/6 (B6) strains, which differ in their behavioral and hormonal stress response. Mice were injected subcutaneously with 1 mg/kg CPF on postnatal days 4–10 and tested as adults for conditioned fear, sucrose preference, and forced swim. Acetylcholinesterase activity was assessed in the brains of pups on the first and last day of treatment. Expression of soluble and synaptic AChE mRNA was assessed in brains of treated pups and fear-conditioned adults using real-time PCR. Adult Balb/C mice exposed postnatally to CPF showed exacerbated fear-conditioning and impaired active avoidance. Adult B6 mice exposed postnatally to CPF showed a more specific fear response to tones and less freezing in the inter-tone intervals, in contrast to the vehicle-pretreated mice. Chlorpyrifos also attenuated sweet preference and enhanced climbing in the forced swim test. Chlorpyrifos-treated mice had increased expression of both synaptic and readthrough AChE transcripts in the hippocampus of Balb/C mice and decreased expression in the amygdala following fear-conditioning. In conclusion, postnatal CPF had long-term effects on fear and depression, as well as on expression of AChE mRNA. These changes may be related to alteration in the interaction between hippocampus and amygdala in regulating negative emotions. PMID:25972795

Insulin-Like Growth Factor-1 Preserves Salivary Gland Function After Fractionated Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Limesand, Kirsten H., E-mail: limesank@u.arizona.ed; Department of Nutritional Sciences, University of Arizona, Tucson, AZ; Avila, Jennifer L.

Purpose: Radiotherapy for head-and-neck cancer consists of fractionated radiation treatments that cause significant damage to salivary glands leading to chronic salivary gland dysfunction with only limited prevention and treatment options currently available. This study examines the feasibility of IGF-1 in preserving salivary gland function following a fractionated radiation treatment regimen in a pre-clinical model. Methods and Materials: Mice were exposed to fractionated radiation, and salivary gland function and histological analyses of structure, apoptosis, and proliferation were evaluated. Results: In this study, we report that treatment with fractionated doses of radiation results in a significant level of apoptotic cells in FVBmore » mice after each fraction, which is significantly decreased in transgenic mice expressing a constitutively active mutant of Akt1 (myr-Akt1). Salivary gland function is significantly reduced in FVB mice exposed to fractionated radiation; however, myr-Akt1 transgenic mice maintain salivary function under the same treatment conditions. Injection into FVB mice of recombinant insulin-like growth factor-1 (IGF-1), which activates endogenous Akt, suppressed acute apoptosis and preserved salivary gland function after fractionated doses of radiation 30 to 90 days after treatment. FVB mice exposed to fractionated radiation had significantly lower levels of proliferating cell nuclear antigen-positive salivary acinar cells 90 days after treatment, which correlated with a chronic loss of function. In contrast, FVB mice injected with IGF-1 before each radiation treatment exhibited acinar cell proliferation rates similar to those of untreated controls. Conclusion: These studies suggest that activation of IGF-1-mediated pathways before head-and-neck radiation could modulate radiation-induced salivary gland dysfunction and maintain glandular homeostasis.« less

Trichloroethylene Exposure Reduces Liver Injury in a Mouse Model of Primary Biliary Cholangitis

PubMed Central

Ray, Jessica L.; Kopec, Anna K.; Joshi, Nikita; Cline-Fedewa, Holly; Lash, Lawrence H.; Williams, Kurt J.; Leung, Patrick S.; Gershwin, M. Eric

2017-01-01

Abstract Trichloroethylene (TCE) is a persistent environmental contaminant proposed to contribute to autoimmune disease. Experimental studies in lupus-prone MRL+/+ mice have suggested that TCE exposure can trigger autoimmune hepatitis. The vast majority of studies examining the connection between TCE and autoimmunity utilize this model, and the impact of TCE exposure in other established models of autoimmune liver disease is not known. We tested the hypothesis that TCE exposure exacerbates experimental hepatic autoimmunity in dominant negative transforming growth factor beta receptor type II (dnTGFBRII) mice, which develop serological and histological features resembling human primary biliary cholangitis. Female 8-week-old wild-type and dnTGFBRII mice were exposed to TCE (0.5 mg/ml) or vehicle (1% ethoxylated castor oil) in the drinking water for 12 or 22 weeks. Liver histopathology in 20- and 30-week-old wild-type mice was unremarkable irrespective of treatment. Mild portal inflammation was observed in vehicle-exposed 20-week-old dnTGFBRII mice and was not exacerbated by TCE exposure. Vehicle-exposed 30-week-old dnTGFBRII mice developed anti-mitochondrial antibodies, marked hepatic inflammation with necrosis, and hepatic accumulation of both B and T lymphocytes. To our surprise, TCE exposure dramatically reduced hepatic parenchymal inflammation and injury in 30-week-old dnTGFBRII mice, reflected by changes in hepatic proinflammatory gene expression, serum chemistry, and histopathology. Interestingly, TCE did not affect hepatic B cell accumulation or induction of the anti-inflammatory cytokine IL10. These data indicate that TCE exposure reduces autoimmune liver injury in female dnTGFBRII mice and suggests that the precise effect of environmental chemicals in autoimmunity depends on the experimental model. PMID:28115651

[Protective effects of WR2721 on early bone marrow hematopoietic function in mice exposed to 6.5 Gy of (60)Co γ-rays].

PubMed

Deng, Zi-Liang; Zhang, Liu-Zhen; Cong, Yue; Liu, Xiao-Lan; Yu, Zu-Ying; Shan, Ya-Jun; Cui, Yu; Wang, Li-Mei; Xing, Shuang; Cong, Yu-Wen; Luo, Qing-Liang

2014-06-01

The aim of this study was to investigate the effect of WR2721(amifostine) against bone marrow hematopoietic damage of mice exposed to 6.5 Gy of (60)Co-γ ray. A total of 60 C57/BL6J mice was divided into 3 groups:normal group (mice were injected with physiological salt solution), irradiation group (mice were injected with physiologic salt solution before irradiation) and WR2721 group (mice were injected with WR2721 before irradiation). The WBC, neutrophil (Neut), Plt and RBC levels in peripheral blood of 3 group mice were counted within 60 days after irradiation; the bone marrow nuclear cells (BMNC) were counted at 2 and 24 hours after irradiation; the hematopoietic stem/progenitor cell (LK/LSK) level and colony formation capability were detected by flow cytometry at 2 and 24 hours after irradiation. The results indicated that the counts of WBC and neut at 4 and 18 days, Plt at 7-18 days and RBC at 10-30 day after irradiation in WR2721 group were higher than those in irradiation group (P < 0.05); the BMNC, LSK and LK levels obviously increased at 24 hours after irradiation (P < 0.05), the CFU-GEMM, CFU-GM, CFU-MK BFU-E and CFU-E all significantly increased at 2 and 24 hours after irradiation (P < 0.01), as compared with irradiation group. It is concluded that WR2721 can effectively alleviate early hematopoietic damage and promote the fast recovery of peripheral blood cells in mice exposed to γ-ray, suggesting that the WR2721 has significant radioprotective effect on hematopoietic system.

Mechanical ventilation causes pulmonary mitochondrial dysfunction and delayed alveolarization in neonatal mice.

PubMed

Ratner, Veniamin; Sosunov, Sergey A; Niatsetskaya, Zoya V; Utkina-Sosunova, Irina V; Ten, Vadim S

2013-12-01

Hyperoxia inhibits pulmonary bioenergetics, causing delayed alveolarization in mice. We hypothesized that mechanical ventilation (MV) also causes a failure of bioenergetics to support alveolarization. To test this hypothesis, neonatal mice were ventilated with room air for 8 hours (prolonged) or for 2 hours (brief) with 15 μl/g (aggressive) tidal volume (Tv), or for 8 hours with 8 μl/g (gentle) Tv. After 24 hours or 10 days of recovery, lung mitochondria were examined for adenosine diphosphate (ADP)-phosphorylating respiration, using complex I (C-I)-dependent, complex II (C-II)-dependent, or cytochrome C oxidase (C-IV)-dependent substrates, ATP production rate, and the activity of C-I and C-II. A separate cohort of mice was exposed to 2,4-dinitrophenol (DNP), a known uncoupler of oxidative phosphorylation. At 10 days of recovery, pulmonary alveolarization and the expression of vascular endothelial growth factor (VEGF) were assessed. Sham-operated littermates were used as control mice. At 24 hours after aggressive MV, mitochondrial ATP production rates and the activity of C-I and C-II were significantly decreased compared with control mice. However, at 10 days of recovery, only mice exposed to prolonged-aggressive MV continued to exhibit significantly depressed mitochondrial respiration. This was associated with significantly poorer alveolarization and VEGF expression. In contrast, mice exposed to brief-aggressive or prolonged-gentle MV exhibited restored mitochondrial ADP-phosphorylation, normal alveolarization and pulmonary VEGF content. Exposure to DNP fully replicated the phenotype consistent with alveolar developmental arrest. Our data suggest that the failure of bioenergetics to support normal lung development caused by aggressive and prolonged ventilation should be considered a fundamental mechanism for the development of bronchopulmonary dysplasia in premature neonates.

Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.

PubMed

Wahlang, Banrida; Prough, Russell A; Falkner, K Cameron; Hardesty, Josiah E; Song, Ming; Clair, Heather B; Clark, Barbara J; States, J Christopher; Arteel, Gavin E; Cave, Matthew C

2016-02-01

Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

[Effect of schistosome ova on Trinitrobenzenesulfonic acid induced colitis in mice].

PubMed

Jiang, Jie; Xue, Ru-yi; Zhang, Shun-cai; Zhou, Jun; Zhou, Kang

2007-08-14

To investigate the effects of intraperitoneal injected schistosome ova on TNBS-induced colitis and on the intestinal TLR4 expression in mice. 40 BALB/c mice were randomized into 3 groups: normal control group (10 mice), TNBS group (20 mice) in which mice were exposed to trinitrobenzesulfonic acid (TNBS) and were induced with colitis, and the schistosome ova group (10 mice) in which mice were intraperitoneal injected with freeze-killed schistosome ova and later exposed to TNBS. The following variables were observed: mortality, pathological appearance of the colon, histological scoring of the specimen, serum TNF-alpha level, and intestinal TLR4 expression detected by RT-PCR and Immunohistochemistry. Mortality of schistosome ova group was lower than that of the TNBS group (20% vs 70%, P < 0.05). Inflammation of the mice colon in the schistosome ova group was less severe than that of the TNBS group (1.4 +/- 0.5 vs 4.2 +/- 0.6, P < 0.01, Ameho criteria scoring). TLR4 expression of colon was up-regulated in mice of TNBS group and down-regulated in schistosome ova group which was still higher than that of normal controls (0.762 +/- 0.054 vs 0.325 +/- 0.029 vs 0.237 +/- 0.021, P < 0.01). Intraperitoneal injected schistosome ova can obviously reduce TNBS-induced colitis in mice, which may be attributed to down-regulated TLR4 expression in colon.

Partial extinction of a conditioned context enhances preference for elements previously associated with cocaine but not with chocolate.

PubMed

Orsini, C; Bonito-Oliva, A; Montanari, C; Conversi, D; Cabib, S

2013-08-15

Drug-associated stimuli are crucial to reinstatement of drug-seeking after periods of abstinence, representing a central problem in treatment of addiction. The present study investigated the influence of partial extinction of the conditioned context on the expression of conditioned place preference (CPP). Mice of the inbred DBA/2J strain were conditioned with cocaine or chocolate in a context identified by multiple elements (A+B) and subsequently CPP expression was evaluated in a context containing only one element (A or B) or both (A+B). Cocaine- and chocolate-conditioned mice showed CPP in presence of the original compound stimulus. However, cocaine-conditioned mice did not show CPP when tested in A or B context, while chocolate-conditioned mice did show CPP to single element context. After conditioning mice were exposed to extinction training of the context A or B and then tested for CPP 1 and 9 days after the end of the extinction (days 9 and 18). Cocaine-conditioned mice showed CPP 9 days after extinction while chocolate-conditioned mice were relatively insensitive to the extinction procedure on day 1 after extinction, but they did not show CPP for the partial or the original compound 9 days after extinction. Cocaine-conditioned mice not submitted to the extinction training (simple passage of time) or submitted to a Sham-extinction procedure (saline injections and confinement in a new environment) did not show CPP on day 9 or 18. Cocaine-conditioned mice exposed to extinction training showed increased c-Fos expression in several brain areas in comparison to mice exposed to Sham-extinction. The extinction procedure did not specifically reduce behavioral sensitization. The results suggest that extinction training involving only elements of a drug-associated context can result in increased associative strength of those elements. © 2013.

Effects of Dim Light at Night on Food Intake and Body Mass in Developing Mice.

PubMed

Cissé, Yasmine M; Peng, Juan; Nelson, Randy J

2017-01-01

Appropriately timed light is critical for circadian organization; exposure to dim light at night (dLAN) disrupts temporal organization of endogenous biological timing. Exposure to dLAN in adult mice is associated with elevated body mass and changes in metabolism putatively driven by voluntary changes in the time of food intake. We predicted that exposure of young mice to LAN could affect adult metabolic function. At 3 weeks (Experiment 1) or 5 weeks (Experiment 2) of age, mice were either maintained in standard light-dark (DARK) cycles or exposed to nightly dLAN (5 lux). In the first two experiments, food intake and locomotor activity were assessed after 4 weeks and a glucose tolerance test was administered after 6 weeks in experimental lighting conditions. In Experiment 3, tissues were collected around the clock at 6 h intervals to investigate rhythmic hepatic clock gene expression in mice exposed to dLAN from 3 or 5 weeks of age. Male and female mice exposed to dLAN beginning at 3 weeks of age displayed similar growth rates and body mass to DARK-reared offspring, despite increasing day-time food intake. Exposure to dLAN beginning at 5 weeks of age increased body mass and daytime food intake in male, but not female, mice. Consistent with the body mass phenotype, clock gene expression was unaltered in the liver. In contrast to adults, dLAN exposure during the development of the peripheral circadian system has sex- and development-dependent effects on body mass gain.

The differential mice response to cat and snake odor.

PubMed

de Oliveira Crisanto, Karen; de Andrade, Wylqui Mikael Gomes; de Azevedo Silva, Kayo Diogenes; Lima, Ramón Hypolito; de Oliveira Costa, Miriam Stela Maris; de Souza Cavalcante, Jeferson; de Lima, Ruthnaldo Rodrigues Melo; do Nascimento, Expedito Silva; Cavalcante, Judney Cley

2015-12-01

Studies from the last two decades have pointed to multiple mechanisms of fear. For responding to predators, there is a group of highly interconnected hypothalamic nuclei formed by the anterior hypothalamic nucleus, the ventromedial hypothalamic nucleus and the dorsal premammillary nucleus—the predator-responsive hypothalamic circuit. This circuit expresses Fos in response to predator presence or its odor. Lesion of any component of this system blocks or reduces the expression of fear and consequently defensive behavior when faced with a predator or its cue. However, most of the knowledge about that circuit has been obtained using the rat as a model of prey and the cat as a source of predator cues. In the present study, we exposed mice to strong cat or snake odors, two known mice predators, and then we used the rat exposure test (RET) to study their behavior when confronted with the same predator's odor. Our data point to a differential response of mice exposed to these odors. When Swiss mice were exposed to the cat odor, they show defensive behavior and the predator-responsive hypothalamic circuit expressed Fos. The opposite was seen when they faced snake's odor. The acute odor exposure was not sufficient to activate the mouse predator-responsive hypothalamic circuit and the mice acted like they were not in a stressful situation, showing almost no sign of fear or defensive posture. This leads us to the conclusion that not all the predator cues are sufficient to activate the predator-responsive hypothalamic circuit of mice and that their response depends on the danger that these predators represent in the natural history of the prey.

Effect of Electromagnetic Pulses (EMP) on associative learning in mice and a preliminary study of mechanism.

PubMed

Chen, Yong Bin; Li, Jing; Liu, Jun Ye; Zeng, Li Hua; Wan, Yi; Li, Yu Rong; Ren, Dongqing; Guo, G Z

2011-12-01

To investigate the effects of electromagnetic pulses (EMP) on associative learning in mice and test a preliminary mechanism for these effects. A tapered parallel plate gigahertz transverse electromagnetic (GTEM) cell with a flared rectangular coaxial transmission line was used to expose male BALB/c mice to EMP (peak-intensity 400 kV/m, rise-time 10 ns, pulse-width 350 ns, 0.5 Hz and total 200 pulses). Concurrent sham-exposed mice were used as a control. Associative learning, oxidative stress in the brain, serum chemistry and the protective action of tocopherol monoglucoside (TMG) in mice were measured, respectively. (1) Twelve hour and 1 day post EMP exposure associative learning was reduced significantly compared with sham control (p<0.05) but recovered at 2 d post EMP exposure. (2) Compared with the sham control, lipid peroxidation of brain tissue and chemiluminescence (CL) intensity increased significantly (p<0.05), while the activity of the antioxidant enzymes Superoxide Dismutase [SOD], Glutathione [GSH], Glutathione Peroxidase [GSH-Px], Catalase [CAT]) decreased significantly (p<0.05) at 3 h, 6 h, 12 h and 1 d post EMP exposure. All these parameters recovered at 2 d post EMP exposure. (3) No significant differences between the sham control group and EMP exposed group were observed in serum cholesterol and triglycerides. (4) Pretreatment of mice with TMG showed protective effects to EMP exposure. EMP exposure significantly decreased associative learning in mice and TMG acted as an effective protective agent from EMP exposure. This mechanism could involve an increase of oxidative stress in brain by EMP exposure.

Carbon monoxide inhalation increases microparticles causing vascular and CNS dysfunction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Jiajun; Yang, Ming; Kosterin, Paul

We hypothesized that circulating microparticles (MPs) play a role in pro-inflammatory effects associated with carbon monoxide (CO) inhalation. Mice exposed for 1 h to 100 ppm CO or more exhibit increases in circulating MPs derived from a variety of vascular cells as well as neutrophil activation. Tissue injury was quantified as 2000 kDa dextran leakage from vessels and as neutrophil sequestration in the brain and skeletal muscle; and central nervous system nerve dysfunction was documented as broadening of the neurohypophysial action potential (AP). Indices of injury occurred following exposures to 1000 ppm for 1 h or to 1000 ppm formore » 40 min followed by 3000 ppm for 20 min. MPs were implicated in causing injuries because infusing the surfactant MP lytic agent, polyethylene glycol telomere B (PEGtB) abrogated elevations in MPs, vascular leak, neutrophil sequestration and AP prolongation. These manifestations of tissue injury also did not occur in mice lacking myeloperoxidase. Vascular leakage and AP prolongation were produced in naïve mice infused with MPs that had been obtained from CO poisoned mice, but this did not occur with MPs obtained from control mice. We conclude that CO poisoning triggers elevations of MPs that activate neutrophils which subsequently cause tissue injuries. - Highlights: • Circulating microparticles (MPs) increase in mice exposed to 100 ppm CO or more. • MPs are lysed by infusing the surfactant polyethylene glycol telomere B. • CO-induced MPs cause neutrophil activation, vascular leak and CNS dysfunction. • Similar tissue injuries do not arise with MPs obtained from air-exposed, control mice.« less

Chronic elevation of phosphocholine containing lipids in mice exposed to Gulf War agents pyridostigmine bromide and permethrin.

PubMed

Abdullah, Laila; Evans, James E; Montague, Hannah; Reed, Jon M; Moser, Ann; Crynen, Gogce; Gonzalez, Ariel; Zakirova, Zuchra; Ross, Ivan; Mullan, Chris; Mullan, Michael; Ait-Ghezala, Ghania; Crawford, Fiona

2013-01-01

For two decades, 25% of the veterans who served in the 1991 Gulf War (GW) have been living with Gulf War Illness (GWI), a chronic multisymptom illness. Evidence suggests that brain structures involved in cognitive function may be affected in GWI. Gulf War agents such as the acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB) and the pesticide permethrin (PER) are considered key etiogenic factors in GWI. We therefore developed a mouse model of GW agent exposure by co-administering PB and PER and showed that this model exhibits cognitive impairment and anxiety, and increased astrogliosis at chronic post-exposure time-points. Since GW agents inhibit AChE, we hypothesized that PB+PER exposure will modulate phosphatidylcholine (PC) and sphingomyelin (SM), which are reservoirs of phosphocholine required for endogenous ACh synthesis. Lipidomic analyses showed that PC and SM were elevated in the brains of exposed compared to control mice. Brain ether PC (ePC) species were increased but lyso-platelet activating factors (lyso-PAF) that are products of ePC were decreased in exposed animals compared to controls. Catalase expression (a marker for peroxisomes) was increased in GW agent exposed mice compared to controls. Ether PC and lyso-PAF modulation was also evident in the plasma of GW agent exposed mice compared to controls. These studies suggest peroxisomal and lysosomal dysfunction in the brain at a chronic post-exposure timepoint following GW agent exposure. Our studies provide a new direction for GWI research, which will be useful for developing suitable therapies for treating GWI. © 2013 Elsevier Inc. All rights reserved.

Short-term social memory deficits in adult female mice exposed to tannery effluent and possible mechanism of action.

PubMed

Estrela, Fernanda Neves; Rabelo, Letícia Martins; Vaz, Boniek Gontijo; de Oliveira Costa, Denys Ribeiro; Pereira, Igor; de Lima Rodrigues, Aline Sueli; Malafaia, Guilherme

2017-10-01

The accumulated organic residues in tannery-plant courtyards are an eating attraction to small rodents; however, the contact of these animals with these residues may change their social behavior. Thus, the aim of the present study is to investigate whether the exposure to tannery effluent (TE) can damage the social recognition memory of female Swiss mice, as well as to assess whether vitamin C supplementation could provide information about how TE constituents can damage these animals' memory. We have observed that resident females exposed to TE (without vitamin supplementation) did not explore the anogenital region, their body or chased intruding females for shorter time or with lower frequency during the retest session of the social recognition test, fact that indicates social recognition memory deficit in these animals. Such finding is reinforced by the confirmation that there was no change in the animals' olfactory function during the buried food test, or locomotor changes in females exposed to the pollutant. Since no behavioral change was observed in the females exposed to TE and treated with vitamin C (before or after the exposure), it is possible saying that these social cognitive impairments seem to be directly related to the imbalance between the cellular production of reactive oxygen species and the counteracting antioxidant mechanisms (oxidative stress) in female mice exposed to the pollutant (without vitamin supplementation). Therefore, the present study evidences that the direct contact with tannery effluent, even for a short period-of-time, may cause short-term social memory deficits in adult female Swiss mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

NTP report on the toxicology studies of dichloroacetic acid (CAS No. 79-43-6) in genetically modified (FVB Tg.AC hemizygous) mice (dermal and drinking water studies) and carcinogenicity studies of dichloroacetic acid in genetically modified [B6.129-Trp53(tm1Brd) (N5) haploinsufficient] mice (drinking water studies).

PubMed

2007-04-01

Dichloroacetic acid was nominated for study by the United States Environmental Protection Agency (EPA) and by the National Institute of Environmental Health Sciences because of its widespread occurrence in drinking water as a by-product of water disinfection using chlorination. It was also nominated because dichloroacetic acid is the most studied representative of the class of haloacetic acids and has been shown to cause liver tumors in both rats and mice. Haloacetic acids are second only to trihalomethanes as a family of disinfection by-products found in many drinking water supplies. Dichloroacetic acid is one of several disinfection by-products being evaluated to determine whether genetically modified mouse models can serve as a more rapid and cost-effective means of evaluating and ranking potential hazards of disinfection by-products. The NTP has explored the use of genetically altered mouse models as adjuncts to 2-year rodent cancer assays. These models may prove to be more rapid, use fewer animals, and provide some mechanistic insights into neoplastic responses. As part of the evaluation of new mouse cancer screening models, dichloroacetic acid was tested for potential toxicity and carcinogenicity in two relatively well-studied models, the Tg.AC hemizygous strain and the p53 haploinsufficient strain. Male and female Tg.AC hemizygous and p53 haploinsufficient mice were exposed to dichloroacetic acid in the drinking water (greater than 98% pure) for 26 or 39 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium strains TA98, TA100, and TA1535 and in mouse peripheral blood erythrocytes. 26- AND 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 31.25, 125, or 500 mg dichloroacetic acid/kg body weight 5 days per week for 26 weeks with additional groups of 10 males and 10 females continued on treatment for 39 weeks. Survival of dosed males and females was similar to that of the vehicle control groups for both studies. Mean body weights of dosed males and females in the 26-week study were similar to those of the vehicle control groups. Mean body weights of dosed males in the 39-week study were similar to those of the vehicle control groups. Mean body weights of the 500 mg/kg females were greater than those of the vehicle controls in the 39-week study. The absolute liver weights were increased by greater than 50% compared to the vehicle controls for the 500 mg/kg males and females in both studies. At the site of application, the incidences of squamous cell papilloma were significantly increased in 500 mg/kg males and females at 39 weeks. In addition, one 125 mg/kg male, two 500 mg/kg males, and two 500 mg/kg females had squamous cell papillomas at 26 weeks. The incidences of epidermal hyperplasia and hyperkeratosis were significantly increased at the site of application in the 125 and 500 mg/kg males and females at 26 weeks. At 39 weeks, the incidence of epidermal hyperkeratosis was increased in the 31.25 mg/kg males, but in females, increased epidermal hyperkeratosis and hyperplasia occurred only in the 500 mg/kg group. There was a modest increase in pulmonary adenomas at 39 weeks that may have been related to the dichloroacetic acid exposure in males and females exposed to 125 or 500 mg/kg. In both studies, there was a dose-related increase in the mean severity of hepatocyte cytoplasmic vacuolization in males and females, and the incidence of nephropathy was increased in 500 mg/kg males. 26- AND 41-WEEK DRINKING WATER STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L dichloroacetic acid for 26 weeks with additional groups of 10 males and 10 females exposed for 41 weeks. The equivalent average daily doses were approximately 75, 145, and 235 mg dichloroacetic acid/kg body weight to males and approximately 100, 185, and 285 mg/kg to females. Survival of exposed males was similar in both studies. In the females, survival was decreased in the 26-week but not the 41-week study. While there was some variability, the mean body weights of mice exposed to dichloroacetic acid tended to be similar to those of the control groups. In the 41-week study, mean body weights of exposed males and females tended to be less than those of the control groups. Water consumption by males and females exposed to 1,000 and 2,000 mg/L was less than that by the controls throughout both studies. The incidences and/or severity of hepatocyte cytoplasmic vacuolization were increased in males and females in both studies. The incidence of pulmonary adenoma was increased in the male mice exposed to 1,000 mg/L dichloroacetic acid for 41 weeks. Two pulmonary adenomas were found in the 2,000 mg/L females at 41 weeks. At 26 weeks, a pulmonary carcinoma was found in one 1,000 mg/L male, one 500 mg/L female, and one 2,000 mg/L female. 26- AND 41-WEEK DRINKING WATER STUDIES IN p53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L dichloroacetic acid for 26 weeks with additional groups of 10 males and 10 females exposed for 41 weeks. The equivalent average daily doses were approximately 45, 80, and 145 mg/kg to males and approximately 75, 145, and 220 mg/kg to females. Survival of all exposed groups was similar to that of the control groups in both studies. Mean body weights of 1,000 and 2,000 mg/L males and females were generally less than those of the control groups throughout most of both studies; mean body weights of 500 mg/L males and females were less than those of the controls for much of the 41-week study. Water consumption by 1,000 and 2,000 mg/L males and females was less than that by the control groups throughout both studies. The incidences and/or severities of hepatocyte cytoplasmic vacuolization were increased in males in the 26-week study and females in both studies. Dichloroacetic acid was mutagenic in Salmonella typhimurium strains TA100 and TA1535 in tests conducted in the absence of S9 liver activation enzymes; no increase in mutations was observed in either strain in the presence of rat or hamster liver S9. Dichloroacetic acid was not mutagenic in S. typhimurium strain TA98 with or without S9. Dichloroacetic acid was also tested for micronucleus induction in peripheral blood erythrocytes of male and female Tg.AC hemizygous and p53 haploinsufficient mice treated by drinking water or dermal application for 26 weeks. No induction of micronuclei was seen in Tg.AC hemizygous mice treated by either route or in the p53 haploinsufficient mice, which were exposed only by the drinking water route. In another study, analysis of peripheral blood samples for frequency of micronucleated erythrocytes in male and female B6C3F1 mice exposed to dichloroacetic acid in drinking water for 3 months revealed no alteration in micronucleus frequencies in male mice; a small increase seen in females was judged to be equivocal. Under the conditions of these drinking water studies, there was no evidence of carcinogenic activity of dichloroacetic acid in male or female p53 haploinsufficient mice exposed to 0, 500, 1,000, or 2,000 mg/L for 26 or 41 weeks. The incidences and/or severities of cytoplasmic vacuolization of the hepatocyte were increased in males and females exposed to dichloroacetic acid for 26 or 41 weeks. Under the conditions of these dermal studies, there were increased incidences of squamous cell papillomas at the site of application in male and female Tg.AC hemizygous mice exposed to 500 mg/kg for 39 weeks. There were dose-related increased incidences of epidermal hyperkeratosis and hyperplasia at the site of application in both male and female mice exposed to dichloroacetic acid for 26 or 39 weeks. Under the conditions of these drinking water studies, there was an increase in the incidence of alveolar/bronchiolar adenoma in male Tg.AC hemizygous mice exposed to 1,000 mg/L for 41 weeks. There were a few bronchiolar/alveolar carcinomas in males and females exposed to dichloroacetic acid in the drinking water for 26 weeks and a few bronchiolar/alveolar adenomas in females exposed to dichloroacetic acid in the drinking water for 41 weeks. There were increased incidences and/or severities of cytoplasmic vacuolization of the hepatocyte in male and female Tg.AC hemizygous mice exposed to dichloroacetic acid in the drinking water study for 26 or 41 weeks. The marginally increased incidences of pulmonary adenomas and/or carcinomas compared to the unexposed groups found in both the dermal and drinking water studies at 39 or 41 weeks were considered to be related to dichloroacetic acid exposure.

Contextual and Serial Discriminations: A New Learning Paradigm to Assess Simultaneously the Effects of Acute Stress on Retrieval of Flexible or Stable Information in Mice

PubMed Central

Célérier, Aurélie; Piérard, Christophe; Rachbauer, Dagmar; Sarrieau, Alain; Béracochéa, Daniel

2004-01-01

The present study was aimed at simultaneously determining on the same subject, the effects of stress on retrieval of flexible (contextual or temporal) or stable (spatial) information. Three behavioral paradigms carried out in a four-hole board were designed as follows: (1) Simple Discrimination (SD), in which mice learned a single discrimination; (2) Contextual and Serial Discriminations (CSD), in which mice learned two successive discriminations on two different internal contexts; (3) Spatial Serial Discriminations (SSD), in which mice learned two successive discriminations on an identical internal context. The stressor (three inescapable electric footshocks) was delivered 5 min before retention, occurring 5 min or 24 h after acquisition. Results showed that this stressor increased plasmatic corticosterone levels and fear reactivity in an elevated-plus-maze, as compared with nonstressed mice. The stressor reversed the normal pattern of retrieval observed in nonstressed controls in the CSD task, this effect being context dependent, as it was not observed in the SSD task. Overall, our study shows that stress affected the retrieval of flexible and old information, but spared the retrieval of stable or recent ones. Therefore, these behavioral paradigms allow us to study simultaneously, on the same animal, the effects of stress on distinct forms of memory retrieval. PMID:15054135

Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARa and T- and B-cell targeting

EPA Pesticide Factsheets

Dosing information, body weights during exposure and immune system endpoints. This dataset is associated with the following publication:DeWitt, J., W. Williams , J. Creech, and R. Luebke. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting. JOURNAL OF IMMUNOTOXICOLOGY. Taylor & Francis, Inc., Philadelphia, PA, USA, 13(1): 38-45, (2016).

Long-Term, Low-Dose Exposure to Microcystin-LR Does not Cause or Increase the Severity of Liver Disease in Rodents.

PubMed

Labine, Meaghan; Gong, Yuewen; Minuk, Gerald Y

Acute exposure to high concentrations of microcystin-LR (MC-LR) can cause significant hepatocyte injury. To document the effects of long-term, low-dose MC-LR exposure on hepatic inflammation and fibrosis in mice with healthy and diseased livers. Male CD1 mice (N = 20/group) were exposed to 1.0 μg/L of MC-LR in drinking water; 1.0 μg/L MC-LR plus 300 mg/L of the hepatotoxin thioacetamide (MC-LR/TAA); or 300 mg/L TAA alone for 28 weeks. Liver biochemistry and histology were documented at the end of the study period. In addition, hepatic stellate cells (HSCs), were exposed in vitro to MC-LR (0.1-10,000 μg/L) and monitored for changes in cell metabolism, proliferation and activation. Liver biochemistry and histology were essentially normal in MC-LR alone exposed mice. MC-LR/TAA and TAA alone exposed mice had significant hepatic inflammation and fibrosis but the extent of the changes were similar in the two groups. In vitro, MC-LR had no effect on HSC metabolism, proliferation or activation. Long-term, low-dose exposure to MC-LR is unlikely to lead to chronic liver disease in the setting of a normal liver or exacerbate existing liver disease in the setting of ongoing hepatitis.

Preferential Elimination of Older Erythrocytes in Circulation and Depressed Bone Marrow Erythropoietic Activity Contribute to Cadmium Induced Anemia in Mice

PubMed Central

Chatterjee, Sreoshi; Saxena, Rajiv K.

2015-01-01

Feeding cadmium chloride (50 or 1000 ppm CdCl2 in drinking water, ad libitum) to C57BL/6 mice resulted in a significant and sustained fall in blood erythrocyte count and hemoglobin levels that started 4 and 3 weeks after the start of 50 and 1000 ppm cadmium doses respectively. A transient yet significant reticulocytosis occurred during the first 4 weeks of cadmium treatment. Using the recently developed double in vivo biotinylation (DIB) technique, turnover of erythrocyte cohorts of different age groups was simultaneously monitored in control and cadmium treated mice. A significant accumulation of younger erythrocytes and a concomitant decline in the relative proportions of older erythrocytes in circulation was observed in both 50 and 1000 ppm cadmium groups indicating that older erythrocytes were preferentially eliminated in cadmium induced anemia. A significant increase in the erythropoietin levels in plasma was seen in mice exposed to 1000 ppm cadmium. Levels of inflammatory cytokines (IL1A, IL6, TNFα, IFNγ) were however not significantly altered in cadmium treated mice. A significant increase in cellular levels of reactive oxygen species (ROS) was observed in older erythrocytes in circulation but not in younger erythrocytes. Erythropoietic activity in the bone marrows and spleens of cadmium treated mice was examined by monitoring the relative proportion of cells belonging to the erythroid line of differentiation in these organs. Erythroid cells in bone marrow declined markedly (about 30%) in mice in the 1000 ppm cadmium group but the decline was not significant in the 50 ppm cadmium group. Cells representing various stages of erythroid differentiation in bone marrow and spleen were enumerated flow cytometrically by double staining with anti-Ter119 and anti-transferrin receptor (CD71) monoclonal antibodies. Decline of erythroid cells was essentially confined to pro-erythroblast and erythroblast-A, along with a concurrent increase in the splenic erythroid population indicating a stress response. In short cadmium exposure causes preferential clearance of older erythrocytes from circulation along with a depressed erythropoietic activity at higher doses. PMID:26161863

Assessment of immunotoxicity in female Fischer 344/N and Sprague Dawley rats and female B6C3F1 mice exposed to hexavalent chromium via the drinking water.

PubMed

Shipkowski, Kelly A; Sheth, Christopher M; Smith, Matthew J; Hooth, Michelle J; White, Kimber L; Germolec, Dori R

2017-12-01

Sodium dichromate dihydrate (SDD), an inorganic compound containing hexavalent chromium (Cr(VI)), is a common environmental contaminant of groundwater sources due to widespread industrial use. There are indications in the literature that Cr(VI) may induce immunotoxic effects following dermal exposure, including acting as both an irritant and a sensitizer; however, the potential immunomodulatory effects of Cr(VI) following oral exposure are relatively unknown. Following the detection of Cr(VI) in drinking water sources, the National Toxicology Program (NTP) conducted extensive evaluations of the toxicity and carcinogenicity of SDD following drinking water exposure, including studies to assess the potential for Cr(VI) to modulate immune function. For the immunotoxicity assessments, female Fischer 344/N (F344/N) and Sprague Dawley (SD) rats and female B 6 C 3 F 1 mice were exposed to SDD in drinking water for 28 consecutive days and evaluated for alterations in cellular and humoral immune function as well as innate immunity. Rats were exposed to concentrations of 0, 14.3, 57.3, 172, or 516 ppm SDD while mice were exposed to concentrations of 0, 15.6, 31.3, 62.5, 125, or 250 ppm SDD. Final mean body weight and body weight gain were decreased relative to controls in 250 ppm B 6 C 3 F 1 mice and 516 ppm SD rats. Water consumption was significantly decreased in F344/N and SD rats exposed to 172 and 516 ppm SDD; this was attributed to poor palatability of the SDD drinking water solutions. Several red blood cell-specific parameters were significantly (5-7%) decreased in 250 ppm mice; however, these parameters were unaffected in rats. Sporadic increases in the spleen IgM antibody response to sheep red blood cells (SRBC) were observed, however, these increases were not dose-dependent and were not reproducible. No significant effects were observed in the other immunological parameters evaluated. Overall, exposure to Cr(VI) in drinking water had limited effects on the immune system in both rats and mice.

Association of Diet With Skin Histological Features in UV-B-Exposed Mice.

PubMed

Bhattacharyya, Tapan K; Hsia, Yvonne; Weeks, David M; Dixon, Tatiana K; Lepe, Jessica; Thomas, J Regan

2017-09-01

Long-term exposure to solar radiation produces deleterious photoaging of the skin. It is not known if diet can influence skin photoaging. To study the influence of a calorie-restricted diet and an obesity diet in mice exposed to long-term UV-B irradiation to assess if there is an association between diet and histopathological response to UV-B irradiation. In this animal model study in an academic setting, the dorsal skin of SKH1 hairless mice receiving normal, calorie-restricted, and obesity diets was exposed to UV-B irradiation 3 times a week for 10 weeks and were compared with corresponding controls. The mice were placed in the following groups, with 8 animals in each group: (1) intact control (C) with regular diet and no UV-B exposure, (2) intact control with UV-B exposure (CR), (3) calorie-restricted diet (CrC), (4) calorie-restricted diet with UV-B exposure (CrR), (5) obesity diet (OC), and (6) obesity diet with UV-B exposure (OR). The experiment was conducted during October through December 2013. Tissue processing and histological analysis were completed in 2016. Histomorphometric analysis was performed on paraffin-embedded skin sections stained by histological and immunohistochemical methods for estimation of epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, mast cells, dermal cellularity, and adipose layer ratio. Changes in wrinkles were noted. Hairless female mice (age range, 6-8 weeks) were obtained. With a normal diet, changes from UV-B irradiation occurred in epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, and mast cells, which were modestly influenced by an obesity diet. Calorie restriction influenced the skin in nonirradiated control animals, with higher values for most variables. After UV-B exposure in animals with calorie restriction, epidermal thickness was increased, but other variables were unaffected. Animals receiving the calorie-restricted diet lost weight when exposed to long-term UV-B irradiation. Wrinkles were reduced in the calorie-restricted control group and in UV-B-exposed animals who received the obesity diet. Dietary alterations seem to modify histopathological responses to UV-B exposure in the skin of hairless mice. NA.

Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B{sub 1} and its dependence on p53 genotype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mulder, Jeanne E.; Bondy, Genevieve S.; Mehta, Rekha

Aflatoxin B{sub 1} (AFB{sub 1}) is biotransformed in vivo into an epoxide metabolite that forms DNA adducts that may induce cancer if not repaired. p53 is a tumor suppressor gene implicated in the regulation of global nucleotide excision repair (NER). Male heterozygous p53 knockout (B6.129-Trp53{sup tm1Brd}N5, Taconic) and wild-type mice were exposed to 0, 0.2 or 1.0 ppm AFB{sub 1} for 26 weeks. NER activity was assessed with an in vitro assay, using AFB{sub 1}-epoxide adducted plasmid DNA as a substrate. For wild-type mice, repair of AFB{sub 1}–N7-Gua adducts was 124% and 96% greater in lung extracts from mice exposedmore » to 0.2 ppm and 1.0 ppm AFB{sub 1} respectively, and 224% greater in liver extracts from mice exposed to 0.2 ppm AFB{sub 1} (p < 0.05). In heterozygous p53 knockout mice, repair of AFB{sub 1}–N7-Gua was only 45% greater in lung extracts from mice exposed to 0.2 ppm AFB{sub 1} (p < 0.05), and no effect was observed in lung extracts from mice treated with 1.0 ppm AFB{sub 1} or in liver extracts from mice treated with either AFB{sub 1} concentration. p53 genotype did not affect basal levels of repair. AFB{sub 1} exposure did not alter repair of AFB{sub 1}-derived formamidopyrimidine adducts in lung or liver extracts of either mouse genotype nor did it affect XPA or XPB protein levels. In summary, chronic exposure to AFB{sub 1} increased NER activity in wild-type mice, and this response was diminished in heterozygous p53 knockout mice, indicating that loss of one allele of p53 limits the ability of NER to be up-regulated in response to DNA damage. - Highlights: • Mice are chronically exposed to low doses of the mycotoxin aflatoxin B{sub 1} (AFB{sub 1}). • The effects of AFB{sub 1} and p53 status on nucleotide excision repair are investigated. • AFB{sub 1} increases nucleotide excision repair in wild type mouse lung and liver. • This increase is attenuated in p53 heterozygous mouse lung and liver. • Results portray the role of p53 in nucleotide excision repair after AFB{sub 1} exposure.« less

Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury

PubMed Central

Ávila, Leonardo C. M.; Bruggemann, Thayse R.; Bobinski, Franciane; da Silva, Morgana Duarte; Oliveira, Regiane Carvalho; Martins, Daniel Fernandes; Mazzardo-Martins, Leidiane; Duarte, Marta Maria Medeiros Frescura; de Souza, Luiz Felipe; Dafre, Alcir; Vieira, Rodolfo de Paula; Santos, Adair Roberto Soares; Bonorino, Kelly Cattelan; Hizume Kunzler, Deborah de C.

2015-01-01

Studies have reported that exposure to diesel exhaust particles (DEPs) induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12), Swimming (30 min/day) (n = 8), DEP (3 mg/mL—10 μL/mouse) (n = 9) and DEP+Swimming (n = 8). The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF), measured the lung homogenate levels of IL-1β, TNF-α, IL-6, INF-ϫ, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH) and the antioxidant enzymes catalase and glutathione peroxidase (GPx) in the lung. Swimming sessions decreased the number of total cells (p<0.001), neutrophils and lymphocytes (p<0.001; p<0.05) in the BALF, as well as lung levels of IL-1β (p = 0.002), TNF-α (p = 0.003), IL-6 (p = 0.0001) and IFN-ϫ (p = 0.0001). However, the levels of IL-10 (p = 0.01) and IL-1ra (p = 0.0002) increased in the swimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001). Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and p<0.002). We concluded that in this experimental model, the high-intensity swimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung inflammation in mice. PMID:26332044

Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury.

PubMed

Ávila, Leonardo C M; Bruggemann, Thayse R; Bobinski, Franciane; da Silva, Morgana Duarte; Oliveira, Regiane Carvalho; Martins, Daniel Fernandes; Mazzardo-Martins, Leidiane; Duarte, Marta Maria Medeiros Frescura; de Souza, Luiz Felipe; Dafre, Alcir; Vieira, Rodolfo de Paula; Santos, Adair Roberto Soares; Bonorino, Kelly Cattelan; Hizume Kunzler, Deborah de C

2015-01-01

Studies have reported that exposure to diesel exhaust particles (DEPs) induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12), Swimming (30 min/day) (n = 8), DEP (3 mg/mL-10 μL/mouse) (n = 9) and DEP+Swimming (n = 8). The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF), measured the lung homogenate levels of IL-1β, TNF-α, IL-6, INF-ϫ, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH) and the antioxidant enzymes catalase and glutathione peroxidase (GPx) in the lung. Swimming sessions decreased the number of total cells (p<0.001), neutrophils and lymphocytes (p<0.001; p<0.05) in the BALF, as well as lung levels of IL-1β (p = 0.002), TNF-α (p = 0.003), IL-6 (p = 0.0001) and IFN-ϫ (p = 0.0001). However, the levels of IL-10 (p = 0.01) and IL-1ra (p = 0.0002) increased in the swimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001). Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and p<0.002). We concluded that in this experimental model, the high-intensity swimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung inflammation in mice.

Polysaccharides induce radioprotection of murine hemopoietic stem cells and increase the LD50/30 days

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maisin, J.R.; Kondi-Tamba, A.; Mattelin, G.

1986-02-01

Intravenous administration of 60 mg/kg of a polysaccharide (MNR, MNZ, GLP/BO4, GLP/BO5) significantly decreases the mortality of mice exposed to a single dose of X rays. The dose reduction factors (DRF) obtained for MNZ, MNR, GLP/BO4, and GLP/BO5 given intraperitoneally 15 min before exposure were 2.16, 1.93, 1.80, and 1.94, respectively. The DRF was not increased when MNZ or GLP/BO4 were combined with injection of AET before X-ray exposure. The LD50 for the CFUs exposed in vivo in mice was 1.13 Gy for the treated mice and 0.75 Gy for the nontreated mice. This corresponds to a DRF of 1.6.more » The DRF calculated from the slope is 1.27.« less

Effect of zinc intake on hepatic autophagy during acute alcohol intoxication.

PubMed

Liuzzi, Juan P; Narayanan, Vijaya; Doan, Huong; Yoo, Changwon

2018-04-01

Autophagy is a conserved mechanism that plays a housekeeping role by eliminating protein aggregates and damaged organelles. Recent studies have demonstrated that acute ethanol intoxication induces hepatic autophagy in mice. The effect of dietary zinc intake on hepatic autophagic flux during ethanol intoxication has not been evaluated using animal models. Herein, we investigated whether zinc deficiency and excess can affect autophagic flux in the liver in mice and in human hepatoma cells acutely exposed to ethanol. A mouse model of binge ethanol feeding was utilized to analyze the effect of low, adequate, and high zinc intake on hepatic autophagic flux during ethanol intoxication. Autophagic flux was inferred by analyzing LC3II/LC3I ratio, protein levels of p62/SQSTM1, Beclin1 and Atg7, and phosphorylation of 4EBP1. In addition, the degradation of the fusion protein LC3-GFP and the formation of autophagosomes and autolysosomes were evaluated in cells. Ethanol treatment stimulated autophagy in mice and cells. High zinc intake resulted in enhanced autophagy in mice exposed to ethanol. Conversely, zinc deficiency was consistently associated with impaired ethanol-induced autophagy in mice and cells. Zinc-deficient mice exhibited a high degree of ethanol-driven steatosis. Furthermore, zinc depletion increased apoptosis in cells exposed to ethanol. The results of this study suggest that adequate zinc intake is necessary for proper stimulation of autophagy by ethanol. Poor zinc status is commonly found among alcoholics and could likely contribute to faulty autophagy.

Effects of exercise training on pulmonary vessel muscularization and right ventricular function in an animal model of COPD.

PubMed

Hassel, Erlend; Berre, Anne Marie; Skjulsvik, Anne Jarstein; Steinshamn, Sigurd

2014-09-28

Right ventricular dysfunction in COPD is common, even in the absence of pulmonary hypertension. The aim of the present study was to examine the effects of high intensity interval training (HIIT) on right ventricular (RV) function, as well as pulmonary blood vessel remodeling in a mouse model of COPD. 42 female A/JOlaHsd mice were randomized to exposure to either cigarette smoke or air for 6 hours/day, 5 days/week for 14 weeks. Mice from both groups were further randomized to sedentariness or HIIT for 4 weeks. Cardiac function was evaluated by echocardiography and muscularization of pulmonary vessel walls by immunohistochemistry. Smoke exposure induced RV systolic dysfunction demonstrated by reduced tricuspid annular plane systolic excursion. HIIT in smoke-exposed mice reversed RV dysfunction. There were no significant effects on the left ventricle of neither smoke exposure nor HIIT. Muscularization of the pulmonary vessels was reduced after exercise intervention, but no significant effects on muscularization were observed from smoke exposure. RV function was reduced in mice exposed to cigarette smoke. No Increase in pulmonary vessel muscularization was observed in these mice, implying that other mechanisms caused the RV dysfunction. HIIT attenuated the RV dysfunction in the smoke exposed mice. Reduced muscularization of the pulmonary vessels due to HIIT suggests that exercise training not only affects the heart muscle, but also has important effects on the pulmonary vasculature.

Mice heterozygous for the ATM gene are more sensitive to both X-ray and heavy ion exposure than are wildtypes

NASA Astrophysics Data System (ADS)

Worgul, B. V.; Smilenov, L.; Brenner, D. J.; Vazquez, M.; Hall, E. J.

Previous studies have shown that the eyes of ATM heterozygous mice exposed to low-LET radiation (X-rays) are significantly more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to high-LET radiation damage. Mice haplodeficient for the ATM gene and wildtypes were exposed to 325 mGy of 1 GeV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per lens epithelial cell nuclear area. Controls consisted of irradiated wildtype as well as unirradiated wildtype and heterozygous mice. Prevalence analyses for stage 0.5-3.0 cataracts indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the ATM gene. The data show that heterozygosity for the ATM gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that ATM heterozygotes in the human population may also be radiosensitive. This may have to be considered in the selection of individuals who will be exposed to both HZE particles and low-LET radiation as they may be predisposed to increased late normal tissue damage.

Global view of the mechanisms of improved learning and memory capability in mice with music-exposure by microarray.

PubMed

Meng, Bo; Zhu, Shujia; Li, Shijia; Zeng, Qingwen; Mei, Bing

2009-08-28

Music has been proved beneficial to improve learning and memory in many species including human in previous research work. Although some genes have been identified to contribute to the mechanisms, it is believed that the effect of music is manifold, behind which must concern a complex regulation network. To further understand the mechanisms, we exposed the mice to classical music for one month. The subsequent behavioral experiments showed improvement of spatial learning capability and elevation of fear-motivated memory in the mice with music-exposure as compared to the naïve mice. Meanwhile, we applied the microarray to compare the gene expression profiles of the hippocampus and cortex between the mice with music-exposure and the naïve mice. The results showed approximately 454 genes in cortex (200 genes up-regulated and 254 genes down-regulated) and 437 genes in hippocampus (256 genes up-regulated and 181 genes down-regulated) were significantly affected in music-exposing mice, which mainly involved in ion channel activity and/or synaptic transmission, cytoskeleton, development, transcription, hormone activity. Our work may provide some hints for better understanding the effects of music on learning and memory.

Lymphoidal involution and delayed homograft rejection in hypoxia-exposed mice.

NASA Technical Reports Server (NTRS)

Kmetz, J. M.; Anthony, A.

1972-01-01

Investigation of the relationship between histologic and cytochemical response patterns of the thymus, spleen, and lymph nodes of mice exposed to moderate hypoxia (380 mm Hg), and study, by histologic analysis, of the effect of hypoxia exposure on the skin homograft reaction used as an index of immunologic potential. The results obtained include the finding that functional changes in lymphatic organs occur during early weeks of hypoxia acclimation and that these changes probably reduce the ability of an animal to react to an immunological challenge.

Influence of heat, wind, and humidity on ultraviolet radiation injury.

PubMed

Owens, D W; Knox, J M

1978-12-01

We investigated the influence of heat, wind, and humidity on UVR-induced acute and chronic skin damage of experimental animals housed in environmental chambers and irradiated under controlled conditions. Hairless mice (strain HRS/J) irradiated after an increase of 10 degrees F in skin temperature had more skin damage than irradiated controls. Significantly more Swiss albino mice irradiated for 400 days while maintained at 90 degrees F developed tumors than did those receiving the same amount of UVR but maintained at room temperature. Mice exposed to UVR daily for 4 weeks while kept in wind of 7 mph had greater damage and slower recovery than animals irradiated but protected from wind. Wind also accelerated tumorigenesis in mice than received chronic UVR. Mice kept at 80% relative humidity and given a single dose of UVR had greater skin injury than animals irradiated while at 5% relative humidity. High midity also appears to accelerate skin cancer formation in animals that were exposed to chronic UVR.

Peculiarities of carcinogenesis under simultaneous oral administration of benzo(a)pyrene and o-cresol in mice.

PubMed Central

Yanysheva NYa; Balenko, N V; Chernichenko, I A; Babiy, V F

1993-01-01

A modifying influence of ortho-cresol (o-cresol) on the carcinogenic effect of benzo(a)pyrene (BaP) with combined oral administration to CC57Br mice had been found. During simultaneous administration of o-cresol (1 mg) and BaP (1 mg), the incidence of tumors, the multiplicity of tumors, and the degree of malignancy all increased, but the latency was shortened. When o-cresol was administered before or after BaP (in identical doses), the carcinogenic effect was weakened. When o-cresol (10 mg) and BaP (5 mg) were administered simultaneously, the incidence of malignant tumors was similar to controls receiving BaP only (13.8%), indicating inhibition of carcinogenesis. PMID:8143642

Mycobacterium ulcerans low infectious dose and mechanical transmission support insect bites and puncturing injuries in the spread of Buruli ulcer.

PubMed

Wallace, John R; Mangas, Kirstie M; Porter, Jessica L; Marcsisin, Renee; Pidot, Sacha J; Howden, Brian; Omansen, Till F; Zeng, Weiguang; Axford, Jason K; Johnson, Paul D R; Stinear, Timothy P

2017-04-01

Addressing the transmission enigma of the neglected disease Buruli ulcer (BU) is a World Health Organization priority. In Australia, we have observed an association between mosquitoes harboring the causative agent, Mycobacterium ulcerans, and BU. Here we tested a contaminated skin model of BU transmission by dipping the tails from healthy mice in cultures of the causative agent, Mycobacterium ulcerans. Tails were exposed to mosquito (Aedes notoscriptus and Aedes aegypti) blood feeding or punctured with sterile needles. Two of 12 of mice with M. ulcerans contaminated tails exposed to feeding A. notoscriptus mosquitoes developed BU. There were no mice exposed to A. aegypti that developed BU. Eighty-eight percent of mice (21/24) subjected to contaminated tail needle puncture developed BU. Mouse tails coated only in bacteria did not develop disease. A median incubation time of 12 weeks, consistent with data from human infections, was noted. We then specifically tested the M. ulcerans infectious dose-50 (ID50) in this contaminated skin surface infection model with needle puncture and observed an ID50 of 2.6 colony-forming units. We have uncovered a biologically plausible mechanical transmission mode of BU via natural or anthropogenic skin punctures.

NMDA receptor GluN2A subunit deletion protects against dependence-like ethanol drinking.

PubMed

Jury, Nicholas J; Radke, Anna K; Pati, Dipanwita; Kocharian, Adrina; Mishina, Masayoshi; Kash, Thomas L; Holmes, Andrew

2018-06-25

The N-methyl- D -aspartate receptor (NMDAR) is mechanistically involved in the behavioral and neurophysiological effects of alcohol, but the specific role of the GluN2A subunit remains unclear. Here, we exposed mice with constitutive GluN2A gene knockout (KO) to chronic intermittent ethanol vapor (CIE) and tested for EtOH consumption/preference using a two-bottle choice paradigm, as well as NMDAR-mediated transmission at basolateral amygdala synapses via ex vivo slice electrophysiology. Results showed that GluN2A KO mice attained comparable blood EtOH levels in response to CIE exposure, but did not exhibit the significant increase in EtOH drinking that was observed in CIE-exposed wildtypes. GluN2A KO mice also showed no alterations in BLA NMDAR-mediated synaptic transmission after CIE, relative to air-exposed, whereas C57BL/6 J mice showed an attenuated synaptic response to GluN2B antagonism. Taken together, these data add to mounting evidence supporting GluN2A-containing NMDARs as a mechanism underlying relative risk for developing EtOH dependence after repeated EtOH exposure. Copyright © 2018. Published by Elsevier B.V.

Oxidative phosphorylation of liver mitochondria from mice acclimatized to hypobaric hypoxia

NASA Astrophysics Data System (ADS)

Leon-Velarde, F.; Whittembury, J.; Monge, C.

1986-09-01

Mice exposed to intermittent hypobaric hypoxia for 20 hours a day, 6 days a week, develop extracellular adaptive responses similar to those found in humans exposed to oxygen tension equivalent to that found at an altitude of 4500 m. Isolated liver mitochondria from these animals show no significant differences in rates of substrate-stimulated respiration, ADP-stimulated respiration and the respiratory control ratio (RCR), when compared with sea level controls. Undetectable or negligible differences in these parameters are also noted when sea level animals are exposed for one hour to severe hypoxia (7% O2). We therefore conclude that the oxidative phosphorylation capacity of the isolated mouse liver mitochondria remains unaltered in both acute and chronic hypoxia. However the in vivo oxygen consumption by mice at this degree of hypoxia was markedly reduced. Lack of observable changes in oxidative phosphorylation could be accounted for by extracellular adaptations in mitochondria isolated from acclimatized animals. This explanation, however, is not consistent with the lack of changes on oxidative phosphorylation in mitochondria isolated from mice undergoing acute hypoxia at sea level. It is then suggested that isolated mitochondrial preparations are of limited value for investigating biochemical mechanisms underlying the variation of cellular respiration occurring in vivo.

Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice

PubMed Central

Alsulimani, Helal Hussain; Ye, Qi

2015-01-01

Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe-/-) and their control wild-type (Hfe+/+) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe+/+ mice, but not in Hfe-/- mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe+/+ compared with water-drinking Hfe+/+ mice. However, Mn-exposed Hfe-/- mice spent more time to find the target hole than Mn-drinking Hfe+/+ mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload disorders. PMID:26877837

Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice.

PubMed

Alsulimani, Helal Hussain; Ye, Qi; Kim, Jonghan

2015-12-01

Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe (-/-)) and their control wild-type (Hfe (+/+)) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe (+/+) mice, but not in Hfe (-/-) mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe (+/+) compared with water-drinking Hfe (+/+) mice. However, Mn-exposed Hfe (-/-) mice spent more time to find the target hole than Mn-drinking Hfe (+/+) mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload disorders.

Leptin deficiency-induced obesity exacerbates ultraviolet B radiation-induced cyclooxygenase-2 expression and cell survival signals in ultraviolet B-irradiated mouse skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sharma, Som D.; Katiyar, Santosh K., E-mail: skatiyar@uab.ed; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294

Obesity has been implicated in several inflammatory diseases and in different types of cancer. Chronic inflammation induced by exposure to ultraviolet (UV) radiation has been implicated in various skin diseases, including melanoma and nonmelanoma skin cancers. As the relationship between obesity and susceptibility to UV radiation-caused inflammation is not clearly understood, we assessed the role of obesity on UVB-induced inflammation, and mediators of this inflammatory response, using the genetically obese (leptin-deficient) mouse model. Leptin-deficient obese (ob/ob) mice and wild-type counterparts (C57/BL6 mice) were exposed to UVB radiation (120 mJ/cm{sup 2}) on alternate days for 1 month. The mice were thenmore » euthanized and skin samples collected for analysis of biomarkers of inflammatory responses using immunohistochemistry, western blotting, ELISA and real-time PCR. Here, we report that the levels of inflammatory responses were higher in the UVB-exposed skin of the ob/ob obese mice than those in the UVB-exposed skin of the wild-type non-obese mice. The levels of UVB-induced cyclooxygenase-2 expression, prostaglandin-E{sub 2} production, proinflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), and proliferating cell nuclear antigen and cell survival signals (phosphatidylinositol-3-kinase and p-Akt-Ser{sup 473}) were higher in the skin of the ob/ob obese mice than the those in skin of their wild-type non-obese counterparts. Compared with the wild-type non-obese mice, the leptin-deficient obese mice also exhibited greater activation of NF-kappaB/p65 and fewer apoptotic cells in the UVB-irradiated skin. Our study suggests for the first time that obesity in mice is associated with greater susceptibility to UVB-induced inflammatory responses and, therefore, obesity may increase susceptibility to UVB-induced inflammation-associated skin diseases, including the risk of skin cancer.« less

Tomato Lycopene Extract Prevents Lipopolysaccharide-Induced NF-κB Signaling but Worsens Dextran Sulfate Sodium-Induced Colitis in NF-κBEGFP Mice

PubMed Central

Joo, Young-Eun; Karrasch, Thomas; Mühlbauer, Marcus; Allard, Brigitte; Narula, Acharan; Herfarth, Hans H.; Jobin, Christian

2009-01-01

Background The impact of tomato lycopene extract (TLE) on intestinal inflammation is currently unknown. We investigated the effect of TLE on lipopolysaccharide (LPS)-induced innate signaling and experimental colitis. Methodology/Principal Findings Mice were fed a diet containing 0.5 and 2% TLE or isoflavone free control (AIN-76). The therapeutic efficacy of TLE diet was assessed using dextran sulfate sodium (DSS) exposed mice and IL-10−/−;NF-κBEGFP mice, representing an acute and spontaneous chronic colitis model respectively. A mini-endoscope was used to determine the extent of macroscopic mucosal lesions. Murine splenocytes and intestinal epithelial cells were used to determine the in vitro impact of TLE on LPS-induced NF-κB signaling. In vitro, TLE blocked LPS-induced IκBα degradation, RelA translocation, NF-κB transcriptional activity and MIP-2 mRNA accumulation in IEC-18 cells. Moreover, LPS-induced IL-12p40 gene expression was dose-dependently inhibited in TLE-treated splenocytes. Interestingly, DSS-induced acute colitis worsened in TLE-fed NF-κBEGFP mice compared to control diet as measured by weight loss, colonoscopic analysis and histological scores. In contrast, TLE-fed IL-10−/−;NF-κBEGFP mice displayed decreased colonic EGFP expression compared to control diet. IL-6, TNFα, and MCP-1 mRNA expression were increased in the colon of TLE-fed, DSS-exposed NF-κBEGFP mice compared to the control diet. Additionally, caspase-3 activation and TUNEL positive cells were enhanced in TLE diet-fed, DSS-exposed mice as compared to DSS control mice. Conclusions/ Significance These results indicate that TLE prevents LPS-induced proinflammatory gene expression by blocking of NF-κB signaling, but aggravates DSS-induced colitis by enhancing epithelial cell apoptosis. PMID:19234608

Effect of Different Stressors on Voluntary Ethanol Intake in Ethanol-Dependent and Nondependent C57BL/6J Mice

PubMed Central

Lopez, Marcelo F.; Anderson, Rachel I.; Becker, Howard C.

2016-01-01

Several animal models have evaluated the effect of stress on voluntary ethanol intake with mixed results. The experiments reported here examined the effects of different stressors on voluntary ethanol consumption in dependent and nondependent adult male C57BL/6J mice. In Experiment 1, restraint, forced swim, and social defeat stress procedures all tended to reduce ethanol intake in nondependent mice regardless of whether the stress experience occurred 1 h or 4 h prior to ethanol access. The reduction in ethanol consumption was most robust following restraint stress. Experiment 2 examined the effects of forced swim stress and social defeat stress on drinking in a dependence model that involved repeated cycles of chronic intermittent ethanol (CIE) exposure. Repeated exposure to forced swim stress prior to intervening test drinking periods that followed repeated cycles of CIE exposure further increased ethanol consumption in CIE-exposed mice while not altering intake in nondependent mice. In contrast, repeated exposure to the social defeat stressor in a similar manner reduced ethanol consumption in CIE-exposed mice while not altering drinking in nondependent mice. Results from Experiment 3 confirmed this selective effect of forced swim stress increasing ethanol consumption in mice with a history of CIE exposure, and also demonstrated that enhanced drinking is only observed when the forced swim stressor is administered during each test drinking week, but not if it is applied only during the final test week. Collectively, these studies point to a unique interaction between repeated stress experience and CIE exposure, and also suggest that such an effect depends on the nature of the stressor. Future studies will need to further explore the generalizability of these results, as well as mechanisms underlying the ability of forced swim stress to selectively further enhance ethanol consumption in dependent (CIE-exposed) mice but not alter intake in nondependent animals. PMID:26992696

Effect of different stressors on voluntary ethanol intake in ethanol-dependent and nondependent C57BL/6J mice.

PubMed

Lopez, Marcelo F; Anderson, Rachel I; Becker, Howard C

2016-03-01

Several animal models have evaluated the effect of stress on voluntary ethanol intake with mixed results. The experiments reported here examined the effects of different stressors on voluntary ethanol consumption in dependent and nondependent adult male C57BL/6J mice. In Experiment 1, restraint, forced swim, and social defeat stress procedures all tended to reduce ethanol intake in nondependent mice regardless of whether the stress experience occurred 1 h or 4 h prior to ethanol access. The reduction in ethanol consumption was most robust following restraint stress. Experiment 2 examined the effects of forced swim stress and social defeat stress on drinking in a dependence model that involved repeated cycles of chronic intermittent ethanol (CIE) exposure. Repeated exposure to forced swim stress prior to intervening test drinking periods that followed repeated cycles of CIE exposure further increased ethanol consumption in CIE-exposed mice while not altering intake in nondependent mice. In contrast, repeated exposure to the social defeat stressor in a similar manner reduced ethanol consumption in CIE-exposed mice while not altering drinking in nondependent mice. Results from Experiment 3 confirmed this selective effect of forced swim stress increasing ethanol consumption in mice with a history of CIE exposure, and also demonstrated that enhanced drinking is only observed when the forced swim stressor is administered during each test drinking week, but not if it is applied only during the final test week. Collectively, these studies point to a unique interaction between repeated stress experience and CIE exposure, and also suggest that such an effect depends on the nature of the stressor. Future studies will need to further explore the generalizability of these results, as well as mechanisms underlying the ability of forced swim stress to selectively further enhance ethanol consumption in dependent (CIE-exposed) mice but not alter intake in nondependent animals. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparison of the metabolic and ventilatory response to hypoxia and H2S in unsedated mice and rats.

PubMed

Haouzi, Philippe; Bell, Harold J; Notet, Veronique; Bihain, Bernard

2009-07-31

Hypoxia alters the control of breathing and metabolism by increasing ventilation through the arterial chemoreflex, an effect which, in small-sized animals, is offset by a centrally mediated reduction in metabolism and respiration. We tested the hypothesis that hydrogen sulfide (H(2)S) is involved in transducing these effects in mammals. The rationale for this hypothesis is twofold. Firstly, inhalation of a 20-80 ppm H(2)S reduces metabolism in small mammals and this effect is analogous to that of hypoxia. Secondly, endogenous H(2)S appears to mediate some of the cardio-vascular effects of hypoxia in non-mammalian species. We, therefore, compared the ventilatory and metabolic effects of exposure to 60 ppm H(2)S and to 10% O(2) in small and large rodents (20g mice and 700g rats) wherein the metabolic response to hypoxia has been shown to differ according to body mass. H(2)S and hypoxia produced profound depression in metabolic rate in the mice, but not in the large rats. The depression was much faster with H(2)S than with hypoxia. The relative hyperventilation produced by hypoxia in the mice was replaced by a depression with H(2)S, which paralleled the drop in metabolic rate. In the larger rats, ventilation was stimulated in hypoxia, with no change in metabolism, while H(2)S affected neither breathing nor metabolism. When mice were simultaneously exposed to H(2)S and hypoxia, the stimulatory effects of hypoxia on breathing were abolished, and a much larger respiratory and metabolic depression was observed than with H(2)S alone. H(2)S had, therefore, no stimulatory effect on the arterial chemoreflex. The ventilatory depression during hypoxia and H(2)S in small mammals appears to be dependent upon the ability to decrease metabolism.

Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

PubMed Central

Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

2016-01-01

Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs of mice to acquire an immune-suppressive phenotype and reduce T-cell mediated anti-tumor responses. Agents that block MCSF prevent this effect, allowing radiation to have increased efficacy in slowing tumor growth. PMID:26946344

Suppression of antigen-specific antibody responses in mice ...

EPA Pesticide Factsheets

T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARa)-dependent and if suppression is associated with specific targeting of T- or B-cells, three separate experiments were conducted: (1) female PPARa constitutive knockout (PPARa KO; B6.129S4-Ppar(tm1Gonz)N12) and wild-type controls (WT; C57BL/6-Tac) exposed to 0, 7.5, or 30 mg PFOA/kg for 15 days were immunized on Day 11 with a T-cell-dependent antigen and sera then collected for measures of antigen-specific lgM titers (TDAR) 5 days later; (2) female C57BL/6N WT mice exposed to 0, 0.94, 1.88, 3.75, or 7.5mg PFOA/kg for 15 days were immunized with a T-cell-independent antigen on Day 11 and sera were then collected foranalyses of antigen-specific lgM titers (TIAR) 7 days later; and (3) splenic lymphocyte phenotypes were assessed in unimmunized female C57BL/6N WT mice exposed to 0, 3.75, or 7.5 mg PFOA/kg for 10 days to investigate effects of PFOA in the absence of specific immunization. Separate groups of mice were immunized with a T-cell-dependent antigen after 11 days of exposure and splenic lymphocyte sub-populations were assessed after 13 or 15 days of exposure to assess numbers of stimulated cells. The results indicated that exposure to ≥1.88mg PFOA/kg suppressed the TIAR; exposure to 30 mg PFOA/k

Toxicogenomic evaluation of microcystin-LR treated with ultrasonic irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hudder, Alice; Song Weihua; O'Shea, Kevin E.

2007-05-01

Microcystins are a family of toxins produced by cyanobacteria found throughout the world in marine and freshwater environments. The most commonly encountered form of microcystin is microcystin-LR (MC-LR). Humans are exposed to MC-LR by drinking contaminated water. The toxin accumulates rapidly in the liver where it exerts most of its damage. Treatment of water containing MC-LR by ultrasonic irradiation leads to the breakdown of the toxin. Both the parent toxin and the treated toxin reaction products (TTRP) were evaluated for toxic effects in mice. Animals were exposed to purified MC-LR or an equivalent dose of the TTRP and sacrificed aftermore » 4 h or 24 h. Serum was collected and assayed for lactate dehydrogenase (LDH) activity as an indicator of hepatotoxicity. LDH activity was detected in the serum of MC-LR exposed mice indicative of liver damage, but not in control mice. Only a fraction of that activity was detectable in mice exposed to TTRP. Liver RNA was used for microarray analysis and real-time PCR. Individual animals varied in their overall genomic response to the toxin; however, only 20 genes showed consistent changes in expression. These include chaperones which may be part of a generalized stress response; cytochrome P450 which may be involved in metabolizing the toxin; and lipid dystrophy genes such as lipin-2, uridine phosphorylase and a homolog to tribbles, a stress-inducible gene involved in cell death. Of the genes that responded to the MC-LR, none showed significant changes in expression profile in response to TTRP. Taken together, the data indicate that ultrasonic irradiation of MC-LR effectively reduces hepatotoxicity in mice and therefore may be a useful method for detoxification of drinking water.« less

Blast biology: a study of the primary and tertiary effects of blast in open underground protective shelters. Project 33. 1 of Operation Plumbbob

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ricmond, D.R.; Taborelli, R.V.; Bowen, I.G.

1959-02-01

Dogs, pigs, rabbits, guinea pigs, and mice were exposed to nuclear detonations in two open underground partitioned shelters. The shelters were of similar construction, and each was exposed to separate detonations. Each inner chamber filled through its own orifice; thus four separate pressure environments were obtained. An aerodynamic mound was placed over the escape hatch of each structure to determine its effect on the pressure-curve shape inside the chamber. In one test a sieve plate bolted across the top of the mound was evaluated. Wind protective baffles of solid plate and of heavy wire screen were installed in the sheltersmore » to compare primary and tertiary blast effects on dogs. The shelters also contained static and dynamic pressure gages, radiation detectors, telemetering devices, and, in one test, air-temperature measuring instruments, dust-collecting trays, and eight pigs for the biological assessment of thermal effects. One dog was severely injured from tertiary blast effects associated with a maximal dynamic pressure (Q) of 10.5 psi, and one was undamaged with a maximal Q of 2 psi. Primary blast effects resulting from peak overpressures of 30.3, 25.5, 9.5, and 4.1 psi were minimal. The mortality was 19% of the mice exposed to a peak pressure of 30.3 psi and 5 and 3% of the guinea pigs and mice exposed to a peak pressure of 25.5 psi. Many of the rabbits, guinea pigs, and mice sustained slight lung hemorrhages at maximum pressues of 25.5 and 30.3 psi. Eardrum perforation data for all species, except mice, were recorded. Following shot 2, thermal effects were noted. Animals of the groups saved for observation have died from ionizing-radiation effects.« less

BLAST BIOLOGY--A STUDY OF THE PRIMARY AND TERTIARY EFFECTS OF BLAST IN OPEN UNDERGROUND PROTECTIVE SHELTERS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ricmond, D.R.; Taborelli, R.V.; Bowen, I.G.

1959-02-01

Dogs, pigs, rabbits, guinea pigs, and mice were exposed to nuclear detonatiors in two open underground pantitioned shelters. The shelters were of similar constructions and each was exposed to separate detonations. Each inner chamber filled through its own orifice; thus four separate pressure enviromments were obtained. An aerodynamic mound was placed over the escape hatch of each structure to determine its effect on the pressurecurve shape inside the chamber. In one test a sieve plate bolted across the top of the mound was evaluated. Wind protective baffles of solid plate and of heavy wire screen were installed in the sheltersmore » to compare primary and tertiary blast effects on dogs. The shelters also contained static and dynamic pressure gages, radiation detectors, telemetering devices, and, in one test, air-temperature measuring instruments, dustcollecting trays, and eight pigs for the biological assessment of thermal effects. One dog was severely injured from tertiary blast effects associated with a maximal dynamic pressure (Q) of 10.5 psi, and one was undamaged with a maximal Q of 2 psi. Primary blast effects resulting from peak overpressures of 30.3, 25.5, 9.5. and 4.1 psi were minimal. The mortality was 19 per cent of the mice exposed to a peak pressure of 30.3 psi and 5 and 3 per cent of the guinea pigs and mice exposed to a peak pressure of 25.5 psi. Many of the rabbits, guinea pigs, and mice sustained slight lung hemorrhages at maximum pressures of 25.5 and 30.3 psi. Eardrum perforation data for all species, except mice, were recorded. Following shot 2, thermal effects were noted. Animals of the groups saved for observation have died from ionizing-radiation effects. (auth)« less

MMP-9-Dependent Serum-Borne Bioactivity Caused by Multiwalled Carbon Nanotube Exposure Induces Vascular Dysfunction via the CD36 Scavenger Receptor

PubMed Central

Aragon, Mario; Erdely, Aaron; Bishop, Lindsey; Salmen, Rebecca; Weaver, John; Liu, Jim; Hall, Pamela; Eye, Tracy; Kodali, Vamsi; Zeidler-Erdely, Patti; Stafflinger, Jillian E.; Ottens, Andrew K.; Campen, Matthew J.

2016-01-01

Inhalation of multiwalled carbon nanotubes (MWCNT) causes systemic effects including vascular inflammation, endothelial dysfunction, and acute phase protein expression. MWCNTs translocate only minimally beyond the lungs, thus cardiovascular effects thereof may be caused by generation of secondary biomolecular factors from MWCNT-pulmonary interactions that spill over into the systemic circulation. Therefore, we hypothesized that induced matrix metalloproteinase-9 (MMP-9) is a generator of factors that, in turn, drive vascular effects through ligand-receptor interactions with the multiligand pattern recognition receptor, CD36. To test this, wildtype (WT; C57BL/6) and MMP-9−/− mice were exposed to varying doses (10 or 40 µg) of MWCNTs via oropharyngeal aspiration and serum was collected at 4 and 24 h postexposure. Endothelial cells treated with serum from MWCNT-exposed WT mice exhibited significantly reduced nitric oxide (NO) generation, as measured by electron paramagnetic resonance, an effect that was independent of NO scavenging. Serum from MWCNT-exposed WT mice inhibited acetylcholine (ACh)-mediated relaxation of aortic rings at both time points. Absence of CD36 on the aortic rings (obtained from CD36-deficient mice) abolished the serum-induced impairment of vasorelaxation. MWCNT exposure induced MMP-9 protein levels in both bronchoalveolar lavage and whole lung lysates. Serum from MMP-9−/− mice exposed to MWCNT did not diminish the magnitude of vasorelaxation in naïve WT aortic rings, although a modest right shift of the ACh dose–response curve was observed in both MWCNT dose groups relative to controls. In conclusion, pulmonary exposure to MWCNT leads to elevated MMP-9 levels and MMP-9-dependent generation of circulating bioactive factors that promote endothelial dysfunction and decreased NO bioavailability via interaction with vascular CD36. PMID:26801584

A Pilot Study Linking Endothelial Injury in Lungs and Kidneys in Chronic Obstructive Pulmonary Disease

PubMed Central

Laucho-Contreras, Maria E.; Petersen, Hans; Bijol, Vanesa; Sholl, Lynette M.; Choi, Mary E.; Divo, Miguel; Pinto-Plata, Victor; Chetta, Alfredo; Tesfaigzi, Yohannes; Celli, Bartolomé R.

2017-01-01

Rationale: Patients with chronic obstructive pulmonary disease (COPD) frequently have albuminuria (indicative of renal endothelial cell injury) associated with hypoxemia. Objectives: To determine whether (1) cigarette smoke (CS)-induced pulmonary and renal endothelial cell injury explains the association between albuminuria and COPD, (2) CS-induced albuminuria is linked to increases in the oxidative stress–advanced glycation end products (AGEs) receptor for AGEs (RAGE) pathway, and (3) enalapril (which has antioxidant properties) limits the progression of pulmonary and renal injury by reducing activation of the AGEs–RAGE pathway in endothelial cells in both organs. Methods: In 26 patients with COPD, 24 ever-smokers without COPD, 32 nonsmokers who underwent a renal biopsy or nephrectomy, and in CS-exposed mice, we assessed pathologic and ultrastructural renal lesions, and measured urinary albumin/creatinine ratios, tissue oxidative stress levels, and AGEs and RAGE levels in pulmonary and renal endothelial cells. The efficacy of enalapril on pulmonary and renal lesions was assessed in CS-exposed mice. Measurements and Main Results: Patients with COPD and/or CS-exposed mice had chronic renal injury, increased urinary albumin/creatinine ratios, and increased tissue oxidative stress and AGEs-RAGE levels in pulmonary and renal endothelial cells. Treating mice with enalapril attenuated CS-induced increases in urinary albumin/creatinine ratios, tissue oxidative stress levels, endothelial cell AGEs and RAGE levels, pulmonary and renal cell apoptosis, and the progression of chronic renal and pulmonary lesions. Conclusions: Patients with COPD and/or CS-exposed mice have pulmonary and renal endothelial cell injury linked to increased endothelial cell AGEs and RAGE levels. Albuminuria could identify patients with COPD in whom angiotensin-converting enzyme inhibitor therapy improves renal and lung function by reducing endothelial injury. PMID:28085500

Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma.

PubMed

McGovern, Toby K; Powell, William S; Day, Brian J; White, Carl W; Govindaraju, Karuthapillai; Karmouty-Quintana, Harry; Lavoie, Normand; Tan, Ju Jing; Martin, James G

2010-10-06

Exposure to chlorine (Cl2) causes airway injury, characterized by oxidative damage, an influx of inflammatory cells and airway hyperresponsiveness. We hypothesized that Cl2-induced airway injury may be attenuated by antioxidant treatment, even after the initial injury. Balb/C mice were exposed to Cl2 gas (100 ppm) for 5 mins, an exposure that was established to alter airway function with minimal histological disruption of the epithelium. Twenty-four hours after exposure to Cl2, airway responsiveness to aerosolized methacholine (MCh) was measured. Bronchoalveolar lavage (BAL) was performed to determine inflammatory cell profiles, total protein, and glutathione levels. Dimethylthiourea (DMTU;100 mg/kg) was administered one hour before or one hour following Cl2 exposure. Mice exposed to Cl2 had airway hyperresponsiveness to MCh compared to control animals pre-treated and post-treated with DMTU. Total cell counts in BAL fluid were elevated by Cl2 exposure and were not affected by DMTU treatment. However, DMTU-treated mice had lower protein levels in the BAL than the Cl2-only treated animals. 4-Hydroxynonenal analysis showed that DMTU given pre- or post-Cl2 prevented lipid peroxidation in the lung. Following Cl2 exposure glutathione (GSH) was elevated immediately following exposure both in BAL cells and in fluid and this change was prevented by DMTU. GSSG was depleted in Cl2 exposed mice at later time points. However, the GSH/GSSG ratio remained high in chlorine exposed mice, an effect attenuated by DMTU. Our data show that the anti-oxidant DMTU is effective in attenuating Cl2 induced increase in airway responsiveness, inflammation and biomarkers of oxidative stress.

Arsenic exposure in pregnant mice disrupts placental vasculogenesis and causes spontaneous abortion.

PubMed

He, Wenjie; Greenwell, Robert J; Brooks, Diane M; Calderón-Garcidueñas, Lilian; Beall, Howard D; Coffin, J Douglas

2007-09-01

Arsenic is an abundant toxicant in ground water and soil around areas with extractive industries. Human epidemiological studies have shown that arsenic exposure is linked to developmental defects and miscarriage. The placenta is known to utilize vasculogenesis to develop its circulation. The hypothesis tested here states the following: arsenic exposure causes placental dysmorphogenesis and defective placental vasculogenesis resulting in placental insufficiency and subsequent spontaneous abortion. To test this hypothesis, pregnant mice were exposed to sodium arsenite (AsIII) through drinking water from conception through weanling stages. Neonatal assessment of birth rates, pup weights, and litter sizes in arsenic exposed and control mothers revealed that AsIII-exposed mothers had only 40% the fecundity of controls. Preterm analysis at E12.5 revealed a loss of fecundity at E12.5 from either 20 ppm or greater exposures to AsIII. There was no loss of fecundity at E7.5 suggesting that spontaneous abortion occurs during placentation. Histomorphometry on E12.5 placentae from arsenic-exposed mice revealed placental dysplasia especially in the vasculature. These results suggest that arsenic toxicity is causative for mammalian spontaneous abortion by virtue of aberrant placental vasculogenesis and placental insufficiency.

Influence of electromagnetic pulse on the offspring sex ratio of male BALB/c mice.

PubMed

Li, Jin-Hui; Jiang, Da-Peng; Wang, Ya-Feng; Yan, Jia-Jia; Guo, Qi-Yan; Miao, Xia; Lang, Hai-Yang; Xu, Sheng-Long; Liu, Jun-Ye; Guo, Guo-Zhen

2017-09-01

Public concern is growing about the exposure to electromagnetic fields (EMF) and its effect on male reproductive health. Detrimental effect of EMF exposure on sex hormones, reproductive performance and sex-ratio was reported. The present study was designed to clarify whether paternal exposure to electromagnetic pulse (EMP) affects offspring sex ratio in mice. 50 male BALB/c mice aged 5-6 weeks were exposed to EMP daily for 2 weeks before mated with non-exposed females at 0d, 7d, 14d, 21d and 28d after exposure. Sex hormones including total testosterone, LH, FSH, and GnRH were detected using radioimmunoassay. The sex ratio was examined by PCR and agarose gel electrophoresis. The results of D0, D21 and D28 showed significant increases compared with sham-exposed groups. The serum testosterone increased significantly in D0, D14, D21, and D28 compared with sham-exposed groups (p<0.05). Overall, this study suggested that EMP exposure may lead to the disturbance of reproductive hormone levels and affect the offspring sex ratio. Copyright © 2017. Published by Elsevier B.V.

Adolescent Methylmercury Exposure Affects Choice and Delay Discounting in Mice

PubMed Central

Boomhower, Steven R.; Newland, M. Christopher

2016-01-01

The developing fetus is vulnerable to low-level exposure to methylmercury (MeHg), an environmental neurotoxicant, but the consequences of exposure during the adolescent period remain virtually unknown. The current experiments were designed to assess the effects of low-level MeHg exposure during adolescence on delay discounting, preference for small, immediate reinforcers over large, delayed ones, using a mouse model. Thirty-six male C57BL/6n mice were exposed to 0, 0.3, or 3.0 ppm mercury (as MeHg) via drinking water from postnatal day 21 through 59, encompassing the murine adolescent period. As adults, mice lever-pressed for a 0.01-cc droplet of milk solution delivered immediately or four 0.01-cc droplets delivered after a delay. Delays ranged from 1.26 to 70.79 seconds, all presented within a session. A model based on the Generalized Matching Law indicated that sensitivity to reinforcer magnitude was lower for MeHg-exposed mice relative to controls; responding in MeHg-exposed mice was relatively indifferent to the larger reinforcer. Sensitivity to reinforcer delay was reduced (delay discounting was decreased) in the 0.3-ppm group, but not in the 3.0-ppm group, compared to controls. Adolescence is a developmental period during which the brain and behavior may be vulnerable to MeHg exposure. As with gestational exposure, the effects are reflected in the impact of reinforcing stimuli. PMID:27677934

The lack of cytotoxic effect and radioadaptive response in splenocytes of mice exposed to low level internal β-particle irradiation through tritiated drinking water in vivo.

PubMed

Flegal, Matthew; Blimkie, Melinda; Roch-Lefevre, Sandrine; Gregoire, Eric; Klokov, Dmitry

2013-12-05

Health effects of tritium, a β-emitter and a by-product of the nuclear industry, is a subject of significant controversy. This mouse in vivo study was undertaken to monitor biological effects of low level tritium exposure. Mice were exposed to tritiated drinking water (HTO) at 10 KBq/L, 1 MBq/L and 20 MBq/L concentrations for one month. The treatment did not result in a significant increase of apoptosis in splenocytes. To examine if this low level tritium exposure alters radiosensitivity, the extracted splenocytes were challenged in vitro with 2 Gy γ-radiation, and apoptotic responses at 1 and 24 h were measured. No alterations in the radiosensitivity were detected in cells from mice exposed to tritium compared to sham-treated mice. In contrast, low dose γ-irradiation at 20 or 100 mGy, resulted in a significant increase in resistance to apoptotic cell death after 2 Gy irradiation; an indication of the radioadaptive response. Overall, our data suggest that low concentrations of tritium given to mice as HTO in drinking water do not exert cytotoxic effect in splenocytes, nor do they change cellular sensitivity to additional high dose γ-radiation. The latter may be considered as the lack of a radioadaptive response, typically observed after low dose γ-irradiation.

Organ specific mapping of in vivo redox state in control and cigarette smoke-exposed mice using EPR/NMR co-imaging

PubMed Central

Caia, George L.; Efimova, Olga V.; Velayutham, Murugesan; El-Mahdy, Mohamed A.; Abdelghany, Tamer M.; Kesselring, Eric; Petryakov, Sergey; Sun, Ziqi; Samouilov, Alexandre; Zweier, Jay L.

2014-01-01

In vivo mapping of alterations in redox status is important for understanding organ specific pathology and disease. While electron paramagnetic resonance imaging (EPRI) enables spatial mapping of free radicals, it does not provide anatomic visualization of the body. Proton MRI is well suited to provide anatomical visualization. We applied EPR/NMR co-imaging instrumentation to map and monitor the redox state of living mice under normal or oxidative stress conditions induced by secondhand cigarette smoke (SHS) exposure. A hybrid co-imaging instrument, EPRI (1.2 GHz) / proton MRI (16.18 MHz), suitable for whole-body co-imaging of mice was utilized with common magnet and gradients along with dual EPR/NMR resonators that enable co-imaging without sample movement. The metabolism of the nitroxide probe, 3–carbamoyl–proxyl (3-CP), was used to map the redox state of control and SHS-exposed mice. Co-imaging allowed precise 3D mapping of radical distribution and reduction in major organs such as the heart, lungs, liver, bladder and kidneys. Reductive metabolism was markedly decreased in SHS-exposed mice and EPR/NMR co-imaging allowed quantitative assessment of this throughout the body. Thus, in vivo EPR/NMR co-imaging enables in vivo organ specific mapping of free radical metabolism and redox stress and the alterations that occur in the pathogenesis of disease. PMID:22296801

Single- and double-walled carbon nanotubes enhance atherosclerogenesis by promoting monocyte adhesion to endothelial cells and endothelial progenitor cell dysfunction.

PubMed

Suzuki, Yuka; Tada-Oikawa, Saeko; Hayashi, Yasuhiko; Izuoka, Kiyora; Kataoka, Misa; Ichikawa, Shunsuke; Wu, Wenting; Zong, Cai; Ichihara, Gaku; Ichihara, Sahoko

2016-10-13

The use of carbon nanotubes has increased lately. However, the cardiovascular effect of exposure to carbon nanotubes remains elusive. The present study investigated the effects of pulmonary exposure to single-walled carbon nanotubes (SWCNTs) and double-walled carbon nanotubes (DWCNTs) on atherosclerogenesis using normal human aortic endothelial cells (HAECs) and apolipoprotein E-deficient (ApoE -/- ) mice, a model of human atherosclerosis. HAECs were cultured and exposed to SWCNTs or DWCNTs for 16 h. ApoE -/- mice were exposed to SWCNTs or DWCNTs (10 or 40 μg/mouse) once every other week for 10 weeks by pharyngeal aspiration. Exposure to CNTs increased the expression level of adhesion molecule (ICAM-1) and enhanced THP-1 monocyte adhesion to HAECs. ApoE -/- mice exposed to CNTs showed increased plaque area in the aorta by oil red O staining and up-regulation of ICAM-1 expression in the aorta, compared with vehicle-treated ApoE -/- mice. Endothelial progenitor cells (EPCs) are mobilized from the bone marrow into the circulation and subsequently migrate to the site of endothelial damage and repair. Exposure of ApoE -/- mice to high-dose SWCNTs or DWCNTs reduced the colony-forming units of EPCs in the bone marrow and diminished their migration function. The results suggested that SWCNTs and DWCNTs enhanced atherosclerogenesis by promoting monocyte adhesion to endothelial cells and inducing EPC dysfunction.

Organ specific mapping of in vivo redox state in control and cigarette smoke-exposed mice using EPR/NMR co-imaging

NASA Astrophysics Data System (ADS)

Caia, George L.; Efimova, Olga V.; Velayutham, Murugesan; El-Mahdy, Mohamed A.; Abdelghany, Tamer M.; Kesselring, Eric; Petryakov, Sergey; Sun, Ziqi; Samouilov, Alexandre; Zweier, Jay L.

2012-03-01

In vivo mapping of alterations in redox status is important for understanding organ specific pathology and disease. While electron paramagnetic resonance imaging (EPRI) enables spatial mapping of free radicals, it does not provide anatomic visualization of the body. Proton MRI is well suited to provide anatomical visualization. We applied EPR/NMR co-imaging instrumentation to map and monitor the redox state of living mice under normal or oxidative stress conditions induced by secondhand cigarette smoke (SHS) exposure. A hybrid co-imaging instrument, EPRI (1.2 GHz)/proton MRI (16.18 MHz), suitable for whole-body co-imaging of mice was utilized with common magnet and gradients along with dual EPR/NMR resonators that enable co-imaging without sample movement. The metabolism of the nitroxide probe, 3-carbamoyl-proxyl (3-CP), was used to map the redox state of control and SHS-exposed mice. Co-imaging allowed precise 3D mapping of radical distribution and reduction in major organs such as the heart, lungs, liver, bladder and kidneys. Reductive metabolism was markedly decreased in SHS-exposed mice and EPR/NMR co-imaging allowed quantitative assessment of this throughout the body. Thus, in vivo EPR/NMR co-imaging enables in vivo organ specific mapping of free radical metabolism and redox stress and the alterations that occur in the pathogenesis of disease.

Sex-based differences in lymphocyte proliferation in the spleen after vanadium inhalation.

PubMed

Rodriguez-Lara, Vianey; Muñiz-Rivera Cambas, Angelica; González Villalva, Adriana; Fortoul, Teresa I

2016-07-01

Vanadium (V) is a transition metal often adhered to particulate matter and released into the atmosphere as vanadium pentoxide (V2O5) by the burning of fossil fuels. This air pollutant causes adverse effects in the immune system. Lymphocytosis and splenomegaly have been reported with increased white pulp in mice after V inhalation. The effect of V on the immune system as related to sex has been poorly investigated. This study sought to determine if V inhalation (a) produced lymphoproliferation that could explain the changes previously observed in the spleen and in peripheral blood lymphocyte counts and (b) whether any observed effects differed due to gender. Immunohistochemical analyses of Ki-67, a specific proliferation marker, was made in the spleens of CD-1 male and female mice exposed for 1 h, twice a week, over a 12-week period to V2O5 (at 1.4 mg V2O5/m(3)) by whole-body inhalation; similar analyses were performed on spleens of control mice exposed to vehicle (filtered air). The results showed that in male mice there was a significant increase in percentage of Ki-67 immunopositive lymphocytes starting from the second week and until the end of the exposure. The Ki-67 signal was cytoplasmic and nuclear in the exposed males, while in controls the signal was only nuclear. In female mice, V inhalation singificantly increased the percentage of proliferating lymphocytes only after 1 week of exposure. Ki-67 signal was observed only in the nucleus of lymphocytes from the control and exposed females. The results here help to explain the splenomegaly and lymphocytosis observed previously in male mice and support the lymphoproliferative effect induced by V. Lastly, the finding that there was a sex difference in the effect of vanadium on lymphocyte proliferation suggests a role for sex hormones in potential protection against V immunotoxicity; however, further studies are needed to support this hypothesis.

Subchronic Exposure to Arsenic Represses the TH/TRβ1-CaMK IV Signaling Pathway in Mouse Cerebellum.

PubMed

Guan, Huai; Li, Shuangyue; Guo, Yanjie; Liu, Xiaofeng; Yang, Yi; Guo, Jinqiu; Li, Sheng; Zhang, Cong; Shang, Lixin; Piao, Fengyuan

2016-01-26

We previously reported that arsenic (As) impaired learning and memory by down-regulating calmodulin-dependent protein kinase IV (CaMK IV) in mouse cerebellum. It has been documented that the thyroid hormone receptor (TR)/retinoid X receptor (RXR) heterodimer and thyroid hormone (TH) may be involved in the regulation of CaMK IV. To investigate whether As affects the TR/RXR heterodimer and TH, we determined As concentration in serum and cerebellum, 3,5,3'-triiodothyronine (T3) and thyroxin (T4) levels in serum, and expression of CaMK IV, TR and RXR in cerebellum of mice exposed to As. Cognition function was examined by the step-down passive avoidance task and Morris water maze (MWM) tests. Morphology of the cerebellum was observed by Hematoxylin-Eosin staining under light microscope. Our results showed that the concentrations of As in the serum and cerebellum of mice both increased with increasing As-exposure level. A significant positive correlation was found between the two processes. Adeficit in learning and memory was found in the exposed mice. Abnormal morphologic changes of Purkinje cells were observed in cerebellum of the exposed mice. Moreover, the cerebellar expressions of CaMK IV protein and the TRβ gene, and TRβ1 protein were significantly lower in As-exposed mice than those in controls. Subchronic exposure to As appears to increase its level in serum and cerebella of mice, impairing learning and memory and down-regulating expression of TRβ1 as well as down-stream CaMK IV. It is also suggested that the increased As may be responsible for down-regulation of TRβ1 and CaMK IV in cerebellum and that the down-regulated TRβ1 may be involved in As-induced impairment of learning and memory via inhibiting CaMK IV and its down-stream pathway.

1950 MHz radiofrequency electromagnetic fields do not aggravate memory deficits in 5xFAD mice.

PubMed

Son, Yeonghoon; Jeong, Ye Ji; Kwon, Jong Hwa; Choi, Hyung-Do; Pack, Jeong-Ki; Kim, Nam; Lee, Yun-Sil; Lee, Hae-June

2016-09-01

The increased use of mobile phones has generated public concern about the impact of radiofrequency electromagnetic fields (RF-EMF) on health. In the present study, we investigated whether RF-EMFs induce molecular changes in amyloid precursor protein (APP) processing and amyloid beta (Aβ)-related memory impairment in the 5xFAD mouse, which is a widely used amyloid animal model. The 5xFAD mice at the age of 1.5 months were assigned to two groups (RF-EMF- and sham-exposed groups, eight mice per group). The RF-EMF group was placed in a reverberation chamber and exposed to 1950 MHz electromagnetic fields for 3 months (SAR 5 W/kg, 2 h/day, 5 days/week). The Y-maze, Morris water maze, and novel object recognition memory test were used to evaluate spatial and non-spatial memory following 3-month RF-EMF exposure. Furthermore, Aβ deposition and APP and carboxyl-terminal fragment β (CTFβ) levels were evaluated in the hippocampus and cortex of 5xFAD mice, and plasma levels of Aβ peptides were also investigated. In behavioral tests, mice that were exposed to RF-EMF for 3 months did not exhibit differences in spatial and non-spatial memory compared to the sham-exposed group, and no apparent change was evident in locomotor activity. Consistent with behavioral data, RF-EMF did not alter APP and CTFβ levels or Aβ deposition in the brains of the 5xFAD mice. These findings indicate that 3-month RF-EMF exposure did not affect Aβ-related memory impairment or Aβ accumulation in the 5xFAD Alzheimer's disease model. Bioelectromagnetics. 37:391-399, 2016. © 2016 The Authors Bioelectromagnetics published by Wiley Periodicals, Inc. on behalf of Bioelectromagnetics Society. © 2016 The Authors Bioelectromagnetics published by Wiley Periodicals, Inc. on behalf of Bioelectromagnetics Society.

From the Cover: Lifelong Exposure of C57bl/6n Male Mice to Bisphenol A or Bisphenol S Reduces Recovery From a Myocardial Infarction.

PubMed

Kasneci, Amanda; Lee, Jun Seong; Yun, Tae Jin; Shang, Jijun; Lampen, Shaun; Gomolin, Tamar; Cheong, Cheolho C; Chalifour, Lorraine E

2017-09-01

Bisphenol A (BPA) leaches from plastics to contaminate foodstuffs. Analogs, such as bisphenol S (BPS), are now used increasingly in manufacturing. Greater BPA exposure has been correlated with exacerbation of cardiovascular disease, including myocardial infarction (MI). To test the hypothesis that bisphenol exposure impairs cardiac healing, we exposed C57bl/6n mice to water containing 25ng/ml BPA or BPS from conception and surgically induced an MI in adult male progeny. Increased early death and cardiac dilation, and reduced cardiac function were found post-MI in BPA- and BPS-exposed mice. Flow cytometry revealed increased monocyte and macrophage infiltration that correlated with increased chemokine C-C motif ligand-2 expression in the infarct. In vitro BPA and BPS addition increased matrix metalloproteinase-9 (MMP) protein and secreted activity in RAW264.7 macrophage cells suggesting that invivo increases in MMP2 and MMP9 in exposed infarcts were myeloid-derived. Bone marrow-derived monocytes isolated from exposed mice had greater expression of pro-inflammatory polarization markers when chemokine stimulated indicating an enhanced susceptibility to develop a pro-inflammatory monocyte population. Chronic BPA exposure of estrogen receptor beta (ERβ) deficient mice did not worsen early death, cardiac structure/function, or expression of myeloid markers after an MI. In contrast, BPS exposure of ERβ-deficient mice resulted in greater death and expression of myeloid markers. We conclude that lifelong exposure to BPA or BPS augmented the monocyte/macrophage inflammatory response and adverse remodeling from an MI thereby reducing the ability to survive and successfully recover, and that the adverse effect of BPA, but not BPS, is downstream of ERβ signaling. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Photocarcinogenesis study of aloe vera [CAS NO. 481-72-1(Aloe-emodin)] in SKH-1 mice (simulated solar light and topical application study).

PubMed

2010-09-01

The popular recognition of the Aloe barbadensis Miller (Aloe vera) plant as a therapeutic dermatologic agent has led to the widespread incorporation of Aloe vera leaf extracts in skincare products. Studies have suggested that Aloe vera in skincare preparations may enhance the induction of skin cancer by ultraviolet radiation. A 1-year study was conducted in mice to determine whether the topical application of creams containing Aloe vera plant extracts (aloe gel, whole leaf, or decolorized whole leaf) or creams containing aloe-emodin would enhance the photocarcinogenicity of simulated solar light (SSL). 1-YEAR STUDY: groups of 36 male and 36 female Crl:SKH-1 (hr -/hr -) hairless mice received topical applications of control cream or creams containing 3% or 6% (w/w) aloe gel, whole leaf, or decolorized whole leaf or 7.46 or 74.6 µg/g aloe-emodin to the dorsal skin region each weekday morning. The mice were irradiated with SSL emitted from filtered 6 kW xenon arc lamps each weekday afternoon. The topical applications of creams and irradiance exposures were conducted 5 days per week for a period of 40 weeks. A 12-week recovery/observation period followed the 40-week treatment/exposure period. Additional groups of 36 male and 36 female mice received no cream and were exposed to 0.00, 6.85, 13.70, or 20.55 mJ⋅CIE/cm2 SSL per day. Mice that received no cream treatment and were exposed to increasing levels of SSL showed significant SSL exposure-dependent decreases in survival and significant increases in the in-life observations of skin lesion onset, incidence, and multiplicity, and significant SSL exposure-dependent increases in the incidences and multiplicities of histopathology-determined squamous cell nonneoplastic skin lesions (squamous hyperplasia and focal atypical hyperplasia) and squamous cell neoplasms (papilloma, carcinoma in situ, and/or carcinoma). Squamous cell neoplasms were not detected in mice that received no SSL exposure. The topical treatment with the control cream of mice that were exposed to SSL did not impart a measurable effect when compared with comparable measurements in mice that received no cream treatment and were exposed to the same level of SSL, suggesting that the control cream used in these studies did not alter the efficiency of the SSL delivered to mice or the tolerability of mice to SSL. The application of aloe gel creams to mice had no effect on body weights, survival, or the in-life observations of skin lesion onset, incidence, or multiplicity. The administration of aloe gel creams to male mice had no effect on the incidences or multiplicities of histopathology-determined squamous cell nonneoplastic skin lesions or neoplasms. Female mice treated with aloe gel creams (3% and 6%) had significantly increased multiplicities of squamous cell neoplasms. There were no treatment-related effects on body weights, survival, or the in-life observations of skin lesion onset, incidence, or multiplicity in mice treated with the whole leaf creams. In male mice exposed to SSL and treated with the 6% whole leaf cream, a significant increase was observed in the multiplicity of squamous cell neoplasms. Female mice exposed to SSL and treated with the 3% whole leaf creams had significantly decreased multiplicity of squamous cell nonneoplastic lesions and significantly increased multiplicity of squamous cell neoplasms. Female mice exposed to SSL and treated with the 6% whole leaf cream had significantly decreased multiplicity of squamous cell nonneoplastic lesions. The application of decolorized whole leaf creams to mice had no effect on body weights, survival, or the in-life observations of skin lesion onset, incidence, or multiplicity. Male mice administered the 3% decolorized whole leaf cream had significantly increased multiplicity of squamous cell neoplasms. Female mice administered the 3% decolorized whole leaf cream had significantly decreased multiplicity of squamous cell nonneoplastic skin lesions and significantly increased multiplicity of squamous cell neoplasms. In female mice that received the 6% decolorized whole leaf cream, there was a significant increase in the multiplicity of squamous cell neoplasms. As with the Aloe vera plant extracts, the application of aloe-emodin creams to mice had no measurable effect on body weights, survival, or the in-life observations of skin lesion onset, incidence, or multiplicity. The administration of aloe-emodin creams to male mice had no effect on the incidence or multiplicity of histopathology-determined nonneoplastic skin lesions or squamous cell neoplasms. Female mice treated with the 74.6 µg/g aloe-emodin cream had significantly decreased multiplicity of histopathology-determined squamous cell nonneoplastic skin lesions and significantly increased multiplicity of squamous cell neoplasms. these experiments investigated the potential of topical application of creams containing extracts of Aloe barbadensis Miller plant (aloe gel, whole leaf, or decolorized whole leaf) or aloe-emodin to alter the photocarcinogenic activity of filtered xenon arc simulated solar light (SSL) in male and female SKH-1 hairless mice. Data on skin lesions were collected both on digital images during the in-life phase and by histopathologic evaluation at necropsy. No effects of creams upon SSL-induced skin lesions were identified from data collected during the in-life phase. ALOE GEL OR ALOE-EMODIN: under the conditions of these studies, there was a weak enhancing effect of aloe gel or aloe-emodin on the photocarcinogenic activity of SSL in female but not in male SKH-1 mice based on an increase in the multiplicity of histopathologically-determined squamous cell neoplasms. under the conditions of these studies, there was a weak enhancing effect of aloe whole leaf or decolorized whole leaf on the photocarcinogenic activity of SSL in both male and female SKH-1 mice based on an increase in the multiplicity of histopathologically-determined squamous cell neoplasms.

Long-term effects of chronic nicotine on emotional and cognitive behaviors and hippocampus cell morphology in mice: comparisons of adult and adolescent nicotine exposure.

PubMed

Holliday, Erica D; Nucero, Paul; Kutlu, Munir G; Oliver, Chicora; Connelly, Krista L; Gould, Thomas J; Unterwald, Ellen M

2016-11-01

Nicotine dependence is associated with increased risk for emotional, cognitive and neurological impairments later in life. This study investigated the long-term effects of nicotine exposure during adolescence and adulthood on measures of depression, anxiety, learning and hippocampal pyramidal cell morphology. Mice (C57BL/6J) received saline or nicotine for 12 days via pumps implanted on postnatal day 32 (adolescent) or 54 (adults). Thirty days after cessation of nicotine/saline, mice were tested for learning using contextual fear conditioning, depression-like behaviors using the forced swim test or anxiety-like behaviors with the elevated plus maze. Brains from nicotine- or saline-exposed mice were processed with Golgi stain for whole neuron reconstruction in the CA1 and CA3 regions of the hippocampus. Results demonstrate higher depression-like responses in both adolescent and adult mice when tested during acute nicotine withdrawal. Heightened depression-like behaviors persisted when tested after 30 days of nicotine abstinence in mice exposed as adolescents, but not adults. Adult, but not adolescent, exposure to nicotine resulted in increased open-arm time when tested after 30 days of abstinence. Nicotine exposure during adolescence caused deficits in contextual fear learning indicated by lower levels of freezing to the context as compared with controls when tested 30 days later. In addition, reduced dendritic length and complexity in the apical CA1 branches in adult mice exposed to nicotine during adolescence were found. These results demonstrate that nicotine exposure and withdrawal can have long-term effects on emotional and cognitive functioning, particularly when nicotine exposure occurs during the critical period of adolescence. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Male aromatase-knockout mice exhibit normal levels of activity, anxiety and "depressive-like" symptomatology.

PubMed

Dalla, C; Antoniou, K; Papadopoulou-Daifoti, Z; Balthazart, J; Bakker, J

2005-09-08

It is well known that estradiol derived from neural aromatization of testosterone plays a crucial role in the development of the male brain and the display of sexual behaviors in adulthood. It was recently found that male aromatase knockout mice (ArKO) deficient in estradiol due to a mutation in the aromatase gene have general deficits in coital behavior and are sexually less motivated. We wondered whether these behavioral deficits of ArKO males could be related to changes in activity, exploration, anxiety and "depressive-like" symptomatology. ArKO and wild type (WT) males were subjected to open field (OF), elevated plus maze (EPM), and forced swim tests (FST), after being exposed or not to chronic mild stress (CMS). CMS was used to evaluate the impact of chronic stressful procedures and to unveil possible differences between genotypes. There was no effect of genotype on OF, EPM and FST behavioral parameters. WT and ArKO mice exposed to CMS or not exhibited the same behavioral profile during these three types of tests. However, all CMS-exposed mice (ArKO and WT) spent less time in the center of the EPM. Additionally, floating duration measured in the FST increased between two tests in both WT and ArKO mice, though that increase was less prominent in mice previously subjected to CMS than in controls. Therefore, both ArKO and WT males displayed the same behavior and had the same response to CMS however CMS exposure slightly modified the behavior displayed by mice of both genotypes in the FST and EPM paradigms. These results show that ArKO males display normal levels of activity, exploration, anxiety and "depressive-like" symptomatology and thus their deficits in sexual behavior are specific in nature and do not result indirectly from other behavioral changes.

Sustained hyperoxia-induced NF-κB activation improves survival and preserves lung development in neonatal mice

PubMed Central

McKenna, Sarah; Michaelis, Katherine A.; Agboke, Fadeke; Liu, Thanh; Han, Kristie; Yang, Guang; Dennery, Phyllis A.

2014-01-01

Oxygen toxicity contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Neonatal mice exposed to hyperoxia develop a simplified lung structure that resembles BPD. Sustained activation of the transcription factor NF-κB and increased expression of protective target genes attenuate hyperoxia-induced mortality in adults. However, the effect of enhancing hyperoxia-induced NF-κB activity on lung injury and development in neonatal animals is unknown. We performed this study to determine whether sustained NF-κB activation, mediated through IκBβ overexpression, preserves lung development in neonatal animals exposed to hyperoxia. Newborn wild-type (WT) and IκBβ-overexpressing (AKBI) mice were exposed to hyperoxia (>95%) or room air from day of life (DOL) 0–14, after which all animals were kept in room air. Survival curves were generated through DOL 14. Lung development was assessed using radial alveolar count (RAC) and mean linear intercept (MLI) at DOL 3 and 28 and pulmonary vessel density at DOL 28. Lung tissue was collected, and NF-κB activity was assessed using Western blot for IκB degradation and NF-κB nuclear translocation. WT mice demonstrated 80% mortality through 14 days of exposure. In contrast, AKBI mice demonstrated 60% survival. Decreased RAC, increased MLI, and pulmonary vessel density caused by hyperoxia in WT mice were significantly attenuated in AKBI mice. These findings were associated with early and sustained NF-κB activation and expression of cytoprotective target genes, including vascular endothelial growth factor receptor 2. We conclude that sustained hyperoxia-induced NF-κB activation improves neonatal survival and preserves lung development. Potentiating early NF-κB activity after hyperoxic exposure may represent a therapeutic intervention to prevent BPD. PMID:24748603

Cerebral hemodynamic responses to seizure in the mouse brain: simultaneous near-infrared spectroscopy-electroencephalography study

NASA Astrophysics Data System (ADS)

Lee, Seungduk; Lee, Mina; Koh, Dalkwon; Kim, Beop-Min; Choi, Jee Hyun

2010-05-01

We applied near-infrared spectroscopy (NIRS) and electroencephalography (EEG) simultaneously on the mouse brain and investigated the hemodynamic response to epileptic episodes under pharmacologically driven seizure. γ-butyrolactone (GBL) and 4-aminopyridine (4-AP) were applied to induce absence and tonic-clonic seizures, respectively. The epileptic episodes were identified from the single-channel EEG, and the corresponding hemodynamic changes in different regions of the brain were characterized by multichannel frequency-domain NIRS. Our results are the following: (i) the oxyhemoglobin level increases in the case of GBL-treated mice but not 4-AP-treated mice compared to the predrug state; (ii) the dominant response to each absence seizure is a decrease in deoxyhemolobin; (iii) the phase shift between oxy- and deoxyhemoglobin reduces in GBL-treated mice but no 4-AP-treated mice; and (iv) the spatial correlation of hemodynamics increased significantly in 4-AP-treated mice but not in GBL-treated mice. Our results shows that spatiotemporal tracking of cerebral hemodynamics using NIRS can be successfully applied to the mouse brain in conjunction with electrophysiological recording, which will support the study of molecular, cellular, and network origin of neurovascular coupling in vivo.

Cooperative role of macrophages and neutrophils in host Antiprotozoan resistance in mice acutely infected with Cryptosporidium parvum.

PubMed

Takeuchi, Dan; Jones, Vickie C; Kobayashi, Makiko; Suzuki, Fujio

2008-08-01

Severe experimental infections with Cryptosporidium parvum have been reported in immunocompromised animals such as SCID mice (mice without functional T cells and B cells). In a C. parvum infection with 1 x 10(6) oocysts/mouse in SCID beige (SCIDbg) mice (SCID mice lacking functional NK cells), oocyst shedding was first demonstrated 18 days after infection. However, shedding was shown as early as 3 days after the same infection in SCIDbgMN mice. All of the SCIDbgMN mice died within 16 days of C. parvum infection, while 100% of the SCIDbg mice exposed to the parasite survived. SCIDbgMN mice are SCIDbg mice depleted of functional macrophages (Mphi) and neutrophils (PMN), suggesting that the severity early after C. parvum infection is strongly influenced by the functions of Mphi and PMN. All SCIDbgMN mice orally infected with a lethal dose of C. parvum survived after they were inoculated with Mphi from SCIDbg mice exposed to C. parvum (CP-Mphi) or resident Mphi previously cultured with PMN from C. parvum-infected SCIDbg mice (CP-PMN). However, all SCIDbgMN mice inoculated with CP-PMN alone or resident Mphi alone died after C. parvum infection. CP-Mphi were identified as classically activated Mphi (M1Mphi), and CP-PMN were characterized as PMN-I. In in vitro studies, resident Mphi converted to M1Mphi after transwell cultivation with CP-PMN. These results indicate that the resistance of SCIDbg mice early after C. parvum infection is displayed through the function of M1Mphi which are converted from resident Mphi influenced by CP-PMN (PMN-I).

Adverse health effects due to arsenic exposure: modification by dietary supplementation of jaggery in mice.

PubMed

Singh, Nrashant; Kumar, D; Lal, Kewal; Raisuddin, S; Sahu, Anand P

2010-02-01

Populations of villages of eastern India and Bangladesh and many other parts of the world are exposed to arsenic mainly through drinking water. Due to non-availability of safe drinking water they are compelled to depend on arsenic-contaminated water. Generally, poverty level is high in those areas and situation is compounded by the lack of proper nutrition. The hypothesis that the deleterious health effects of arsenic can be prevented by modification of dietary factors with the availability of an affordable and indigenous functional food jaggery (sugarcane juice) has been tested in the present study. Jaggery contains polyphenols, vitamin C, carotene and other biologically active components. Arsenic as sodium-m-arsenite at low (0.05 ppm) and high (5 ppm) doses was orally administered to Swiss male albino mice, alone and in combination with jaggery feeding (250 mg/mice), consecutively for 180 days. The serum levels of total antioxidant, glutathione peroxidase and glutathione reductase were substantially reduced in arsenic-exposed groups, while supplementation of jaggery enhanced their levels in combined treatment groups. The serum levels of interleukin-1beta, interleukin-6 and TNF-alpha were significantly increased in arsenic-exposed groups, while in the arsenic-exposed and jaggery supplemented groups their levels were normal. The comet assay in bone marrow cells showed the genotoxic effects of arsenic, whereas combination with jaggery feeding lessened the DNA damage. Histopathologically, the lung of arsenic-exposed mice showed the necrosis and degenerative changes in bronchiolar epithelium with emphysema and thickening of alveolar septa which was effectively antagonized by jaggery feeding. These results demonstrate that jaggery, a natural functional food, effectively antagonizes many of the adverse effects of arsenic. Copyright 2009 Elsevier Inc. All rights reserved.

Genome-Wide Alteration of Histone H3K9 Acetylation Pattern in Mouse Offspring Prenatally Exposed to Arsenic

PubMed Central

Cronican, Andrea A.; Fitz, Nicholas F.; Carter, Alexis; Saleem, Muzamil; Shiva, Sruti; Barchowsky, Aaron; Koldamova, Radosveta; Schug, Jonathan; Lefterov, Iliya

2013-01-01

Chronic exposure to arsenic in drinking water, especially in utero or perinatal exposure, can initiate neurological and cognitive dysfunction, as well as memory impairment. Several epidemiological studies have demonstrated cognitive and learning deficits in children with early exposure to low to moderate levels of arsenic, but pathogenic mechanisms or etiology for these deficits are poorly understood. Since in vivo studies show a role for histone acetylation in cognitive performance and memory formation, we examined if prenatal exposure to arsenic causes changes in the epigenomic landscape. We exposed C57Bl6/J mice to 100 μg/L arsenic in the drinking water starting 1 week before conception till birth and applied chromatin immunoprecipitation followed by high-throughput massive parallel sequencing (ChIP-seq) to evaluate H3K9 acetylation pattern in the offspring of exposed and control mice. Arsenic exposure during embryonic life caused global hypo-acetylation at H3K9 and changes in functional annotation with highly significant representation of Krüppel associated box (KRAB) transcription factors in brain samples from exposed pups. We also found that arsenic exposure of adult mice impaired spatial and episodic memory, as well as fear conditioning performance. This is the first study to demonstrate: a) genome wide changes in H3K9 acetylation pattern in an offspring prenatally exposed to arsenic, and b) a connection between moderate arsenic exposure and cognitive impairment in adult mice. The results also emphasize the applicability of Next Generation Sequencing methodology in studies aiming to reveal the role of environmental factors, other than dietary restriction, in developmental reprogramming through histone modifications during embryonic development. PMID:23405071

Eradication of Murine Norovirus from a Mouse Barrier Facility

PubMed Central

Kastenmayer, Robin J; Perdue, Kathy A; Elkins, William R

2008-01-01

Murine norovirus (MNV) is a common viral infection of mice in many research facilities. MNV infects hematopoietic cells and alters their cellular morphology. Because of MNV's probable effects on the systemic immune response of infected mice the decision was made to eradicate the virus from 2 rooms containing infected animals in our vivarium. Two different eradication methods were selected. One room, in which most of the indirectly exposed sentinels had antibodies to MNV, was depopulated and thoroughly cleaned prior to repopulation. In the other room, in which only 13% of the sentinels had positive MNV titers, selective testing was used, and MNV-positive animals were removed. Data from surveillance of the sentinel mice exposed to dirty bedding indicate that the test-and-removal method was ineffective in eliminating MNV from the room, whereas sentinel mice in the room that underwent depopulation and cleaning prior to repopulation have not shown any evidence of MNV since December 2006. PMID:18210995

Cotinine Concentration in Serum Correlates with Tobacco Smoke-Induced Emphysema in Mice

NASA Astrophysics Data System (ADS)

Xu, Xin; Su, Yunchao; Fan, Z. Hugh

2014-01-01

Secondhand smoke (SHS) has been associated with a variety of adverse health outcomes in nonsmokers, including emphysema (a chronic obstructive pulmonary disease). One way to detect SHS exposure is to measure the concentration of cotinine, the primary metabolite of nicotine, in bodily fluids. We have developed a method for cotinine analysis by combining micellar electrokinetic chromatography with enrichment techniques. We employed the method to measure cotinine concentrations in serum samples of mice exposed to tobacco smoke for 12 or 24 weeks and found that it was 3.1-fold or 4.8-fold higher than those exposed to room air for the same period. Further, we investigated the morphological changes in lungs of mice and observed tobacco smoke induced emphysema. Our results indicate that the method can be used to measure cotinine and there is an association between the serum cotinine concentration and tobacco smoke-induced emphysema in mice.

Dim light at night increases body mass of female mice.

PubMed

Aubrecht, Taryn G; Jenkins, Richelle; Nelson, Randy J

2015-05-01

During the past century, the prevalence of light at night has increased in parallel with obesity rates. Dim light at night (dLAN) increases body mass in male mice. However, the effects of light at night on female body mass remain unspecified. Thus, female mice were exposed to a standard light/dark (LD; 16 h light at ∼150 lux/8 h dark at ∼0 lux) cycle or to light/dim light at night (dLAN; 16 h light at ∼150 lux/8 h dim light at ∼5 lux) cycles for six weeks. Females exposed to dLAN increased the rate of change in body mass compared to LD mice despite reduced total food intake during weeks five and six, suggesting that dLAN disrupted circadian rhythms resulting in deranged metabolism.

Effect of acute ozone exposure on the lung metabolomes of obese and lean mice.

PubMed

Mathews, Joel Andrew; Kasahara, David Itiro; Cho, Youngji; Bell, Lauren Nicole; Gunst, Philip Ross; Karoly, Edward D; Shore, Stephanie Ann

2017-01-01

Pulmonary responses to the air pollutant, ozone, are increased in obesity. Both obesity and ozone cause changes in systemic metabolism. Consequently, we examined the impact of ozone on the lung metabolomes of obese and lean mice. Lean wildtype and obese db/db mice were exposed to acute ozone (2 ppm for 3 h) or air. 24 hours later, the lungs were excised, flushed with PBS to remove blood and analyzed via liquid-chromatography or gas-chromatography coupled to mass spectrometry for metabolites. Both obesity and ozone caused changes in the lung metabolome. Of 321 compounds identified, 101 were significantly impacted by obesity in air-exposed mice. These included biochemicals related to carbohydrate and lipid metabolism, which were each increased in lungs of obese versus lean mice. These metabolite changes may be of functional importance given the signaling capacity of these moieties. Ozone differentially affected the lung metabolome in obese versus lean mice. For example, almost all phosphocholine-containing lysolipids were significantly reduced in lean mice, but this effect was attenuated in obese mice. Glutathione metabolism was also differentially affected by ozone in obese and lean mice. Finally, the lung metabolome indicated a role for the microbiome in the effects of both obesity and ozone: all measured bacterial/mammalian co-metabolites were significantly affected by obesity and/or ozone. Thus, metabolic derangements in obesity appear to impact the response to ozone.

Gene Expression in Parp1 Deficient Mice Exposed to a Median Lethal Dose of Gamma Rays.

PubMed

Kumar, M A Suresh; Laiakis, Evagelia C; Ghandhi, Shanaz A; Morton, Shad R; Fornace, Albert J; Amundson, Sally A

2018-05-10

There is a current interest in the development of biodosimetric methods for rapidly assessing radiation exposure in the wake of a large-scale radiological event. This work was initially focused on determining the exposure dose to an individual using biological indicators. Gene expression signatures show promise for biodosimetric application, but little is known about how these signatures might translate for the assessment of radiological injury in radiosensitive individuals, who comprise a significant proportion of the general population, and who would likely require treatment after exposure to lower doses. Using Parp1 -/- mice as a model radiation-sensitive genotype, we have investigated the effect of this DNA repair deficiency on the gene expression response to radiation. Although Parp1 is known to play general roles in regulating transcription, the pattern of gene expression changes observed in Parp1 -/- mice 24 h postirradiation to a LD 50/30 was remarkably similar to that in wild-type mice after exposure to LD 50/30 . Similar levels of activation of both the p53 and NFκB radiation response pathways were indicated in both strains. In contrast, exposure of wild-type mice to a sublethal dose that was equal to the Parp1 -/- LD 50/30 , which resulted in a lower magnitude gene expression response. Thus, Parp1 -/- mice displayed a heightened gene expression response to radiation, which was more similar to the wild-type response to an equitoxic dose than to an equal absorbed dose. Gene expression classifiers trained on the wild-type data correctly identified all wild-type samples as unexposed, exposed to a sublethal dose or exposed to an LD 50/30 . All unexposed samples from Parp1 -/- mice were also correctly classified with the same gene set, and 80% of irradiated Parp1 -/- samples were identified as exposed to an LD 50/30 . The results of this study suggest that, at least for some pathways that may influence radiosensitivity in humans, specific gene expression signatures have the potential to accurately detect the extent of radiological injury, rather than serving only as a surrogate of physical radiation dose.

Hydrogen-rich pure water prevents cigarette smoke-induced pulmonary emphysema in SMP30 knockout mice.

PubMed

Suzuki, Yohei; Sato, Tadashi; Sugimoto, Masataka; Baskoro, Hario; Karasutani, Keiko; Mitsui, Aki; Nurwidya, Fariz; Arano, Naoko; Kodama, Yuzo; Hirano, Shin-Ichi; Ishigami, Akihito; Seyama, Kuniaki; Takahashi, Kazuhisa

2017-10-07

Chronic obstructive pulmonary disease (COPD) is predominantly a cigarette smoke (CS)-triggered disease with features of chronic systemic inflammation. Oxidants derived from CS can induce DNA damage and stress-induced premature cellular senescence in the respiratory system, which play significant roles in COPD. Therefore, antioxidants should provide benefits for the treatment of COPD; however, their therapeutic potential remains limited owing to the complexity of this disease. Recently, molecular hydrogen (H 2 ) has been reported as a preventive and therapeutic antioxidant. Molecular H 2 can selectively reduce hydroxyl radical accumulation with no known side effects, showing potential applications in managing oxidative stress, inflammation, apoptosis, and lipid metabolism. However, there have been no reports on the efficacy of molecular H 2 in COPD patients. In the present study, we used a mouse model of COPD to investigate whether CS-induced histological damage in the lungs could be attenuated by administration of molecular H 2 . We administered H 2 -rich pure water to senescence marker protein 30 knockout (SMP30-KO) mice exposed to CS for 8 weeks. Administration of H 2 -rich water attenuated the CS-induced lung damage in the SMP30-KO mice and reduced the mean linear intercept and destructive index of the lungs. Moreover, H 2 -rich water significantly restored the static lung compliance in the CS-exposed mice compared with that in the CS-exposed H 2 -untreated mice. Moreover, treatment with H 2 -rich water decreased the levels of oxidative DNA damage markers such as phosphorylated histone H2AX and 8-hydroxy-2'-deoxyguanosine, and senescence markers such as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase inhibitor 1, and β-galactosidase in the CS-exposed mice. These results demonstrated that H 2 -rich pure water attenuated CS-induced emphysema in SMP30-KO mice by reducing CS-induced oxidative DNA damage and premature cell senescence in the lungs. Our study suggests that administration of molecular H 2 may be a novel preventive and therapeutic strategy for COPD. Copyright © 2017 Elsevier Inc. All rights reserved.

Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

ERIC Educational Resources Information Center

Kaczorowski, Catherine C.; Disterhoft, John F.

2009-01-01

Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CD1 Mice

EPA Science Inventory

Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the bi...

Bone-specific gene expression patterns and whole bone tissue of female mice are programmed by early life exposure to soy isoflavones and folic acid.

PubMed

Kaludjerovic, Jovana; Ward, Wendy E

2015-10-01

Female mice exposed to soy isoflavones (ISO) during early postnatal life have improved bone outcomes at adulthood. Since long-lasting effects may be mediated by DNA methylation, we hypothesized that providing supplemental folic acid (FA), a methyl donor, during early life, would enhance the positive effect of ISO to bone health. Bone-specific gene expression patterns were studied to understand potential mechanisms. CD-1 dams (n=36) were randomized to adequate or supplemental levels of FA (2 or 8 mg/kg diet) during pregnancy and lactation, and offspring received corn oil or ISO (7 mg/kg body weight/d) from postnatal day 1 to 10. From weaning, pups were fed an adequate FA diet and were studied to 4 months of age. Female offspring exposed to supplemental FA+ISO had higher bone mineral density (BMD), trabecular connectivity and peak load at the lumbar spine compared to females exposed to adequate FA. Female offspring exposed to adequate FA+ISO or supplemental FA had higher (P<.05) BMD and greater resistance to fracture at the lumbar spine and the femur; higher trabecular connectivity at the lumbar spine; and lower expression of DNA methyltransferase 3a (Dnmt3a) and neuropeptide Y (NPY) in the femur compared to mice exposed to adequate FA. In addition, only mice exposed to adequate FA+ISO had microstructural improvements at the femur neck and higher serum osteoprotegrin (OPG) and insulin growth factor-I (IGF-I). In summary, exposure to supplemental FA did not enhance the positive effect of ISO in bone. However, exposure to adequate FA+ISO or supplemental FA improved bone at least in part by suppressing Dnmt3a and NPY. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

The administration of a high refined carbohydrate diet promoted an increase in pulmonary inflammation and oxidative stress in mice exposed to cigarette smoke

PubMed Central

Pena, Karina Braga; Ramos, Camila de Oliveira; Soares, Nícia Pedreira; da Silva, Pamela Félix; Bandeira, Ana Carla Balthar; Costa, Guilherme de Paula; Cangussú, Sílvia Dantas; Talvani, André; Bezerra, Frank Silva

2016-01-01

This study aimed to evaluate the effects of a high refined carbohydrate diet and pulmonary inflammatory response in C57BL/6 mice exposed to cigarette smoke (CS). Twenty-four male mice were divided into four groups: control group (CG), which received a standard diet; cigarette smoke group (CSG), which was exposed to CS; a high refined carbohydrate diet group (RG), which received a high refined carbohydrate diet; and a high refined carbohydrates diet and cigarette smoke group (RCSG), which received a high refined carbohydrate diet and was exposed to CS. The animals were monitored for food intake and body weight gain for 12 weeks. After this period, the CSG and RCSG were exposed to CS for five consecutive days. At the end of the experimental protocol, all animals were euthanized for subsequent analyses. There was an increase of inflammatory cells in the bronchoalveolar lavage fluid (BALF) of CSG compared to CG and RCSG compared to CG, CSG, and RG. In addition, in the BALF, there was an increase of tumor necrosis factor alpha in RCSG compared to CG, CSG, and RG; interferon gamma increase in RCSG compared to the CSG; and increase in interleukin-10 in RCSG compared to CG and RG. Lipid peroxidation increased in RCSG compared to CG, CSG, and RG. Furthermore, the oxidation of proteins increased in CSG compared to CG. The analysis of oxidative stress showed an increase in superoxide dismutase in RCSG compared to CG, CSG, and RG and an increase in the catalase activity in RCSG compared with CG. In addition, there was a decrease in the glutathione reduced/glutathione total ratio of CSG, RG, and RCSG compared to CG. Therefore, the administration of a high refined carbohydrate diet promoted an increase in pulmonary inflammation and oxidative stress in mice exposed to CS. PMID:28008246

A single dose of trichloroethylene given during development does not substantially alter markers of neuroinflammation in brains of adult mice.

PubMed

Meadows, Jacqueline R; Parker, Chevonne; Gilbert, Kathleen M; Blossom, Sarah J; DeWitt, Jamie C

2017-12-01

Trichloroethylene (TCE) is a widespread environmental contaminant associated with developmental immunotoxicity and neurotoxicity. Previous studies have shown that MRL +/+ mice exposed to TCE from gestation through early-life demonstrate robust increases in inflammatory markers in peripheral CD4 + T-cells, as well as glutathione depletion and increased oxidative stress in cerebellum-associated with alterations in behavior. Since increased oxidative stress is associated with neuroinflammation, we hypothesized that neuroinflammatory markers could be altered relative to unexposed mice. MRL +/+ mice were given 0.5 mg/ml of TCE in vehicle or vehicle (water with 1% Alkamuls EL-620) from conception through early adulthood via drinking water to dams and then directly to post-weaning offspring. Animals were euthanized at 49 days of age and levels of pro- and anti-inflammatory cytokines, density of T-cell staining, and micro-glial morphology were evaluated in brains to begin to ascertain a neuroinflammatory profile. Levels of IL-6 were decreased in female animals and while not statistically significant, and levels of IL-10 were higher in brains of exposed male and female animals. Supportive of this observation, although not statistically significant, the number of ameboid microglia was higher in exposed relative to unexposed animals. This overall profile suggests the emergence of an anti-inflammatory/neuroprotective phenotype in exposed animals, possibly as a compensatory response to neuroinflammation that is known to be induced by developmental exposure to TCE.

Autoantibodies against the inner aspect of erythrocyte membranes in NZB mice.

PubMed Central

Linder, E

1977-01-01

Erythrocyte autoantibodies in NZB mice react by hemagglutination methods with exposed and hidden red cell antigens. The hidden antigens can be exposed by treatment with proteolytic enzymes. By indirect immunofluorescence one antibody population can be shown to react with modified red cells. In the present study the location of the corresponding autoantigen within the membrane was studied. Mechanical or hypotonic lysis of the red cells exposed the antigen. Proteolytic digestion known to expose other erythrocyte autoantigens had no effect. The autoantigen was exposed on 'inside out' erythrocyte membrane vesicles, but not on 'right-side out' vesicles, prepared from isolated erythrocyte ghosts. Frezzing and thawing as well as mechanical disintergration of red cells liberated antigenically active material as saline-insuluble fibrillar material. The observations indicate that the autoantigen studied is located at the inner aspect of the erythrocyte membrane and suggest that it is associated with fibril-forming structural components. The observed reactivity distinguishes the described antibodies from previously identified erythrocyte autoantibodies. PMID:862240

Increased Radioresistance to Lethal Doses of Gamma Rays in Mice and Rats after Exposure to Microwave Radiation Emitted by a GSM Mobile Phone Simulator

PubMed Central

Mortazavi, SMJ; Mosleh-Shirazi, MA; Tavassoli, AR; Taheri, M; Mehdizadeh, AR; Namazi, SAS; Jamali, A; Ghalandari, R; Bonyadi, S; Haghani, M; Shafie, M

2013-01-01

The aim of this study was to investigate the effect of pre-irradiation with microwaves on the induction of radioadaptive response. In the 1st phase of the study, 110 male mice were divided into 8 groups. The animals in these groups were exposed/sham-exposed to microwave, low dose rate gamma or both for 5 days. On day six, the animals were exposed to a lethal dose (LD). In the 2nd phase, 30 male rats were divided into 2 groups of 15 animals. The 1st group received microwave exposure. The 2nd group (controls) received the same LD but there was no treatment before the LD. On day 5, all animals were whole-body irradiated with the LD. Statistically significant differences between the survival rate of the mice only exposed to lethal dose of gamma radiation before irradiation with a lethal dose of gamma radiation with those of the animals pre-exposed to either microwave (p=0.02), low dose rate gamma (p=0.001) or both of these physical adapting doses (p=0.003) were observed. Likewise, a statistically significant difference between survival rates of the rats in control and test groups was observed. Altogether, these experiments showed that exposure to microwave radiation may induce a significant survival adaptive response. PMID:23930107

Bioactive grape proanthocyanidins enhance immune reactivity in UV-irradiated skin through functional activation of dendritic cells in mice

PubMed Central

Vaid, Mudit; Singh, Tripti; Prasad, Ram; Elmets, Craig A.; Xu, Hui; Katiyar, Santosh K.

2013-01-01

Ultraviolet (UV) radiation-induced immunosuppression has been implicated in skin carcinogenesis. Grape seed proanthocyanidins (GSPs) have anti-skin carcinogenic effects in mice and GSPs-fed mice exhibit a reduction in UV-induced suppression of allergic contact hypersensitivity (CHS), a prototypic T cell-mediated response. Here, we report that dietary GSPs did not inhibit UVB-induced suppression of CHS in xeroderma pigmentosum complementation group A (XPA)-deficient mice, which lack nucleotide excision repair mechanisms. GSPs enhanced repair of UVB-induced DNA damage (cyclobutane pyrimidine dimers) in wild-type, but not XPA-deficient, dendritic cells (DCs). Co-culture of CD4+ T cells with DCs from UVB-irradiated wild-type mice resulted in suppression of T-cell proliferation and secretion of Th-1 type cytokines that was ameliorated when the DCs were obtained from GSPs-fed mice; whereas, DCs obtained from GSPs-fed XPA-KO mice failed to restore T-cell proliferation. In adoptive transfer experiments, donor DCs were positively selected from the draining lymph nodes of UVB-exposed donor mice that were sensitized to 2,4, dinitrofluorobenzene were transferred into naïve recipient mice and the CHS response assessed. Naïve recipients that received DCs from UVB-exposed wild-type donors that had been fed GSPs exhibited a full CHS response, whereas no significant CHS was observed in mice that received DCs from XPA-KO mice fed GSPs. These results suggest that GSPs prevent UVB-induced immunosuppression through DNA repair-dependent functional activation of dendritic cells in mice. PMID:23321928

Phenotypic Dichotomy Following Developmental Exposure to ...

EPA Pesticide Factsheets

The synthetic surfactant, perfluorooctanoic acid (PFOA) is a proven developmental toxicant in mice, causing prenatal pregnancy loss, increased neonatal mortality, delayed eye opening, and abnormal mammary gland growth in animals exposed during fetal life. PFOA is found in the sera of wildlife and humans throughout the world, but is especially high in the sera of children. These studies in CD-1 mice aim to determine the latent health effects of PFOA following an in utero exposure, a developmental exposure followed by ovariectomy (ovx), or exposure as an adult. Mice were exposed to 0, 0.01, 0.1, 0.3, 1, 3, or 5 mg PFOA/kg BW for 17 days of pregnancy or as an adult. Body weight was reduced in the highest doses on postnatal day (PND) 1 and at weaning. However, the lowest exposures (0.01-0.3 mg/kg) induced excessive weight gain between 20-40 weeks, as well as a significant increase in serum leptin (0.01-0.1 mg/kg). Although body weight was significantly increased due to ovx, there was no longer a body weight effect of PFOA in ovx animals. Further, there was no effect of adult exposure to PFOA on body weight gain. At 18 months of age, the effects of PFOA on body weight were no longer detected. The white adipose tissue and spleen weights were decreased at high doses of PFOA in intact developmentally exposed mice, and spleen weight was reduced in ovx mice. But, brown adipose tissue weight was significantly increased in both ovx and intact mice at high doses. Liver weigh

Exacerbation of allergic inflammation in mice exposed to diesel exhaust particles prior to viral infection

PubMed Central

Jaspers, Ilona; Sheridan, Patricia A; Zhang, Wenli; Brighton, Luisa E; Chason, Kelly D; Hua, Xiaoyang; Tilley, Stephen L

2009-01-01

Background Viral infections and exposure to oxidant air pollutants are two of the most important inducers of asthma exacerbation. Our previous studies have demonstrated that exposure to diesel exhaust increases the susceptibility to influenza virus infections both in epithelial cells in vitro and in mice in vivo. Therefore, we examined whether in the setting of allergic asthma, exposure to oxidant air pollutants enhances the susceptibility to respiratory virus infections, which in turn leads to increased virus-induced exacerbation of asthma. Ovalbumin-sensitized (OVA) male C57BL/6 mice were instilled with diesel exhaust particles (DEP) or saline and 24 hours later infected with influenza A/PR/8. Animals were sacrificed 24 hours post-infection and analyzed for markers of lung injury, allergic inflammation, and pro-inflammatory cytokine production. Results Exposure to DEP or infection with influenza alone had no significant effects on markers of injury or allergic inflammation. However, OVA-sensitized mice that were exposed to DEP and subsequently infected with influenza showed increased levels of eosinophils in lung lavage and tissue. In addition Th2-type cytokines, such as IL-4 and IL-13, and markers of eosinophil chemotaxis, such as CCL11 and CCR3, were increased in OVA-sensitized mice exposed to DEP prior to infection with influenza. These mice also showed increased levels of IL-1α, but not IL-10, RANTES, and MCP-1 in lung homogenates. Conclusion These data suggest that in the setting of allergic asthma, exposure to diesel exhaust could enhance virus-induced exacerbation of allergic inflammation. PMID:19682371

Risk Assessment of Neonatal Exposure to Low Frequency Noise Based on Balance in Mice

PubMed Central

Ohgami, Nobutaka; Oshino, Reina; Ninomiya, Hiromasa; Li, Xiang; Kato, Masashi; Yajima, Ichiro; Kato, Masashi

2017-01-01

General electric devices and ventilation systems are known to generate low frequency noise (LFN) with frequencies of <100 Hz. Previous studies showed that exposure to LFN caused impairments of balance in humans and mice during adulthood. On the other hand, a previous study showed that noise levels in the neonatal intensive care unit (NICU) were greater than those in general home or office environments. Therefore, it is possible that neonates have a potential risk to be exposed to LFN in the NICU. However, the risk of neonatal exposure to LFN remains unclear in humans and mice. In this study, male ICR mice were exposed to LFN at 100 Hz for 4 weeks after birth and then subjected to rotarod and beam crossing tests in order to assess LFN-mediated risk of imbalance during the neonatal period. Exposure to LFN at 70 dB, but not exposure to LFN up to 60 dB, during the neonatal period significantly decreased performance scores for rotarod and beam crossing tests compared to the scores of the control group. The number of calbindin-positive hair cells in the saccule and utricle was decreased in mice exposed to LFN at 70 dB for 4 weeks in the neonatal phase. Cessation of exposure for 10 weeks did not result in recovery of the decreased performance in rotarod and beam crossing tests. Thus, our results suggest that 70 dB is a possible threshold for exposure to LFN for 4 weeks during the neonatal period causing unrecoverable imbalance in mice. PMID:28275341

Genetic Analysis of Mice Skin Exposed by Hyper-Gravity

NASA Astrophysics Data System (ADS)

Takahashi, Rika; Terada, Masahiro; Seki, Masaya; Higashibata, Akira; Majima, Hideyuki J.; Ohira, Yoshinobu; Mukai, Chiaki; Ishioka, Noriaki

2013-02-01

In the space environment, physiological alterations, such as low bone density, muscle weakness and decreased immunity, are caused by microgravity and cosmic radiation. On the other hand, it is known that the leg muscles are hypertrophy by 2G-gravity. An understanding of the effects on human body from microgravity to hyper-gravity is very important. Recently, the Japan Aerospace Exploration Agency (JAXA) has started a project to detect the changes on gene expression and mineral metabolism caused by microgravity by analyzing the hair of astronauts who stay in the international Space Station (ISS) for a long time. From these results of human hair’s research, the genetic effects of human hair roots by microgravity will become clear. However, it is unclear how the gene expression of hair roots was effected by hypergravity. Therefore, in this experiment, we analyzed the effect on mice skin contained hair roots by comparing microgravity or hypergravity exposed mice. The purpose of this experiment is to evaluate the genetic effects on mice skin by microgravity or 2G-gravity. The samples were taken from mice exposed to space flight (FL) or hypergravity environment (2G) for 3-months, respectively. The extracted and amplified RNA from these mice skin was used to DNA microarray analysis. in this experiment, we analyzed the effect of gravity by using mice skin contained hair roots, which exposed space (FL) and hyper-gravity (2G) for 3 months and each control. By DNA microarray analysis, we found the common 98 genes changed in both FL and 2G. Among these 98 genes, the functions and pathways were identified by Gene Ontology (GO) analysis and Ingenuity Pathways Analysis (IPA) software. Next, we focused the one of the identified pathways and compared the effects on each molecules in this pathways by the different environments, such as FL and 2G. As the results, we could detect some interesting molecules, which might be depended on the gravity levels. In addition, to investigate the relationships between genes and protein expression, the proteome analysis was performed. From the result of 2-dimentional electrophoresis, we could detect the some different spots between FL and 2G. These identifications are now in progress using by MALDI-TOF-MS/MS. These results suggested that many genes or proteins on the mice skin might be effected by the different gravity levels.

A Recombinant Raccoon Poxvirus Vaccine Expressing both Yersinia pestis F1 and Truncated V Antigens Protects Animals against Lethal Plague

PubMed Central

Rocke, Tonie E.; Kingstad-Bakke, Brock; Berlier, Willy; Osorio, Jorge E.

2014-01-01

In previous studies, we demonstrated in mice and prairie dogs that simultaneous administration of two recombinant raccoon poxviruses (rRCN) expressing Yersinia pestis antigens (F1 and V307—a truncated version of the V protein) provided superior protection against plague challenge compared to individual single antigen constructs. To reduce costs of vaccine production and facilitate implementation of a sylvatic plague vaccine (SPV) control program for prairie dogs, a dual antigen construct is more desirable. Here we report the construction and characterization of a novel RCN-vectored vaccine that simultaneously expresses both F1 and V307 antigens. This dual antigen vaccine provided similar levels of protection against plague in both mice and prairie dogs as compared to simultaneous administration of the two single antigen constructs and was also shown to protect mice against an F1 negative strain of Y. pestis. The equivalent safety, immunogenicity and efficacy profile of the dual RCN-F1/V307 construct warrants further evaluation in field efficacy studies in sylvatic plague endemic areas. PMID:26344891

A recombinant raccoon poxvirus vaccine expressing both Yersinia pestis F1 and truncated V antigens protects animals against lethal plague.

USGS Publications Warehouse

Rocke, Tonie E.; Kingstad-Bakke, B; Berlier, W; Osorio, J.E.

2014-01-01

In previous studies, we demonstrated in mice and prairie dogs that simultaneous administration of two recombinant raccoon poxviruses (rRCN) expressing Yersinia pestis antigens (F1 and V307-a truncated version of the V protein) provided superior protection against plague challenge compared to individual single antigen constructs. To reduce costs of vaccine production and facilitate implementation of a sylvatic plague vaccine (SPV) control program for prairie dogs, a dual antigen construct is more desirable. Here we report the construction and characterization of a novel RCN-vectored vaccine that simultaneously expresses both F1 and V307 antigens. This dual antigen vaccine provided similar levels of protection against plague in both mice and prairie dogs as compared to simultaneous administration of the two single antigen constructs and was also shown to protect mice against an F1 negative strain of Y. pestis.. The equivalent safety, immunogenicity and efficacy profile of the dual RCN-F1/V307 construct warrants further evaluation in field efficacy studies in sylvatic plague endemic areas.

Trait anxiety and ethanol: anxiolysis in high-anxiety mice and no relation to intake behavior in an addiction model.

PubMed

Correia, Diego; Ribeiro, Andrea Frozino; Brunialti Godard, Ana Lúcia; Boerngen-Lacerda, Roseli

2009-08-01

Anxiety has been proposed to play a role in the development of alcohol addiction, but the exact mechanisms by which this occurs remain unclear. The present study aimed to verify the relationship between basal anxiety levels, the anxiolytic-like effect of ethanol, and ethanol intake in mice exposed to an addiction model. In one experiment Swiss mice were characterized as high-anxiety (HA), medium-anxiety (MA), or non-anxiety (NA) in the elevated plus maze and then received saline or ethanol 2 g/kg acutely and chronically and were again exposed to the same test. NA mice decreased while MA mice maintained anxiety indices over the test days, regardless of treatment. HA ethanol-treated mice showed an anxiolytic-like effect, both acutely and chronically, while the saline-treated ones maintained their basal anxiety levels. In another experiment HA and MA mice were exposed to an addiction model based on a 3-bottle free-choice paradigm (ethanol 5% and 10%, and water) consisting of four phases: acquisition (10 weeks), withdrawal (W, 2 weeks), reexposure (2 weeks), and quinine-adulteration (2 weeks). HA and MA control mice had access only to water. Mice were characterized as addicted, heavy-drinker and light-drinker [Fachin-Scheit DJ, Ribeiro AF, Pigatto G, Goeldner FO, Boerngen-Lacerda R. Development of a mouse model of ethanol addiction: naltrexone efficacy in reducing consumption but not craving. J Neural Transm 2006;113:1305-21.]. No difference was observed between HA and MA mice in their preference for and intake of ethanol. No correlation was observed between ethanol intake, during any phase, and anxiety indices measured in the basal tests and during the W phase. The differences in anxiety indices between HA and MA groups persisted in the test performed during ethanol withdrawal, suggesting a "trait" anxiety profile. The data suggest that despite the fact that high anxiety trait levels are important for the anxiolytic-like effects of ethanol, they are not a determining factor for high ethanol intake, at least not under these experimental conditions.

Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

PubMed

Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

2016-06-01

The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages murine PDA to acquire an immune-suppressive phenotype and disabled T-cell-mediated anti-tumor responses. MCSF blockade negates this effect, allowing radiation to have increased efficacy in slowing tumor growth. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Expression of metallothionein protein in the lungs of Wistar rats and C57 and DBA mice exposed to cadmium oxide fumes.

PubMed

McKenna, I M; Gordon, T; Chen, L C; Anver, M R; Waalkes, M P

1998-12-01

Chronic exposure to inhaled cadmium (Cd) has been shown to induce lung tumors in rats (Wistar strain) but not in mice (NMRI strain). The protein metallothionein (MT) plays an important role in Cd detoxification, and it has been suggested that differential inducibility of pulmonary MT may lead to interspecies susceptibility differences to inhaled Cd. Interstrain differences in the pulmonary response of the MT gene to Cd stimuli have not been examined in rats or mice. We compared pulmonary MT expression in Wistar Furth (WF) rats with that in DBA and C57 mice, following a single 3-h exposure to CdO fumes containing 1 mg Cd/m3. Induction of the MT gene was assessed by the levels of MT-I and MT-II transcripts, MT-protein content, and number of MT-labeled alveolar and bronchiolar epithelial cells immediately after Cd exposure and 1, 3, and 5 days later. Control animals were exposed to air/argon furnace gases. We observed differential intra- and interspecies inducibility of the MT gene in the lung following Cd inhalation. DBA mice exhibited greater levels of MT-mRNA, mainly for the MT-I isoform, MT-protein content, and number of MT positive cells relative to C57 mice. WF rats showed lower transcription and translation responses of the MT gene upon Cd stimuli than C57 mice. The present results, in concert with our previous findings of higher lung cell proliferation in Cd-exposed C57 relative to DBA mice, predict greater susceptibility of C57 to the carcinogenic effects of inhaled Cd. Furthermore, the low transcriptional and translation responses of the MT gene to Cd stimuli in WF rats might explain the higher susceptibility of this rat strain to develop malignant lung tumors after chronic exposure to Cd via inhalation. Parallel to our findings in mice, differences in the responsiveness of lung MT gene may exist across rat strains. Thus intraspecies genetic variability in pulmonary MT may influence the susceptibility of rats or mice to lung carcinogenesis induced by inhalation of Cd compounds. Copyright 1998 Academic Press.

Trichloroethylene Exposure Reduces Liver Injury in a Mouse Model of Primary Biliary Cholangitis.

PubMed

Ray, Jessica L; Kopec, Anna K; Joshi, Nikita; Cline-Fedewa, Holly; Lash, Lawrence H; Williams, Kurt J; Leung, Patrick S; Gershwin, M Eric; Luyendyk, James P

2017-04-01

Trichloroethylene (TCE) is a persistent environmental contaminant proposed to contribute to autoimmune disease. Experimental studies in lupus-prone MRL+/+ mice have suggested that TCE exposure can trigger autoimmune hepatitis. The vast majority of studies examining the connection between TCE and autoimmunity utilize this model, and the impact of TCE exposure in other established models of autoimmune liver disease is not known. We tested the hypothesis that TCE exposure exacerbates experimental hepatic autoimmunity in dominant negative transforming growth factor beta receptor type II (dnTGFBRII) mice, which develop serological and histological features resembling human primary biliary cholangitis. Female 8-week-old wild-type and dnTGFBRII mice were exposed to TCE (0.5 mg/ml) or vehicle (1% ethoxylated castor oil) in the drinking water for 12 or 22 weeks. Liver histopathology in 20- and 30-week-old wild-type mice was unremarkable irrespective of treatment. Mild portal inflammation was observed in vehicle-exposed 20-week-old dnTGFBRII mice and was not exacerbated by TCE exposure. Vehicle-exposed 30-week-old dnTGFBRII mice developed anti-mitochondrial antibodies, marked hepatic inflammation with necrosis, and hepatic accumulation of both B and T lymphocytes. To our surprise, TCE exposure dramatically reduced hepatic parenchymal inflammation and injury in 30-week-old dnTGFBRII mice, reflected by changes in hepatic proinflammatory gene expression, serum chemistry, and histopathology. Interestingly, TCE did not affect hepatic B cell accumulation or induction of the anti-inflammatory cytokine IL10. These data indicate that TCE exposure reduces autoimmune liver injury in female dnTGFBRII mice and suggests that the precise effect of environmental chemicals in autoimmunity depends on the experimental model. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

PubMed Central

D’Alessio, Franco R.; Eto, Yoshiki; Chau, Eric; Avalos, Claudia; Waickman, Adam T.; Garibaldi, Brian T.; Mock, Jason R.; Files, Daniel C.; Sidhaye, Venkataramana; Polotsky, Vsevolod Y.; Powell, Jonathan; Horton, Maureen; King, Landon S.

2013-01-01

Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality. Exacerbating factors increasing the risk of ARDS remain unknown. Supplemental oxygen is often necessary in both mild and severe lung disease. The potential effects of supplemental oxygen may include augmentation of lung inflammation by inhibiting anti-inflammatory pathways in alveolar macrophages. We sought to determine oxygen-derived effects on the anti-inflammatory A2A adenosinergic (ADORA2A) receptor in macrophages, and the role of the ADORA2A receptor in lung injury. Wild-type (WT) and ADORA2A−/− mice received intratracheal lipopolysaccharide (IT LPS), followed 12 hours later by continuous exposure to 21% oxygen (control mice) or 60% oxygen for 1 to 3 days. We measured the phenotypic endpoints of lung injury and the alveolar macrophage inflammatory state. We tested an ADORA2A-specific agonist, CGS-21680 hydrochloride, in LPS plus oxygen-exposed WT and ADORA2A−/− mice. We determined the specific effects of myeloid ADORA2A, using chimera experiments. Compared with WT mice, ADORA2A−/− mice exposed to IT LPS and 60% oxygen demonstrated significantly more histologic lung injury, alveolar neutrophils, and protein. Macrophages from ADORA2A−/− mice exposed to LPS plus oxygen expressed higher concentrations of proinflammatory cytokines and cosignaling molecules. CGS-21680 prevented the oxygen-induced augmentation of lung injury after LPS only in WT mice. Chimera experiments demonstrated that the transfer of WT but not ADORA2A−/− bone marrow cells into irradiated ADORA2A−/− mice reduced lung injury after LPS plus oxygen, demonstrating myeloid ADORA2A protection. ADORA2A is protective against lung injury after LPS and oxygen. Oxygen after LPS increases macrophage activation to augment lung injury by inhibiting the ADORA2A pathway. PMID:23349051

Chronic inhalation study of mice subjected to diethylhydroxylamine, nitroethane, and diethylamine hydrogen sulfite

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heicklen, J.; Lundgard, R.; Partymiller, K.

1982-04-01

Institute of Cancer Research Swiss strain mice were subjected to the inhalation of 10.3 +/- 3.7 ppm diethylhydroxylamine, 10.1 +/- 4.1 ppm nitroethane, and the vapor of diethylamine hydrogen sulfite for over 2 years. Histopathologic evaluation of all organs indicated only a few significant findings. The incidence of all tumors, as well as subcutaneous tumors (principally fibrosarcomas), increased in exposed males with marginal statistical significance (P = 0.12 and 0.048, respectively). The incidence of all tumors in exposed females decreased with marked statistical significance (P < 0.0005).

Toxicology and carcinogenesis studies of milk thistle extract (CAS No. 84604-20-6) in F344/N rats and B6C3F1 mice (Feed Studies).

PubMed

2011-05-01

Milk thistle extracts have been used as medicinal herbs in the treatment of liver cirrhosis, chronic hepatitis (liver inflammation), and gallbladder disorders. Treatment claims also include lowering cholesterol levels; reducing insulin resistance; reducing the growth of cancer cells in breast, cervical, and prostate gland cancers; and antiviral activity. Other reported uses of milk thistle in folk medicine include as a treatment for malarial fever, bronchitis, gallstones, jaundice, peritonitis, uterine congestion, varicose veins, and as a milk production stimulant for nursing mothers. The roots soaked in water overnight are used in food, and the despined leaves are added to salads. Roasted milk thistle fruit has been used as a coffee substitute. Milk thistle extract was nominated for study by the National Institute of Environmental Health Sciences because it is one of the most widely used herbs in the United States. Male and female F344/N rats and B6C3F1 mice were exposed to an ethanol/water extract of milk thistle fruit (milk thistle extract) containing approximately 65% silymarin in feed for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 260, 525, 1,050, 2,180, or 4,500 mg milk thistle extract/kilogram body weight to males and 260, 510, 1,050, 2,150, or 4,550 mg/kg to females) for 14 weeks. All rats survived to the end of the study. Mean body weights of exposed groups were within 10% of those of the controls. Feed consumption by exposed and control groups was similar. The sperm motility in 12,500, 25,000, and 50,000 ppm males was decreased by 5%, 11%, and 9%, respectively, relative to that of the controls; the total number of spermatid heads per testis decreased by 11%, 21%, and 9% in 12,500, 25,000, and 50,000 ppm males. No significant differences in estrous cyclicity were observed between exposed and control groups of female rats. No exposure-related histopathologic lesions were observed. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 640, 1,340, 2,500, 5,280, or 11,620 mg/kg to males and 580, 1,180, 2,335, 4,800, or 9,680 mg/kg to females) for 14 weeks. All mice survived to the end of the study. Mean body weights and feed consumption of all exposed groups were similar to those of the controls. Absolute and relative thymus weights were significantly decreased in 25,000 and 50,000 ppm males. No significant differences were observed between exposed and control groups, for sperm parameters of male mice, for estrous cyclicity of female mice, or for reproductive organ weights of male or female mice, when mice were administered milk thistle extract in feed at 12,500, 25,000, or 50,000 ppm. No exposure-related histopathologic lesions were observed. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 570, 1,180, or 2,520 mg/kg to males and 630, 1,300, or 2,750 mg/kg to females) for 105 to 106 weeks. Exposure to milk thistle extract had no effect on survival of male or female rats. Mean body weights of all exposed groups were similar to those of the controls throughout the study. Feed consumption by exposed groups of males and females was generally similar to that by the controls throughout the study. Significantly decreased incidences of mammary gland fibroadenoma, adenoma, or carcinoma (combined) occurred in females exposed to 25,000 or 50,000 ppm. Significantly increased incidences of clear cell and mixed cell focus of the liver occurred in 25,000 and 50,000 ppm females. The incidences of bile duct hyperplasia were significantly decreased in 50,000 ppm males and in all exposed groups of females, and the incidence of mixed inflammatory cell infiltration was significantly decreased in 50,000 ppm males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 1,610, 3,530, or 7,770 mg/kg to males and 1,500, 3,175, or 7,180 mg/kg to females) for 105 to 106 weeks. Exposure to milk thistle extract had no effect on survival of male or female mice. The mean body weights of the 25,000 ppm groups were less than those of controls after week 25; mean body weights of 50,000 ppm groups were less than those of controls after week 12. Feed consumption by exposed groups of males and females was generally similar to that by the controls throughout the study. Significantly decreased incidences of hepatocellular adenoma and hepatocellular carcinoma occurred in 50,000 ppm males, and decreased incidences of hepatocellular adenoma or carcinoma (combined) occurred in 25,000 and 50,000 ppm males. Five milk thistle extracts were tested independently in bacterial mutagenicity studies using a variety of S. typhimurium tester strains and one E. coli strain. Results were negative in three of the five studies, with and without exogenous metabolic activation. In two studies, milk thistle extract was mutagenic in S. typhimurium strain TA98 in the presence of exogenous metabolic activation enzymes. Silymarin, a major constituent of milk thistle extract, was positive in S. typhimurium strains TA98 and TA100, when testing occurred in the presence of exogenous metabolic activation enzymes. Silybin, another component of milk thistle extract, was negative in a S. typhimurium gene mutation assay, with and without liver S9 activation enzymes. Administration of milk thistle extract in feed for 3 months did not increase the frequencies of micronucleated normochromatic erythrocytes, an indication of chromosomal abnormalities, in the peripheral blood of male or female B6C3F1 mice. Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of milk thistle extract in male or female F344/N rats or B6C3F1 mice exposed to 12,500, 25,000, or 50,000 ppm. Exposure to milk thistle extract resulted in increased incidences of clear cell and mixed cell foci in the liver of female rats and decreases in body weights of exposed groups of male and female mice. Decreased incidences of mammary gland neoplasms occurred in exposed groups of female rats, and decreased incidences of hepatocellular neoplasms occurred in exposed groups of male mice.

Partial correction of the dwarf phenotype by non-viral transfer of the growth hormone gene in mice: Treatment age is critical.

PubMed

Higuti, Eliza; Cecchi, Cláudia R; Oliveira, Nélio A J; Lima, Eliana R; Vieira, Daniel P; Aagaard, Lars; Jensen, Thomas G; Jorge, Alexander A L; Bartolini, Paolo; Peroni, Cibele N

2016-02-01

Non-viral transfer of the growth hormone gene to different muscles of immunodeficient dwarf (lit/scid) mice is under study with the objective of improving phenotypic correction via this particular gene therapy approach. Plasmid DNA was administered into the exposed quadriceps or non-exposed tibialis cranialis muscle of lit/scid mice followed by electroporation, monitoring several growth parameters. In a 6-month bioassay, 50μg DNA were injected three times into the quadriceps muscle of 80-day old mice. A 50% weight increase, with a catch-up growth of 21%, together with a 16% increase for nose-to-tail and tail lengths (catch-up=19-21%) and a 24-28% increase for femur length (catch-up=53-60%), were obtained. mIGF1 serum levels were ~7-fold higher than the basal levels for untreated mice, but still ~2-fold lower than in non-dwarf scid mice. Since treatment age was found to be particularly important in a second bioassay utilizing 40-day old mice, these pubertal mice were compared in a third bioassay with adult (80-day old) mice, all treated twice with 50μg DNA injected into each tibialis cranialis muscle, via a less invasive approach. mIGF1 concentrations at the same level as co-aged scid mice were obtained 15days after administration in pubertal mice. Catch-up growth, based on femur length (77%), nose-to-tail (36%) and tail length (39%) increases was 40 to 95% higher than those obtained upon treating adult mice. These data pave the way for the development of more effective pre-clinical assays in pubertal dwarf mice for the treatment of GH deficiency via plasmid-DNA muscular administration. Copyright © 2015 Elsevier Ltd. All rights reserved.

Differential effects of thiopurine methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on mercaptopurine toxicity.

PubMed

Liu, Chengcheng; Janke, Laura J; Yang, Jun J; Evans, William E; Schuetz, John D; Relling, Mary V

2017-08-01

Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in mercaptopurine tolerance can influence treatment outcome. Thiopurine methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear. We studied the metabolism of and tolerance to mercaptopurine in murine knockout models of Tpmt, Mrp4, and both genes simultaneously. Upon mercaptopurine treatment, Tpmt -/- Mrp4 -/- mice had the highest concentration of bone marrow thioguanine nucleotides (8.5 pmol/5 × 10 6 cells, P = 7.8 × 10 -4 compared with 2.7 pmol/5 × 10 6 cells in wild-types), followed by those with Mrp4 or Tpmt deficiency alone (6.1 and 4.3 pmol/5 × 10 6 cells, respectively). Mrp4-deficient mice accumulated higher concentrations of methylmercaptopurine metabolites compared with wild-type (76.5 vs. 23.2 pmol/5 × 10 6 cells, P = 0.027). Mice exposed to a clinically relevant mercaptopurine dosing regimen displayed differences in toxicity and survival among the genotypes. The double knock-out of both genes experienced greater toxicity and shorter survival compared to the single knockout of either Tpmt (P = 1.7 × 10 -6 ) or Mrp4 (P = 7.4 × 10 -10 ). We showed that both Tpmt and Mrp4 influence mercaptopurine disposition and toxicity.

Cold stimulates the behavioral response to hypoxia in newborn mice.

PubMed

Bollen, Bieke; Bouslama, Myriam; Matrot, Boris; Rotrou, Yann; Vardon, Guy; Lofaso, Frédéric; Van den Bergh, Omer; D'Hooge, Rudi; Gallego, Jorge

2009-05-01

In newborns, hypoxia elicits increased ventilation, arousal followed by defensive movements, and cries. Cold is known to affect the ventilatory response to hypoxia, but whether it affects the arousal response remains unknown. The aim of the present study was to assess the effects of cold on the ventilatory and arousal responses to hypoxia in newborn mice. We designed an original platform measuring noninvasively and simultaneously the breathing pattern by whole body plethysmography, body temperature by infrared thermography, as well as motor and ultrasonic vocal (USV) responses. Six-day-old mice were exposed twice to 10% O(2) for 3 min at either cold temperature (26 degrees C) or thermoneutrality (33 degrees C). At 33 degrees C, hypoxia elicited a marked increase in ventilation followed by a small ventilatory decline, small motor response, and almost no USVs. Body temperature was not influenced by hypoxia, and oxygen consumption (Vo(2)) displayed minimal changes. At 26 degrees C, hypoxia elicited a slight increase in ventilation with a large ventilatory decline and a large drop of Vo(2). This response was accompanied by marked USV and motor responses. Hypoxia elicited a small decrease in temperature after the return to normoxia, thus precluding any causal influence on the motor and USV responses to hypoxia. In conclusion, cold stimulated arousal and stress responses to hypoxia, while depressing hypoxic hyperpnea. Arousal is an important defense mechanism against sleep-disordered breathing. The dissociation between ventilatory and behavioral responses to hypoxia suggests that deficits in the arousal response associated with sleep breathing disorders cannot be attributed to a depressed hypoxic response.

Developmental and hematological responses to low level continuous exposure of nitrogen dioxide in mice

NASA Technical Reports Server (NTRS)

Singh, J.

1977-01-01

Young healthy mice were continuously exposed to 0ppm, 0.5ppm, 1.0ppm and 5ppm nitrogen dioxide gas for eight weeks. Nitrogen dioxide exposure for eight weeks decreased the average weight of mice, increased the average weight of lungs, heart, and brain and decreased the average weight of liver. Nitrogen dioxide exposure did not have any effects on the WBC and RBC in mice blood but it increased the HCT and HGB in mice blood. Nitrogen dioxide exposure increased the MCV and decreased the MCH and MCHC in mice blood.

Pre-Exposure to Context Affects Learning Strategy Selection in Mice

ERIC Educational Resources Information Center

Tunur, Tumay; Dohanich, Gary P.; Schrader, Laura A.

2010-01-01

The multiple memory systems hypothesis proposes that different types of learning strategies are mediated by distinct neural systems in the brain. Male and female mice were tested on a water plus-maze task that could be solved by either a place or response strategy. One group of mice was pre-exposed to the same context as training and testing (PTC)…

Ultraviolet carcinogenesis in the hairless mouse skin. Influence of the sunscreen 2-ethylhexyl-p-methoxycinnamate.

PubMed

Gallagher, C H; Greenoak, G E; Reeve, V E; Canfield, P J; Baker, R S; Bonin, A M

1984-10-01

The mutagenicity of some samples of a commonly used sunscreen, 2-ethylhexyl-p-methoxycinnamate (2-EHMC), led to these studies of its potential carcinogenicity in the HRA/Skh hairless mouse. In a daily treatment regime, repeated for 9 weeks, groups of mice were painted on the dorsum with 2-EHMC, and were then exposed to low doses of one of two artificial ultraviolet (UV) light sources. Mice were also treated with UV alone and with 2-EHMC alone. The accumulated UV exposure alone produced tumours in 40-100% of mice. However, 2-EHMC-treated mice were protected. Subsequent treatment of the 2-EHMC-protected mice, and mice previously treated with 2-EHMC alone, with the tumour promoter, croton oil, produced tumours on a significant number of animals. We conclude that 2-EHMC protects from UV tumorigenesis in the absence of a tumour promoter. However, although tumours appeared on only 4 out of 160 2-EHMC-treated mice exposed to UV, the carcinogenic process had been initiated in others, as application of the tumour promoter, croton oil, produced tumours. Statistical analysis of the incidence of promoted tumours inferred that prior irradiation with UV may not have been implicated. Therefore, 2-EHMC itself may initiate tumours in this strain of hairless mouse.

Npvf: Hypothalamic Biomarker of Ambient Temperature Independent of Nutritional Status

PubMed Central

Jaroslawska, Julia; Chabowska-Kita, Agnieszka; Kaczmarek, Monika M.; Kozak, Leslie P.

2015-01-01

The mechanism by which mice, exposed to the cold, mobilize endogenous or exogenous fuel sources for heat production is unknown. To address this issue we carried out experiments using 3 models of obesity in mice: C57BL/6J+/+ (wild-type B6) mice with variable susceptibility to obesity in response to being fed a high-fat diet (HFD), B6. Ucp1-/- mice with variable diet-induced obesity (DIO) and a deficiency in brown fat thermogenesis and B6. Lep-/- with defects in thermogenesis, fat mobilization and hyperphagia. Mice were exposed to the cold and monitored for changes in food intake and body composition to determine their energy balance phenotype. Upon cold exposure wild-type B6 and Ucp1-/- mice with diet-induced obesity burned endogenous fat in direct proportion to their fat reserves and changes in food intake were inversely related to fat mass, whereas leptin-deficient and lean wild-type B6 mice fed a chow diet depended on increased food intake to fuel thermogenesis. Analysis of gene expression in the hypothalamus to uncover a central regulatory mechanism revealed suppression of the Npvf gene in a manner that depends on the reduced ambient temperature and degree of exposure to the cold, but not on adiposity, leptin levels, food intake or functional brown fat. PMID:26070086

Association of Diet With Skin Histological Features in UV-B–Exposed Mice

PubMed Central

Hsia, Yvonne; Weeks, David M.; Dixon, Tatiana K.; Lepe, Jessica; Thomas, J. Regan

2017-01-01

Importance Long-term exposure to solar radiation produces deleterious photoaging of the skin. It is not known if diet can influence skin photoaging. Objectives To study the influence of a calorie-restricted diet and an obesity diet in mice exposed to long-term UV-B irradiation to assess if there is an association between diet and histopathological response to UV-B irradiation. Design, Setting, and Participants In this animal model study in an academic setting, the dorsal skin of SKH1 hairless mice receiving normal, calorie-restricted, and obesity diets was exposed to UV-B irradiation 3 times a week for 10 weeks and were compared with corresponding controls. The mice were placed in the following groups, with 8 animals in each group: (1) intact control (C) with regular diet and no UV-B exposure, (2) intact control with UV-B exposure (CR), (3) calorie-restricted diet (CrC), (4) calorie-restricted diet with UV-B exposure (CrR), (5) obesity diet (OC), and (6) obesity diet with UV-B exposure (OR). The experiment was conducted during October through December 2013. Tissue processing and histological analysis were completed in 2016. Main Outcomes and Measures Histomorphometric analysis was performed on paraffin-embedded skin sections stained by histological and immunohistochemical methods for estimation of epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, mast cells, dermal cellularity, and adipose layer ratio. Changes in wrinkles were noted. Results Hairless female mice (age range, 6-8 weeks) were obtained. With a normal diet, changes from UV-B irradiation occurred in epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, and mast cells, which were modestly influenced by an obesity diet. Calorie restriction influenced the skin in nonirradiated control animals, with higher values for most variables. After UV-B exposure in animals with calorie restriction, epidermal thickness was increased, but other variables were unaffected. Animals receiving the calorie-restricted diet lost weight when exposed to long-term UV-B irradiation. Wrinkles were reduced in the calorie-restricted control group and in UV-B–exposed animals who received the obesity diet. Conclusions and Relevance Dietary alterations seem to modify histopathological responses to UV-B exposure in the skin of hairless mice. Level of Evidence NA. PMID:28418519

PFOS induces behavioral alterations, including spontaneous hyperactivity that is corrected by dexamfetamine in zebrafish larvae.

PubMed

Spulber, Stefan; Kilian, Pascal; Wan Ibrahim, Wan Norhamidah; Onishchenko, Natalia; Ulhaq, Mazhar; Norrgren, Leif; Negri, Sara; Di Tuccio, Marcello; Ceccatelli, Sandra

2014-01-01

Perfluorooctane sulfonate (PFOS) is a widely spread environmental contaminant. It accumulates in the brain and has potential neurotoxic effects. The exposure to PFOS has been associated with higher impulsivity and increased ADHD prevalence. We investigated the effects of developmental exposure to PFOS in zebrafish larvae, focusing on the modulation of activity by the dopaminergic system. We exposed zebrafish embryos to 0.1 or 1 mg/L PFOS (0.186 or 1.858 µM, respectively) and assessed swimming activity at 6 dpf. We analyzed the structure of spontaneous activity, the hyperactivity and the habituation during a brief dark period (visual motor response), and the vibrational startle response. The findings in zebrafish larvae were compared with historical data from 3 months old male mice exposed to 0.3 or 3 mg/kg/day PFOS throughout gestation. Finally, we investigated the effects of dexamfetamine on the alterations in spontaneous activity and startle response in zebrafish larvae. We found that zebrafish larvae exposed to 0.1 mg/L PFOS habituate faster than controls during a dark pulse, while the larvae exposed to 1 mg/L PFOS display a disorganized pattern of spontaneous activity and persistent hyperactivity. Similarly, mice exposed to 0.3 mg/kg/day PFOS habituated faster than controls to a new environment, while mice exposed to 3 mg/kg/day PFOS displayed more intense and disorganized spontaneous activity. Dexamfetamine partly corrected the hyperactive phenotype in zebrafish larvae. In conclusion, developmental exposure to PFOS in zebrafish induces spontaneous hyperactivity mediated by a dopaminergic deficit, which can be partially reversed by dexamfetamine in zebrafish larvae.

Paroxetine exposure skews litter sex ratios in mice suggesting a Trivers–Willard process

PubMed Central

Gaukler, Shannon Marie; Ruff, James Steven; Potts, Wayne K.

2016-01-01

While conducting a toxicity assessment of the antidepressant paroxetine (Paxil®), in wild-derived mice (Mus musculus), we observed that exposed dams (P0) produced female biased litters (32:68 M:F). Though numerous experimental manipulations have induced sex ratio bias in mice, none have assessed the fitness of the offspring from these litters relative to controls. Here, we retrospectively analyze experimentally derived fitness data gathered for the purpose of toxicological assessment in light of 2 leading hypothesis (Trivers–Willard hypothesis [TWH] and cost of reproduction hypothesis [CRH]), seeking to test if this facultative sex ratio adjustment fits into an adaptive framework. Control F1 males were heavier than F1 females, but no differences in mass were detected between exposed F1 males and females, suggesting that exposed dams did not save energy by producing fewer males, despite producing 29.2% lighter litters relative to controls. F1 offspring of both treatments were released into seminatural enclosures where fitness was quantified. In enclosures, the relative reproductive success of F1-exposed males (compared with controls) was reduced by ~20% compared with the relative reproductive success of F1-exposed females. Thus, exposed dams increased their fitness by adjusting litters toward females who were less negatively affected by the exposure than males. Collectively, these data provide less support that the observed sex ratio bias results in energetic savings (CRH), and more support for the TWH because fitness was increased by biasing litters toward female offspring. These mammalian data are unique in their ability to support the TWH through the use of relevant fitness data. PMID:27418753

Dual-Color Bioluminescence Imaging for Simultaneous Monitoring of the Intestinal Persistence of Lactobacillus plantarum and Lactococcus lactis in Living Mice

PubMed Central

Poiret, Sabine; Dennin, Véronique; Boutillier, Denise; Lacorre, Delphine Armelle; Foligné, Benoit; Pot, Bruno

2015-01-01

Lactic acid bacteria are found in the gastrointestinal tract of mammals and have received tremendous attention due to their health-promoting properties. We report the development of two dual-color luciferase-producing Lactobacillus (Lb.) plantarum and Lactococcus (Lc.) lactis strains for noninvasive simultaneous tracking in the mouse gastrointestinal tract. We previously described the functional expression of the red luciferase mutant (CBRluc) from Pyrophorus plagiophthalamus in Lb. plantarum NCIMB8826 and Lc. lactis MG1363 (C. Daniel, S. Poiret, V. Dennin, D. Boutillier, and B. Pot, Appl Environ Microbiol 79:1086–1094, 2013, http://dx.doi.org/10.1128/AEM.03221-12). In this study, we determined that CBRluc is a better-performing luciferase for in vivo localization of both lactic acid bacteria after oral administration than the green click beetle luciferase mutant construct developed in this study. We further established the possibility to simultaneously detect red- and green-emitting lactic acid bacteria by dual-wavelength bioluminescence imaging in combination with spectral unmixing. The difference in spectra of light emission by the red and green click beetle luciferase mutants and dual bioluminescence detection allowed in vitro and in vivo quantification of the red and green emitted signals; thus, it allowed us to monitor the dynamics and fate of the two bacterial populations simultaneously. Persistence and viability of both strains simultaneously administered to mice in different ratios was studied in vivo in anesthetized mice and ex vivo in mouse feces. The application of dual-luciferase-labeled bacteria has considerable potential to simultaneously study the interactions and potential competitions of different targeted bacteria and their hosts. PMID:26025906

Effect of ammonia on Swiss albino mice

NASA Technical Reports Server (NTRS)

Hilado, C. J.; Casey, C. J.; Furst, A.

1977-01-01

Times to incapacitation and death and LC /50/ values were determined for Swiss albino male mice exposed to different concentrations of ammonia in a 4.2 liter hemispherical chamber. The LC/50/ for a 30 minute exposure was 21,430 ppm.

Prenatal stress and ethanol exposure produces inversion of sexual partner preference in mice.

PubMed

Popova, Nina K; Morozova, Maryana V; Amstislavskaya, Tamara G

2011-02-01

The presence of a sexually receptive female behind perforated transparent partition induced sexual arousal and specific behavior in male mice so they spent more time near partition in an attempt to make their way to the female. Three-chambered free-choice model was used to evaluate sexual partner preference. The main pattern of sexual preference was the time spent by a male mouse at the partition dividing female (F-partition time) versus a partition dividing male (M-partition time). Pregnant mice were given ethanol (11vol.%) for 1-21 gestational days, and were exposed to restraint stress (2h daily for 15-21 day of the gestation). Control pregnant mice had free access to water and food and were not stressed. Adult male offspring of ethanol and stress exposed dams (E+S) showed decreased F-partition time and increased M-partition time. Whereas F-partition time in all control mice prevailed over M-partition time, 78% E+S mice demonstrated prevailed M-partition time. E+S mice were more active in social interaction with juvenile male. No significant differences between E+S and control mice in the open field and novelty tests were revealed. Therefore, E+S exposure during dam gestation inverted sexual partner preference in male offspring, suggesting that stress and alcohol in pregnancy produces predisposition to homosexuality. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Effect of Chorda Tympani Nerve Transection on Salt Taste Perception in Mice

PubMed Central

Ishiwatari, Yutaka; Theodorides, Maria L.; Bachmanov, Alexander A.

2011-01-01

Effects of gustatory nerve transection on salt taste have been studied extensively in rats and hamsters but have not been well explored in the mouse. We examined the effects of chorda tympani (CT) nerve transection on NaCl taste preferences and thresholds in outbred CD-1 mice using a high-throughput phenotyping method developed in our laboratory. To measure taste thresholds, mice were conditioned by oral self-administration of LiCl or NaCl and then presented with NaCl concentration series in 2-bottle preference tests. LiCl-conditioned and control NaCl-exposed mice were given bilateral transections of the CT nerve (LiCl-CTX, NaCl-CTX) or were left intact as controls (LiCl-CNT, NaCl-CNT). After recovery from surgery, mice received a concentration series of NaCl (0–300 mM) in 48-h 2-bottle tests. CT transection increased NaCl taste thresholds in LiCl-conditioned mice and eliminated avoidance of concentrated NaCl in control NaCl-exposed mice. This demonstrates that in mice, the CT nerve is important for detection and recognition of NaCl taste and is necessary for the normal avoidance of high concentrations of NaCl. The results of this experiment also show that the method of high-throughput phenotyping of salt taste thresholds is suitable for detecting changes in the taste periphery in mouse genetic studies. PMID:21743094

Social stress induces changes in urinary bladder function, bladder NGF content, and generalized bladder inflammation in mice

PubMed Central

Peterson, Abbey; Erickson, Cuixia Shi; Nelson, Mark T.; Vizzard, Margaret A.

2014-01-01

Social stress may play a role in urinary bladder dysfunction in humans, but the underlying mechanisms are unknown. In the present study, we explored changes in bladder function caused by social stress using mouse models of stress and increasing stress. In the stress paradigm, individual submissive FVB mice were exposed to C57BL/6 aggressor mice directly/indirectly for 1 h/day for 2 or 4 wk. Increased stress was induced by continuous, direct/indirect exposure of FVB mice to aggressor mice for 2 wk. Stressed FVB mice exhibited nonvoiding bladder contractions and a decrease in both micturition interval (increased voiding frequency) and bladder capacity compared with control animals. ELISAs demonstrated a significant increase in histamine protein expression with no change in nerve growth factor protein expression in the urinary bladder compared with controls. Unlike stressed mice, mice exposed to an increased stress paradigm exhibited increased bladder capacities and intermicturition intervals (decreased voiding frequency). Both histamine and nerve growth factor protein expression were significantly increased with increased stress compared with control bladders. The change in bladder function from increased voiding frequency to decreased voiding frequency with increased stress intensity suggests that changes in social stress-induced urinary bladder dysfunction are context and duration dependent. In addition, changes in the bladder inflammatory milieu with social stress may be important contributors to changes in urinary bladder function. PMID:25100077

Atorvastatin and Simvastatin Promoted Mouse Lung Repair After Cigarette Smoke-Induced Emphysema.

PubMed

Pinho-Ribeiro, Vanessa; Melo, Adriana Correa; Kennedy-Feitosa, Emanuel; Graca-Reis, Adriane; Barroso, Marina Valente; Cattani-Cavalieri, Isabella; Carvalho, Giovanna Marcella Cavalcante; Zin, Walter Araújo; Porto, Luis Cristóvão; Gitirana, Lycia Brito; Lanzetti, Manuella; Valença, Samuel Santos

2017-06-01

Cigarette smoke (CS) induces pulmonary emphysema by inflammation, oxidative stress, and metalloproteinase (MMP) activation. Pharmacological research studies have not focused on tissue repair after the establishment of emphysema but have instead focused on inflammatory stimulation. The aim of our study was to analyze the effects of atorvastatin and simvastatin on mouse lung repair after emphysema caused by CS. Male mice (C57BL/6, n = 45) were divided into the following groups: control (sham-exposed), CSr (mice exposed to 12 cigarettes a day for 60 days and then treated for another 60 days with the vehicle), CSr+A (CSr mice treated with atorvastatin for 60 days), and CSr+S (CSr mice treated with simvastatin for 60 days). The treatment with atorvastatin and simvastatin was administered via inhalation (15 min with 1 mg/mL once a day). Mice were sacrificed 24 h after the completion of the 120-day experimental procedure. We performed biochemical, morphological, and physiological analyses. We observed decreased levels of leukocytes and cytokines in statin-treated mice, accompanied by a reduction in oxidative stress markers. We also observed a morphological improvement confirmed by a mean linear intercept counting in statin-treated mice. Finally, statins also ameliorated lung function. We conclude that inhaled atorvastatin and simvastatin improved lung repair after cigarette smoke-induced emphysema in mice.

Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice.

PubMed

Verhein, Kirsten C; McCaw, Zachary; Gladwell, Wesley; Trivedi, Shweta; Bushel, Pierre R; Kleeberger, Steven R

2015-08-01

Ozone is a highly toxic air pollutant and global health concern. Mechanisms of genetic susceptibility to ozone-induced lung inflammation are not completely understood. We hypothesized that Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation. Wild-type (WT), Notch3 (Notch3-/-), and Notch4 (Notch4-/-) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6-72 hr. Relative to air-exposed controls, ozone increased bronchoalveolar lavage fluid (BALF) protein, a marker of lung permeability, in all genotypes, but significantly greater concentrations were found in Notch4-/- compared with WT and Notch3-/- mice. Significantly greater mean numbers of BALF neutrophils were found in Notch3-/- and Notch4-/- mice compared with WT mice after ozone exposure. Expression of whole lung Tnf was significantly increased after ozone in Notch3-/- and Notch4-/- mice, and was significantly greater in Notch3-/- compared with WT mice. Statistical analyses of the transcriptome identified differentially expressed gene networks between WT and knockout mice basally and after ozone, and included Trim30, a member of the inflammasome pathway, and Traf6, an inflammatory signaling member. These novel findings are consistent with Notch3 and Notch4 as susceptibility genes for ozone-induced lung injury, and suggest that Notch receptors protect against innate immune inflammation.

Immunological aspects of circulating DNA.

PubMed

Anker, Philippe; Stroun, Maurice

2006-09-01

Nude mice were injected with DNA released by T lymphocytes previously exposed to inactivated herpes symplex type 1 or polio viruses. The serum of these mice was tested for its neutralizing activity. Injected nude mice synthesized antiherpetic or antipolio antibodies, depending on the antigen used to sensitize the T lymphocytes. Mice injected with DNA released by human T cells produced antibodies carrying human allotypes as they could be neutralized by antiallotype sera. However, mice that were injected with DNA released by antigen-stimulated murine T lymphocytes produced antiviral antibodies, which were not neutralized by anti-human allotype sera.

Microstructural Changes to the Brain of Mice after Methamphetamine Exposure as Identified with Diffusion Tensor Imaging

PubMed Central

McKenna, Benjamin S.; Brown, Gregory G.; Archibald, Sarah; Scadeng, Miriam; Bussell, Robert; Kesby, James P.; Markou, Athina; Soontornniyomkij, Virawudh; Achim, Cristian; Semenova, Svetlana

2016-01-01

Methamphetamine (METH) is an addictive psychostimulant inducing neurotoxicity. Human magnetic resonance imaging and diffusion tensor imaging (DTI) of METH-dependent participants find various structural abnormities. Animal studies demonstrate immunohistochemical changes in multiple cellular pathways after METH exposure. Here, we characterized the long-term effects of METH on brain microstructure in mice exposed to an escalating METH binge regimen using in vivo DTI, a methodology directly translatable across species. Results revealed four patterns of differential fractional anisotropy (FA) and mean diffusivity (MD) response when comparing METH-exposed (n=14) to saline-treated mice (n=13). Compared to the saline group, METH-exposed mice demonstrated: 1) decreased FA with no change in MD [corpus callosum (posterior forceps), internal capsule (left), thalamus (medial aspects), midbrain], 2) increased MD with no change in FA [posterior isocortical regions, caudate-putamen, hypothalamus, cerebral peduncle, internal capsule (right)], 3) increased FA with decreased MD [frontal isocortex, corpus callosum (genu)], and 4) increased FA with no change or increased MD [hippocampi, amygdala, lateral thalamus]. MD was negatively associated with calbindin-1 in hippocampi and positively with dopamine transporter in caudate-putamen. These findings highlight distributed and differential METH effects within the brain suggesting several distinct mechanisms. Such mechanisms likely change brain tissue differentially dependent upon neural location. PMID:27000304

Evaluation of Isoflurane Overdose for Euthanasia of Neonatal Mice.

PubMed

Seymour, Travis L; Nagamine, Claude M

2016-01-01

Neonatal mice (that is, pups younger than 6 d) must be exposed to CO2 for as long as 50 min to achieve euthanasia. Alternatively, other inhalant anesthetic agents have been used to euthanize laboratory rodent species. We investigated the efficacy of isoflurane at saturated vapor pressure to euthanize neonatal mice. Neonatal mice (n = 76; age, 1 or 2 d) were exposed to isoflurane in a sealed, quart-size (0.95-L) plastic bag at room temperature. Righting and withdrawal reflexes were absent in less than 2 min. After 30 min of exposure to isoflurane, pups were removed and monitored for recovery. All pups were cyanotic and showed no detectable signs of life when they were removed from the bag. However, after 30 to 120 min after removal from the bag, 24% of isoflurane-overexposed pups began gasping and then resumed normal respiration and regained a normal pink coloration. These results demonstrate that isoflurane overexposure at saturated vapor pressure for 30 min is insufficient to euthanize neonatal mice and that isoflurane overexposure must be followed by a secondary means of euthanasia.

Evaluation of Isoflurane Overdose for Euthanasia of Neonatal Mice

PubMed Central

Seymour, Travis L; Nagamine, Claude M

2016-01-01

Neonatal mice (that is, pups younger than 6 d) must be exposed to CO2 for as long as 50 min to achieve euthanasia. Alternatively, other inhalant anesthetic agents have been used to euthanize laboratory rodent species. We investigated the efficacy of isoflurane at saturated vapor pressure to euthanize neonatal mice. Neonatal mice (n = 76; age, 1 or 2 d) were exposed to isoflurane in a sealed, quart-size (0.95-L) plastic bag at room temperature. Righting and withdrawal reflexes were absent in less than 2 min. After 30 min of exposure to isoflurane, pups were removed and monitored for recovery. All pups were cyanotic and showed no detectable signs of life when they were removed from the bag. However, after 30 to 120 min after removal from the bag, 24% of isoflurane-overexposed pups began gasping and then resumed normal respiration and regained a normal pink coloration. These results demonstrate that isoflurane overexposure at saturated vapor pressure for 30 min is insufficient to euthanize neonatal mice and that isoflurane overexposure must be followed by a secondary means of euthanasia. PMID:27177567

Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus

PubMed Central

Li, Shuang; Kalappa, Bopanna I; Tzounopoulos, Thanos

2015-01-01

Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus. DOI: http://dx.doi.org/10.7554/eLife.07242.001 PMID:26312501

Papain-induced experimental pulmonary emphysema in male and female mice.

PubMed

Machado, Mariana Nascimento; Figueirôa, Silviane Fernandes da Silva; Mazzoli-Rocha, Flavia; Valença, Samuel dos Santos; Zin, Walter Araújo

2014-08-15

In papain-induced models of emphysema, despite the existing extensive description of the cellular and molecular aspects therein involved, sexual hormones may play a complex and still not fully understood role. Hence, we aimed at exploring the putative gender-related differences in lung mechanics, histology and oxidative stress in papain-exposed mice. Thirty adult BALB/c mice received intratracheally either saline (50 μL) or papain (10 U/50 μL saline) once a week for 2 weeks. In males papain increased lung resistive and viscoelastic/inhomogeneous pressures, static elastance, and viscoelastic component of elastance, while females showed higher static elastance and resistive pressure only. Both genders presented similar higher parenchymal cellularity and mean alveolar diameter, and less collagen-elastic fiber content and body weight gain than their respective controls. Increased functional residual capacity was more prominent in males. Female papain-treated mice were more susceptible to oxidative stress. Thus, male and female papain-exposed mice respond differently, which should be carefully considered to avoid confounding results. Copyright © 2014 Elsevier B.V. All rights reserved.

Human dendritic cells in the severe combined immunodeficiency mouse model: their potentiating role in the allergic reaction.

PubMed

Hammad, H; Duez, C; Fahy, O; Tsicopoulos, A; André, C; Wallaert, B; Lebecque, S; Tonnel, A B; Pestel, J

2000-04-01

Dendritic cells (DCs) are present in the lungs and airways of healthy and allergic subjects where they are exposed to inhaled antigens. After the uptake of antigens, DCs migrate to lymphoid organs where T cells initiate and control the immune response. The migratory properties of DCs are an essential component of their function but remain unclear in the situation of allergic diseases. To better understand the role of DCs in response to allergens, we first investigated their presence in an original experimental model of allergic asthma: the humanized severe combined immunodeficiency (SCID) mouse reconstituted with peripheral blood mononuclear cells from patients sensitive to Dermatophagoides pteronyssinus (Dpt). Human DCs were detected in lungs of mice developing an inflammatory pulmonary infiltrate and appeared to be mainly located in the alveolar spaces. In a second step, human DCs were generated in vitro from monocytes and injected into naive SCID mice exposed or not exposed to Dpt aerosols. Their migratory behavior was explored, as well as their potential role in modulating the IgE production after exposure to Dpt. After exposure to Dpt, the number of DCs present in airways decreased, while it increased into the spleen and thymus of the mice. The IgE production increased in the presence of DCs as compared with mice not injected with DCs. These results suggest that DCs may play a role in the pulmonary allergic reaction developed in response to Dpt in SCID mice.

Different responses of tumor and normal cells to low-dose radiation

PubMed Central

Liu, Ning; Wang, Hao; Shang, Qingjun; Jiang, Peng; Zhang, Yuanmei

2013-01-01

Aim of the study We demonstrated stimulation of both erythrocyte immune function and superoxide dismutase activity in tumor-bearing mice in response to whole-body 75 mGy X-rays. In addition, we enhanced the chemotherapeutic effect by exposing tumor-bearing mice to low-dose radiation (LDR). This study aims to investigate the different responses of tumor cells and normal cells to LDR. Material and methods Survival fraction, micronucleus frequency, and cell cycle of Lewis cells and primary human fibroblast AG01522 cells were measured. S180 sarcoma cells were implanted in mice, and tumor sizes were measured in vivo. Results In response to LDR exposure in vitro, a stimulating effect was observed in AG01522 cells but not in Lewis cells. Low-dose radiation did not cause an adaptive response in the Lewis cell cycle. Lack of an LDR-induced radioadaptive response in tumor cells was observed in tumor-bearing mouse models. Furthermore, a higher apoptotic effect and lower expression of the anti-apoptosis gene Bcl-2 were found in tumor cells of tumor-bearing mice exposed to D1 + D2 than those in tumor cells of tumor-bearing mice exposed to D2 alone. Conclusions Different responses of tumor cells and normal cells to LDR were found. Low-dose radiation was found to stimulate the growth of normal cells but not of tumor cells in vitro and in vivo, which is a very important and clinically relevant phenomenon. PMID:24592123

Ultraviolet radiation-induced cataract in mice: the effect of age and the potential biochemical mechanism.

PubMed

Zhang, Jie; Yan, Hong; Löfgren, Stefan; Tian, Xiaoli; Lou, Marjorie F

2012-10-19

To study the effect of age on the morphologic and biochemical alterations induced by in vivo exposure of ultraviolet radiation (UV). Young and old C57BL/6 mice were exposed to broadband UVB+UVA and euthanized after 2 days. Another batch of UV-exposed young mice was monitored for changes after 1, 2, 4, and 8 days. Age-matched nonexposed mice served as controls. Lens changes were documented in vivo by slit-lamp biomicroscopy and dark field microscopy photographs ex vivo. Lens homogenates were analyzed for glutathione (GSH) level, and the activities of thioredoxin (Trx), thioltransferase (TTase), and glyceraldehyde-3-phosphate dehydrogenase (G3PD). Glutathionylated lens proteins (PSSGs) were detected by immunoblotting using GSH antibody. Western blot analysis was also done for the expression levels of TTase and Trx. Both age groups developed epithelial and superficial anterior subcapsular cataract at 2 days postexposure. The lens GSH level and G3PD activity were decreased, and PSSGs were elevated in both age groups, but more prominent in the older mice. TTase and Trx activity and protein expression were elevated only in the young mice. Interestingly, lens TTase and Trx in the young mice showed a transient increase, peaking at 2 days after UV exposure and returning to baseline at day 8, corroborated by lens transparency. The lenses of old mice were more susceptible to UV radiation-induced cataract. The upregulated TTase and Trx likely provided oxidation damage repair in the young mice.

An elevated level of copper zinc superoxide dismutase fails to prevent oxygen induced retinopathy in mice.

PubMed

Klaeger, C; de Sa, L; Klaeger, A J; Carlson, E J; Good, W V; Epstein, C J

1996-05-01

To determine whether a higher level of copper zinc superoxide dismutase (CuZnSOD) can reduce the severity of oxygen induced retinopathy (OIR) in a mouse model. CuZnSOD transgenic mice with a threefold increase in CuZnSOD activity and control non-transgenic mice were exposed to 90% oxygen for 12 hours a day during the first 5 days of life. After oxygen treatment, all mice were reared in room air for 10 days. Another group of transgenic and non-transgenic mice were kept in room air for 15 days and served as control groups for the oxygen effect. At day 15, all mice were killed and perfused with India ink. The retinas were flat mounted on slides and examined with a light microscope. There was a statistically significant increase in the incidence of OIR in mice exposed to high levels of oxygen, whether or not they were transgenic. However, there was no statistically significant difference in the severity of OIR between oxygen treated transgenic and non-transgenic mice. A threefold higher CuZnSOD activity does not protect against OIR in mice. This is an unexpected finding, since oxygen radicals are considered a major factor causing OIR, and increased CuZnSOD activity has reduced oxygen radical induced damage in several neuronal and non-neuronal systems. The possibility of a damaging role for other radicals not affected by CuZnSOD cannot be excluded.

Transgenic up-regulation of Claudin-6 decreases fine diesel particulate matter (DPM)-induced pulmonary inflammation.

PubMed

Lewis, Joshua B; Bodine, Jared S; Gassman, Jason R; Muñoz, Samuel Arce; Milner, Dallin C; Dunaway, Todd M; Egbert, Kaleb M; Monson, Troy D; Broberg, Dallin S; Arroyo, Juan A; Reynolds, Paul R

2018-04-25

Claudin-6 (Cldn6) is a tetraspanin transmembrane protein that contributes to tight junctional complexes and has been implicated in the maintenance of lung epithelial barriers. In the present study, we tested the hypothesis that genetic up-regulation of Cldn-6 influences inflammation in mice exposed to short-term environmental diesel particulate matter (DPM). Mice were subjected to ten exposures of nebulized DPM (PM2.5) over a period of 20 days via a nose-only inhalation system (Scireq, Montreal, Canada). Using real-time RT-PCR, we discovered that the Cldn6 gene was up-regulated in control mice exposed to DPM and in lung-specific transgenic mice that up-regulate Cldn-6 (Cldn-6 TG). Interestingly, DPM did not further enhance Cldn-6 expression in Cldn-6 TG mice. DPM caused increased cell diapedesis into bronchoalveolar lavage fluid (BALF) from control mice; however, Cldn-6 TG mice had less total cells and PMNs in BALF following DPM exposure. Because Cldn-6 TG mice had diminished cell diapedesis, other inflammatory intermediates were screened to characterize the impact of increased Cldn-6 on inflammatory signaling. Cytokines that mediate inflammatory responses including TNF-α and IL-1β were differentially regulated in Cldn6 TG mice and controls following DPM exposure. These results demonstrate that epithelial barriers organized by Cldn-6 mediate, at least in part, diesel-induced inflammation. Further work may show that Cldn-6 is a key target in understanding pulmonary epithelial gateways exacerbated by environmental pollution.

Bacterial infection causes stress-induced memory dysfunction in mice.

PubMed

Gareau, Mélanie G; Wine, Eytan; Rodrigues, David M; Cho, Joon Ho; Whary, Mark T; Philpott, Dana J; Macqueen, Glenda; Sherman, Philip M

2011-03-01

The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.

Two-hour methyl isocyanate inhalation and 90-day recovery study in B6C3F1 mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boorman, G.A.; Uraih, L.C.; Gupta, B.N.

1987-06-01

B6C3F1 mice were exposed by inhalation to 0, 3, 10, and 30 ppm methyl isocyanate for 2 hr followed by a 90-day recovery period. Sixteen of eight (20%) male mice in the 30 ppm group died following exposure. There were no other unscheduled deaths in the mice. Five mice/sex/group were examined at 2 hr or at 1, 3, 7, 14, 28, 49, or 91 days following exposure. Chemical-related changes were restricted to the respiratory system. At 30 ppm there were extensive necrosis and erosion of the respiratory and olfactory epithelium in the nasal cavity. Severe necrosis and epithelial erosion weremore » also found in the trachea and main bronchi. Regeneration of the mucosal epithelium occurred rapidly in the nasal cavity and airways. In the turbinates, mild incomplete olfactory epithelial regeneration persisted to day 91 in the male mice. Intraluminal fibrotic projections covered by respiratory epithelium and bronchial fibrosis were found in the major airways of the 30 ppm male and female mice by day 7. The intraluminal fibrosis persisted to day 91. In males with severe bronchial fibrosis, chronic alveolitis and atelectasis were found. In mice exposed to 3 or 10 ppm, persistent pulmonary changes were not found. These studies indicate that methyl isocyanate inhalation at or near lethal concentrations can cause persistent fibrosis of the major bronchi in mice.« less

Low-Dose Oxygen Enhances Macrophage-Derived Bacterial Clearance following Cigarette Smoke Exposure

PubMed Central

Bain, William G.; Tripathi, Ashutosh; Mandke, Pooja; Gans, Jonathan H.; D'Alessio, Franco R.; Sidhaye, Venkataramana K.; Aggarwal, Neil R.

2016-01-01

Background. Chronic obstructive pulmonary disease (COPD) is a common, smoking-related lung disease. Patients with COPD frequently suffer disease exacerbations induced by bacterial respiratory infections, suggestive of impaired innate immunity. Low-dose oxygen is a mainstay of therapy during COPD exacerbations; yet we understand little about whether oxygen can modulate the effects of cigarette smoke on lung immunity. Methods. Wild-type mice were exposed to cigarette smoke for 5 weeks, followed by intratracheal instillation of Pseudomonas aeruginosa (PAO1) and 21% or 35–40% oxygen. After two days, lungs were harvested for PAO1 CFUs, and bronchoalveolar fluid was sampled for inflammatory markers. In culture, macrophages were exposed to cigarette smoke and oxygen (40%) for 24 hours and then incubated with PAO1, followed by quantification of bacterial phagocytosis and inflammatory markers. Results. Mice exposed to 35–40% oxygen after cigarette smoke and PAO1 had improved survival and reduced lung CFUs and inflammation. Macrophages from these mice expressed less TNF-α and more scavenger receptors. In culture, macrophages exposed to cigarette smoke and oxygen also demonstrated decreased TNF-α secretion and enhanced phagocytosis of PAO1 bacteria. Conclusions. Our findings demonstrate a novel, protective role for low-dose oxygen following cigarette smoke and bacteria exposure that may be mediated by enhanced macrophage phagocytosis. PMID:27403445

Bioactive grape proanthocyanidins enhance immune reactivity in UV-irradiated skin through functional activation of dendritic cells in mice.

PubMed

Vaid, Mudit; Singh, Tripti; Prasad, Ram; Elmets, Craig A; Xu, Hui; Katiyar, Santosh K

2013-03-01

Ultraviolet (UV) radiation-induced immunosuppression has been implicated in skin carcinogenesis. Grape seed proanthocyanidins (GSPs) have anti-skin carcinogenic effects in mice and GSPs-fed mice exhibit a reduction in UV-induced suppression of allergic contact hypersensitivity (CHS), a prototypic T-cell-mediated response. Here, we report that dietary GSPs did not inhibit UVB-induced suppression of CHS in xeroderma pigmentosum complementation group A (XPA)-deficient mice, which lack nucleotide excision repair mechanisms. GSPs enhanced repair of UVB-induced DNA damage (cyclobutane pyrimidine dimers) in wild-type, but not XPA-deficient, dendritic cells (DC). Co-culture of CD4(+) T cells with DCs from UVB-irradiated wild-type mice resulted in suppression of T-cell proliferation and secretion of T-helper (TH) 1-type cytokines that was ameliorated when the DCs were obtained from GSP-fed mice, whereas DCs obtained from GSP-fed XPA-KO mice failed to restore T-cell proliferation. In adoptive transfer experiments, donor DCs were positively selected from the draining lymph nodes of UVB-exposed donor mice that were sensitized to 2,4,-dinitrofluorobenzene were transferred into naïve recipient mice and the CHS response assessed. Naïve recipients that received DCs from UVB-exposed wild-type donors that had been fed GSPs exhibited a full CHS response, whereas no significant CHS was observed in mice that received DCs from XPA-KO mice fed GSPs. These results suggest that GSPs prevent UVB-induced immunosuppression through DNA repair-dependent functional activation of dendritic cells in mice. Cancer Prev Res; 6(3); 242-52. ©2013 AACR. ©2013 AACR.

Effects of gasoline engine emissions on preexisting allergic airway responses in mice.

PubMed

Day, Kimberly C; Reed, Matthew D; McDonald, Jacob D; Seilkop, Steven K; Barrett, Edward G

2008-10-01

Gasoline-powered vehicle emissions contribute significantly to ambient air pollution. We hypothesized that exposure to gasoline engine emissions (GEE) may exacerbate preexisting allergic airway responses. Male BALB/c mice were sensitized by injection with ovalbumin (OVA) and then received a 10-min aerosolized OVA challenge. Parallel groups were sham-sensitized with saline. Mice were exposed 6 h/day to air (control, C) or GEE containing particulate matter (PM) at low (L), medium (M), or high (H) concentrations, or to the H level with PM removed by filtration (high-filtered, HF). Immediately after GEE exposure mice received another 10-min aerosol OVA challenge (pre-OVA protocol). In a second (post-OVA) protocol, mice were similarly sensitized but only challenged to OVA before air or GEE exposure. Measurements of airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL), and blood collection were performed approximately 24 h after the last exposure. In both protocols, M, H, and HF GEE exposure significantly decreased BAL neutrophils from nonsensitized mice but had no significant effect on BAL cells from OVA-sensitized mice. In the pre-OVA protocol, GEE exposure increased OVA-specific IgG(1) but had no effect on BAL interleukin (IL)-2, IL-4, IL-13, or interferon (IFN)-gamma in OVA-sensitized mice. Nonsensitized GEE-exposed mice had increased OVA-specific IgG(2a), IgE, and IL-2, but decreased total IgE. In the post-OVA protocol, GEE exposure reduced BAL IL-4, IL-5, and IFN-gamma in nonsensitized mice but had no effect on sensitized mice. These results suggest acute exposure to the gas-vapor phase of GEE suppressed inflammatory cells and cytokines from nonsensitized mice but did not substantially exacerbate allergic responses.

Environmental Challenges and Physiological Solutions: Comparative Energetic Daily Rhythms of Field Mice Populations from Different Ecosystems

PubMed Central

Scantlebury, Michael; Haim, Abraham

2012-01-01

Daily and seasonal variations in physiological characteristics of mammals can be considered adaptations to temporal habitat variables. Across different ecosystems, physiological adjustments are expected to be sensitive to different environmental signals such as changes in photoperiod, temperature or water and food availability; the relative importance of a particular signal being dependent on the ecosystem in question. Energy intake, oxygen consumption (VO2) and body temperature (Tb) daily rhythms were compared between two populations of the broad-toothed field mouse Apodemus mystacinus, one from a Mediterranean and another from a sub-Alpine ecosystem. Mice were acclimated to short-day (SD) ‘winter’ and long-day (LD) ‘summer’ photoperiods under different levels of salinity simulating osmotic challenges. Mediterranean mice had higher VO2 values than sub-Alpine mice. In addition, mice exposed to short days had higher VO2 values when given water with a high salinity compared with mice exposed to long days. By comparison, across both populations, increasing salinity resulted in a decreased Tb in SD- but not in LD-mice. Thus, SD-mice may conserve energy by decreasing Tb during (‘winter’) conditions which are expected to be cool, whereas LD-mice might do the opposite and maintain a higher Tb during (‘summer’) conditions which are expected to be warm. LD-mice behaved to reduce energy expenditure, which might be considered a useful trait during ‘summer’ conditions. Overall, increasing salinity was a clear signal for Mediterranean-mice with resultant effects on VO2 and Tb daily rhythms but had less of an effect on sub-Alpine mice, which were more responsive to changes in photoperiod. Results provide an insight into how different populations respond physiologically to various environmental challenges. PMID:23251469

Environmental challenges and physiological solutions: comparative energetic daily rhythms of field mice populations from different ecosystems.

PubMed

Scantlebury, Michael; Haim, Abraham

2012-01-01

Daily and seasonal variations in physiological characteristics of mammals can be considered adaptations to temporal habitat variables. Across different ecosystems, physiological adjustments are expected to be sensitive to different environmental signals such as changes in photoperiod, temperature or water and food availability; the relative importance of a particular signal being dependent on the ecosystem in question. Energy intake, oxygen consumption (VO(2)) and body temperature (T(b)) daily rhythms were compared between two populations of the broad-toothed field mouse Apodemus mystacinus, one from a Mediterranean and another from a sub-Alpine ecosystem. Mice were acclimated to short-day (SD) 'winter' and long-day (LD) 'summer' photoperiods under different levels of salinity simulating osmotic challenges. Mediterranean mice had higher VO(2) values than sub-Alpine mice. In addition, mice exposed to short days had higher VO(2) values when given water with a high salinity compared with mice exposed to long days. By comparison, across both populations, increasing salinity resulted in a decreased T(b) in SD- but not in LD-mice. Thus, SD-mice may conserve energy by decreasing T(b) during ('winter') conditions which are expected to be cool, whereas LD-mice might do the opposite and maintain a higher T(b) during ('summer') conditions which are expected to be warm. LD-mice behaved to reduce energy expenditure, which might be considered a useful trait during 'summer' conditions. Overall, increasing salinity was a clear signal for Mediterranean-mice with resultant effects on VO(2) and T(b) daily rhythms but had less of an effect on sub-Alpine mice, which were more responsive to changes in photoperiod. Results provide an insight into how different populations respond physiologically to various environmental challenges.

SPERMATID MICRONUCLEUS ANALYSES OF TRICHLOROETHYLENE AND CHLORAL HYDRATE EFFECTS IN MICE

EPA Science Inventory

Mice were exposed by inhalation to trichloroethylene (TCE), or by i.p. injection to the TCE metabolite, chloral hydrate (CH). arly spermatids were analyzed for micronucleus (MN) frequency and kinetochore status (presence or absence) using fluorochrome-labeled anti-kinetochore ant...

Reactor vessel seal service fixture

DOEpatents

Ritz, W.C.

1975-12-01

An apparatus for the preparation of exposed sealing surfaces along the open rim of a nuclear reactor vessel comprised of a motorized mechanism for traveling along the rim and simultaneously brushing the exposed surfaces is described.

Feasibility of chemohyperthermia with docetaxel-embedded magnetoliposomes as minimally invasive local treatment for cancer.

PubMed

Yoshida, Motohira; Watanabe, Yuji; Sato, Mitsunori; Maehara, Tsunehiro; Aono, Hiromichi; Naohara, Takashi; Hirazawa, Hideyuki; Horiuchi, Atsushi; Yukumi, Shungo; Sato, Koichi; Nakagawa, Hiromichi; Yamamoto, Yuji; Sugishita, Hiroki; Kawachi, Kanji

2010-04-15

Hyperthermia is a minimally invasive approach to cancer treatment, but it is difficult to heat only the tumor without damaging surrounding tissue. To solve this problem, we studied the effectiveness of chemohyperthermia with docetaxel-embedded magnetoliposomes (DMLs) and an applied alternating current (AC) magnetic field. Human MKN45 gastric cancer cells were implanted in the hind limb of Balb-c/nu/nu mice. Various concentrations of docetaxel-embedded DMLs were injected into the tumors and exposed to an AC magnetic field (n = 6, each). For comparison with hyperthermia alone, magnetite-loaded liposome (ML)-injected tumors were exposed to an AC magnetic field. Furthermore, the results of DML without AC treatment and docetaxel diluted into PBS with AC treatment were also compared (n = 10, each). Tumor surface temperature was maintained between 42 and 43 degrees C. Tumor volume was reduced in the DML group with a docetaxel concentration > 56.8 microg/ml, while a docetaxel concentration > 568.5 microg/ml was required for tumor reduction without hyperthermia. Statistically significant differences in tumor volume and survival rate were observed between the DML group exposed to the magnetic field and the other groups. The tumor disappeared in 3 mice in the DML group exposed to the magnetic field; 2 mice survived over 6 months after treatment, whereas all mice of the other groups died by 15 weeks. Histologically, hyperthermia with DML damaged tumor cells and DML diffused homogeneously. To the best of our knowledge, this is the first report to show that hyperthermia using chemotherapeutic agent-embedded magnetoliposomes has an anticancer effect.

Reduced infectivity of waterborne viable but nonculturable Helicobacter pylori strain SS1 in mice.

PubMed

Boehnke, Kevin F; Eaton, Kathryn A; Fontaine, Clinton; Brewster, Rebecca; Wu, Jianfeng; Eisenberg, Joseph N S; Valdivieso, Manuel; Baker, Laurence H; Xi, Chuanwu

2017-08-01

Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of viable but nonculturable (VBNC) H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne VBNCH. pylori could cause gastric infection. We performed five mouse experiments to assess the infectivity of VBNCH. pylori in various exposure scenarios. VBNC viability was examined using Live/Dead staining and Biolog phenotype metabolism arrays. High doses of VBNCH. pylori in water were chosen to test the "worst-case" scenario for different periods of time. One experiment also investigated the infectious capabilities of VBNC SS1 using gavage. Further, immunocompromised mice were exposed to examine infectivity among potentially vulnerable groups. After exposure, mice were euthanized and their stomachs were examined for H. pylori infection using culture and PCR methodology. VBNC cells were membrane intact and retained metabolic activity. Mice exposed to VBNCH. pylori via drinking water and gavage were not infected, despite the various exposure scenarios (immunocompromised, high doses) that might have permitted infection with VBNCH. pylori. The positive controls exposed to viable, culturable H. pylori did become infected. While other studies that have used viable, culturable SS1 via gavage or drinking water exposures to successfully infect mice, in our study, waterborne VBNC SS1 failed to colonize mice under all test conditions. Future studies could examine different H. pylori strains in similar exposure scenarios to compare the relative infectivity of the VBNC vs the viable, culturable state, which would help inform future risk assessments of H. pylori in water. © 2017 The Authors. Helicobacter Published by John Wiley & Sons Ltd.

Slope climbing challenges, fear of heights, anxiety and time of the day.

PubMed

Ennaceur, A; Hussain, M D; Abuhamdah, R M; Mostafa, R M; Chazot, P L

2017-01-01

When exposed to an unfamiliar open space, animals experience fear and attempt to find an escape route. Anxiety emerges when animals are confronted with a challenging obstacle to this fear motivated escape. High anxiety animals do not take risks; they avoid the challenge. The present experiments investigated this risk avoidant behavior in mice. In experiment 1, BALB/c, C57BL/6J and CD-1 mice were exposed to a large platform with downward inclined steep slopes attached on two opposite sides. The platform was elevated 75 and 100cm from the ground, in a standard (SPDS) and in a raised (RPDS) configuration, respectively. In experiment 2, the platform was elevated 75cm from the ground. Mice had to climb onto a stand at the top of upward inclined slopes (SPUS). In experiment 3, BALB/c mice were exposed to SPDS with steep or shallow slopes either in early morning or in late afternoon. In all 3 test configurations, mice spent more time in the areas adjacent to the slopes than in the areas adjacent to void, however only C57BL/6J and CD-1 crossed onto the slopes in SPDS, and crossed onto the stands in SPUS whereas BALB/c remained on the platform in SPDS and explored the slopes in SPUS. Elevation of the platform from the ground reduced the crossings onto the slopes in C57BL/6J and CD-1, and no differences were observed between BALB/c and C57BL/6J. BALB/c mice demonstrated no difference in anxiety when tested early morning or late afternoon; they crossed onto shallow slopes and avoided the steep one. Copyright © 2016 Elsevier B.V. All rights reserved.

Postnatal light alters hypothalamic-pituitary-adrenal axis function and induces a depressive-like phenotype in adult mice.

PubMed

Coleman, Georgia; Gigg, John; Canal, Maria Mercè

2016-11-01

The postnatal light environment that a mouse experiences during the critical first three postnatal weeks has long-term effects on both its circadian rhythm output and clock gene expression. Furthermore, data from our lab suggest that postnatal light may also impact the hypothalamic-pituitary-adrenal (HPA) axis, which is a key regulator of stress. To test the effect of postnatal light exposure on adult stress responses and circadian rhythmicity, we raised mice under either 24-h light-dark cycles (LD), constant light (LL) or constant dark (DD) during the first three postnatal weeks. After weaning we then exposed all animals to LD cycles (basal conditions), followed by LL (stressed conditions) environments. We examined brain neuropeptide and glucocorticoid receptor (GR) expression, plasma corticosterone concentration rhythm and body temperature rhythm, together with depression- and anxiety-related behaviour. Results showed that LL- and DD-raised mice exhibited decreased GR expression in the hippocampus, increased plasma corticosterone concentration at the onset of the dark phase and a depressive phenotype when exposed to LD cycles later in life. Furthermore, LL-raised mice showed increased corticotrophin-releasing hormone mRNA expression in the paraventricular nucleus of the hypothalamus. When exposed to LL as adults, LL-raised mice showed a significant circadian rhythm of plasma corticosterone concentration, together with a shorter period and stronger circadian rhythm of body temperature compared to DD-raised mice. Taken together, these data suggest that altered postnatal light environments have long-term effects on the HPA axis and the circadian system, which can lead to altered stress responses and a depressive phenotype in adulthood. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Increased liver-specific proteins in circulating extracellular vesicles as potential biomarkers for drug- and alcohol-induced liver injury

PubMed Central

Cho, Young-Eun; Im, Eun-Ju; Moon, Pyong-Gon; Mezey, Esteban; Song, Byoung-Joon; Baek, Moon-Chang

2017-01-01

Drug- and alcohol-induced liver injury are a leading cause of liver failure and transplantation. Emerging evidence suggests that extracellular vesicles (EVs) are a source of biomarkers because they contain unique proteins reflecting the identity and tissue-specific origin of the EV proteins. This study aimed to determine whether potentially hepatotoxic agents, such as acetaminophen (APAP) and binge alcohol, can increase the amounts of circulating EVs and evaluate liver-specific EV proteins as potential biomarkers for liver injury. The circulating EVs, isolated from plasma of APAP-exposed, ethanol-fed mice, or alcoholic hepatitis patients versus normal control counterparts, were characterized by proteomics and biochemical methods. Liver specific EV proteins were analyzed by immunoblots and ELISA. The amounts of total and liver-specific proteins in circulating EVs from APAP-treated mice significantly increased in a dose- and time-dependent manner. Proteomic analysis of EVs from APAP-exposed mice revealed that the amounts of liver-specific and/or hepatotoxic proteins were increased compared to those of controls. Additionally, the increased protein amounts in EVs following APAP exposure returned to basal levels when mice were treated with N-acetylcysteine or glutathione. Similar results of increased amounts and liver-specific proteins in circulating EVs were also observed in mice exposed to hepatotoxic doses of thioacetamide or d-galactosamine but not by non-hepatotoxic penicillin or myotoxic bupivacaine. Additionally, binge ethanol exposure significantly elevated liver-specific proteins in circulating EVs from mice and alcoholics with alcoholic hepatitis, compared to control counterparts. These results indicate that circulating EVs in drug- and alcohol-mediated hepatic injury contain liver-specific proteins that could serve as specific biomarkers for hepatotoxicity. PMID:28225807

Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors.

PubMed

Chung, Woosuk; Park, Saegeun; Hong, Jiso; Park, Sangil; Lee, Soomin; Heo, Junyoung; Kim, Daesoo; Ko, Youngkwon

2015-10-01

To examine whether neonatal exposure to sevoflurane induces autism-like behaviors in mice. There are continuing reports regarding the potential negative effects of anesthesia on the developing brain. Recently, several studies suggest that neurotoxicity caused by anesthesia may lead to neurodevelopmental impairments. However, unlike reports focusing on learning and memory, there are only a few animal studies focusing on neurodevelopmental disorders after general anesthesia. Therefore, we have focused on autism, a representative neurodevelopmental disorder. Neonatal mice (P6-7) were exposed to a titrated dose of sevoflurane for 6 h. Apoptosis was evaluated by assessing the expression level of cleaved (activated) caspase-3. Autism-like behaviors, general activity, anxiety level, and long-term memory were evaluated with multiple behavioral assays. Western blotting confirmed that neonatal exposure to sevoflurane increased the expression level of activated caspase-3, indicative of apoptosis. Mice exposed to sevoflurane also showed impaired long-term memory in fear tests. However, sevoflurane-exposed mice did not exhibit autism-like features in all of the following assays: social interaction (three-chamber test, caged social interaction), social communication (ultrasonic vocalization test), or repetitive behavior (self-grooming test, digging). There were also no differences in general activity (open field test, home cage activity) and anxiety (open field test, light-dark box) after sevoflurane exposure. Our results confirm previous studies that neonatal sevoflurane exposure causes neurodegeneration and long-term memory impairment in mice. However, sevoflurane did not induce autism-like features. Our study suggests that mice are more vulnerable to long-term memory deficits than autism-like behaviors after exposure to sevoflurane. © 2015 John Wiley & Sons Ltd.

Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice

USDA-ARS?s Scientific Manuscript database

IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote Th2 while suppressing Th1 and Th17 cytokine responses. We investigated the contribution of endogenous IL-25 to DSS-induced colitis in mice. Mice were exposed to DSS in drinking water ad li...

The impact of surfactant protein-A on ozone-induced changes in the mouse bronchoalveolar lavage proteome

PubMed Central

2009-01-01

Background Ozone is a major component of air pollution. Exposure to this powerful oxidizing agent can cause or exacerbate many lung conditions, especially those involving innate immunity. Surfactant protein-A (SP-A) plays many roles in innate immunity by participating directly in host defense as it exerts opsonin function, or indirectly via its ability to regulate alveolar macrophages and other innate immune cells. The mechanism(s) responsible for ozone-induced pathophysiology, while likely related to oxidative stress, are not well understood. Methods We employed 2-dimensional difference gel electrophoresis (2D-DIGE), a discovery proteomics approach, coupled with MALDI-ToF/ToF to compare the bronchoalveolar lavage (BAL) proteomes in wild type (WT) and SP-A knockout (KO) mice and to assess the impact of ozone or filtered air on the expression of BAL proteins. Using the PANTHER database and the published literature most identified proteins were placed into three functional groups. Results We identified 66 proteins and focused our analysis on these proteins. Many of them fell into three categories: defense and immunity; redox regulation; and protein metabolism, modification and chaperones. In response to the oxidative stress of acute ozone exposure (2 ppm; 3 hours) there were many significant changes in levels of expression of proteins in these groups. Most of the proteins in the redox group were decreased, the proteins involved in protein metabolism increased, and roughly equal numbers of increases and decreases were seen in the defense and immunity group. Responses between WT and KO mice were similar in many respects. However, the percent change was consistently greater in the KO mice and there were more changes that achieved statistical significance in the KO mice, with levels of expression in filtered air-exposed KO mice being closer to ozone-exposed WT mice than to filtered air-exposed WT mice. Conclusion We postulate that SP-A plays a role in reactive oxidant scavenging in WT mice and that its absence in the KO mice in the presence or absence of ozone exposure results in more pronounced, and presumably chronic, oxidative stress. PMID:19323824

Hypomyelination, memory impairment, and blood-brain barrier permeability in a model of sleep apnea.

PubMed

Kim, Lenise Jihe; Martinez, Denis; Fiori, Cintia Zappe; Baronio, Diego; Kretzmann, Nélson Alexandre; Barros, Helena Maria Tannhauser

2015-02-09

We investigated the effect of intermittent hypoxia, mimicking sleep apnea, on axonal integrity, blood-brain barrier permeability, and cognitive function of mice. Forty-seven C57BL mice were exposed to intermittent or sham hypoxia, alternating 30s of progressive hypoxia and 30s of reoxigenation, during 8h/day. The axonal integrity in cerebellum was evaluated by transmission electron microscopy. Short- and long-term memories were assessed by novel object recognition test. The levels of endothelin-1 were measured by ELISA. Blood-brain barrier permeability was quantified by Evans Blue dye. After 14 days, animals exposed to intermittent hypoxia showed hypomyelination in cerebellum white matter and higher serum levels of endothelin-1. The short and long-term memories in novel object recognition test was impaired in the group exposed to intermittent hypoxia as compared to controls. Blood-brain barrier permeability was similar between the groups. These results indicated that hypomyelination and impairment of short- and long-term working memories occurred in C57BL mice after 14 days of intermittent hypoxia mimicking sleep apnea. Copyright © 2014 Elsevier B.V. All rights reserved.

Cubozoan Venom-Induced Cardiovascular Collapse Is Caused by Hyperkalemia and Prevented by Zinc Gluconate in Mice

PubMed Central

Yanagihara, Angel A.; Shohet, Ralph V.

2012-01-01

Chironex fleckeri (Australian box jellyfish) stings can cause acute cardiovascular collapse and death. We developed methods to recover venom with high specific activity, and evaluated the effects of both total venom and constituent porins at doses equivalent to lethal envenomation. Marked potassium release occurred within 5 min and hemolysis within 20 min in human red blood cells (RBC) exposed to venom or purified venom porin. Electron microscopy revealed abundant ∼12-nm transmembrane pores in RBC exposed to purified venom porins. C57BL/6 mice injected with venom showed rapid decline in ejection fraction with progression to electromechanical dissociation and electrocardiographic findings consistent with acute hyperkalemia. Recognizing that porin assembly can be inhibited by zinc, we found that zinc gluconate inhibited potassium efflux from RBC exposed to total venom or purified porin, and prolonged survival time in mice following venom injection. These findings suggest that hyperkalemia is the critical event following Chironex fleckeri envenomation and that rapid administration of zinc could be life saving in human sting victims. PMID:23251508

Auditory stimulation of opera music induced prolongation of murine cardiac allograft survival and maintained generation of regulatory CD4+CD25+ cells.

PubMed

Uchiyama, Masateru; Jin, Xiangyuan; Zhang, Qi; Hirai, Toshihito; Amano, Atsushi; Bashuda, Hisashi; Niimi, Masanori

2012-03-23

Interactions between the immune response and brain functions such as olfactory, auditory, and visual sensations are likely. This study investigated the effect of sounds on alloimmune responses in a murine model of cardiac allograft transplantation. Naïve CBA mice (H2k) underwent transplantation of a C57BL/6 (B6, H2b) heart and were exposed to one of three types of music--opera (La Traviata), classical (Mozart), and New Age (Enya)--or one of six different single sound frequencies, for 7 days. Additionally, we prepared two groups of CBA recipients with tympanic membrane perforation exposed to opera for 7 days and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment). An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Immunohistochemical, cell-proliferation, cytokine, and flow cytometry assessments were also performed. CBA recipients of a B6 cardiac graft that were exposed to opera music and Mozart had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to a single sound frequency (100, 500, 1000, 5000, 10,000, or 20,000 Hz) or Enya did not (MSTs, 7.5, 8, 9, 8, 7.5, 8.5 and 11 days, respectively). Untreated, CBA mice with tympanic membrane perforations and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment) rejected B6 cardiac grafts acutely (MSTs, 7, 8 and 8 days, respectively). Adoptive transfer of whole splenocytes, CD4+ cells, or CD4+CD25+ cells from opera-exposed primary allograft recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and > 100 days, respectively). Proliferation of splenocytes, interleukin (IL)-2 and interferon (IFN)-γ production was suppressed in opera-exposed mice, and production of IL-4 and IL-10 from opera-exposed transplant recipients increased compared to that from splenocytes of untreated recipients. Flow cytometry studies showed an increased CD4+CD25+ Forkhead box P3 (Foxp3)+ cell population in splenocytes from those mice. Our findings indicate that exposure to opera music, such as La traviata, could affect such aspects of the peripheral immune response as generation of regulatory CD4+CD25+ cells and up-regulation of anti-inflammatory cytokines, resulting in prolonged allograft survival.

Auditory stimulation of opera music induced prolongation of murine cardiac allograft survival and maintained generation of regulatory CD4+CD25+ cells

PubMed Central

2012-01-01

Background Interactions between the immune response and brain functions such as olfactory, auditory, and visual sensations are likely. This study investigated the effect of sounds on alloimmune responses in a murine model of cardiac allograft transplantation. Methods Naïve CBA mice (H2k) underwent transplantation of a C57BL/6 (B6, H2b) heart and were exposed to one of three types of music--opera (La Traviata), classical (Mozart), and New Age (Enya)--or one of six different single sound frequencies, for 7 days. Additionally, we prepared two groups of CBA recipients with tympanic membrane perforation exposed to opera for 7 days and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment). An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Immunohistochemical, cell-proliferation, cytokine, and flow cytometry assessments were also performed. Results CBA recipients of a B6 cardiac graft that were exposed to opera music and Mozart had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to a single sound frequency (100, 500, 1000, 5000, 10,000, or 20,000 Hz) or Enya did not (MSTs, 7.5, 8, 9, 8, 7.5, 8.5 and 11 days, respectively). Untreated, CBA mice with tympanic membrane perforations and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment) rejected B6 cardiac grafts acutely (MSTs, 7, 8 and 8 days, respectively). Adoptive transfer of whole splenocytes, CD4+ cells, or CD4+CD25+ cells from opera-exposed primary allograft recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and > 100 days, respectively). Proliferation of splenocytes, interleukin (IL)-2 and interferon (IFN)-γ production was suppressed in opera-exposed mice, and production of IL-4 and IL-10 from opera-exposed transplant recipients increased compared to that from splenocytes of untreated recipients. Flow cytometry studies showed an increased CD4+CD25+ Forkhead box P3 (Foxp3)+ cell population in splenocytes from those mice. Conclusion Our findings indicate that exposure to opera music, such as La traviata, could affect such aspects of the peripheral immune response as generation of regulatory CD4+CD25+ cells and up-regulation of anti-inflammatory cytokines, resulting in prolonged allograft survival. PMID:22445281

Poppers: large cancer increase and immune suppression in animal tests.

PubMed

James, J S

1999-04-16

A study on mice injected with cancer cells and then exposed to isobutyl nitrite (poppers) revealed that inhalant-treated mice developed tumors more readily and rapidly than control mice. The control mice were also injected with cancer cells, but only breathed air. Related studies found that poppers suppress certain immune functions involved in killing tumor cells. These studies suggest that further research of persons with HIV/AIDS who use poppers is needed to determine if they are at a high risk for developing malignancies.

Lyophilized airborne Clostridium botulinum spores as inocula that intestinally colonize antimicrobially pretreated adult mice.

PubMed Central

Sugiyama, H; Prather, J L; Woller, M J

1986-01-01

Adult mice, made susceptible to Clostridium botulinum by feedings of metronidazole, were immobilized with an anesthetic and held for 30 min in isolators in which a fine powder of lyophilized pathogen spores was made airborne. Exposed mice were surface decontaminated before being kept for 2 days in holding isolators. Mice were intestinally colonized by the pathogen. Colonization rates were related to spore numbers (10(4) to 10(7) type A or B) seeded into isolators. PMID:3531017

Altered host resistance to Listeria monocytogenes in mice exposed to 1-chloroacetophenone (CN) vapours

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, P.; Kumar, P.; Zachariah, K.

1992-06-01

Short term repeated exposure of 1-chloroacetophenone (CN) vapours at a concentration of 0.153 mg per litre for 15 minutes daily on 10 consecutive days in Swiss albino male mice resulted in increased mortality to Listeria monocytogenes. Significantly elevated bacterial growth was observed in the spleen and liver of the CN exposed animals. The increased bacterial count in these organs was evident within 4-6 days post challenge as compared to vehicle exposed infected and unexposed infected animals. Increased susceptibility to infection has been considered to be the function of immune alteration due to cumulative short term effects of CN vapour inhalation.more » This may be attributed to immunotoxic effects of CN on T-cells mediated macrophage functions.« less

Increased survival of honeybees in the laboratory after simultaneous exposure to low doses of pesticides and bacteria.

PubMed

Dickel, Franziska; Münch, Daniel; Amdam, Gro Vang; Mappes, Johanna; Freitak, Dalial

2018-01-01

Recent studies of honeybees and bumblebees have examined combinatory effects of different stressors, as insect pollinators are naturally exposed to multiple stressors. At the same time the potential influences of simultaneously occurring agricultural agents on insect pollinator health remain largely unknown. Due to different farming methods, and the drift of applied agents and manure, pollinators are most probably exposed to insecticides but also bacteria from organic fertilizers at the same time. We orally exposed honeybee workers to sub-lethal doses of the insecticide thiacloprid and two strains of the bacterium Enterococcus faecalis, which can occur in manure from farming animals. Our results show that under laboratory conditions the bees simultaneously exposed to the a bacterium and the pesticide thiacloprid thiacloprid had significant higher survival rates 11 days post exposure than the controls, which surprisingly showed the lowest survival. Bees that were exposed to diet containing thiacloprid showed decreased food intake. General antibacterial activity is increased by the insecticide and the bacteria, resulting in a higher immune response observed in treated individuals compared to control individuals. We thus propose that caloric restriction through behavioural and physiological adaptations may have mediated an improved survival and stress resistance in our tests. However, the decreased food consumption could in long-term also result in possible negative effects at colony level. Our study does not show an additive negative impact of sub-lethal insecticide and bacteria doses, when tested under laboratory conditions. In contrast, we report seemingly beneficial effects of simultaneous exposure of bees to agricultural agents, which might demonstrate a surprising biological capacity for coping with stressors, possibly through hormetic regulation.

EFFECTS OF MARINE ALGAL TOXINS ON THERMOREGULATION IN MICE.

EPA Science Inventory

Hypothermia is often seen in mice and rats exposed acutely to marine algal toxins, but the mechanism of action of these toxins on thermoregulation is not well understood. Our laboratory has assessed the thermoregulatory mechanisms of two marine algal toxins, maitotoxin and brevet...

Vagotomy Reverses Established Allergen-Induced Airway Hyperreactivity to Methacholine in the Mouse

EPA Science Inventory

We evaluated the role of vagal reflexes in a mouse model of allergen-induced airway hyperreactivity. Mice were actively sensitized to ovalbumin then exposed to the allergen via inhalation. Prior to ovalbumin inhalation, mice also received intratracheally-instilled particulate ma...

COMPARISON OF HEPATIC GENE EXPRESSION PROFILES FROM MICE EXPOSED TO THREE TOXICOLOGICALLY DIFFERENT CONAZOLES

EPA Science Inventory

Conazoles comprise a chemical class of fungicides used as agricultural and pham-taceutical products. Both propiconazole and triadimefon are hepatotoxic and hepatotumorigenic in mice, while myclobutanil is not a mouse liver tumorigen. The tumorigenic activities of these conazoles ...

Behavioral and endocrine consequences of simultaneous exposure to two different stressors in rats: interaction or independence?

PubMed

Muñoz-Abellán, Cristina; Rabasa, Cristina; Daviu, Nuria; Nadal, Roser; Armario, Antonio

2011-01-01

Although behavioral and endocrine consequences of acute exposure to stressors have been extensively studied, little is known about how simultaneous exposure to two different stressors interacts to induce short- and long-term effects. In the present experiment we studied this interaction in adult male rats exposed to cat fur odor (impregnated cloth) or immobilization on boards either separately or simultaneously. We reasoned that exposure to the odor of a potential predator while immobilized, may potentiate its negative consequences as compared to exposure to only one of the stressors. Exposure to cat odor elicited the expected reduction of activity and avoidance of the area where the impregnated cloth was located. The endocrine response (plasma levels of ACTH and corticosterone, as a measure of the hypothalamic-pituitary-adrenal axis, HPA) was markedly greater after immobilization than after cat fur odor and no additive effects were found by simultaneous exposure to both stressors. Cat odor, but not immobilization, increased anxiety-like behavior as evaluated in the elevated plus-maze 7 days after the stressors, with no evidence of enhanced HPA activation. In addition, cat odor exposure resulted in long-lasting (8 days later) fear conditioning to the box containing a clean cloth, which was reflected by hypoactivity, avoidance of the cloth area and enhanced HPA activation. All these effects were similarly observed in rats exposed simultaneously to cat odor and immobilization. In rats only exposed to immobilization, only some weak behavioral signs of fear conditioning were found, but HPA activation in response to the context paired to immobilization was enhanced to the same extent as in cat odor-exposed animals, supporting a certain degree of endocrine conditioning. The present results did not reveal important behavioral interactions between the two stressors when animals experienced both simultaneously, whereas some interactions were found regarding HPA activation. Theoretical implications are discussed.

Behavioral and Endocrine Consequences of Simultaneous Exposure to Two Different Stressors in Rats: Interaction or Independence?

PubMed Central

Muñoz-Abellán, Cristina; Rabasa, Cristina; Daviu, Nuria; Nadal, Roser; Armario, Antonio

2011-01-01

Although behavioral and endocrine consequences of acute exposure to stressors have been extensively studied, little is known about how simultaneous exposure to two different stressors interacts to induce short- and long-term effects. In the present experiment we studied this interaction in adult male rats exposed to cat fur odor (impregnated cloth) or immobilization on boards either separately or simultaneously. We reasoned that exposure to the odor of a potential predator while immobilized, may potentiate its negative consequences as compared to exposure to only one of the stressors. Exposure to cat odor elicited the expected reduction of activity and avoidance of the area where the impregnated cloth was located. The endocrine response (plasma levels of ACTH and corticosterone, as a measure of the hypothalamic-pituitary-adrenal axis, HPA) was markedly greater after immobilization than after cat fur odor and no additive effects were found by simultaneous exposure to both stressors. Cat odor, but not immobilization, increased anxiety-like behavior as evaluated in the elevated plus-maze 7 days after the stressors, with no evidence of enhanced HPA activation. In addition, cat odor exposure resulted in long-lasting (8 days later) fear conditioning to the box containing a clean cloth, which was reflected by hypoactivity, avoidance of the cloth area and enhanced HPA activation. All these effects were similarly observed in rats exposed simultaneously to cat odor and immobilization. In rats only exposed to immobilization, only some weak behavioral signs of fear conditioning were found, but HPA activation in response to the context paired to immobilization was enhanced to the same extent as in cat odor-exposed animals, supporting a certain degree of endocrine conditioning. The present results did not reveal important behavioral interactions between the two stressors when animals experienced both simultaneously, whereas some interactions were found regarding HPA activation. Theoretical implications are discussed. PMID:21731743

Dose-dependent effects of alpha-naphthylisothiocyanate disconnect biliary fibrosis from hepatocellular necrosis.

PubMed

Joshi, Nikita; Ray, Jessica L; Kopec, Anna K; Luyendyk, James P

2017-01-01

Exposure of rodents to the xenobiotic α-naphthylisothiocyanate (ANIT) is an established model of experimental intrahepatic bile duct injury. Administration of ANIT to mice causes neutrophil-mediated hepatocellular necrosis. Prolonged exposure of mice to ANIT also produces bile duct hyperplasia and liver fibrosis. However, the mechanistic connection between ANIT-induced hepatocellular necrosis and bile duct hyperplasia and fibrosis is not well characterized. We examined impact of two different doses of ANIT, by feeding chow containing ANIT (0.05%, 0.1%), on the severity of various liver pathologies in a model of chronic ANIT exposure. ANIT-elicited increases in liver inflammation and hepatocellular necrosis increased with dose. Remarkably, there was no connection between increased hepatocellular necrosis and bile duct hyperplasia and peribiliary fibrosis, as these pathologies increased similarly in mice exposed to either dose of ANIT. The results indicate that the severity of hepatocellular necrosis does not dictate the extent of bile duct hyperplasia/fibrosis in ANIT-exposed mice. © 2016 Wiley Periodicals, Inc.

Dosimetry of a set-up for the exposure of newborn mice to 2.45-GHZ WiFi frequencies.

PubMed

Pinto, R; Lopresto, V; Galloni, P; Marino, C; Mancini, S; Lodato, R; Pioli, C; Lovisolo, G A

2010-08-01

This work describes the dosimetry of a two waveguide cell system designed to expose newborn mice to electromagnetic fields associated with wireless fidelity signals in the frequency band of 2.45 GHz. The dosimetric characterisation of the exposure system was performed both numerically and experimentally. Specific measures were adopted with regard to the increase in both weight and size of the biological target during the exposure period. The specific absorption rate (SAR, W kg(-1)) for 1 W of input power vs. weight curve was assessed. The curve evidenced an SAR pattern varying from <1 W kg(-1) to >6 W kg(-1) during the first 5 weeks of the life of mice, with a peak resonance phenomenon at a weight around 5 g. This curve was used to set the appropriate level of input power during experimental sessions to expose the growing mice to a defined and constant dose.

The effects of graded levels of calorie restriction: IV. Non-linear change in behavioural phenotype of mice in response to short-term calorie restriction.

PubMed

Lusseau, David; Mitchell, Sharon E; Barros, Ceres; Derous, Davina; Green, Cara; Chen, Luonan; Han, Jing-Dong Jackie; Wang, Yingchun; Promislow, Daniel E L; Douglas, Alex; Speakman, John R

2015-08-25

Animals have to adjust their activities when faced with caloric restriction (CR) to deal with reduced energy intake. If CR is pronounced, allostasis can push individuals into alternate physiological states which can result in important health benefits across a wide range of taxa. Here we developed a new approach to determine the changes in behavioural phenotype associated with different levels of CR. We exposed C57BL/6 male mice to graded CR (from 0 to 40%) for three months and defined their behavioural phenotype using hidden Markov models of their movement and body temperature. All 40% CR mice exhibited a state-shift in behavioural phenotype and only some exposed to 30% CR did. We show for the first time that mice changed their activity characteristics rather than changed their activities. This new phenotyping approach provides an avenue to determine the mechanisms linking CR to healthspan.

Dose-Dependent Effects of Alpha-Naphthylisothiocyanate Disconnect Biliary Fibrosis from Hepatocellular Necrosis

PubMed Central

Joshi, Nikita; Ray, Jessica L.; Kopec, Anna K.; Luyendyk, James P.

2017-01-01

Exposure of rodents to the xenobiotic α-naphthylisothiocyanate (ANIT) is an established model of experimental intrahepatic bile duct injury. Administration of ANIT to mice causes neutrophil-mediated hepatocellular necrosis. Prolonged exposure of mice to ANIT also produces bile duct hyperplasia and liver fibrosis. However, the mechanistic connection between ANIT-induced hepatocellular necrosis and bile duct hyperplasia and fibrosis is not well-characterized. We examined impact of two different doses of ANIT, by feeding chow containing ANIT (0.05%, 0.1%), on the severity of various liver pathologies in a model of chronic ANIT exposure. ANIT-elicited increases in liver inflammation and hepatocellular necrosis increased with dose. Remarkably, there was no connection between increased hepatocellular necrosis and bile duct hyperplasia and peribiliary fibrosis, as these pathologies increased similarly in mice exposed to either dose of ANIT. The results indicate that the severity of hepatocellular necrosis does not dictate the extent of bile duct hyperplasia/fibrosis in ANIT-exposed mice. PMID:27605088

Effects of the phosphodiesterase type 4 inhibitor roflumilast on early and late allergic response and airway hyperresponsiveness in Aspergillus-fumigatus-sensitized mice.

PubMed

Hoymann, Heinz-Gerd; Wollin, Lutz; Muller, Meike; Korolewitz, Regina; Krug, Norbert; Braun, Armin; Beume, Rolf

2009-01-01

Inhibitory effects of roflumilast on responses characteristic of allergic asthma were investigated in a fungal asthma model in BALB/c mice. Mice were sensitized with Aspergillus antigen (Afu) and exposed to Afu or vehicle, and given roflumilast 1 or 5 mg/kg. Early airway response (EAR) and late airway hyperresponsiveness (AHR) to methacholine were measured via plethysmography. Bronchoalveolar lavage (BAL) was used to assess inflammatory cell count. In Afu-exposed mice, roflumilast dose-dependently reduced the EAR [26% at 1 mg/kg (NS) and 94% at 5 mg/kg (p < 0.01)] and AHR [46% at 1 mg/kg (NS) and 128% at 5 mg/kg (p < 0.05)]. Roflumilast 5 mg/kg reduced neutrophil, eosinophil and lymphocyte counts [87% (p < 0.01), 40% (NS) and 67% (p < 0.01), respectively] in BAL fluid versus controls. In this model, roflumilast inhibited the EAR, suppressed AHR and reduced inflammatory cell infiltration. 2009 S. Karger AG, Basel.

NTP Toxicology and Carcinogenesis Studies of Cobalt Sulfate Heptahydrate (CAS No. 10026-24-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

PubMed

1998-08-01

Cobalt sulfate is used in the electroplating and electro chemical industries. It is also used as a coloring agent for ceramics and as a drying agent in inks, paints, varnishes, and linoleum. Cobalt sulfate may be added to animal feed as a mineral supplement and has been used as a top dressing on pasture lands. Cobalt sulfate was nominated by the National Cancer Institute for study based on a lack of information on the toxicity of soluble salts. Male and female F344/N rats and B6C3F1 mice were exposed to cobalt sulfate heptahydrate (approximately 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. The results of prechronic inhalation toxicity studies were reported previously (Bucher et al., 1990; NTP, 1991). 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate heptahydrate 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of exposed male and female rats were similar to those of the chamber controls throughout the study. Pathology Findings The incidences and severities of proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were markedly greater in all exposed groups of male and female rats than in the chamber controls. The incidences of alveolar epithelial hyperplasia in all groups of exposed males and in females exposed to 3.0 mg/m3 were significantly greater than those in the chamber control groups, as were the incidences of squamous metaplasia in 1.0 mg/m3 females and atypical alveolar epithelial hyperplasia in 3.0 mg/m3 females. In 3.0 mg/m3 males, the combined incidence of alveolar/ bronchiolar neoplasms (adenoma and/or carcinoma) was significantly greater than in the chamber controls. In female rats exposed to 1.0 or 3.0 mg/m3, the incidences of alveolar/bronchiolar neoplasms were significantly greater than those in the chamber control group and exceeded the NTP historical control ranges. A squamous cell carcinoma was observed in one 1.0 mg/m3 and one 3.0 mg/m3 female. The incidences of benign, complex, or malignant pheochromocytoma (combined) in 1.0 mg/m3 males and in 3.0 mg/m3 females were significantly greater than those in the chamber controls and exceeded the historical control ranges. Hyperplasia of the lateral wall of the nose, atrophy of the olfactory epithelium, and squamous metaplasia of the epiglottis were observed in all exposed groups of males and females, and the severities of these lesions increased with increasing exposure concentration. The incidences of squamous metaplasia of the lateral wall of the nose and metaplasia of the olfactory epithelium were increased in 3.0 mg/m3 males and females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate heptahydrate 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of 3.0 mg/m3 male mice were less than those of the chamber controls from week 96 until the end of the study. The mean body weights of all exposed groups of female mice were generally greater than those of the chamber controls from week 20 until the end of the study. Pathology Findings The incidences of diffuse histiocytic cell infiltration in 3.0 mg/m3 males and of focal histiocytic cell infil tration in 3.0 mg/m3 females were significantly greater than those in the chamber controls. The incidences of alveolar/bronchiolar neoplasms in 3.0 mg/m3 males and females were significantly greater than those in the chamber control groups. The combined incidences of alveolar/bronchiolar adenoma or carcinoma and the incidences of alveolar/bronchiolar carcinoma in 3.0 mg/m3 males and females and the incidence of alveolar/bronchiolar adenoma in 3.0 mg/m3 females exceeded the NTP historical crical control ranges for inhalation studies. The incidences of atrophy of the olfactory epithelium in 1.0 and 3.0 mg/m3 males and females and hyper plasia of the olfactory epithelium in 3.0 mg/m3 males and females were significantly greater than in the chamber controls. Squamous metaplasia of the larynx was observed in all exposed groups of males and females. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver, characteristic of an infection with Helico bacter hepaticus. In NTP studies with H. hepaticus- associated hepatitis, increased incidences of hemangiosarcoma were seen in the liver of male mice. In this study of cobalt sulfate heptahydrate, incidences of hemangiosarcoma were increased in exposed groups of male mice. Because of the above association, interpretation of the increased incidences of hemangiosarcoma in the livers of male mice was confounded. Incidences of lesions at other sites in this study of cobalt sulfate heptahydrate were not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: Cobalt sulfate heptahydrate was mutagenic in S. typhimurium strain TA100 with and without liver S9 metabolic activation enzymes; no mutagenic activity was detected in strain TA98 or TA1535, with or without S9. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of cobalt sulfate heptahydrate in male F344/N rats based on increased incidences of alveolar/bronchiolar neoplasms. Marginal increases in incidences of pheochromocytomas of the adrenal medulla may have been related to exposure to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of alveolar/bronchiolar neo-plasms and pheochromocytomas of the adrenal medulla in groups exposed to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity of cobalt sulfate heptahydrate in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Exposure to cobalt sulfate heptahydrate caused a spectrum of inflammatory, fibrotic, and proliferative lesions in the respiratory tract of male and female rats and mice. Synonyms: Bieberite; cobalt(II) sulfate (1:1) heptahydrate; cobalt monosulfate heptahydrate; cobalt(II) sulphate heptahydrate; sulfuric acid, cobalt(2+) salt (1:1) heptahydrate

Time-course effects of aerobic physical training in the prevention of cigarette smoke-induced COPD.

PubMed

Toledo-Arruda, Alessandra C; Vieira, Rodolfo P; Guarnier, Flávia A; Suehiro, Camila L; Caleman-Neto, Agostinho; Olivo, Clarice R; Arantes, Petra M M; Almeida, Francine M; Lopes, Fernanda D T Q S; Ramos, Ercy M C; Cecchini, Rubens; Lin, Chin Jia; Martins, Milton Arruda

2017-09-01

A previous study by our group showed that regular exercise training (ET) attenuated pulmonary injury in an experimental model of chronic exposure to cigarette smoke (CS) in mice, but the time-course effects of the mechanisms involved in this protection remain poorly understood. We evaluated the temporal effects of regular ET in an experimental model of chronic CS exposure. Male C57BL/6 mice were divided into four groups: Control (sedentary + air), Exercise (aerobic training + air), Smoke (sedentary + smoke), and Smoke + Exercise (aerobic training + smoke). Mice were exposed to CS and ET for 4, 8, or 12 wk. Exercise protected mice exposed to CS from emphysema and reductions in tissue damping and tissue elastance after 12 wk ( P < 0.01). The total number of inflammatory cells in the bronchoalveolar lavage increased in the Smoke group, mainly due to the recruitment of macrophages after 4 wk, neutrophils and lymphocytes after 8 wk, and lymphocytes and macrophages after 12 wk ( P < 0.01). Exercise attenuated this increase in mice exposed to CS. The protection conferred by exercise was mainly observed after exercise adaptation. Exercise increased IL-6 and IL-10 in the quadriceps and lungs ( P < 0.05) after 12 wk. Total antioxidant capacity and SOD was increased and TNF-α and oxidants decreased in lungs of mice exposed to CS after 12 wk ( P < 0.05). The protective effects of exercise against lung injury induced by cigarette smoke exposure suggests that anti-inflammatory mediators and antioxidant enzymes play important roles in chronic obstructive pulmonary disease development mainly after the exercise adaptation. NEW & NOTEWORTHY These experiments investigated for the first time the temporal effects of regular moderate exercise training in cigarette smoke-induced chronic obstructive pulmonary disease. We demonstrate that aerobic conditioning had a protective effect in emphysema development induced by cigarette smoke exposure. This effect was most likely secondary to an effect of exercise on oxidant-antioxidant balance and anti-inflammatory mediators. Copyright © 2017 the American Physiological Society.

Chronic Ethanol During Adolescence Impacts Corticolimbic Dendritic Spines and Behavior.

PubMed

Jury, Nicholas J; Pollack, Gabrielle A; Ward, Meredith J; Bezek, Jessica L; Ng, Alexandra J; Pinard, Courtney R; Bergstrom, Hadley C; Holmes, Andrew

2017-07-01

Risk for alcohol use disorders (AUDs) in adulthood is linked to alcohol drinking during adolescence, but understanding of the neural and behavioral consequences of alcohol exposure during adolescence remains incomplete. Here, we examined the neurobehavioral impact of adolescent chronic intermittent EtOH (CIE) vapor exposure in mice. C57BL/6J-background Thy1-EGFP mice were CIE-exposed during adolescence or adulthood and examined, as adults, for alterations in the density and morphology of dendritic spines in infralimbic (IL) cortex, prelimbic (PL) cortex, and basolateral amygdala (BLA). In parallel, adolescent- and adult-exposed C57BL/6J mice were tested as adults for 2-bottle EtOH drinking, sensitivity to EtOH intoxication (loss of righting reflex [LORR]), blood EtOH clearance, and measures of operant responding for food reward. CIE during adolescence decreased IL neuronal spine density and increased the head width of relatively wide-head IL and BLA spines, whereas CIE decreased head width of relatively narrow-head BLA spines. Adolescents had higher EtOH consumption prior to CIE than adults, while CIE during adulthood, but not adolescence, increased EtOH consumption relative to pre-CIE baseline. CIE produced a tolerance-like decrease in LORR sensitivity to EtOH challenge, irrespective of the age at which mice received CIE exposure. Mice exposed to CIE during adolescence, but not adulthood, required more sessions than AIR controls to reliably respond for food reward on a fixed-ratio (FR) 1, but not subsequent FR3, reinforcement schedule. On a progressive ratio reinforcement schedule, break point responding was higher in the adolescent- than the adult-exposed mice, regardless of CIE. Finally, footshock punishment markedly suppressed responding for reward in all groups. Exposure to CIE during adolescence altered dendritic spine density and morphology in IL and BLA neurons, in parallel with a limited set of behavioral alterations. Together, these data add to growing evidence that key corticolimbic circuits are vulnerable to the effects of alcohol during adolescence, with lasting, potentially detrimental, consequences for behavior. Copyright © 2017 by the Research Society on Alcoholism.

Chronic ethanol during adolescence impacts corticolimbic dendritic spines and behavior

PubMed Central

Jury, Nicholas J.; Pollack, Gabrielle A.; Ward, Meredith J.; Bezek, Jessica L.; Ng, Alexandra J.; Pinard, Courtney R.; Bergstrom, Hadley C.; Holmes, Andrew

2017-01-01

Background Risk for alcohol use disorders (AUDs) is linked to alcohol drinking during adolescence, but understanding of the neural and behavioral consequences of alcohol exposure during adolescence remains incomplete. Here, we examined the neurobehavioral impact of adolescent chronic intermittent EtOH (CIE) vapor exposure in mice. Methods C57BL/6J-background Thy1-EGFP mice were CIE-exposed during adolescence or adulthood and examined, as adults, for alterations in the density and morphology of dendritic spines in infralimbic cortex (IL), prelimbic cortex (PL) and basolateral amygdala (BLA). In parallel, adolescent- and adult-exposed C57BL/6J mice were tested as adults for two-bottle EtOH drinking, sensitivity to EtOH intoxication (loss of righting reflex, LORR), blood EtOH clearance, and measures of operant responding for food reward. Results CIE during adolescence decreased IL neuronal spine density and increased the head-width of relatively wide-head IL and BLA spines, whereas CIE decreased head-width of relatively narrow-head BLA spines. Adolescents had higher EtOH consumption prior to CIE than adults, while CIE during adulthood, but not adolescence, increased EtOH consumption relative to pre-CIE baseline. CIE produced a tolerance-like decrease in LORR sensitivity to EtOH challenge, irrespective of the age at which mice received CIE exposure. Mice exposed to CIE during adolescence, but not adulthood, required more sessions than AIR controls to reliably respond for food reward on a fixed-ratio (FR1), but not subsequent FR3, reinforcement schedule. On a progressive ratio reinforcement schedule, breakpoint responding was higher in the adolescent- than the adult-exposed mice, regardless of CIE. Finally, footshock-punishment markedly suppressed responding for reward in all groups. Conclusions Exposure to CIE during adolescence altered dendritic spine density and morphology in IL and BLA neurons, in parallel with a limited set of behavioral alterations. Together, these data add to growing evidence that key corticolimbic circuits are vulnerable to the effects of alcohol during adolescence, with lasting, potentially detrimental, consequences for behavior. PMID:28614590

Environmental exposure to low-doses of ionizing radiation. Effects on early nephrotoxicity in mice.

PubMed

Bellés, Montserrat; Gonzalo, Sergio; Serra, Noemí; Esplugas, Roser; Arenas, Meritxell; Domingo, José Luis; Linares, Victoria

2017-07-01

Nuclear accidents of tremendous magnitude, such as those of Chernobyl (1986) and Fukushima (2011), mean that individuals living in the contaminated areas are potentially exposed to ionizing radiation (IR). However, the dose-response relationship for effects of low doses of radiation is not still established. The present study was aimed at investigating in mice the early effects of low-dose internal radiation exposure on the kidney. Adult male (C57BL/6J) mice were divided into three groups. Two groups received a single subcutaneous (s.c.) doses of cesium ( 137 Cs) with activities of 4000 and 8000Bq/kg bw. A third group (control group) received a single s.c. injection of 0.9% saline. To evaluate acute and subacute effects, mice (one-half of each group) were euthanized at 72h and 10 days post-exposure to 137 Cs, respectively. Urine samples were collected for biochemical analysis, including the measurement of F2-isoprostane (F2-IsoP) and kidney injury molecule-1 (KIM-1) levels. Moreover, the concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a sensitive marker of oxidative DNA damage, were measured in renal tissue. Urinary excretion of total protein significantly increased at 72h in mice exposed to Cs4000. Uric acid and lactate dehydrogenase (LDH) decreased significantly at both times post-exposure in animals exposed to Cs8000. After 72h and 10d of exposure to Cs4000, a significant increase in the γ-glutamil transferase (GGT) and N-acetyl-β-D-glucosaminidase (NAG) activities was observed. In turn, F2-IsoP levels increased -mainly in the Cs4000 group- at 72h post-exposure. Following irradiation ( 137 Cs), the highest level of KIM-1 was corresponded to the Cs4000 group at 72h. Likewise, the main DNA damage was detected in mice exposed to Cs4000, mainly at 10d after irradiation. The alterations observed in several biomarkers suggest an immediate renal damage following exposure to low doses of IR (given as 137 Cs). Further investigations are required to clarify the mechanisms involved in the internal IR-induced nephrotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

[Effect of glutathione and sodium selenite on the metabolism of arsenic in mice exposed to arsenic through drinking water].

PubMed

Yu, Xiao-Yun; Zhong, Yuan; Niu, Yu-Hong; Qu, Chun-Qing; Li, Ge-Xin; Lü, Xiu-Qiang; Sun, Gui-Fan; Jin, Ya-Ping

2008-09-01

To explore the effect of glutathione (GSH) and sodium selenite on the metabolism of arsenic in the liver, kidney and blood of mice exposed to iAsIII through drinking water. The mice were randomly divided into control, arsenic, GSH and sodium selenite group, respectively. And each group had eight mice and the mice were exposed to 50 mg/L arsenite by drinking water for 4 weeks. Mice were intraperitoneally injected with GSH (600 mg/kg) and sodium selenite (1 mg/kg) for seven days from the beginning of the fourth week. At the end of the fourth week, liver, kidney and blood were sampled to assess the concentrations of inorganic arsenic (iAs), monomethylarsenic acid (MMA), dimethylarsenic acid (DMA) by hydride generation trapping by ultra-hypothermia coupled with atomic absorption spectrometry. The liver DMA (233.76 +/- 60.63 ng/g) concentration in GSH group was significantly higher than the arsenic group (218.36 +/- 42.71 ng/g). The concentration of DMA (88.52 +/- 30.86 ng/g) and total arsenic (TAs) (162.32 +/- 49.45 ng/g) in blood of GSH group was significantly higher than those [(45.32 +/- 12.19 ng/g), (108.51 +/- 18.00 ng/g), respectively] of arsenic groups(q values were 3.06, 6.40, 10.72 respectively, P < 0.05). The primary methylated index (PMI) (0.65 +/- 0.050) and secondary methylated index (SMI) (0.55 +/- 0.050) in liver sample of GSH group were significantly higher than those (0.58 +/- 0.056, 0.44 +/- 0. 093) in arsenic group. In blood samples, the PMI (0.85 +/- 0.066) in GSH group was significantly higher than that (0.54 +/- 0.113) in arsenic group (q values were 3.75, 5.26, 4.21 respectively, P < 0.05). However, no significant difference was identified between sodium selenite and arsenic groups in liver, kidney or blood samples. And no significant difference was detected in kidney samples among all arsenic exposing groups. Exogenous GSH could promote the methylated metabolism of iAsIII, but sodium selenite showed no significant effects.

The Protective Effect of Selenium on Oxidative Stress Induced by Waterpipe (Narghile) Smoke in Lungs and Liver of Mice.

PubMed

Charab, Mohamad A; Abouzeinab, Noura S; Moustafa, Mohamed E

2016-12-01

Waterpipe smoking is common in the Middle East populations and results in health problems. In this study, we investigated the effects of exposure of mice to waterpipe smoke on oxidative stress in lungs and liver and the effects of selenium administration before smoke exposure on the oxidative stress. Twenty-four mice were divided equally into four groups: (i) the control mice received no exposure or treatment; (ii) mice exposed to waterpipe smoke; (iii) mice received intraperitoneal injection of 0.59 μg selenium/kg body weight as sodium selenite 15 min before the exposure to waterpipe smoke; and (iv) mice received intraperitoneal injection of 1.78 μg selenium/kg body weight as sodium selenite 15 min before the exposure to waterpipe smoke. Mice were exposed to waterpipe smoke every other day for four times within 8 successive days. Malondialdehyde and nitric oxide levels were significantly higher in the lungs and liver, while the activities of superoxide dismutase, glutathione peroxidase-1, and catalase were significantly lower in the waterpipe smoke group when compared to control mice. Treating mice with 1.78 μg selenium/kg body weight significantly restored the normal levels of these parameters. Histological examinations of lungs and liver confirmed the protective actions of selenium against the effects of exposure to waterpipe smoke. In conclusion, exposure of mice to waterpipe smoke-induced oxidative stress in lungs and liver. Administration of low level of selenium, 1.78 μg selenium/kg body weight as sodium selenite, exerted protective effects against oxidative stress induced by exposure to waterpipe smoke.

Atomic Layer Deposition Coating of Carbon Nanotubes with Aluminum Oxide Alters Pro-Fibrogenic Cytokine Expression by Human Mononuclear Phagocytes In Vitro and Reduces Lung Fibrosis in Mice In Vivo

PubMed Central

Taylor, Alexia J.; McClure, Christina D.; Shipkowski, Kelly A.; Thompson, Elizabeth A.; Hussain, Salik; Garantziotis, Stavros; Parsons, Gregory N.; Bonner, James C.

2014-01-01

Background Multi-walled carbon nanotubes (MWCNTs) pose a possible human health risk for lung disease as a result of inhalation exposure. Mice exposed to MWCNTs develop pulmonary fibrosis. Lung macrophages engulf MWCNTs and produce pro-fibrogenic cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and osteopontin (OPN). Atomic layer deposition (ALD) is a novel process used to enhance functional properties of MWCNTs, yet the consequence of ALD-modified MWCNTs on macrophage biology and fibrosis is unknown. Methods The purpose of this study was to determine whether ALD coating with aluminum oxide (Al2O3) would alter the fibrogenic response to MWCNTs and whether cytokine expression in human macrophage/monocytes exposed to MWCNTs in vitro would predict the severity of lung fibrosis in mice. Uncoated (U)-MWCNTs or ALD-coated (A)-MWCNTs were incubated with THP-1 macrophages or human peripheral blood mononuclear cells (PBMC) and cell supernatants assayed for cytokines by ELISA. C57BL6 mice were exposed to a single dose of A- or U-MWCNTs by oropharyngeal aspiration (4 mg/kg) followed by evaluation of histopathology, lung inflammatory cell counts, and cytokine levels at day 1 and 28 post-exposure. Results ALD coating of MWCNTs with Al2O3 enhanced IL-1β secretion by THP-1 and PBMC in vitro, yet reduced protein levels of IL-6, TNF-α, and OPN production by THP-1 cells. Moreover, Al2O3 nanoparticles, but not carbon black NPs, increased IL-1β but decreased OPN and IL-6 in THP-1 and PBMC. Mice exposed to U-MWCNT had increased levels of all four cytokines assayed and developed pulmonary fibrosis by 28 days, whereas ALD-coating significantly reduced fibrosis and cytokine levels at the mRNA or protein level. Conclusion These findings indicate that ALD thin film coating of MWCNTs with Al2O3 reduces fibrosis in mice and that in vitro phagocyte expression of IL-6, TNF-α, and OPN, but not IL-1β, predict MWCNT-induced fibrosis in the lungs of mice in vivo. PMID:25216247

Lack of acute phase response in the livers of mice exposed to diesel exhaust particles or carbon black by inhalation

PubMed Central

Saber, Anne T; Halappanavar, Sabina; Folkmann, Janne K; Bornholdt, Jette; Boisen, Anne Mette Z; Møller, Peter; Williams, Andrew; Yauk, Carole; Vogel, Ulla; Loft, Steffen; Wallin, Håkan

2009-01-01

Background Epidemiologic and animal studies have shown that particulate air pollution is associated with increased risk of lung and cardiovascular diseases. Although the exact mechanisms by which particles induce cardiovascular diseases are not known, studies suggest involvement of systemic acute phase responses, including C-reactive protein (CRP) and serum amyloid A (SAA) in humans. In this study we test the hypothesis that diesel exhaust particles (DEP) – or carbon black (CB)-induced lung inflammation initiates an acute phase response in the liver. Results Mice were exposed to filtered air, 20 mg/m3 DEP or CB by inhalation for 90 minutes/day for four consecutive days; we have previously shown that these mice exhibit pulmonary inflammation (Saber AT, Bornholdt J, Dybdahl M, Sharma AK, Loft S, Vogel U, Wallin H. Tumor necrosis factor is not required for particle-induced genotoxicity and pulmonary inflammation., Arch. Toxicol. 79 (2005) 177–182). As a positive control for the induction of an acute phase response, mice were exposed to 12.5 mg/kg of lipopolysaccharide (LPS) intraperitoneally. Quantitative real time RT-PCR was used to examine the hepatic mRNA expression of acute phase proteins, serum amyloid P (Sap) (the murine homologue of Crp) and Saa1 and Saa3. While significant increases in the hepatic expression of Sap, Saa1 and Saa3 were observed in response to LPS, their levels did not change in response to DEP or CB. In a comprehensive search for markers of an acute phase response, we analyzed liver tissue from these mice using high density DNA microarrays. Globally, 28 genes were found to be significantly differentially expressed in response to DEP or CB. The mRNA expression of three of the genes (serine (or cysteine) proteinase inhibitor, clade A, member 3C, apolipoprotein E and transmembrane emp24 domain containing 3) responded to both exposures. However, these changes were very subtle and were not confirmed by real time RT-PCR. Conclusion Our findings collectively suggest that Sap, Saa1 and Saa3 are not induced in livers of mice exposed to DEP or CB. Despite pulmonary inflammation in these mice, global transcriptional profiling of liver did not reveal any hepatic response following exposure by inhalation. PMID:19374780

Differential effects of context on psychomotor sensitization to ethanol and cocaine.

PubMed

Didone, Vincent; Quoilin, Caroline; Dieupart, Julie; Tirelli, Ezio; Quertemont, Etienne

2016-04-01

Repeated drug injections lead to sensitization of their stimulant effects in mice, a phenomenon sometimes referred to as drug psychomotor sensitization. Previous studies showed that sensitization to cocaine is context dependent as its expression is reduced in an environment that was not paired with cocaine administration. In contrast, the effects of the test context on ethanol sensitization remain unclear. In the present study, female OF1 mice were repeatedly injected with 1.5 g/kg ethanol to test for both the effects of context novelty/familiarity and association on ethanol sensitization. A first group of mice was extensively pre-exposed to the test context before ethanol sensitization and ethanol injections were paired with the test context (familiar and paired group). A second group was not pre-exposed to the test context, but ethanol injections were paired with the test context (nonfamiliar and paired group). Finally, a third group of mice was not pre-exposed to the test context and ethanol was repeatedly injected in the home cage (unpaired group). Control groups were similarly exposed to the test context, but were injected with saline. In a second experiment, cocaine was used as a positive control. The same behavioral procedure was used, except that mice were injected with 10 mg/kg cocaine instead of ethanol. The results show a differential involvement of the test context in the sensitization to ethanol and cocaine. Cocaine sensitization is strongly context dependent and is not expressed in the unpaired group. In contrast, the expression of ethanol sensitization is independent of the context in which it was administered, but is strongly affected by the relative novelty/familiarity of the environment. Extensive pre-exposure to the test context prevented the expression of ethanol sensitization. One possible explanation is that expression of ethanol sensitization requires an arousing environment.

20-HETE mediates ozone-induced, neutrophil-independent airway hyper-responsiveness in mice.

PubMed

Cooper, Philip R; Mesaros, A Clementina; Zhang, Jie; Christmas, Peter; Stark, Christopher M; Douaidy, Karim; Mittelman, Michael A; Soberman, Roy J; Blair, Ian A; Panettieri, Reynold A

2010-04-20

Ozone, a pollutant known to induce airway hyper-responsiveness (AHR), increases morbidity and mortality in patients with obstructive airway diseases and asthma. We postulate oxidized lipids mediate in vivo ozone-induced AHR in murine airways. Male BALB/c mice were exposed to ozone (3 or 6 ppm) or filtered air (controls) for 2 h. Precision cut lung slices (PCLS; 250 microm thickness) containing an intrapulmonary airway ( approximately 0.01 mm(2) lumen area) were prepared immediately after exposure or 16 h later. After 24 h, airways were contracted to carbachol (CCh). Log EC(50) and E(max) values were then calculated by measuring the airway lumen area with respect to baseline. In parallel studies, dexamethasone (2.5 mg/kg), or 1-aminobenzotriazol (ABT) (50 mg/kg) were given intraperitoneal injection to naïve mice 18 h prior to ozone exposure. Indomethacin (10 mg/kg) was administered 2 h prior. Cell counts, cytokine levels and liquid chromatography-mass spectrometry (LC-MS) for lipid analysis were assessed in bronchoalveolar lavage (BAL) fluid from ozone exposed and control mice. Ozone acutely induced AHR to CCh. Dexamethasone or indomethacin had little effect on the ozone-induced AHR; while, ABT, a cytochrome P450 inhibitor, markedly attenuated airway sensitivity. BAL fluid from ozone exposed animals, which did not contain an increase in neutrophils or interleukin (IL)-6 levels, increased airway sensitivity following in vitro incubation with a naïve PCLS. In parallel, significant increases in oxidized lipids were also identified using LC-MS with increases of 20-HETE that were decreased following ABT treatment. These data show that ozone acutely induces AHR to CCh independent of inflammation and is insensitive to steroid treatment or cyclooxygenase (COX) inhibition. BAL fluid from ozone exposed mice mimicked the effects of in vivo ozone exposure that were associated with marked increases in oxidized lipids. 20-HETE plays a pivotal role in mediating acute ozone-induced AHR.

Effects of Diesel Engine Exhaust Origin Secondary Organic Aerosols on Novel Object Recognition Ability and Maternal Behavior in BALB/C Mice

PubMed Central

Win-Shwe, Tin-Tin; Fujitani, Yuji; Kyi-Tha-Thu, Chaw; Furuyama, Akiko; Michikawa, Takehiro; Tsukahara, Shinji; Nitta, Hiroshi; Hirano, Seishiro

2014-01-01

Epidemiological studies have reported an increased risk of cardiopulmonary and lung cancer mortality associated with increasing exposure to air pollution. Ambient particulate matter consists of primary particles emitted directly from diesel engine vehicles and secondary organic aerosols (SOAs) are formed by oxidative reaction of the ultrafine particle components of diesel exhaust (DE) in the atmosphere. However, little is known about the relationship between exposure to SOA and central nervous system functions. Recently, we have reported that an acute single intranasal instillation of SOA may induce inflammatory response in lung, but not in brain of adult mice. To clarify the whole body exposure effects of SOA on central nervous system functions, we first created inhalation chambers for diesel exhaust origin secondary organic aerosols (DE-SOAs) produced by oxidation of diesel exhaust particles caused by adding ozone. Male BALB/c mice were exposed to clean air (control), DE and DE-SOA in inhalation chambers for one or three months (5 h/day, 5 days/week) and were examined for memory function using a novel object recognition test and for memory function-related gene expressions in the hippocampus by real-time RT-PCR. Moreover, female mice exposed to DE-SOA for one month were mated and maternal behaviors and the related gene expressions in the hypothalamus examined. Novel object recognition ability and N-methyl-d-aspartate (NMDA) receptor expression in the hippocampus were affected in male mice exposed to DE-SOA. Furthermore, a tendency to decrease maternal performance and significantly decreased expression levels of estrogen receptor (ER)-α, and oxytocin receptor were found in DE-SOA exposed dams compared with the control. This is the first study of this type and our results suggest that the constituents of DE-SOA may be associated with memory function and maternal performance based on the impaired gene expressions in the hippocampus and hypothalamus, respectively. PMID:25361045

Effects of exogenous glutathione on arsenic burden and NO metabolism in brain of mice exposed to arsenite through drinking water.

PubMed

Wang, Yan; Zhao, Fenghong; Jin, Yaping; Zhong, Yuan; Yu, Xiaoyun; Li, Gexin; Lv, Xiuqiang; Sun, Guifan

2011-03-01

Chronic exposure to inorganic arsenic (iAs) is associated with neurotoxicity. Studies to date have disclosed that methylation of ingested iAs is the main metabolic pathway, and it is a process relying on reduced glutathione (GSH). The aim of this study was to explore the effects of exogenous GSH on arsenic burden and metabolism of nitric oxide (NO) in the brain of mice exposed to arsenite via drinking water. Mice were exposed to sodium arsenite through drinking water contaminated with 50 mg/L arsenic for 4 weeks and treated intraperitoneally with saline solution, 200 mg/kg body weight (b.w), 400 mg/kg b.w, or 800 mg/kg b.w GSH, respectively, at the 4th week. Levels of iAs, monomethylarsenic acid, and dimethylarsenic acid (DMAs) in the liver, blood, and brain were determined by method of hydride generation coupled with atomic absorption spectrophotometry. Activities of nitric oxide synthase (NOS) and contents of NO in the brain were determined by colorimetric method. Compared with mice exposed to arsenite alone, administration of GSH increased dose-dependently the primary and secondary methylation ratio in the liver, which caused the decrease in percent iAs and increase in percent DMAs in the liver, as a consequence, resulted in significant decrease in iAs levels in the blood and total arsenic levels in both blood and brain. NOS activities and NO levels in the brain of mice in iAs group were significantly lower than those in control; however, administration of GSH could increase significantly activities of NOS and contents of NO. Findings from this study suggested that exogenous GSH could promote both primary and secondary arsenic methylation capacity in the liver, which might facilitate excretion of arsenicals, and consequently reduce arsenic burden in both blood and brain and furthermore ameliorate the effects of arsenicals on NO metabolism in the brain.

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice.

PubMed

Yadav, Pankaj; Ellinghaus, David; Rémy, Gaëlle; Freitag-Wolf, Sandra; Cesaro, Anabelle; Degenhardt, Frauke; Boucher, Gabrielle; Delacre, Myriam; Peyrin-Biroulet, Laurent; Pichavant, Muriel; Rioux, John D; Gosset, Philippe; Franke, Andre; Schumm, L Philip; Krawczak, Michael; Chamaillard, Mathias; Dempfle, Astrid; Andersen, Vibeke

2017-08-01

The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene-smoking interactions) that affect risk for Crohn's disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD. We used 55 Immunochip-wide datasets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10 -/- and Nod2 -/- mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription polymerase chain reaction. We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P < 5.0 × 10 -5 ; heterogeneity Cochrane Q test P > .05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of Interleukin 10 (il10)-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wild-type mice exposed to smoke. In an analysis of 55 Immunochip-wide datasets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene-smoking interactions were confirmed in mice with disruption of Il10 and Nod2-variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Bile Acids and Tryptophan Metabolism Are Novel Pathways Involved in Metabolic Abnormalities in BPA-Exposed Pregnant Mice and Male Offspring.

PubMed

Susiarjo, Martha; Xin, Frances; Stefaniak, Martha; Mesaros, Clementina; Simmons, Rebecca A; Bartolomei, Marisa S

2017-08-01

Increasing evidence has demonstrated that exposure to endocrine-disrupting chemicals impacts maternal and fetal health, but the underlying mechanisms are still unclear. We previously showed that dietary exposure to 10 µg/kg body weight (bw)/d and 10 mg/kg bw/d of bisphenol A (BPA) during pregnancy induced metabolic abnormalities in F1 male offspring and gestational glucose intolerance in F0 pregnant mice. The aim of this study was to elucidate the underlying etiologies of BPA exposure-induced metabolic disease by analyzing the male fetal liver metabolome. Using the Metabolon Discover HD4 Platform, our laboratory identified metabolic pathways that were altered by BPA exposure, including biochemicals in lipid and amino acid metabolism. Specifically, primary and secondary bile acids were increased in liver from BPA-exposed embryonic day 18.5 male fetuses. We subsequently showed that increased bile acid was associated with a defective farnesoid X receptor-dependent negative feedback mechanism in BPA-exposed fetuses. In addition, through metabolomics, we observed that BPA-exposed fetuses had elevated tryptophan levels. Independent liquid chromatography and mass spectrometry measurement revealed that BPA-exposed dams also had increased tryptophan levels relative to those of controls. Because several key enzymes in tryptophan catabolism are vitamin B6 dependent and vitamin B6 deficiencies have been linked to gestational diabetes, we tested the impact of vitamin B6 supplementation and showed that it rescued gestational glucose intolerance in BPA-exposed pregnant mice. Our study has therefore identified two pathways (bile acid and tryptophan metabolism) that potentially underlie BPA-induced maternal and fetal metabolic disease. Copyright © 2017 Endocrine Society.

Diesel engine exhaust accelerates plaque formation in a mouse model of Alzheimer's disease.

PubMed

Hullmann, Maja; Albrecht, Catrin; van Berlo, Damiën; Gerlofs-Nijland, Miriam E; Wahle, Tina; Boots, Agnes W; Krutmann, Jean; Cassee, Flemming R; Bayer, Thomas A; Schins, Roel P F

2017-08-30

Increasing evidence from toxicological and epidemiological studies indicates that the central nervous system is an important target for ambient air pollutants. We have investigated whether long-term inhalation exposure to diesel engine exhaust (DEE), a dominant contributor to particulate air pollution in urban environments, can aggravate Alzheimer's Disease (AD)-like effects in female 5X Familial AD (5XFAD) mice and their wild-type female littermates. Following 3 and 13 weeks exposures to diluted DEE (0.95 mg/m 3 , 6 h/day, 5 days/week) or clean air (controls) behaviour tests were performed and amyloid-β (Aβ) plaque formation, pulmonary histopathology and systemic inflammation were evaluated. In a string suspension task, assessing for grip strength and motor coordination, 13 weeks exposed 5XFAD mice performed significantly less than the 5XFAD controls. Spatial working memory deficits, assessed by Y-maze and X-maze tasks, were not observed in association with the DEE exposures. Brains of the 3 weeks DEE-exposed 5XFAD mice showed significantly higher cortical Aβ plaque load and higher whole brain homogenate Aβ42 levels than the clean air-exposed 5XFAD littermate controls. After the 13 weeks exposures, with increasing age and progression of the AD-phenotype of the 5XFAD mice, DEE-related differences in amyloid pathology were no longer present. Immunohistochemical evaluation of lungs of the mice revealed no obvious genetic background-related differences in tissue structure, and the DEE exposure did not cause histopathological changes in the mice of both backgrounds. Luminex analysis of plasma cytokines demonstrated absence of sustained systemic inflammation upon DEE exposure. Inhalation exposure to DEE causes accelerated plaque formation and motor function impairment in 5XFAD transgenic mice. Our study provides further support that the brain is a relevant target for the effects of inhaled DEE and suggests that long-term exposure to this ubiquitous air pollution mixture may promote the development of Alzheimer's disease.

Ketogenic diet exposure during the juvenile period increases social behaviors and forebrain neural activation in adult Engrailed 2 null mice.

PubMed

Verpeut, Jessica L; DiCicco-Bloom, Emanuel; Bello, Nicholas T

2016-07-01

Prolonged consumption of ketogenic diets (KD) has reported neuroprotective benefits. Several studies suggest KD interventions could be useful in the management of neurological and developmental disorders. Alterations in the Engrailed (En) genes, specifically Engrailed 2 (En2), have neurodevelopmental consequences and produce autism-related behaviors. The following studies used En2 knockout (KO; En2(-/-)), and wild-type (WT; En2(+/+)), male mice fed either KD (80% fat, 0.1% carbohydrates) or control diet (CD; 10% fat, 70% carbohydrates). The objective was to determine whether a KD fed from weaning at postnatal day (PND) 21 to adulthood (PND 60) would alter brain monoamines concentrations, previously found dysregulated, and improve social outcomes. In WT animals, there was an increase in hypothalamic norepinephrine content in the KD-fed group. However, regional monoamines were not altered in KO mice in KD-fed compared with CD-fed group. In order to determine the effects of juvenile exposure to KD in mice with normal blood ketone levels, separate experiments were conducted in mice removed from the KD or CD and fed standard chow for 2days (PND 62). In a three-chamber social test with a novel mouse, KO mice previously exposed to the KD displayed similar social and self-grooming behaviors compared with the WT group. Groups previously exposed to a KD, regardless of genotype, had more c-Fos-positive cells in the cingulate cortex, lateral septal nuclei, and anterior bed nucleus of the stria terminalis. In the novel object condition, KO mice previously exposed to KD had similar behavioral responses and pattern of c-Fos immunoreactivity compared with the WT group. Thus, juvenile exposure to KD resulted in short-term consequences of improving social interactions and appropriate exploratory behaviors in a mouse model that displays autism-related behaviors. Such findings further our understanding of metabolic-based therapies for neurological and developmental disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Perinatal programming of depressive-like behavior by inflammation in adult offspring mice whose mothers were fed polluted eels: Gender selective effects.

PubMed

Soualeh, Nidhal; Dridi, Imen; Eppe, Gauthier; Némos, Christophe; Soulimani, Rachid; Bouayed, Jaouad

2017-07-01

Several lines of evidence indicate that early-life inflammation may predispose to mental illness, including depression, in later-life. We investigated the impact of perinatal exposure to polluted eels on neonatal, postnatal, and adult brain inflammation, and on the resignation behavior of male and female adult offspring mice. The effects of maternal standard diet (laboratory food) were compared to the same diet enriched with low, intermediate, or highly polluted eels. Brain inflammatory markers including cytokines were assessed in offspring mice on the day of birth (i.e., on the postnatal day-PND 1), upon weaning (PND 21) and at adulthood (PND 100). Plasma myeloperoxidase and corticosterone levels were evaluated at PND 100. Immobility behavior of offspring was assessed in adulthood (i.e., at PNDs 95-100), using the tail suspension and forced swimming tests. Chronic brain inflammation was found in male and female offspring mice compared to controls, as assessed at PNDs 1, 21, and 100. The level of myeloperoxidase was found to be significantly higher in both adult males and females vs. control offspring. However, high corticosterone levels were only found in male offspring mice that were perinatally exposed to eels, suggesting a gender-selective dysregulation of the adult hypothalamic-pituitaryadrenal (HPA) axis. Gender-specific differences were also detected in adulthood in regard to offspring resignation behavior. Thus, compared to controls, males, but not females, whose mothers were fed eels during pregnancy and lactation exhibited a depressive-like behavior in adult age in both behavioral models of depression. Depressive symptoms were more pronounced in male mice perinatally exposed to either intermediate or highly polluted eels than those exposed to only lowly polluted eels. Our results indicate that early-life inflammatory insult is a plausible causative factor that induces the depressive phenotype exhibited by male adult offspring mice, most likely through a gender-specific HPA axis enhanced activation. Copyright © 2016 Elsevier Inc. All rights reserved.

Changes in photoperiod alter Glut4 expression in skeletal muscle of C57BL/6J mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tashiro, Ayako; Shibata, Satomi; Takai, Yusuke

Seasonal changes in photoperiod influence body weight and metabolism in mice. Here, we examined the effect of changes in photoperiod on the expression of glucose transporter genes in the skeletal muscle and adipose tissue of C57BL/6J mice. Glut4 expression was lower in the gastrocnemius muscle of mice exposed to a short-duration day (SD) than those to a long-duration day (LD), with accompanying changes in GLUT4 protein levels. Although Glut4 expression in the mouse soleus muscle was higher under SD than under LD, GLUT4 protein levels remained unchanged. To confirm the functional significance of photoperiod-induced changes in Glut4 expression, we checkedmore » for variations in insulin sensitivity. Blood glucose levels after insulin injection remained high under SD, suggesting that the mice exposed to SD showed lower sensitivity to insulin than those exposed to LD. We also attempted to clarify the relationship between Glut4 expression and physical activity in the mice following changes in photoperiod. Locomotor activity, as detected via infrared beam sensor, was lower under SD than under LD. However, when we facilitated voluntary activity by using running wheels, the rotation of wheels was similar for both groups of mice. Although physical activity levels were enhanced due to running wheels, Glut4 expression in the gastrocnemius muscle remained unchanged. Thus, variations in photoperiod altered Glut4 expression in the mouse skeletal muscle, with subsequent changes in GLUT4 protein levels and insulin sensitivity; these effects might be independent of physical activity. - Highlights: • Glut4 expression in the gastrocnemius muscle was lowered under short photoperiod. • Insulin sensitivity was lowered under short photoperiod. • Access to running wheels did not alter Glut4 expression in the gastrocnemius muscle. • Photoperiodic changes in Glut4 expression may be independent of physical activity.« less

The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice.

PubMed

Lopez, Marcelo F; Moorman, David E; Aston-Jones, Gary; Becker, Howard C

2016-04-01

The orexin/hypocretin (ORX) system plays a major role in motivation for natural and drug rewards. In particular, a number of studies have shown that ORX signaling through the orexin 1 receptor (OX1R) regulates alcohol seeking and consumption. Despite the association between ORX signaling and motivation for alcohol, no study to date has investigated what role the ORX system plays in alcohol dependence, an understanding of which would have significant clinical relevance. This study was designed to evaluate the effect of the highly selective OX1R antagonist GSK1059865 on voluntary ethanol intake in ethanol-dependent and control non-dependent mice. Mice were subjected to a protocol in which they were evaluated for baseline ethanol intake and then exposed to intermittent ethanol or air exposure in inhalation chambers. Each cycle of chronic intermittent ethanol (CIE), or air, exposure was followed by a test of ethanol intake. Once the expected effect of increased voluntary ethanol intake was obtained in ethanol dependent mice, mice were tested for the effect of GSK1059865 on ethanol and sucrose intake. Treatment with GSK1059865 significantly decreased ethanol drinking in a dose-dependent manner in CIE-exposed mice. In contrast GSK1059865 decreased drinking in air-exposed mice only at the highest dose used. There was no effect of GSK1059865 on sucrose intake. Thus, ORX signaling through the OX1R, using a highly-selective antagonist, has a profound influence on high levels of alcohol drinking induced in a dependence paradigm, but limited or no influence on moderate alcohol drinking or sucrose drinking. These results indicate that the ORX system may be an important target system for treating disorders of compulsive reward seeking such as alcoholism and other addictions in which motivation is strongly elevated. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuropathogenesis of Zika Virus in a Highly Susceptible Immunocompetent Mouse Model after Antibody Blockade of Type I Interferon

PubMed Central

Smith, Darci R.; Hollidge, Bradley; Daye, Sharon; Zeng, Xiankun; Blancett, Candace; Kuszpit, Kyle; Bocan, Thomas; Koehler, Jeff W.; Coyne, Susan; Minogue, Tim; Kenny, Tara; Chi, Xiaoli; Yim, Soojin; Miller, Lynn; Schmaljohn, Connie; Bavari, Sina; Golden, Joseph W.

2017-01-01

Animal models are needed to better understand the pathogenic mechanisms of Zika virus (ZIKV) and to evaluate candidate medical countermeasures. Adult mice infected with ZIKV develop a transient viremia, but do not demonstrate signs of morbidity or mortality. Mice deficient in type I or a combination of type I and type II interferon (IFN) responses are highly susceptible to ZIKV infection; however, the absence of a competent immune system limits their usefulness for studying medical countermeasures. Here we employ a murine model for ZIKV using wild-type C57BL/6 mice treated with an antibody to disrupt type I IFN signaling to study ZIKV pathogenesis. We observed 40% mortality in antibody treated mice exposed to ZIKV subcutaneously whereas mice exposed by intraperitoneal inoculation were highly susceptible incurring 100% mortality. Mice infected by both exposure routes experienced weight loss, high viremia, and severe neuropathologic changes. The most significant histopathological findings occurred in the central nervous system where lesions represent an acute to subacute encephalitis/encephalomyelitis that is characterized by neuronal death, astrogliosis, microgliosis, scattered necrotic cellular debris, and inflammatory cell infiltrates. This model of ZIKV pathogenesis will be valuable for evaluating medical countermeasures and the pathogenic mechanisms of ZIKV because it allows immune responses to be elicited in immunologically competent mice with IFN I blockade only induced at the time of infection. PMID:28068342

Beta2-adrenergic activity modulates vascular tone regulation in lecithin:cholesterol acyltransferase knockout mice.

PubMed

Manzini, S; Pinna, C; Busnelli, M; Cinquanta, P; Rigamonti, E; Ganzetti, G S; Dellera, F; Sala, A; Calabresi, L; Franceschini, G; Parolini, C; Chiesa, G

2015-11-01

Lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with hypoalphalipoproteinemia, generally a predisposing factor for premature coronary heart disease. The evidence of accelerated atherosclerosis in LCAT-deficient subjects is however controversial. In this study, the effect of LCAT deficiency on vascular tone and endothelial function was investigated in LCAT knockout mice, which reproduce the human lipoprotein phenotype. Aortas from wild-type (Lcat(wt)) and LCAT knockout (Lcat(KO)) mice exposed to noradrenaline showed reduced contractility in Lcat(KO) mice (P<0.005), whereas acetylcholine exposure showed a lower NO-dependent relaxation in Lcat(KO) mice (P<0.05). Quantitative PCR and Western blotting analyses suggested an adequate eNOS expression in Lcat(KO) mouse aortas. Real-time PCR analysis indicated increased expression of β2-adrenergic receptors vs wild-type mice. Aorta stimulation with noradrenaline in the presence of propranolol, to abolish the β-mediated relaxation, showed the same contractile response in the two mouse lines. Furthermore, propranolol pretreatment of mouse aortas exposed to L-NAME prevented the difference in responses between Lcat(wt) and Lcat(KO) mice. The results indicate that LCAT deficiency leads to increased β2-adrenergic relaxation and to a consequently decreased NO-mediated vasodilation that can be reversed to guarantee a correct vascular tone. The present study suggests that LCAT deficiency is not associated with an impaired vascular reactivity. Copyright © 2015. Published by Elsevier Inc.

Beta2-adrenergic activity modulates vascular tone regulation in lecithin:cholesterol acyltransferase knockout mice

PubMed Central

Manzini, S.; Pinna, C.; Busnelli, M.; Cinquanta, P.; Rigamonti, E.; Ganzetti, G.S.; Dellera, F.; Sala, A.; Calabresi, L.; Franceschini, G.; Parolini, C.; Chiesa, G.

2015-01-01

Lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with hypoalphalipoproteinemia, generally a predisposing factor for premature coronary heart disease. The evidence of accelerated atherosclerosis in LCAT-deficient subjects is however controversial. In this study, the effect of LCAT deficiency on vascular tone and endothelial function was investigated in LCAT knockout mice, which reproduce the human lipoprotein phenotype. Aortas from wild-type (Lcatwt) and LCAT knockout (LcatKO) mice exposed to noradrenaline showed reduced contractility in LcatKO mice (P < 0.005), whereas acetylcholine exposure showed a lower NO-dependent relaxation in LcatKO mice (P < 0.05). Quantitative PCR and Western blotting analyses suggested an adequate eNOS expression in LcatKO mouse aortas. Real-time PCR analysis indicated increased expression of β2-adrenergic receptors vs wild-type mice. Aorta stimulation with noradrenaline in the presence of propranolol, to abolish the β-mediated relaxation, showed the same contractile response in the two mouse lines. Furthermore, propranolol pretreatment of mouse aortas exposed to L-NAME prevented the difference in responses between Lcatwt and LcatKO mice. The results indicate that LCAT deficiency leads to increased β2-adrenergic relaxation and to a consequently decreased NO-mediated vasodilation that can be reversed to guarantee a correct vascular tone. The present study suggests that LCAT deficiency is not associated with an impaired vascular reactivity. PMID:26254103

Fear-related behaviors in Lurcher mutant mice exposed to a predator.

PubMed

Lorivel, T; Roy, V; Hilber, P

2014-11-01

The Lurcher mutant mice are characterized by massive cerebellar cortex degeneration. Besides their motor and cognitive disturbances, they exhibit both exaggerated blood corticosterone (CORT) level surge and behavioral disinhibition when confronted to anxiogenic conditions (i.e. to a potential threat). In this study, we assessed if such physiological and behavioral hyperactivity was also detectable in a fear-eliciting situation (actual threat). For this purpose, the behaviors and CORT level elevations in Lurcher mice were compared with those of littermate controls in the predator exposure test: mice were exposed either to a rat (exposure) or to a brief wave of the experimenter's hand (sham exposure). While the basal CORT concentrations (24 h before testing) were not significantly different between mice of both genotypes, the post-exposure ones were higher in Lurcher than in control mice whatever the condition of the experimental design (exposure or sham exposure). Predator exposure did not provoke significant increase of CORT levels whatever the genotype. On the contrary, our data clearly showed that fear-related behaviors of cerebellar mutants facing a real threat were exacerbated in comparison to those of control mice. These results suggest that the cerebellar cortex not only participates to fear conditioning and anxiety but also actively contributes to the modulation of the innate fear-related behaviors. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Long-term Autophagy and Nrf2 Signaling in the Hippocampi of Developing Mice after Carbon Ion Exposure

NASA Astrophysics Data System (ADS)

Ye, Fei; Zhao, Ting; Liu, Xiongxiong; Jin, Xiaodong; Liu, Xinguo; Wang, Tieshan; Li, Qiang

2015-12-01

To explore charged particle radiation-induced long-term hippocampus damage, we investigated the expression of autophagy and antioxidant Nrf2 signaling-related proteins in the mouse hippocampus after carbon ion radiation. Heads of immature female Balb/c mice were irradiated with carbon ions of different LETs at various doses. Behavioral tests were performed on the mice after maturation. Acute and chronic expression of LC3-II, p62/SQSTM1, nuclear Nrf2, activated caspase-3 and the Bax/Bcl-2 ratio were measured in the hippocampi. Secondary X-ray insult was adopted to amplify potential damages. Long-term behavioral changes were observed in high-LET carbon ion-irradiated mice. There were no differences in the rates of LC3-II induction and p62/SQSTM1 degradation compared to the control group regardless of whether the mice received the secondary X-ray insult. A high nuclear Nrf2 content and low apoptosis level in hippocampal cells subjected to secondary X-rays were observed for the mice exposed to relatively low-LET carbon ions. Therefore, carbon ion exposure in the immature mouse led to an LET-dependent behavioral change after maturation. Although autophagy was intact, the persistently high nuclear Nrf2 content in the hippocampus might account for the unchanged behavioral pattern in mice exposed to the relatively low-LET carbon ions and the subsequent increased radioresistance of the hippocampus.

Study of acetylcholinesterase activity and apoptosis in SH-SY5Y cells and mice exposed to ethanol.

PubMed

Sun, Wenjun; Chen, Liangjing; Zheng, Wei; Wei, Xiaoan; Wu, Wenqi; Duysen, Ellen G; Jiang, Wei

2017-06-01

Ethanol is one of the most commonly abused psychotropic substances with deleterious effects on the central nervous system. Ethanol exposure during development results in the loss of neurons in brain regions and when exposed to ethanol cultured cells undergo apoptosis. To date no information is available on whether abnormally high AChE activity is characteristic of apoptosis in animals exposed to ethanol. The aims of the present study were to determine whether induction of AChE activity is associated with ethanol-induced apoptosis and to explore the mechanism of enhanced AChE activity induced by ethanol. For this purpose, in vitro and in vivo experiments were performed. AChE activity was quantified by spectrophotometry and apoptosis by flow cytometer in SH-SY5Y cells exposed to ethanol. The results showed that cells treated with 500mM ethanol for 24h had a 9-fold increase in apoptotic cells and a 6-fold increase in AChE activity compared with controls. Mice exposed acutely to 200μl of 20% ethanol daily on days 1-4 had elevated AChE activity in plasma on days 3-7. On day 4, plasma AChE activity was 2.4-fold higher than pretreatment activity. More apoptotic cells were found in the brains of treated mice compared to controls. Cells in brain sections that were positive in the TUNEL assay stained for AChE activity. In conclusion, AChE activity and apoptosis were induced in SH-SY5Y cells and mice treated with ethanol, which may indicate that increased AChE may related to apoptosis induced by ethanol. Unusually high AChE activity may be an effect marker of exposure to ethanol. The relationship between AChE and apoptosis might represent a novel mechanism of ethanol-associated neuronal injury. Copyright © 2017 Elsevier B.V. All rights reserved.

Proinflammatory and anti-inflammatory cytokine balance in gasoline exhaust induced pulmonary injury in mice.

PubMed

Sureshkumar, Veerapandian; Paul, Bholanath; Uthirappan, Mani; Pandey, Renu; Sahu, Anand Prakash; Lal, Kewal; Prasad, Arun Kumar; Srivastava, Suresh; Saxena, Ashok; Mathur, Neeraj; Gupta, Yogendra Kumar

2005-03-01

Proinflammatory and anti-inflammatory cytokine balance and associated changes in pulmonary bronchoalveolar lavage fluid (BALF) of unleaded gasoline exhaust (GE) exposed mice were investigated. Animals were exposed to GE (1 L/min of GE mixed with 14 L/min of compressed air) using a flow-past, nose-only, dynamic inhalation exposure chamber for different durations (7, 14, and 21 days). The particulate content of the GE was found to be 0.635, +/-0.10 mg PM/m3. Elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were observed in BALF of GE-exposed mice, but interleukin 1beta(IL-1beta) and the anti-inflammatory cytokine interleukin-10 (IL-10) remained unaffected. GE induced higher activities of alkaline phosphatase (ALP), gamma-glutamyl transferase (gammaGT), and lactate dehydrogenase (LDH) in the BALF, indicating Type II alveolar epithelial cell injury, Clara-cell injury, and general toxicity, respectively. Total protein in the BALF increased after 14 and 21 days of exposure, indicating enhanced alveolar-capillary permeability. However, the difference in the mean was found statistically insignificant in comparison to the compressed air control. Total cell count in the BALF of GE-exposed mice ranged between 0.898 and 0.813x10(6) cells/ml, whereas the compressed air control showed 0.65x10(6) cells/mL. The histopathological changes in GE-exposed lung includes perivascular, and peribronchiolar cuffing of mononuclear cells, migration of polymorphonuclear cells in the alveolar septa, alveolar thickening, and mild alveolar edematous changes indicating inflammation. The shift in pro- and anti-inflammatory cytokine balance and elevation of the pulmonary marker enzymes indicate toxic insult of GE. This study will help in our understanding of the mechanism of pulmonary injury by GE in the light of cytokine profiles, pulmonary marker enzymes, and lung architecture.

Role of the Oxytocin Receptor Expressed in the Rostral Medullary Raphe in Thermoregulation During Cold Conditions

PubMed Central

Kasahara, Yoshiyuki; Tateishi, Yuko; Hiraoka, Yuichi; Otsuka, Ayano; Mizukami, Hiroaki; Ozawa, Keiya; Sato, Keisuke; Hidema, Shizu; Nishimori, Katsuhiko

2015-01-01

Recent papers have reported that oxytocin (Oxt) and the oxytocin receptor (Oxtr) may be involved in the regulation of food intake in mammals. We therefore suspected the Oxt/Oxtr system to be involved in energy homeostasis. In previous studies, we found a tendency toward obesity in Oxtr-deficient (Oxtr−/−) mice, as well as impaired thermoregulation when these mice were exposed to cold conditions. In the present study, we observed the expression of Oxtr in the rostral medullary raphe (RMR), the brain region known to control thermogenesis in brown adipose tissue (BAT). Through immunohistochemistry, we detected neurons expressing Oxtr and c-Fos in the RMR of mice exposed to cold conditions. Up to 40% of Oxtr-positive neurons in RMR were classified as glutamatergic neurons, as shown by immunostaining using anti-VGLUT3 antibody. In addition, mice with exclusive expression of Oxtr in the RMR were generated by injecting an AAV-Oxtr vector into the RMR region of Oxtr−/− mice. We confirmed the recovery of thermoregulatory ability in the manipulated mice during exposure to cold conditions. Moreover, mice with RMR-specific expression of Oxtr lost the typical morphological change in BAT observed in Oxtr−/− mice. Additionally, increased expression of the β3-adrenergic receptor gene, Adrb3, was observed in BAT. These results are the first to show the critical role of RMR Oxtr expression in thermoregulation during cold conditions. PMID:26635729

ENDOGENOUS FORMATION OF N-NITROSOMORPHOLINE IN MICE FROM 15NO2 BY INHALATION AND MORPHOLINE BY GAVAGE

EPA Science Inventory

Male CD-1 mice were exposed to a nominal concentration of 20 ppm of 15N-nitrogen dioxide (15NO2) for 6 hr/day for 4 days and for 2 hr on the fifth day, and to 1g morpholine/kg body weight by gavage daily for 5 consecutive days. -nitrosomorpholine (NMOR) was found in whole mice, s...

PENTACHLOROPHENOL POTENTIATES BENZO[A]PYRENE DNA ADDUCT FORMATION IN ADULT BUT NOT INFANT B6C3F1 MALE MICE

EPA Science Inventory

Abstract

The objective of this study is to determine whether pentachlorophenol (PCP) alters benzo[a]pyrene (B[a]P) induced DNA adduct formation in infant and adult B6C3Fl mice. Mice were exposed to 55 ug B[a]P/g body weight (BW) alone and in combination with several dose...

Effects of Early-Life Stress on Social and Anxiety-Like Behaviors in Adult Mice: Sex-Specific Effects

PubMed Central

Lepeshko, Arina A.; Reshetnikov, Vasiliy V.

2018-01-01

Stressful events in an early postnatal period have critical implications for the individual's life and can increase later risk for psychiatric disorders. The aim of this study was to investigate the influence of early-life stress on the social behavior of adult male and female mice. C57Bl/6 mice were exposed to maternal separation (MS, 3 h once a day) or handling (HD, 15 min once a day) on postnatal day 2 through 14. Adult male and female mice were tested for social behavior in the social interaction test and for individual behavior in the plus-maze and open-field tests. Female mice exposed to maternal separation had increased social behavior and increased anxiety. MS male mice had no changes in social behavior but had significantly disrupted individual behavior, including locomotor and exploratory activity. Handling had positive effects on social behavior in males and females and decreased anxiety in males. Our results support the hypothesis that brief separation of pups from their mothers (handling), which can be considered as moderate stress, may result in future positive changes in behavior. Maternal separation has deleterious effects on individual behavior and significant sex-specific effects on social behavior. PMID:29619126

Meta-analysis of the effects of insect vector saliva on host immune responses and infection of vector-transmitted pathogens: a focus on leishmaniasis.

PubMed

Ockenfels, Brittany; Michael, Edwin; McDowell, Mary Ann

2014-10-01

A meta-analysis of the effects of vector saliva on the immune response and progression of vector-transmitted disease, specifically with regard to pathology, infection level, and host cytokine levels was conducted. Infection in the absence or presence of saliva in naïve mice was compared. In addition, infection in mice pre-exposed to uninfected vector saliva was compared to infection in unexposed mice. To control for differences in vector and pathogen species, mouse strain, and experimental design, a random effects model was used to compare the ratio of the natural log of the experimental to the control means of the studies. Saliva was demonstrated to enhance pathology, infection level, and the production of Th2 cytokines (IL-4 and IL-10) in naïve mice. This effect was observed across vector/pathogen pairings, whether natural or unnatural, and with single salivary proteins used as a proxy for whole saliva. Saliva pre-exposure was determined to result in less severe leishmaniasis pathology when compared with unexposed mice infected either in the presence or absence of sand fly saliva. The results of further analyses were not significant, but demonstrated trends toward protection and IFN-γ elevation for pre-exposed mice.

Propylene glycol monomethyl ether (PGME): inhalation toxicity and carcinogenicity in Fischer 344 rats and B6C3F1 mice.

PubMed

Spencer, Pamela J; Crissman, James W; Stott, William T; Corley, Richard A; Cieszlak, Frank S; Schumann, Alan M; Hardisty, Jerry F

2002-01-01

A series of inhalation studies with propylene glycol monomethyl ether (PGME) vapor were undertaken to characterize its subchronic toxicity in mice and chronic toxicity/oncogenicity in rats and mice. Groups of male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 300, 1,000, or 3,000 ppm vapor from 1 week to 2 years. Primary treatment-related effects included: initial sedation of animals exposed to 3,000 ppm and its subsequent resolution correlating with induction of hepatic mixed function oxidase activity and S-phase DNA synthesis; elevated mortality in high-exposure male rats and mice (chronic study); elevated deposition of alpha2u-globulin (alpha2U-G) and associated nephropathy and S-phase DNA synthesis in male rat kidneys; accelerated atrophy of the adrenal gland X-zone in female mice (subchronic study only); and increased occurrence and/or severity of eosinophilic foci of altered hepatocytes in male rats. No toxicologically relevant statistically significant increases in neoplasia occurred in either species. A numerical increase in the incidence of kidney adenomas occurred in intermediate-exposure male rats; however, the association with alpha2U-G nephropathy, a male rat specific effect, indicated a lack of relevance for human risk assessment.

Effects of Lycium barbarum Polysaccharides on Apoptosis, Cellular Adhesion, and Oxidative Damage in Bone Marrow Mononuclear Cells of Mice Exposed to Ionizing Radiation Injury

PubMed Central

Zhou, Jing; Pang, Hua; Li, Wenbo; Liu, Qiong; Xu, Lu; Liu, Qian; Liu, Ying

2016-01-01

Lycium barbarum has been used for more than 2500 years as a traditional herb and food in China. We investigated the effects of Lycium barbarum polysaccharides (LBP) on apoptosis, oxidative damage, and expression of adhesion molecules in bone marrow mononuclear cells (BMNC) of mice injured by ionizing radiation. Kunming mice were exposed to X-rays; then mice in the LBP groups were continuously injected with various concentrations of LBP intraperitoneally for 14 days. Mice in the control group were continuously injected with normal saline (NS) by the same route for 14 days. A normal group was set up. After 1, 7, and 14 days of treatment, mice were killed and BMNC were extracted. Cell cycle, apoptosis, and the expression of adhesion molecules CD44 and CD49d were detected by flow cytometry. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were identified by colorimetric analyses. LBP significantly decreased the percentage of G0/G1 phase, apoptosis, MDA level, and expression of CD44 and CD49d and distinctly increased the activity of SOD. LBP showed a protective effect on BMNC against ionizing radiation-induced apoptosis and oxidative damage and altered the expression of adhesion molecule. PMID:27314019

Exercise attenuates the metabolic effects of dim light at night.

PubMed

Fonken, Laura K; Meléndez-Fernández, O Hecmarie; Weil, Zachary M; Nelson, Randy J

2014-01-30

Most organisms display circadian rhythms that coordinate complex physiological and behavioral processes to optimize energy acquisition, storage, and expenditure. Disruptions to the circadian system with environmental manipulations such as nighttime light exposure alter metabolic energy homeostasis. Exercise is known to strengthen circadian rhythms and to prevent weight gain. Therefore, we hypothesized providing mice a running wheel for voluntary exercise would buffer against the effects of light at night (LAN) on weight gain. Mice were maintained in either dark (LD) or dim (dLAN) nights and provided either a running wheel or a locked wheel. Mice exposed to dim, rather than dark, nights increased weight gain. Access to a functional running wheel prevented body mass gain in mice exposed to dLAN. Voluntary exercise appeared to limit weight gain independently of rescuing changes to the circadian system caused by dLAN; increases in daytime food intake induced by dLAN were not diminished by increased voluntary exercise. Furthermore, although all of the LD mice displayed a 24h rhythm in wheel running, nearly half (4 out of 9) of the dLAN mice did not display a dominant 24h rhythm in wheel running. These results indicate that voluntary exercise can prevent weight gain induced by dLAN without rescuing circadian rhythm disruptions. © 2013.

Neuroprotective effects of sildenafil against oxidative stress and memory dysfunction in mice exposed to noise stress.

PubMed

Sikandaner, Hu Erxidan; Park, So Young; Kim, Min Jung; Park, Shi Nae; Yang, Dong Won

2017-02-15

Noise exposure has been well characterized as an environmental stressor, and is known to have auditory and non-auditory effects. Phosphodiesterase 5 (PDE5) inhibitors affect memory and hippocampus plasticity through various signaling cascades which are regulated by cGMP. In this study, we investigated the effects of sildenafil on memory deficiency, neuroprotection and oxidative stress in mice caused by chronic noise exposure. Mice were exposed to noise for 4h every day up to 14days at 110dB SPL of noise level. Sildenafil (15mg/kg) was orally administered 30min before noise exposure for 14days. Behavioral assessments were performed using novel object recognition (NOR) test and radial arm maze (RAM) test. Higher levels of memory dysfunction and oxidative stress were observed in noise alone-induced mice compared to control group. Interestingly, sildenafil administration increased memory performance, decreased oxidative stress, and increased neuroprotection in the hippocampus region of noise alone-induced mice likely through affecting memory related pathways such as cGMP/PKG/CREB and p25/CDK5, and induction of free radical scavengers such as SOD1, SOD2, SOD3, Prdx5, and catalase in the brain of stressed mice. Copyright © 2016. Published by Elsevier B.V.

Multi-neuron intracellular recording in vivo via interacting autopatching robots

PubMed Central

Holst, Gregory L; Singer, Annabelle C; Han, Xue; Brown, Emery N

2018-01-01

The activities of groups of neurons in a circuit or brain region are important for neuronal computations that contribute to behaviors and disease states. Traditional extracellular recordings have been powerful and scalable, but much less is known about the intracellular processes that lead to spiking activity. We present a robotic system, the multipatcher, capable of automatically obtaining blind whole-cell patch clamp recordings from multiple neurons simultaneously. The multipatcher significantly extends automated patch clamping, or 'autopatching’, to guide four interacting electrodes in a coordinated fashion, avoiding mechanical coupling in the brain. We demonstrate its performance in the cortex of anesthetized and awake mice. A multipatcher with four electrodes took an average of 10 min to obtain dual or triple recordings in 29% of trials in anesthetized mice, and in 18% of the trials in awake mice, thus illustrating practical yield and throughput to obtain multiple, simultaneous whole-cell recordings in vivo. PMID:29297466

Preflight studies on tolerance of pocket mice to oxygen and heat. III - Effects on eyes

NASA Technical Reports Server (NTRS)

Philpott, D. E.; Corbett, R. L.; Black, S.; Takahashi, A.; Leaffer, D.

1975-01-01

A study was made of the eyes of eight pocket mice exposed to oxygen at partial pressures of 8, 10, or 12 psi over a period of 7 d. At the termination of the exposure, the animals were decompressed to sea-level O2, either immediately or over a period of 30, 60, or 90 min. No pathological changes were found in any of the eyes, except in the retina of one of the animals exposed to 12 psi O2. Here, only a single rod photoreceptor was found damaged, an observation not regarded as significant. Hence, an oxygen partial pressure as high as 12 psi in the canister in which pocket mice were expected to fly on Apollo XVII would probably have no deleterious effect on the eyes of the animals.

Cigarette smoke-induced hypercapnic emphysema in C3H mice is associated with increases of macrophage metalloelastase and substance P in the lungs.

PubMed

Xu, J; Xu, F; Wang, R; Seagrave, Jc; Lin, Y; March, T H

2007-01-01

The authors tested whether macrophage metalloelastase (MMP-12) and substance P (SP) were increased in the cigarette smoke (CS)-exposed female C3H/HeN mice with hypercapnic emphysema. The authors found that as compared to control (filtered air), 16 weeks of CS exposure significantly up-regulated mRNA and protein levels of MMP-12, the ratio of MMP-12/tissue inhibitor of matrix metalloproteinase-1, and SP/preprotachykinin-A (a precursor to SP) in the lungs. Importantly, a significant correlation was found between MMP-12 and SP, and between MMP-12/SP and the degrees of hypoxemia/hypercapnia denoted in CS-exposed mice. These data suggest a possible involvement of SP and MMP-12 in the pathogenesis of severe COPD.

Clarifying carcinogenicity of ethylbenzene

PubMed Central

Huff, James; Chan, Po; Melnick, Ronald

2010-01-01

Ethylbenzene has been evaluated for carcinogenic activity in Fischer rats and B6C3F1 mice exposed by inhalation [Chan et al 1998;Chan & NTP 1999] and in Sprague-Dawley rats after oral exposure [Maltoni et al 1985,1997]. Bioassay findings are summarized below to expand on those not stated clearly or completely in Saghir et al [2010]. Overall in these three studies animals exposed to ethylbenzene had increased tumors in rats for kidneys, testes, head [including rare neuroesthesioepitheliomas], and total malignant tumors, whilst in mice tumors incidences were increased in the lung and liver [Huff,2002]. Thus ethylbenzene was carcinogenic by two exposure routes to both sexes of two species of rodents, two strains of rats, and one strain of mice, causing collectively tumors in five different target organs and a composite of “total malignant”tumors. PMID:20723573

Inhaled Diesel Emissions Alter Atherosclerotic Plaque Composition in ApoE−/− Mice

PubMed Central

Campen, Matthew J.; Lund, Amie K.; Knuckles, Travis L.; Conklin, Daniel J.; Bishop, Barbara; Young, David; Seilkop, Steven; Seagrave, JeanClare; Reed, Matthew D.; McDonald, Jacob D.

2009-01-01

Recent epidemiological studies suggest that traffic-related air pollution may have detrimental effects on cardiovascular health. Previous studies reveal that gasoline emissions can induce several enzyme pathways involved in the formation and development of atherosclerotic plaques. As a direct comparison, the present study examined the impact of diesel engine emissions on these pathways, and further examined the effects on vascular lesion pathology. Apolipoprotein E-null mice were simultaneously placed on a high fat chow diet and exposed to four concentrations, plus a high concentration exposure with particulates (PM) removed by filtration, of diesel emissions for 6 h/d for 50 days. Aortas were subsequently assayed for alteration in matrix metalloproteinase-9, endothelin-1, and several other biomarkers. Diesel induced dose-related alterations in gene markers of vascular remodeling and aortic lipid peroxidation; filtration of PM did not significantly alter these vascular responses, indicating that the gaseous portion of the exhaust was a principal driver. Immunohistochemical analysis of aortic leaflet sections revealed no net increase in lesion area, but a significant decrease in lipid-rich regions and increasing trends in macrophage accumulation and collagen content, suggesting that plaques were advanced to a more fragile, potentially more vulnerable state by diesel exhaust exposure. Combined with previous studies, these results indicate that whole emissions from mobile sources may have a significant role in promoting chronic vascular disease. PMID:19891982

The therapeutic protection of a living and dead Lactobacillus strain against aluminum-induced brain and liver injuries in C57BL/6 mice

PubMed Central

Zhai, Qixiao; Xiao, Yue; Shi, Ying; Jiang, Jinchi; Liu, Xiaoming; Zhao, Jianxin; Zhang, Hao

2017-01-01

Our previous study found that Lactobacillus plantarum CCFM639 had the ability to alleviate acute aluminum (Al) toxicity when the strain was introduced simultaneously with Al exposure. This research was designed to elucidate the therapeutic effects of living and dead L. plantarum CCFM639 against chronic Al toxicity and to gain insight into the protection modes of this strain. Animals were assigned into control, Al only, Al + living CCFM639, and Al + dead CCFM639 groups. The Al exposure model was established by drinking water for the first 4 weeks. The strain was given after Al exposure by oral gavage at 109 colony-forming units once per day for 12 weeks. The results show that the Al binding ability of dead CCFM639 was similar to that of living CCFM639 in vitro. The ingestion of living or dead CCFM639 has similar effects on levels of Al and trace element in tissues, but living strains led to more significant amelioration of oxidative stress and improvement of memory deficits in Al-exposed mice. In conclusion, in addition to intestinal Al sequestration, CCFM639 treatment offers direct protection against chronic Al toxicity by alleviation of oxidative stress. Therefore, L. plantarum CCFM639 has a potential as dietary supplement ingredient that provides protection against Al-induced injury. PMID:28388664

Rapid eye movement sleep debt accrues in mice exposed to volatile anesthetics

PubMed Central

Pick, Jeremy; Chen, Yihan; Moore, Jason T.; Sun, Yi; Wyner, Abraham J.; Friedman, Eliot B.; Kelz, Max B.

2011-01-01

Background General anesthesia has been likened to a state in which anesthetized subjects are locked out of access to both rapid eye movement (REM) sleep and wakefulness. Were this true for all anesthetics, one might expect a significant REM rebound following anesthetic exposure. However, for the intravenous anesthetic propofol, studies demonstrate that no sleep debt accrues. Moreover, pre-existing sleep debts dissipate during propofol anesthesia. To determine whether these effects are specific to propofol or are typical of volatile anesthetics we tested the hypothesis that REM sleep debt would accrue in rodents anesthetized with volatile anesthetics. Methods Electroencephalographic and electromyographic electrodes were implanted in 10 mice. After 9–11 days of recovery and habituation to a 12h:12h light:dark cycle, baseline states of wakefulness, non-rapid eye movement sleep, and REM sleep were recorded in mice exposed to 6 hours of an oxygen control and on separate days to 6 hours of isoflurane, sevoflurane, or halothane in oxygen. All exposures were conducted at the onset of light. Results Mice in all three anesthetized groups exhibited a significant doubling of REM sleep during the first six-hours of the dark phase of the circadian schedule while only mice exposed to halothane displayed a significant increase in non-rapid eye movement sleep that peaked at 152% of baseline. Conclusion REM sleep rebound following exposure to volatile anesthetics suggests that these volatile anesthetics do not fully substitute for natural sleep. This result contrasts with the published actions of propofol for which no REM sleep rebound occurred. PMID:21934405

Altered gene expression and spine density in nucleus accumbens of adolescent and adult male mice exposed to emotional and physical stress

PubMed Central

Warren, Brandon L; Sial, Omar K.; Alcantara, Lyonna F.; Greenwood, Maria A.; Brewer, Jacob S.; Rozofsky, John P.; Parise, Eric M.; Bolaños-Guzmán, Carlos A.

2014-01-01

Stressful early life experiences are implicated in lifelong health. However, little is known about the consequences of emotional or physical stress on neurobiology. Therefore, the following set of experiments was designed to assess changes in transcription and translation of key proteins within the nucleus accumbens (NAc). Male adolescent (postnatal day [PD] 35) or adult (eight-week old) mice were exposed to emotional (ES) or physical stress (PS) using a vicarious social defeat paradigm. Twenty-four hours after the last stress session, we measured levels of specific mRNAs and proteins within the NAc. Spine density was also assessed in separate groups of mice. Exposure to ES or PS disrupted ERK2, reduced transcription of ΔFosB, and had no effect on CREB mRNA. Western blots revealed that exposure to ES or PS decreased ERK2 phosphorylation in adolescents, whereas the same stress regimen increased ERK2 phosphorylation in adults. Exposure to ES or PS had no effect on ΔFosB or CREB phosphorylation. ES and PS increased spine density in the NAc of adolescent-exposed mice, but only exposure to PS increased spine density in adults. Together, these findings demonstrate that exposure to ES or PS is a potent stressor in adolescent and adult mice, and can disturb the integrity of the NAc by altering transcription and translation of important signaling molecules in an age-dependent manner. Furthermore, exposure to ES and PS induces substantial synaptic plasticity of the NAc. PMID:24943326