Science.gov

Sample records for 2-knockout mice exposed

  1. Arginase enzymes in isolated airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin

    SciTech Connect

    Bratt, Jennifer M.; Franzi, Lisa M.; Linderholm, Angela L.; Last, Michael S.; Kenyon, Nicholas J. Last, Jerold A.

    2009-02-01

    Arginase has been suggested to compete with nitric oxide synthase (NOS) for their common substrate, L-arginine. To study the mechanisms underlying this interaction, we compared arginase expression in isolated airways and the consequences of inhibiting arginase activity in vivo with NO production, lung inflammation, and lung function in both C57BL/6 and NOS2 knockout mice undergoing ovalbumin-induced airway inflammation, a mouse model of asthma. Arginases I and II were measured by western blot in isolated airways from sensitized C57BL/6 mice exposed to ovalbumin aerosol. Physiological and biochemical responses - inflammation, lung compliance, airway hyperreactivity, exhaled NO concentration, arginine concentration - were compared with the responses of NOS2 knockout mice. NOS2 knockout mice had increased total cells in lung lavage, decreased lung compliance, and increased airway hyperreactivity. Both arginase I and arginase II were constitutively expressed in the airways of normal C57BL/6 mice. Arginase I was up-regulated approximately 8-fold in the airways of C57BL/6 mice exposed to ovalbumin. Expression of both arginase isoforms were significantly upregulated in NOS2 knockout mice exposed to ovalbumin, with about 40- and 4-fold increases in arginases I and II, respectively. Arginine concentration in isolated airways was not significantly different in any of the groups studied. Inhibition of arginase by systemic treatment of C57BL/6 mice with a competitive inhibitor, N{omega}-hydroxy-nor-L-arginine (nor-NOHA), significantly decreased the lung inflammatory response to ovalbumin in these animals. We conclude that NOS2 knockout mice are more sensitive to ovalbumin-induced airway inflammation and its sequelae than are C57BL/6 mice, as determined by increased total cells in lung lavage, decreased lung compliance, and increased airway hyperreactivity, and that these findings are strongly correlated with increased expression of both arginase isoforms in the airways of the

  2. ARGINASE ENZYMES IN ISOLATED AIRWAYS FROM NORMAL AND NITRIC OXIDE SYNTHASE 2-KNOCKOUT MICE EXPOSED TO OVALBUMIN

    PubMed Central

    Bratt, Jennifer M.; Franzi, Lisa M.; Linderholm, Angela L.; Last, Michael S.; Kenyon, Nicholas J.; Last, Jerold A.

    2009-01-01

    Arginase has been suggested to compete with nitric oxide synthase (NOS) for their common substrate, L-arginine. To study the mechanisms underlying this interaction, we compared arginase expression in isolated airways and the consequences of inhibiting arginase activity in vivo with NO production, lung inflammation, and lung function in both C57BL/6 and NOS2 knockout mice undergoing ovalbumin-induced airway inflammation, a mouse model of asthma. Arginases I and II were measured by western blot in isolated airways from sensitized C57BL/6 mice exposed to ovalbumin aerosol. Physiological and biochemical responses---inflammation, lung compliance, airway hyperreactivity, exhaled NO concentration, arginine concentration--were compared with the responses of NOS2 knockout mice. NOS2 knockout mice had increased total cells in lung lavage, decreased lung compliance, and increased airway hyperreactivity. Both arginase I and arginase II were constitutively expressed in the airways of normal C57BL/6 mice. Arginase I was up-regulated approximately 8-fold in the airways of C57BL/6 mice exposed to ovalbumin. Expression of both arginase isoforms were significantly upregulated in NOS2 knockout mice exposed to ovalbumin, with about 40- and 4-fold increases in arginases I and II, respectively. Arginine concentration in isolated airways was not significantly different in any of the groups studied. Inhibition of arginase by systemic treatment of C57BL/6 mice with a competitive inhibitor, Nω-hydroxy-nor-L-arginine (nor-NOHA), significantly decreased the lung inflammatory response to ovalbumin in these animals. We conclude that NOS2 knockout mice are more sensitive to ovalbumin-induced airway inflammation and its sequelae than are C57BL/6 mice, as determined by increased total cells in lung lavage, decreased lung compliance, and increased airway hyperreactivity, and that these findings are strongly correlated with increased expression of both arginase isoforms in the airways of the NOS2

  3. Arginase enzymes in isolated airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin.

    PubMed

    Bratt, Jennifer M; Franzi, Lisa M; Linderholm, Angela L; Last, Michael S; Kenyon, Nicholas J; Last, Jerold A

    2009-02-01

    Arginase has been suggested to compete with nitric oxide synthase (NOS) for their common substrate, l-arginine. To study the mechanisms underlying this interaction, we compared arginase expression in isolated airways and the consequences of inhibiting arginase activity in vivo with NO production, lung inflammation, and lung function in both C57BL/6 and NOS2 knockout mice undergoing ovalbumin-induced airway inflammation, a mouse model of asthma. Arginases I and II were measured by western blot in isolated airways from sensitized C57BL/6 mice exposed to ovalbumin aerosol. Physiological and biochemical responses - inflammation, lung compliance, airway hyperreactivity, exhaled NO concentration, arginine concentration - were compared with the responses of NOS2 knockout mice. NOS2 knockout mice had increased total cells in lung lavage, decreased lung compliance, and increased airway hyperreactivity. Both arginase I and arginase II were constitutively expressed in the airways of normal C57BL/6 mice. Arginase I was up-regulated approximately 8-fold in the airways of C57BL/6 mice exposed to ovalbumin. Expression of both arginase isoforms were significantly upregulated in NOS2 knockout mice exposed to ovalbumin, with about 40- and 4-fold increases in arginases I and II, respectively. Arginine concentration in isolated airways was not significantly different in any of the groups studied. Inhibition of arginase by systemic treatment of C57BL/6 mice with a competitive inhibitor, Nomega-hydroxy-nor-l-arginine (nor-NOHA), significantly decreased the lung inflammatory response to ovalbumin in these animals. We conclude that NOS2 knockout mice are more sensitive to ovalbumin-induced airway inflammation and its sequelae than are C57BL/6 mice, as determined by increased total cells in lung lavage, decreased lung compliance, and increased airway hyperreactivity, and that these findings are strongly correlated with increased expression of both arginase isoforms in the airways of the

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

    SciTech Connect

    Bratt, Jennifer M.; Franzi, Lisa M.; Linderholm, Angela L.; O'Roark, Erin M.; Kenyon, Nicholas J.; Last, Jerold A.

    2010-01-01

    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 and 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

  5. Arginase Inhibition in Airways from Normal and Nitric Oxide Synthase 2-Knockout Mice Exposed to Ovalbumin

    PubMed Central

    Bratt, Jennifer M.; Franzi, Lisa M.; Linderholm, Angela L.; O’Roark, Erin M.; Kenyon, Nicholas J.; Last, Jerold A.

    2011-01-01

    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 Nω-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 hyper-reactivity 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 and would demonstrate higher amounts of airway hyper-reactivity and eosinophilia under conditions of arginase inhibition than C57BL/6 animals. We found that administration of nor-NOHA significantly decreased airway hyper-reactivity 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 hyper-reactivity in all treatment groups. NOS2−/− mice had a 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 hyper-reactivity 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

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

    PubMed

    Bratt, Jennifer M; Franzi, Lisa M; Linderholm, Angela L; O'Roark, Erin M; Kenyon, Nicholas J; Last, Jerold A

    2010-01-01

    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(omega)-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 and 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

  7. Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice.

    PubMed

    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2013-09-15

    Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500ppm ETBE for 1-6h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000ppm ETBE for 6h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose-dependent manner in KO male mice, while only 5000ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females. PMID:23810710

  8. Behavior training reverses asymmetry in hippocampal transcriptome of the cav3.2 knockout mice.

    PubMed

    Chung, Ni-Chun; Huang, Ying-Hsueh; Chang, Chuan-Hsiung; Liao, James C; Yang, Chih-Hsien; Chen, Chien-Chang; Liu, Ingrid Y

    2015-01-01

    Homozygous Cav3.2 knockout mice, which are defective in the pore-forming subunit of a low voltage activated T-type calcium channel, have been documented to show impaired maintenance of late-phase long-term potentiation (L-LTP) and defective retrieval of context-associated fear memory. To investigate the role of Cav3.2 in global gene expression, we performed a microarray transcriptome study on the hippocampi of the Cav3.2-/- mice and their wild-type littermates, either naïve (untrained) or trace fear conditioned. We found a significant left-right asymmetric effect on the hippocampal transcriptome caused by the Cav3.2 knockout. Between the naive Cav3.2-/- and the naive wild-type mice, 3522 differentially expressed genes (DEGs) were found in the left hippocampus, but only 4 DEGs were found in the right hippocampus. Remarkably, the effect of Cav3.2 knockout was partially reversed by trace fear conditioning. The number of DEGs in the left hippocampus was reduced to 6 in the Cav3.2 knockout mice after trace fear conditioning, compared with the wild-type naïve mice. To our knowledge, these results demonstrate for the first time the asymmetric effects of the Cav3.2 and its partial reversal by behavior training on the hippocampal transcriptome. PMID:25768289

  9. Altered behavioral development in Nrf2 knockout mice following early postnatal exposure to valproic acid

    PubMed Central

    Furnari, Melody A.; Saw, Constance Lay-Lay; Kong, Ah-Ng; Wagner, George C

    2015-01-01

    Early exposure to valproic acid results in autism-like neural and behavioral deficits in humans and other animals through oxidative stress-induced neural damage. In the present study, valproic acid was administered to genetically altered mice lacking the Nrf2 (nuclear factor-erythroid 2 related factor 2) gene on postnatal day 14 (P14). Nrf2 is a transcription factor that induces genes that protect against oxidative stress. It was found that valproic acid-treated Nrf2 knockout mice were less active in open field activity chambers, less successful on the rotorod, and had deficits in learning and memory in the Morris water maze compared to the valproic acid-treated wild type mice. Given these results, it appears that Nrf2 knockout mice were more sensitive to the neural damage caused by valproic acid administered during early development. PMID:25454122

  10. Kv4.2 Knockout Mice Have Hippocampal-Dependent Learning and Memory Deficits

    ERIC Educational Resources Information Center

    Lugo, Joaquin N.; Brewster, Amy L.; Spencer, Corinne M.; Anderson, Anne E.

    2012-01-01

    Kv4.2 channels contribute to the transient, outward K[superscript +] current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit…

  11. Cnga2 Knockout Mice Display Alzheimer's-Like Behavior Abnormities and Pathological Changes.

    PubMed

    Xie, Ao-Ji; Liu, En-Jie; Huang, He-Zhou; Hu, Yu; Li, Ke; Lu, Youming; Wang, Jian-Zhi; Zhu, Ling-Qiang

    2016-09-01

    Olfactory dysfunction is recognized as a potential risk factor for Alzheimer's disease (AD). We have reported previously that olfactory deprivation by olfactory bulbectomy (OBX) induced Alzheimer's-like pathological changes and behavioral abnormalities. However, the acute OBX model undergoes surgical-induced brain parenchyma loss and unexpected massive hemorrhage so that it cannot fully mimic the progressive olfactory loss and neurodegeneration in AD. Here, we employed the mice loss of cyclic nucleotide-gated channel alpha 2 (Cnga2) which is critical for olfactory sensory transduction, to investigate the role of olfactory dysfunction in AD pathological process. We found that impaired learning and memory abilities, loss of dendrite spines, as well as decrement of synaptic proteins were displayed in Cnga2 knockout mice. Moreover, Aβ overproduction, tau hyperphosphorylation, and somatodendritic translocation were also found in Cnga2 knockout mice. Our findings suggest that progressive olfactory loss leads to Alzheimer's-like behavior abnormities and pathological changes. PMID:26377105

  12. Lack of stress responses to long-term effects of corticosterone in Caps2 knockout mice.

    PubMed

    Mishima, Yuriko; Shinoda, Yo; Sadakata, Tetsushi; Kojima, Masami; Wakana, Shigeharu; Furuichi, Teiichi

    2015-01-01

    Chronic stress is associated with anxiety and depressive disorders, and can cause weight gain. Ca(2+)-dependent activator protein for secretion 2 (CAPS2) is involved in insulin release. Caps2 knockout (KO) mice exhibit decreased body weight, reduced glucose-induced insulin release, and abnormal psychiatric behaviors. We chronically administered the stress hormone corticosterone (CORT), which induces anxiety/depressive-like behavior and normally increases plasma insulin levels, via the drinking water for 10 weeks, and we examined the stress response in KO mice. Chronic CORT exposure inhibited stress-induced serum CORT elevation in wild-type (WT) mice, but not in KO mice. Poor weight gain in CORT-treated animals was observed until week 6 in WT mice, but persisted for the entire duration of the experiment in KO mice, although there is no difference in drug*genotype interaction. Among KO mice, food consumption was unchanged, while water consumption was higher, over the duration of the experiment in CORT-treated animals, compared with untreated animals. Moreover, serum insulin and leptin levels were increased in CORT-treated WT mice, but not in KO mice. Lastly, both WT and KO mice displayed anxiety/depressive-like behavior after CORT administration. These results suggest that Caps2 KO mice have altered endocrine responses to CORT administration, while maintaining CORT-induced anxiety/depressive-like behavior. PMID:25754523

  13. Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits.

    PubMed

    Lugo, Joaquin N; Brewster, Amy L; Spencer, Corinne M; Anderson, Anne E

    2012-05-01

    Kv4.2 channels contribute to the transient, outward K(+) current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit in the learning phase of the Morris water maze (MWM) and significant impairment in the probe trial compared with wild type (WT). Kv4.2 KO mice also demonstrated a specific deficit in contextual learning in the fear-conditioning test, without impairment in the conditioned stimulus or new context condition. Kv4.2 KO mice had normal activity, anxiety levels, and prepulse inhibition compared with WT mice. A compensatory increase in tonic inhibition has been previously described in hippocampal slice recordings from Kv4.2 KO mice. In an attempt to decipher whether increased tonic inhibition contributed to the learning and memory deficits in Kv4.2 KO mice, we administered picrotoxin to block GABA(A) receptors (GABA(A)R), and thereby tonic inhibition. This manipulation had no effect on behavior in the WT or KO mice. Furthermore, total protein levels of the α5 or δ GABA(A)R subunits, which contribute to tonic inhibition, were unchanged in hippocampus. Overall, our findings add to the growing body of evidence, suggesting an important role for Kv4.2 channels in hippocampal-dependent learning and memory. PMID:22505720

  14. Idebenone and Resveratrol Extend Lifespan and Improve Motor Function of HtrA2 Knockout Mice

    PubMed Central

    Szegő, Éva M.; Moisoi, Nicoleta; Martins, L. Miguel; Outeiro, Tiago F.; Kermer, Pawel

    2011-01-01

    Heterozygous loss-of-function mutation of the human gene for the mitochondrial protease HtrA2 has been associated with increased risk to develop mitochondrial dysfunction, a process known to contribute to neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). Knockout of HtrA2 in mice also leads to mitochondrial dysfunction and to phenotypes that resemble those found in neurodegenerative disorders and, ultimately, lead to death of animals around postnatal day 30. Here, we show that Idebenone, a synthetic antioxidant of the coenzyme Q family, and Resveratrol, a bioactive compound extracted from grapes, are both able to ameliorate this phenotype. Feeding HtrA2 knockout mice with either compound extends lifespan and delays worsening of the motor phenotype. Experiments conducted in cell culture and on brain tissue of mice revealed that each compound has a different mechanism of action. While Idebenone acts by downregulating the integrated stress response, Resveratrol acts by attenuating apoptosis at the level of Bax. These activities can account for the delay in neuronal degeneration in the striata of these mice and illustrate the potential of these compounds as effective therapeutic approaches against neurodegenerative disorders such as HD or PD. PMID:22205977

  15. Gut Microbiota Is a Key Modulator of Insulin Resistance in TLR 2 Knockout Mice

    PubMed Central

    Caricilli, Andréa M.; Picardi, Paty K.; de Abreu, Lélia L.; Ueno, Mirian; Prada, Patrícia O.; Ropelle, Eduardo R.; Hirabara, Sandro Massao; Castoldi, Ângela; Vieira, Pedro; Camara, Niels O. S.; Curi, Rui; Carvalheira, José B.; Saad, Mário J. A.

    2011-01-01

    Environmental factors and host genetics interact to control the gut microbiota, which may have a role in the development of obesity and insulin resistance. TLR2-deficient mice, under germ-free conditions, are protected from diet-induced insulin resistance. It is possible that the presence of gut microbiota could reverse the phenotype of an animal, inducing insulin resistance in an animal genetically determined to have increased insulin sensitivity, such as the TLR2 KO mice. In the present study, we investigated the influence of gut microbiota on metabolic parameters, glucose tolerance, insulin sensitivity, and signaling of TLR2-deficient mice. We investigated the gut microbiota (by metagenomics), the metabolic characteristics, and insulin signaling in TLR2 knockout (KO) mice in a non-germ free facility. Results showed that the loss of TLR2 in conventionalized mice results in a phenotype reminiscent of metabolic syndrome, characterized by differences in the gut microbiota, with a 3-fold increase in Firmicutes and a slight increase in Bacteroidetes compared with controls. These changes in gut microbiota were accompanied by an increase in LPS absorption, subclinical inflammation, insulin resistance, glucose intolerance, and later, obesity. In addition, this sequence of events was reproduced in WT mice by microbiota transplantation and was also reversed by antibiotics. At the molecular level the mechanism was unique, with activation of TLR4 associated with ER stress and JNK activation, but no activation of the IKKβ-IκB-NFκB pathway. Our data also showed that in TLR2 KO mice there was a reduction in regulatory T cell in visceral fat, suggesting that this modulation may also contribute to the insulin resistance of these animals. Our results emphasize the role of microbiota in the complex network of molecular and cellular interactions that link genotype to phenotype and have potential implications for common human disorders involving obesity, diabetes, and even other

  16. Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice.

    PubMed

    Zunino, G; Messina, A; Sgadò, P; Baj, G; Casarosa, S; Bozzi, Y

    2016-06-01

    Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD. PMID:26987954

  17. Laminin γ2 knockout mice rescued with the human protein exhibit enamel maturation defects.

    PubMed

    Wazen, Rima M; Viegas-Costa, Luiz C; Fouillen, Aurélien; Moffatt, Pierre; Adair-Kirk, Tracy L; Senior, Robert M; Nanci, Antonio

    2016-01-01

    The epithelial ameloblasts are separated from the maturing enamel by an atypical basement membrane (BM) that is enriched in laminin 332 (LM-332). This heterotrimeric protein (α3, ß3 and γ2 chains) provides structural integrity to BMs and influences various epithelial cell processes including cell adhesion and differentiation. Mouse models that lack expression of individual LM-332 chains die shortly after birth. The lethal phenotype of laminin γ2 knockout mice can be rescued by human laminin γ2 (LAMC2) expressed using a doxycycline-inducible (Tet-on) cytokeratin 14 promoter-rtTA. These otherwise normal-looking rescued mice exhibit white spot lesions on incisors. We therefore investigated the effect of rescue with human LAMC2 on enamel maturation and structuring of the atypical BM. The maturation stage enamel organ in transgenic mice was severely altered as compared to wild type controls, a structured BM was no longer discernible, dystrophic matrix appeared in the maturing enamel layer, and there was residual enamel matrix late into the maturation stage. Microtomographic scans revealed excessive wear of occlusal surfaces on molars, chipping of enamel on incisor tips, and hypomineralization of the enamel layer. No structural alterations were observed at other epithelial sites, such as skin, palate and tongue. These results indicate that while this humanized mouse model is capable of rescue in various epithelial tissues, it is unable to sustain structuring of a proper BM at the interface between ameloblasts and maturing enamel. This failure may be related to the atypical composition of the BM in the maturation stage and reaffirms that the atypical BM is essential for enamel maturation. PMID:26956061

  18. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors

    PubMed Central

    2012-01-01

    Mutations in the LRRK2 gene are the most common cause of genetic Parkinson’s disease. Although the mechanisms behind the pathogenic effects of LRRK2 mutations are still not clear, data emerging from in vitro and in vivo models suggests roles in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation. We created mice lacking exon 41 that encodes the activation hinge of the kinase domain of LRRK2. We have performed a comprehensive analysis of these mice up to 20 months of age, including evaluation of dopamine storage, release, uptake and synthesis, behavioral testing, dendritic spine and proliferation/neurogenesis analysis. Our results show that the dopaminergic system was not functionally comprised in LRRK2 knockout mice. However, LRRK2 knockout mice displayed abnormal exploratory activity in the open-field test. Moreover, LRRK2 knockout mice stayed longer than their wild type littermates on the accelerated rod during rotarod testing. Finally, we confirm that loss of LRRK2 caused degeneration in the kidney, accompanied by a progressive enhancement of autophagic activity and accumulation of autofluorescent material, but without evidence of biphasic changes. PMID:22647713

  19. Serotonin abnormalities in Engrailed-2 knockout mice: New insight relevant for a model of Autism Spectrum Disorder.

    PubMed

    Viaggi, Cristina; Gerace, Claudio; Pardini, Carla; Corsini, Giovanni U; Vaglini, Francesca

    2015-08-01

    Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appears in early childhood. Recent human genetic studies identified the homeobox transcription factor, Engrailed 2 (EN2), as a possible ASD susceptibility gene. En2 knockout mice (En2-/-) display subtle cerebellar neuropathological changes and reduced levels of tyrosine hydroxylase, noradrenaline and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain. Furthermore other similarities link En2 knockout mice to ASD patients. Several lines of evidence suggest that serotonin may play an important role in the pathophysiology of the disease. In the present study we measured, by using an HPLC, the 5-HT levels in different brain areas and at different ages in En2-/- mice. In the frontal and occipital cortex, the content of 5HT was reduced in En2-/- 1 and 3 months old mice; in 6 month old mice, the difference was still present, but it was not statistically significant. The 5-HT content of cerebellar cortex was significantly reduced at 1 month old but significantly high when the KO mice reached 3 months of age. The increase was present even at 6 months of age. A similar trend was highlighted by SERT immunolabeling in En2-/- mice compared to control in the same areas and age analyzed. Our findings, in agreement with the current knowledge on the 5-HT system alterations in ASD, confirm the early neurotransmitter deficit with a late compensatory recovery in En2 KO-mice further suggesting that this experimental animal may be considered a good predictive model for the human disease. PMID:26002543

  20. Basal Bone Phenotype and Increased Anabolic Responses to Intermittent Parathyroid Hormone in Healthy Male COX-2 Knockout Mice

    PubMed Central

    Xu, Manshan; Choudhary, Shilpa; Voznesensky, Olga; Gao, Qi; Adams, Douglas; Diaz-Doran, Vilmaris; Wu, Qian; Goltzman, David; Raisz, Lawrence G.; Pilbeam, Carol C.

    2011-01-01

    Cyclooxygenase-2 (COX-2) knockout (KO) mice in inbred strains can have renal dysfunction with secondary hyperparathyroidism (HPTH), making direct effects of COX-2 KO on bone difficult to assess. COX-2 KO mice in an outbred CD-1 background did not have renal dysfunction but still had two-fold elevated PTH compared to wild type (WT) mice. Compared to WT mice, KO mice had increased serum markers of bone turnover, decreased femoral bone mineral density (BMD) and cortical bone thickness, but no differences in trabecular bone volume by μCT or dynamic histomorphometry. Because PTH is a potent inducer of COX-2 and prostaglandin (PG) production, we examined effects of COX-2 KO on bone responses after three weeks of intermittent PTH. Intermittent PTH increased femoral BMD and cortical bone area more in KO mice than in WT mice and increased trabecular bone volume in the distal femur in both WT and KO mice. Although not statistically significant, PTH-stimulated increases in trabecular bone tended to be greater in KO mice than in WT mice. PTH increased serum markers of bone formation and resorption more in KO than in WT mice but increased the ratio of osteoblastic surface to osteoclastic surface only in KO mice. PTH also increased femoral mineral apposition rates and bone formation rates in KO mice more than in WT mice. Acute mRNA responses to PTH of genes that might mediate some anabolic and catabolic effects of PTH tended to be greater in KO than WT mice. We conclude that (1) the basal bone phenotype in male COX-2 KO mice might reflect HPTH, COX-2 deficiency or both, and (2) increased responses to intermittent PTH in COX-2 KO mice, despite the presence of chronic HPTH, suggest that absence of COX-2 increased sensitivity to PTH. It is possible that manipulation of endogenous PGs could have important clinical implications for anabolic therapy with PTH. PMID:20471507

  1. Hepatic Gene Expression Profiling in Nrf2 Knockout Mice after Long-Term High-Fat Diet-Induced Obesity

    PubMed Central

    Chartoumpekis, Dionysios V.; Ziros, Panos G.; Zaravinos, Apostolos; Iskrenova, Ralitsa P.; Psyrogiannis, Agathoklis I.; Kyriazopoulou, Venetsana E.; Sykiotis, Gerasimos P.; Habeos, Ioannis G.

    2013-01-01

    Introduction. The transcription factor NFE2-related factor 2 (Nrf2) is a central regulator of antioxidant and detoxification gene expression in response to electrophilic or oxidative stress. Nrf2 has recently been shown to cross-talk with metabolic pathways, and its gene deletion protected mice from high-fat-diet-(HFD-) induced obesity and insulin resistance. This study aimed to identify potential Nrf2-regulated genes of metabolic interest by comparing gene expression profiles of livers of wild-type (WT) versus Nrf2 knockout (Nrf2-KO) mice after a long-term HFD. Methods. WT and Nrf2-KO mice were fed an HFD for 180 days; total RNA was prepared from liver and used for microarray analysis and quantitative real-time RT-PCR (qRT-PCR). Results. The microarray analysis identified 601 genes that were differentially expressed between WT and Nrf2-KO mice after long-term HFD. Selected genes, including ones known to be involved in metabolic regulation, were prioritized for verification by qRT-PCR: Cyp7a1 and Fabp5 were significantly overexpressed in Nrf2-KO mice; in contrast, Car, Cyp2b10, Lipocalin 13, Aquaporin 8, Cbr3, Me1, and Nqo1 were significantly underexpressed in Nrf2-KO mice. Conclusion. Transcriptome profiling after HFD-induced obesity confirms that Nrf2 is implicated in liver metabolic gene networks. The specific genes identified here may provide insights into Nrf2-dependent mechanisms of metabolic regulation. PMID:23710285

  2. Aldh2 knockout mice were more sensitive to DNA damage in leukocytes due to ethyl tertiary butyl ether exposure.

    PubMed

    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2011-01-01

    To clarify the genotoxicity of ethyl tertiary butyl ether (ETBE), a gasoline additive, male and female C57BL/6 mice of Aldh2+/+ and Aldh2-/- genotypes, aged 8 wk, were exposed to 0, 500, 1,750, or 5,000 ppm ETBE for 6 h/day, 5 d per week for 13 wk. DNA damage in leukocytes was measured by the alkaline comet assay and expressed quantitatively as Tail Intensity (TI). For male mice, TI was significantly higher in all three groups exposed to ETBE than in those without exposure within Aldh2-/- mice, whereas within Aldh2+/+ mice, TI increased only in those exposed to 5,000 ppm of ETBE as compared with mice without exposure. For female mice, a significant increase in TI values was observed in the group exposed to 5,000 ppm of ETBE as compared with those without exposure within Aldh2-/- mice; TI in Aldh2-/- mice exposed to 1,750 and 5,000 ppm was significantly higher than in Aldh2+/+ mice without exposure. TI did not significantly increase in any of the groups exposed to ETBE within female Aldh2+/+ mice. Based on the results we suggest that Aldh2-/- mice are more sensitive to DNA damage caused by ETBE than Aldh2+/+ mice and that males seem more susceptible to this effect than females. PMID:21372431

  3. Glucose and fat metabolism in adipose tissue of acetyl-CoA carboxylase 2 knockout mice

    PubMed Central

    Oh, WonKeun; Abu-Elheiga, Lutfi; Kordari, Parichher; Gu, Zeiwei; Shaikenov, Tattym; Chirala, Subrahmanyam S.; Wakil, Salih J.

    2005-01-01

    Acc2-/- mutant mice, when fed a high-fat/high-carbohydrate (HF/HC) diet, were protected against diet-induced obesity and diabetes. To investigate the role of acetyl-CoA carboxylase 2 (ACC2) in the regulation of energy metabolism in adipose tissues, we studied fatty acid and glucose oxidation in primary cultures of adipocytes isolated from wild-type and Acc2-/- mutant mice fed either normal chow or a HF/HC diet. When fed normal chow, oxidation of [14C]palmitate in adipocytes of Acc2-/- mutant mice was ≈80% higher than in adipocytes of WT mice, and it remained significantly higher in the presence of insulin. Interestingly, in addition to increased fatty acid oxidation, we also observed increased glucose oxidation in adipocytes of Acc2-/- mutant mice compared with that of WT mice. When fed a HF/HC diet for 4-5 months, adipocytes of Acc2-/- mutant mice maintained a 25% higher palmitate oxidation and a 2-fold higher glucose oxidation than WT mice. The mRNA level of glucose transporter 4 (GLUT4) decreased several fold in the adipose tissue of WT mice fed a HF/HC diet; however, in the adipose tissue of Acc2-/- mutant mice, it was 7-fold higher. Moreover, lipolysis activity was higher in adipocytes of Acc2-/- mutant mice compared with that in WT mice. These findings suggest that continuous fatty acid oxidation in the adipocytes of Acc2-/- mutant mice, combined with a higher level of glucose oxidation and a higher rate of lipolysis, are major factors leading to efficient maintenance of insulin sensitivity and leaner Acc2-/- mutant mice. PMID:15677334

  4. Hyperaldosteronism after decreased renal K+ excretion in KCNMB2 knockout mice.

    PubMed

    Larsen, Casper K; Jensen, Iben S; Sorensen, Mads V; de Bruijn, Pauline I; Bleich, Markus; Praetorius, Helle A; Leipziger, Jens

    2016-05-15

    The kidney is the primary organ ensuring K(+) homeostasis. K(+) is secreted into the urine in the distal tubule by two mechanisms: by the renal outer medullary K(+) channel (Kir1.1) and by the Ca(2+)-activated K(+) channel (KCa1.1). Here, we report a novel knockout mouse of the β2-subunit of the KCa1.1 channel (KCNMB2), which displays hyperaldosteronism after decreased renal K(+) excretion. KCNMB2(-/-) mice displayed hyperaldosteronism, normal plasma K(+) concentration, and produced dilute urine with decreased K(+) concentration. The normokalemia indicated that hyperaldosteronism did not result from primary aldosteronism. Activation of the renin-angiotensin-aldosterone system was also ruled out as renal renin mRNA expression was reduced in KCNMB2(-/-) mice. Renal K(+) excretion rates were similar in the two genotypes; however, KCNMB2(-/-) mice required elevated plasma aldosterone to achieve K(+) balance. Blockade of the mineralocorticoid receptor with eplerenone triggered mild hyperkalemia and unmasked reduced renal K(+) excretion in KCNMB2(-/-) mice. Knockout mice for the α-subunit of the KCa1.1 channel (KCNMA1(-/-) mice) have hyperaldosteronism, are hypertensive, and lack flow-induced K(+) secretion. KCNMB2(-/-) mice share the phenotypic traits of normokalemia and hyperaldosteronism with KCNMA1(-/-) mice but were normotensive and displayed intact flow-induced K(+) secretion. Despite elevated plasma aldosterone, KNCMB2(-/-) mice did not display salt-sensitive hypertension and were able to decrease plasma aldosterone on a high-Na(+) diet, although plasma aldosterone remained elevated in KCNMB2(-/-) mice. In summary, KCNMB2(-/-) mice have a reduced ability to excrete K(+) into the urine but achieve K(+) balance through an aldosterone-mediated, β2-independent mechanism. The phenotype of KCNMB2 mice was similar but milder than the phenotype of KCNMA1(-/-) mice. PMID:26962098

  5. Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients

    PubMed Central

    Sadakata, Tetsushi; Washida, Miwa; Iwayama, Yoshimi; Shoji, Satoshi; Sato, Yumi; Ohkura, Takeshi; Katoh-Semba, Ritsuko; Nakajima, Mizuho; Sekine, Yukiko; Tanaka, Mika; Nakamura, Kazuhiko; Iwata, Yasuhide; Tsuchiya, Kenji J.; Mori, Norio; Detera-Wadleigh, Sevilla D.; Ichikawa, Hironobu; Itohara, Shigeyoshi; Yoshikawa, Takeo; Furuichi, Teiichi

    2007-01-01

    Autism, characterized by profound impairment in social interactions and communicative skills, is the most common neurodevelopmental disorder, and its underlying molecular mechanisms remain unknown. Ca2+-dependent activator protein for secretion 2 (CADPS2; also known as CAPS2) mediates the exocytosis of dense-core vesicles, and the human CADPS2 is located within the autism susceptibility locus 1 on chromosome 7q. Here we show that Cadps2-knockout mice not only have impaired brain-derived neurotrophic factor release but also show autistic-like cellular and behavioral phenotypes. Moreover, we found an aberrant alternatively spliced CADPS2 mRNA that lacks exon 3 in some autistic patients. Exon 3 was shown to encode the dynactin 1–binding domain and affect axonal CADPS2 protein distribution. Our results suggest that a disturbance in CADPS2-mediated neurotrophin release contributes to autism susceptibility. PMID:17380209

  6. Virally-expressed connexin26 restores gap junction function in the cochlea of conditional Gjb2 knockout mice

    PubMed Central

    Yu, Qing; Wang, Yunfeng; Chang, Qing; Wang, Jianjun; Gong, Shushen; Li, Huawei; Lin, Xi

    2013-01-01

    Mutations in GJB2, which codes for the gap junction protein connexin26, are the most common causes of human nonsyndromic hereditary deafness. We inoculated modified adeno-associated viral vectors into the scala media of early postnatal conditional Gjb2 knockout mice to drive exogenous connexin26 expression. We found extensive virally-expressed connexin26 in cells lining the scala media, and intercellular gap junction network was re-established in the organ of Corti of mutant mouse cochlea. Widespread ectopic connexin26 expression neither formed ectopic gap junctions nor affected normal hearing thresholds in wild type mice, suggesting that autonomous cellular mechanisms regulate proper membrane trafficking of exogenously-expressed connexin26 and govern the functional manifestation of them. Functional recovery of gap-junction-mediated coupling among the supporting cells was observed. We found that both cell death in the organ of Corti and degeneration of spiral ganglion neurons in the cochlea of mutant mice were substantially reduced, although auditory brainstem responses did not show significant hearing improvement. This is the first report demonstrating that virally-mediated gene therapy restored extensive gap junction intercellular network among cochlear non-sensory cells in vivo. Such a treatment performed at early postnatal stages resulted in a partial rescue of disease phenotypes in the cochlea of the mutant mice. PMID:24225640

  7. Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice

    PubMed Central

    Houghtaling, Scott; Timmers, Cynthia; Noll, Meenakshi; Finegold, Milton J.; Jones, Stephen N.; Meyn, M. Stephen; Grompe, Markus

    2003-01-01

    Fanconi anemia (FA) is a genetic disorder characterized by hypersensitivity to DNA damage, bone marrow failure, congenital defects, and cancer. To further investigate the in vivo function of the FA pathway, mice with a targeted deletion in the distally acting FA gene Fancd2 were created. Similar to human FA patients and other FA mouse models, Fancd2 mutant mice exhibited cellular sensitivity to DNA interstrand cross-links and germ cell loss. In addition, chromosome mispairing was seen in male meiosis. However, Fancd2 mutant mice also displayed phenotypes not observed in other mice with disruptions of proximal FA genes. These include microphthalmia, perinatal lethality, and epithelial cancers, similar to mice with Brca2/Fancd1 hypomorphic mutations. These additional phenotypes were not caused by defects in the ATM-mediated S-phase checkpoint, which was intact in primary Fancd2 mutant fibroblasts. The phenotypic overlap between Fancd2-null and Brca2/Fancd1 hypomorphic mice is consistent with a common function for both proteins in the same pathway, regulating genomic stability. PMID:12893777

  8. Maneb causes pro-oxidant effects in the hippocampus of Nrf2 knockout mice.

    PubMed

    Kurzatkowski, Daniela M; Trombetta, Louis D

    2013-09-01

    The effects of maneb were investigated in C57BL/6 Nrf2 wildtype and knockout mice. Treated KO mice showed significant weight loss as compared to WT counterparts. ICPAAS analysis demonstrated a significant increase in manganese concentration in the tissues of treated KO mice as compared to WT. Biochemical analysis revealed significant decreases of antioxidants including glutathione, glutathione reductase and heme oxygenase-1. Levels of TBARS were significantly increased in hippocampal tissue in Nrf2 KO mice at the 30 and 60mg doses. qPCR demonstrated that the only gene mediated by the Nrf2 transcription pathway that was significantly modulated by at least 1.5 fold was glutathione peroxidase 4. GPX4 was significantly upregulated in Nrf2 WT mice treated with 30mg/kg maneb and significantly downregulated in Nrf2 KO mice treated with the same dose. Microscopy revealed neuronal pyknosis and eosinophilia of the cytoplasm in the hippocampi of both WT and KO animals treated with 60mg/kg maneb. PMID:23764462

  9. Raman spectroscopy for assessment of bone quality in MMP-2 knockout mice

    NASA Astrophysics Data System (ADS)

    Bi, Xiaohong; Nyman, Jeffry S.; Patil, Chetan A.; Masui, Philip; Lynch, Conor; Mahadevan-Jansen, Anita

    2009-02-01

    Knocking out a gene in mice provide the means to investigate potential regulators of the compositional, structural, and biomechanical properties of bone. Suppressing genes related to matrix turnover (bone remodeling) can have a significant effect on properties related to overall bone quality, which are normally measured using tests such as micro-computed tomography (μ-CT) and three point-bending to determine the structural and mechanical properties, respectively. Although Raman spectroscopy is known to non-destructively characterize biochemical properties of bone such as degree of mineralization and crystallinity, the correlation between these measurements and those of overall bone quality has not yet been systematically investigated. In this study we present a comparison of structural and mechanical properties of bone from mice deficient in matrix metalloproteinase 2 (MMP2) to compositional properties measured with RS. Femora were collected from MMP2+/+ and MMP2-/- mice at 16 weeks of age. Multiple Raman spectra were collected from the mid-diaphysis of intact femora in order to measure the bone's average compositional properties. In addition, μ-CT was used to characterize the structure and bone mineral density (BMD) at the mid-diaphysis, and three-point bending assessed the biomechanical properties of the same bones. Raman derived measurements of mineralization (ratio of Phosphate ν1 to CH2 bending), mineral crystallinity, collagen and mineral contents were significantly lower in the MMP null mice and demonstrated correlation with volumetric BMD, bending strength and modulus. In addition, all these measurements were shown to inversely correlate with post-yield-deflection (p<0.01). These results indicate the potential for RS to qualitatively assess bone quality.

  10. 2,3,7, 8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)-MEDIATED OXIDATIVE STRESS IN FEMALE CYP1A-2 KNOCKOUT (CYP1A2-/-) MICE

    EPA Science Inventory

    2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD)-Mediated Oxidative Stress in Female CYP1A2 Knockout (CYP1A2-/-) Mice

    Deborah Burgin1, Janet Diliberto2, Linda Birnbaum2
    1UNC Toxicology; 2USEPA/ORD/NHEERL, RTP, NC

    Most of the effects due to TCDD exposure are mediated via...

  11. Cadium pathways during gestation and lactation in control vs. metallothionein 1,2-knockout mice.

    SciTech Connect

    Brako, E. E.; Wilson, A. K.; Jonah, M. M.; Blum, C. A.; Cerny, E. A.; Williams, K. L.; Bhattacharyya, M. H.; Winona State Univ.; Benedictine Univ.; Dominican Univ.

    2003-01-01

    Effects of metallothionein (MT) on cadmium absorption and transfer pathways during gestation and lactation in mice were investigated. Female 129/SvJ metallothionein-knockout (MT1,2KO) and metallothionein-normal (MTN) mice received drinking water containing trace amounts of {sup 109}CdCl{sub 2} (0.15 ng Cd/ml; 0.074 {mu}Ci {sup 109}Cd/ml). {sup 109}Cd and MT in maternal, fetal, and pup tissues were measured on gestation days 7, 14, and 17 and lactation day 11. In dams, MT influenced both the amount of {sup 109}Cd transferred from intestine into body (two- to three-fold higher in MT1,2KO than MTN dams) and tissue-specific {sup 109}Cd distribution (higher liver/kidney ratio in MT1,2KO dams). Placental {sup 109}Cd concentrations in MT1,2KO dams were three- and seven-fold higher on gestation days 14 and 17, respectively, than in MTN dams. Fetal {sup 109}Cd levels were low in both mouse types, but at least 10-fold lower in MTN fetuses. MT had no effect on the amount of {sup 109}Cd transferred to pups via milk; furthermore, 85--90% of total pup {sup 109}Cd was recovered in gastrointestinal tracts of both types, despite high duodenal MT only in MTN pups. A relatively large percentage of milk-derived intestinal {sup 109}Cd was transferred to other pup tissues in both MT1,2KO and MTN pups (14 and 10%, respectively). These results demonstrate that specific sequestration of cadmium by both maternal and neonatal intestinal tract does not require MT. Although MT decreased oral cadmium transfer from intestine to body tissues at low cadmium exposure levels, MT did not play a major role in restricting transfer of cadmium from dam to fetus via placenta and to neonate via milk.

  12. Excitation/inhibition imbalance and impaired synaptic inhibition in hippocampal area CA3 of Mecp2 knockout mice.

    PubMed

    Calfa, Gaston; Li, Wei; Rutherford, John M; Pozzo-Miller, Lucas

    2015-02-01

    Rett syndrome (RTT) is a neurodevelopment disorder associated with intellectual disabilities and caused by loss-of-function mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding Protein-2 (MeCP2). Neuronal dysfunction and changes in cortical excitability occur in RTT individuals and Mecp2-deficient mice, including hippocampal network hyperactivity and higher frequency of spontaneous multiunit spikes in the CA3 cell body layer. Here, we describe impaired synaptic inhibition and an excitation/inhibition (E/I) imbalance in area CA3 of acute slices from symptomatic Mecp2 knockout male mice (referred to as Mecp2(-/y) ). The amplitude of TTX-resistant miniature inhibitory postsynaptic currents (mIPSC) was smaller in CA3 pyramidal neurons of Mecp2(-/y) slices than in wildtype controls, while the amplitude of miniature excitatory postsynaptic currents (mEPSC) was significantly larger in Mecp2(-/y) neurons. Consistently, quantitative confocal immunohistochemistry revealed significantly lower intensity of the alpha-1 subunit of GABAA Rs in the CA3 cell body layer of Mecp2(-/y) mice, while GluA1 puncta intensities were significantly higher in the CA3 dendritic layers of Mecp2(-/y) mice. In addition, the input/output (I/O) relationship of evoked IPSCs had a shallower slope in CA3 pyramidal neurons Mecp2(-/y) neurons. Consistent with the absence of neuronal degeneration in RTT and MeCP2-based mouse models, the density of parvalbumin- and somatostatin-expressing interneurons in area CA3 was not affected in Mecp2(-/y) mice. Furthermore, the intrinsic membrane properties of several interneuron subtypes in area CA3 were not affected by Mecp2 loss. However, mEPSCs are smaller and less frequent in CA3 fast-spiking basket cells of Mecp2(-/y) mice, suggesting an impaired glutamatergic drive in this interneuron population. These results demonstrate that a loss-of-function mutation in Mecp2 causes impaired E/I balance onto CA3 pyramidal neurons, leading to a

  13. Autism-Relevant Social Abnormalities and Cognitive Deficits in Engrailed-2 Knockout Mice

    PubMed Central

    Brielmaier, Jennifer; Matteson, Paul G.; Silverman, Jill L.; Senerth, Julia M.; Kelly, Samantha; Genestine, Matthieu; Millonig, James H.

    2012-01-01

    ENGRAILED 2 (En2), a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders. PMID:22829897

  14. Effects of treadmill exercise on neural stem cells, cell proliferation, and neuroblast differentiation in the subgranular zone of the dentate gyrus in cyclooxygenase-2 knockout mice.

    PubMed

    Nam, Sung Min; Kim, Jong Whi; Yoo, Dae Young; Choi, Jung Hoon; Kim, Woosuk; Jung, Hyo Young; Won, Moo-Ho; Hwang, In Koo; Seong, Je Kyung; Yoon, Yeo Sung

    2013-12-01

    Cyclooxygenase-2 (COX-2) function has been implicated in a number of physiological processes, including inflammatory responses, synaptic transmission, and synaptic plasticity in the brain. However, the specific role of COX-2 in exercise-induced neurogenesis is still debatable. Here, we assessed the role of COX-2 in exercise-induced plasticity by comparing COX-2 knockout mice to wild-type control littermates. We investigated the number of neural stem cells, and the degree of cell proliferation and neuronal differentiation in COX-2 knockout and its wild-type mice that either exercised or remained inactive. Wild-type and COX-2 knockout mice were put on a treadmill and were either sedentary or were forced to run 1 h/day for five consecutive days at a pace of 10-12 m/min for 5 weeks. Loss of COX-2 expression in the knockout mice was confirmed with two measures: (1) COX immunolabeling in the hippocampus, and (2) the identification of abnormal kidney development using hematoxylin and eosin staining, including subcapsular glomerular hypoplasia and hypertrophy of the deeper cortical glomeruli. Compared to wild-type mice, COX-2 knockout mice exhibited a significant reduction in the neural stem cells (nestin-positive cells), cell proliferation (Ki67-positive cells), and neuroblast differentiation (doublecortin-positive cells). In contrast, exercise significantly increased the neural stem cells, cell proliferation, and neuroblast differentiation in both the wild-type and COX-2 knockout mice although the NeuN-immunoreactive neurons were similar in all groups. Expression of phosphorylated cAMP-response element binding protein was decreased in knockout mice. Exercise increased its expression in the subgranular zone of the dentate gyrus in both wild-type and knockout mice. These results suggest that the COX-2 pathway is one of important factors on neural stem cells, cell proliferation and neuroblast differentiation in sedentary mice. The ability of exercise to increase these

  15. Effects of postweaning administration of conjugated linoleic acid on development of obesity in nescient basic helix-loop-helix 2 knockout mice.

    PubMed

    Kim, Yoo; Kim, Daeyoung; Good, Deborah J; Park, Yeonhwa

    2015-06-01

    Conjugated linoleic acid (CLA) has been reported to prevent body weight gain and fat accumulation in part by improving physical activity in mice. However, the effects of postweaning administration of CLA on the development of obesity later in life have not yet been demonstrated. The current study investigated the role of postweaning CLA treatment on skeletal muscle energy metabolism in genetically induced inactive adult-onset obese model, nescient basic helix-loop-helix 2 knockout (N2KO) mice. Four-week-old male N2KO and wild type mice were fed either control or a CLA-containing diet (0.5%) for 4 weeks, and then CLA was withdrawn and control diet provided to all mice for the following 8 weeks. Postweaning CLA supplementation in wild type animals, but not N2KO mice, may activate AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-δ (PPARδ) as well as promote desensitization of phosphatase and tensin homologue (PTEN) and sensitization of protein kinase B (AKT) at threonine 308 in gastrocnemius skeletal muscle, improving voluntary activity and glucose homeostasis. We suggest that postweaning administration of CLA may in part stimulate the underlying molecular targets involved in muscle energy metabolism to reduce weight gain in normal animals, but not in the genetically induced inactive adult-onset animal model. PMID:25976059

  16. Reduced phosphorylation of synapsin I in the hippocampus of Engrailed-2 knockout mice, a model for autism spectrum disorders.

    PubMed

    Provenzano, G; Pangrazzi, L; Poli, A; Sgadò, P; Berardi, N; Bozzi, Y

    2015-02-12

    Mice lacking the homeodomain transcription factor Engrailed-2 (En2(-/-) mice) are a well-characterized model for autism spectrum disorders (ASD). En2(-/-) mice present molecular, neuropathological and behavioral deficits related to ASD, including down-regulation of ASD-associated genes, cerebellar hypoplasia, interneuron loss, enhanced seizure susceptibility, decreased sociability and impaired cognition. Specifically, impaired spatial learning in the Morris water maze (MWM) is associated with reduced expression of neurofibromin and increased phosphorylation of extracellular-regulated kinase (ERK) in the hippocampus of En2(-/-) adult mice. In the attempt to better understand the molecular cascades underlying neurofibromin-dependent cognitive deficits in En2 mutant mice, we investigated the expression and phosphorylation of synapsin I (SynI; a major target of neurofibromin-dependent signaling) in the hippocampus of wild-type (WT) and En2(-/-) mice before and after MWM. Here we show that SynI mRNA and protein levels are down-regulated in the hippocampus of naïve and MWM-treated En2(-/-) mice, as compared to WT controls. This down-regulation is paralleled by reduced levels of SynI phosphorylation at Ser549 and Ser553 residues in the hilus of mutant mice, before and after MWM. These data indicate that in En2(-/-) hippocampus, neurofibromin-dependent pathways converging on SynI phosphorylation might underlie hippocampal-dependent learning deficits observed in En2(-/-) mice. PMID:25463523

  17. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.

    PubMed

    Nicolas, G; Bennoun, M; Devaux, I; Beaumont, C; Grandchamp, B; Kahn, A; Vaulont, S

    2001-07-17

    We previously reported the disruption of the murine gene encoding the transcription factor USF2 and its consequences on glucose-dependent gene regulation in the liver. We report here a peculiar phenotype of Usf2(-/-) mice that progressively develop multivisceral iron overload; plasma iron overcomes transferrin binding capacity, and nontransferrin-bound iron accumulates in various tissues including pancreas and heart. In contrast, the splenic iron content is strikingly lower in knockout animals than in controls. To identify genes that may account for the abnormalities of iron homeostasis in Usf2(-/-) mice, we used suppressive subtractive hybridization between livers from Usf2(-/-) and wild-type mice. We isolated a cDNA encoding a peptide, hepcidin (also referred to as LEAP-1, for liver-expressed antimicrobial peptide), that was very recently purified from human blood ultrafiltrate and from urine as a disulfide-bonded peptide exhibiting antimicrobial activity. Accumulation of iron in the liver has been recently reported to up-regulate hepcidin expression, whereas our data clearly show that a complete defect in hepcidin expression is responsible for progressive tissue iron overload. The striking similarity of the alterations in iron metabolism between HFE knockout mice, a murine model of hereditary hemochromatosis, and the Usf2(-/-) hepcidin-deficient mice suggests that hepcidin may function in the same regulatory pathway as HFE. We propose that hepcidin acts as a signaling molecule that is required in conjunction with HFE to regulate both intestinal iron absorption and iron storage in macrophages. PMID:11447267

  18. Not all water mazes are created equal: cyclin D2 knockout mice with constitutively suppressed adult hippocampal neurogenesis do show specific spatial learning deficits

    PubMed Central

    Garthe, A; Huang, Z; Kaczmarek, L; Filipkowski, R K; Kempermann, G

    2014-01-01

    Studies using the Morris water maze to assess hippocampal function in animals, in which adult hippocampal neurogenesis had been suppressed, have yielded seemingly contradictory results. Cyclin D2 knockout (Ccnd2−/−) mice, for example, have constitutively suppressed adult hippocampal neurogenesis but had no overt phenotype in the water maze. In other paradigms, however, ablation of adult neurogenesis was associated with specific deficits in the water maze. Therefore, we hypothesized that the neurogenesis-related phenotype might also become detectable in Ccnd2−/− mice, if we used the exact setup and protocol that in our previous study had revealed deficits in mice with suppressed adult neurogenesis. Ccnd2−/− mice indeed learned the task and developed a normal preference for the goal quadrant, but were significantly less precise for the exact goal position and were slower in acquiring efficient and spatially more precise search strategies. Upon goal reversal (when the hidden platform was moved to a new position) Ccnd2−/− mice showed increased perseverance at the former platform location, implying that they were less flexible in updating the previously learned information. Both with respect to adult neurogenesis and behavioral performance, Ccnd2+/− mice ranged between wild types and knockouts. Importantly, hippocampus-dependent learning was not generally impaired by the mutation, but specifically functional aspects relying on precise and flexible encoding were affected. Whether ablation of adult neurogenesis causes a specific behavioral phenotype thus also depends on the actual task demands. The test parameters appear to be important variables influencing whether a task can pick up a contribution of adult neurogenesis to test performance. PMID:24602283

  19. The drusen-like phenotype in aging Ccl2 knockout mice is caused by an accelerated accumulation of swollen autofluorescent subretinal macrophages

    PubMed Central

    Luhmann, Ulrich F.O.; Robbie, Scott; Munro, Peter M.G.; Barker, Susie E.; Duran, Yanai; Luong, Vy; Fitzke, Frederick W.; Bainbridge, James W.B.; Ali, Robin R.; MacLaren, Robert E.

    2009-01-01

    Purpose Drusen, which can be defined clinically as yellowish white spots in the outer retina, are cardinal features of age-related macular degeneration (AMD). Ccl2 knockout (Ccl2-/-) mice have been reported to develop drusen and phenotypic features similar to AMD including an increased susceptibility to choroidal neovascularisation (CNV). Here we investigate the nature of the drusen-like lesions in vivo and further evaluate the Ccl2-/- mouse as a model for AMD. Methods We examined eyes of 2-25 month old Ccl2-/- and C57Bl/6 mice in vivo by autofluorescence scanning laser ophthalmoscopy (AF-SLO), electroretinography, and measured the extent of laser- induced CNV by fluorescein fundus angiography. We also assessed retinal morphology using immunohistochemistry and quantitative histological and ultrastructural morphometry. Results The drusen-like lesions of Ccl2-/- mice comprise accelerated accumulation of swollen CD68+, F4/80+ macrophages in the subretinal space that are apparent as autofluorescent foci on AF-SLO. These macrophages contain pigment granules and phagosomes with outer segment and lipofuscin inclusions that might account for their autofluorescence. We only observed age-related RPE damage, photoreceptor loss and sub-RPE deposits but, despite the accelerated accumulation of macrophages, we identified no spontaneous CNV development in senescent mice and found a reduced susceptibility to laser-induced CNV in Ccl2-/- mice. Conclusion These findings suggest that the lack of Ccl2 leads to a monocyte/macrophage trafficking defect during aging and to an impaired recruitment of these cells to sites of laser injury. Other, previously described features of Ccl2-/- mice that are similar to AMD may be the result of aging alone. PMID:19578022

  20. Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model.

    PubMed

    Baquedano, Eva; Burgos-Ramos, Emma; Canelles, Sandra; González-Rodríguez, Agueda; Chowen, Julie A; Argente, Jesús; Barrios, Vicente; Valverde, Angela M; Frago, Laura M

    2016-05-01

    Insulin receptor substrate-2-deficient (IRS2(-/-)) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2(-/-) mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2(-/-) mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2(-/-) mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2(-/-) mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus. PMID:27013528

  1. Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model

    PubMed Central

    Canelles, Sandra; Argente, Jesús; Barrios, Vicente

    2016-01-01

    ABSTRACT Insulin receptor substrate-2-deficient (IRS2−/−) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2−/− mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2−/− mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2−/− mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2−/− mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus. PMID:27013528

  2. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice

    PubMed Central

    Nicolas, Gaël; Bennoun, Myriam; Devaux, Isabelle; Beaumont, Carole; Grandchamp, Bernard; Kahn, Axel; Vaulont, Sophie

    2001-01-01

    We previously reported the disruption of the murine gene encoding the transcription factor USF2 and its consequences on glucose-dependent gene regulation in the liver. We report here a peculiar phenotype of Usf2−/− mice that progressively develop multivisceral iron overload; plasma iron overcomes transferrin binding capacity, and nontransferrin-bound iron accumulates in various tissues including pancreas and heart. In contrast, the splenic iron content is strikingly lower in knockout animals than in controls. To identify genes that may account for the abnormalities of iron homeostasis in Usf2−/− mice, we used suppressive subtractive hybridization between livers from Usf2−/− and wild-type mice. We isolated a cDNA encoding a peptide, hepcidin (also referred to as LEAP-1, for liver-expressed antimicrobial peptide), that was very recently purified from human blood ultrafiltrate and from urine as a disulfide-bonded peptide exhibiting antimicrobial activity. Accumulation of iron in the liver has been recently reported to up-regulate hepcidin expression, whereas our data clearly show that a complete defect in hepcidin expression is responsible for progressive tissue iron overload. The striking similarity of the alterations in iron metabolism between HFE knockout mice, a murine model of hereditary hemochromatosis, and the Usf2−/− hepcidin-deficient mice suggests that hepcidin may function in the same regulatory pathway as HFE. We propose that hepcidin acts as a signaling molecule that is required in conjunction with HFE to regulate both intestinal iron absorption and iron storage in macrophages. PMID:11447267

  3. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development.

    PubMed

    Baardman, Maria E; Zwier, Mathijs V; Wisse, Lambertus J; Gittenberger-de Groot, Adriana C; Kerstjens-Frederikse, Wilhelmina S; Hofstra, Robert M W; Jurdzinski, Angelika; Hierck, Beerend P; Jongbloed, Monique R M; Berger, Rolf M F; Plösch, Torsten; DeRuiter, Marco C

    2016-04-01

    Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts ofLrp2knockout (KO) mice have not yet been investigated. We studied the cardiovascular development ofLrp2KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. TheLrp2KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in theLrp2KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans withLRP2mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis. PMID:26822476

  4. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development

    PubMed Central

    Baardman, Maria E.; Zwier, Mathijs V.; Wisse, Lambertus J.; Gittenberger-de Groot, Adriana C.; Kerstjens-Frederikse, Wilhelmina S.; Hofstra, Robert M. W.; Jurdzinski, Angelika; Hierck, Beerend P.; Jongbloed, Monique R. M.; Berger, Rolf M. F.; Plösch, Torsten; DeRuiter, Marco C.

    2016-01-01

    ABSTRACT Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the cardiovascular development of Lrp2 KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. The Lrp2 KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis. PMID:26822476

  5. Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice.

    PubMed

    Costa, Diana K; Huckestein, Brydie R; Edmunds, Lia R; Petersen, Max C; Nasiri, Ali; Butrico, Gina M; Abulizi, Abudukadier; Harmon, Daniel B; Lu, Canying; Mantell, Benjamin S; Hartman, Douglas J; Camporez, João-Paulo G; O'Doherty, Robert M; Cline, Gary W; Shulman, Gerald I; Jurczak, Michael J

    2016-07-01

    Mitochondrial dysfunction is associated with many human diseases and results from mismatch of damage and repair over the life of the organelle. PARK2 is a ubiquitin E3 ligase that regulates mitophagy, a repair mechanism that selectively degrades damaged mitochondria. Deletion of PARK2 in multiple in vivo models results in susceptibility to stress-induced mitochondrial and cellular dysfunction. Surprisingly, Park2 knockout (KO) mice are protected from nutritional stress and do not develop obesity, hepatic steatosis or insulin resistance when fed a high-fat diet (HFD). However, these phenomena are casually related and the physiological basis for this phenotype is unknown. We therefore undertook a series of acute HFD studies to more completely understand the physiology of Park2 KO during nutritional stress. We find that intestinal lipid absorption is impaired in Park2 KO mice as evidenced by increased fecal lipids and reduced plasma triglycerides after intragastric fat challenge. Park2 KO mice developed hepatic steatosis in response to intravenous lipid infusion as well as during incubation of primary hepatocytes with fatty acids, suggesting that hepatic protection from nutritional stress was secondary to changes in energy balance due to altered intestinal triglyceride absorption. Park2 KO mice showed reduced adiposity after 1-wk HFD, as well as improved hepatic and peripheral insulin sensitivity. These studies suggest that changes in intestinal lipid absorption may play a primary role in protection from nutritional stress in Park2 KO mice by preventing HFD-induced weight gain and highlight the need for tissue-specific models to address the role of PARK2 during metabolic stress. PMID:27166280

  6. Nox2 Knockout Delays Infarct Progression and Increases Vascular Recovery through Angiogenesis in Mice following Ischaemic Stroke with Reperfusion

    PubMed Central

    McCann, Sarah K.; Dusting, Gregory J.; Roulston, Carli L.

    2014-01-01

    Evidence suggests the NADPH oxidases contribute to ischaemic stroke injury and Nox2 is the most widely studied subtype in the context of stroke. There is still conjecture however regarding the benefits of inhibiting Nox2 to improve stroke outcome. The current study aimed to examine the temporal effects of genetic Nox2 deletion on neuronal loss after ischaemic stroke using knockout (KO) mice with 6, 24 and 72 hour recovery. Transient cerebral ischaemia was induced via intraluminal filament occlusion and resulted in reduced infarct volumes in Nox2 KO mice at 24 h post-stroke compared to wild-type controls. No protection was evident at either 6 h or 72 h post-stroke, with both genotypes exhibiting similar volumes of damage. Reactive oxygen species were detected using dihydroethidium and were co-localised with neurons and microglia in both genotypes using immunofluorescent double-labelling. The effect of Nox2 deletion on vascular damage and recovery was also examined 24 h and 72 h post-stroke using an antibody against laminin. Blood vessel density was decreased in the ischaemic core of both genotypes 24 h post-stroke and returned to pre-stroke levels only in Nox2 KO mice by 72 h. Overall, these results are the first to show that genetic Nox2 deletion merely delays the progression of neuronal loss after stroke but does not prevent it. Additionally, we show for the first time that Nox2 deletion increases re-vascularisation of the damaged brain by 72 h, which may be important in promoting endogenous brain repair mechanisms that rely on re-vascularisation. PMID:25375101

  7. Matrix Metalloproteinase-2 Knockout and Heterozygote Mice Are Protected from Hydronephrosis and Kidney Fibrosis after Unilateral Ureteral Obstruction

    PubMed Central

    Tveitarås, Maria K.; Skogstrand, Trude; Leh, Sabine; Helle, Frank; Chatziantoniou, Christos; Reed, Rolf K.; Hultström, Michael

    2015-01-01

    Matrix Metalloproteinase-2 (Mmp2) is a collagenase known to be important in the development of renal fibrosis. In unilateral ureteral obstruction (UUO) the obstructed kidney (OK) develops fibrosis, while the contralateral (CL) does not. In this study we investigated the effect of UUO on gene expression, fibrosis and pelvic remodeling in the kidneys of Mmp2 deficient mice (Mmp2-/-), heterozygous animals (Mmp2+/-) and wild-type mice (Mmp2+/+). Sham operated animals served as controls (Cntrl). UUO was prepared under isoflurane anaesthesia, and the animals were sacrificed after one week. UUO caused hydronephrosis, dilation of renal tubules, loss of parenchymal thickness, and fibrosis. Damage was most severe in Mmp2+/+ mice, while both Mmp2-/- and Mmp2+/- groups showed considerably milder hydronephrosis, no tubular necrosis, and less tubular dilation. Picrosirius red quantification of fibrous collagen showed 1.63±0.25% positivity in OK and 0.29±0.11% in CL (p<0.05) of Mmp2+/+, Mmp2-/- OK and Mmp2-/- CL exhibited only 0.49±0.09% and 0.23±0.04% (p<0.05) positivity, respectively. Mmp2+/- OK and Mmp2+/- CL showed 0.43±0.09% and 0.22±0.06% (p<0.05) positivity, respectively. Transcriptomic analysis showed that 26 genes (out of 48 examined) were differentially expressed by ANOVA (p<0.05). 25 genes were upregulated in Mmp2+/+ OK compared to Mmp2+/+ CL: Adamts1, -2, Col1a1, -2, -3a1, -4a1, -5a1, -5a2, Dcn, Fbln1, -5, Fmod, Fn1, Itga2, Loxl1, Mgp, Mmp2, -3, Nid1, Pdgfb, Spp1, Tgfb1, Timp2, Trf, Vim. In Mmp2-/- and Mmp2+/- 18 and 12 genes were expressed differentially between OK and CL, respectively. Only Mmp2 was differentially regulated when comparing Mmp2-/- OK and Mmp2+/- OK. Under stress, it appears that Mmp2+/- OK responds with less Mmp2 upregulation than Mmp2+/+ OK, suggesting that there is a threshold level of Mmp2 necessary for damage and fibrosis to occur. In conclusion, reduced Mmp2 expression during UUO protects mice against hydronephrosis and renal fibrosis

  8. USE OF CYP1A2(-/-) KNOCKOUT AND CYP1A2(+/+) C57BL/6N PARENTAL STRAINS OF MICE TO COMPARE METABOLISM OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)

    EPA Science Inventory

    USE OF CYP1A2 (-/-) KNOCKOUT AND CYP1A2 (+/+) C57BL/6N PARENTAL STRAINS OF MICE TO COMPARE METABOLISM OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD). J J Diliberto1 and H Hakk2. 1USEPA ORD, NHEERL, ETD, PKB, Research Triangle Park, NC, USA; 2USDA-ARS, BRL, Fargo, ND, USA. Spons...

  9. COMPARISON OF OVERALL METABOLISM OF 2, 3, 7, 8-TETRACHLORODIBENZO-P-DIOXIN IN CYP1A2(-/-) KNOCKOUT AND C57BL/6N PARENTAL STRAINS OF MICE

    EPA Science Inventory

    Comparison of Overall Metabolism of 2,3,7,8-TCDD
    in CYP1A2 (-/-) Knockout and C57BL/6N Parental Strains of Mice

    Heldur Hakk* and Janet J. Diliberto**

    * USDA-ARS Biosciences Research Laboratory, P.O. Box 5674, Fargo, ND, USA
    ** US-EPA ORD, National Health Eff...

  10. Islets of Langerhans from prohormone convertase-2 knockout mice show α-cell hyperplasia and tumorigenesis with elevated α-cell neogenesis

    PubMed Central

    Jones, Huw B; Reens, Jaimini; Brocklehurst, Simon R; Betts, Catherine J; Bickerton, Sue; Bigley, Alison L; Jenkins, Richard P; Whalley, Nicky M; Morgan, Derrick; Smith, David M

    2014-01-01

    Antagonism of the effects of glucagon as an adjunct therapy with other glucose-lowering drugs in the chronic treatment of diabetes has been suggested to aggressively control blood glucose levels. Antagonism of glucagon effects, by targeting glucagon secretion or disabling the glucagon receptor, is associated with α-cell hyperplasia. We evaluated the influence of total glucagon withdrawal on islets of Langerhans using prohormone convertase-2 knockout mice (PC2-ko), in which α-cell hyperplasia is present from a young age and persists throughout life, in order to understand whether or not sustained glucagon deficit would lead to islet tumorigenesis. PC2-ko and wild-type (WT) mice were maintained drug-free, and cohorts of these groups sampled at 3, 12 and 18 months for plasma biochemical and morphological (histological, immunohistochemical, electron microscopical and image analytical) assessments. WT mice showed no islet tumours up to termination of the study, but PC2-ko animals displayed marked changes in islet morphology from α-cell hypertrophy/hyperplasia/atypical hyperplasia, to adenomas and carcinomas, these latter being first encountered at 6–8 months. Islet hyperplasias and tumours primarily consisted of α-cells associated to varying degrees with other islet endocrine cell types. In addition to substantial increases in islet neoplasia, increased α-cell neogenesis associated primarily with pancreatic duct(ule)s was present. We conclude that absolute blockade of the glucagon signal results in tumorigenesis and that the PC2-ko mouse represents a valuable model for investigation of islet tumours and pancreatic ductal neogenesis. PMID:24456331

  11. Alternative Roles of STAT3 and MAPK Signaling Pathways in the MMPs Activation and Progression of Lung Injury Induced by Cigarette Smoke Exposure in ACE2 Knockout Mice.

    PubMed

    Hung, Yi-Han; Hsieh, Wen-Yeh; Hsieh, Jih-Sheng; Liu, Fon-Chang; Tsai, Chin-Hung; Lu, Li-Che; Huang, Chen-Yi; Wu, Chien-Liang; Lin, Chih-Sheng

    2016-01-01

    Inflammation-mediated abnormalities in the renin-angiotensin system (RAS) and expression of matrix metalloproteinases (MMPs) are implicated in the pathogenesis of lung injury. Angiotensin converting enzyme II (ACE2), an angiotensin converting enzyme (ACE) homologue that displays antagonist effects on ACE/angiotensin II (Ang II) axis, could also play a protective role against lung diseases. However, the relationship between ACE2 and MMPs activation in lung injury is still largely unclear. The purpose of this study is to investigate whether MMPs activity could be affected by ACE2 and which ACE2 derived signaling pathways could be also involved via using a mouse model with lung injury induced by cigarette smoke (CS) exposure for 1 to 3 weeks. Wild-type (WT; C57BL/6) and ACE2 KO mice (ACE2(-/-)) were utilized to study CS-induced lung injury. Increases in the resting respiratory rate (RRR), pulmonary immunokines, leukocyte infiltration and bronchial hyperplasia were observed in the CS-exposed mice. Compared to WT mice, more serious physiopathological changes were found in ACE2(-/-) mice in the first week of CS exposure. CS exposure increased pulmonary ACE and ACE2 activities in WT mice, and significantly increased ACE in ACE2(-/-) mice. Furthermore, the activity of pulmonary MMPs was decreased in CS-exposed WT mice, whereas this activity was increased in ACE2(-/-) mice. CS exposure increased the pulmonary p-p38, p-JNK and p-ERK1/2 level in all mice. In ACE2(-/-) mice, a significant increase p-STAT3 signaling was detected; however, no effect was observed on the p-STAT3 level in WT mice. Our results support the hypothesis that ACE2 deficiency influences MMPs activation and STAT3 phosphorylation signaling to promote more pulmonary inflammation in the development of lung injury. PMID:27019629

  12. Alternative Roles of STAT3 and MAPK Signaling Pathways in the MMPs Activation and Progression of Lung Injury Induced by Cigarette Smoke Exposure in ACE2 Knockout Mice

    PubMed Central

    Hung, Yi-Han; Hsieh, Wen-Yeh; Hsieh, Jih-Sheng; Liu, Fon-Chang; Tsai, Chin-Hung; Lu, Li-Che; Huang, Chen-Yi; Wu, Chien-Liang; Lin, Chih-Sheng

    2016-01-01

    Inflammation-mediated abnormalities in the renin-angiotensin system (RAS) and expression of matrix metalloproteinases (MMPs) are implicated in the pathogenesis of lung injury. Angiotensin converting enzyme II (ACE2), an angiotensin converting enzyme (ACE) homologue that displays antagonist effects on ACE/angiotensin II (Ang II) axis, could also play a protective role against lung diseases. However, the relationship between ACE2 and MMPs activation in lung injury is still largely unclear. The purpose of this study is to investigate whether MMPs activity could be affected by ACE2 and which ACE2 derived signaling pathways could be also involved via using a mouse model with lung injury induced by cigarette smoke (CS) exposure for 1 to 3 weeks. Wild-type (WT; C57BL/6) and ACE2 KO mice (ACE2-/-) were utilized to study CS-induced lung injury. Increases in the resting respiratory rate (RRR), pulmonary immunokines, leukocyte infiltration and bronchial hyperplasia were observed in the CS-exposed mice. Compared to WT mice, more serious physiopathological changes were found in ACE2-/- mice in the first week of CS exposure. CS exposure increased pulmonary ACE and ACE2 activities in WT mice, and significantly increased ACE in ACE2-/- mice. Furthermore, the activity of pulmonary MMPs was decreased in CS-exposed WT mice, whereas this activity was increased in ACE2-/- mice. CS exposure increased the pulmonary p-p38, p-JNK and p-ERK1/2 level in all mice. In ACE2-/- mice, a significant increase p-STAT3 signaling was detected; however, no effect was observed on the p-STAT3 level in WT mice. Our results support the hypothesis that ACE2 deficiency influences MMPs activation and STAT3 phosphorylation signaling to promote more pulmonary inflammation in the development of lung injury. PMID:27019629

  13. Improved Survival and Reduced Phenotypic Severity Following AAV9/MECP2 Gene Transfer to Neonatal and Juvenile Male Mecp2 Knockout Mice

    PubMed Central

    Gadalla, Kamal KE; Bailey, Mark ES; Spike, Rosemary C; Ross, Paul D; Woodard, Kenton T; Kalburgi, Sahana Nagabhushan; Bachaboina, Lavanya; Deng, Jie V; West, Anne E; Samulski, R Jude; Gray, Steven J; Cobb, Stuart R

    2013-01-01

    Typical Rett syndrome (RTT) is a pediatric disorder caused by loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. The demonstrated reversibility of RTT-like phenotypes in mice suggests that MECP2 gene replacement is a potential therapeutic option in patients. We report improvements in survival and phenotypic severity in Mecp2-null male mice after neonatal intracranial delivery of a single-stranded (ss) AAV9/chicken β-actin (CBA)-MECP2 vector. Median survival was 16.6 weeks for MECP2-treated versus 9.3 weeks for green fluorescent protein (GFP)-treated mice. ssAAV9/CBA-MECP2–treated mice also showed significant improvement in the phenotype severity score, in locomotor function, and in exploratory activity, as well as a normalization of neuronal nuclear volume in transduced cells. Wild-type (WT) mice receiving neonatal injections of the same ssAAV9/CBA-MECP2 vector did not show any significant deficits, suggesting a tolerance for modest MeCP2 overexpression. To test a MECP2 gene replacement approach in a manner more relevant for human translation, a self-complementary (sc) adeno-associated virus (AAV) vector designed to drive MeCP2 expression from a fragment of the Mecp2 promoter was injected intravenously (IV) into juvenile (4–5 weeks old) Mecp2-null mice. While the brain transduction efficiency in juvenile mice was low (~2–4% of neurons), modest improvements in survival were still observed. These results support the concept of MECP2 gene therapy for RTT. PMID:23011033

  14. 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...

  15. Rescue of Cyclic AMP Mediated Long Term Potentiation Impairment in the Hippocampus of Mecp2 Knockout (Mecp2-/y) Mice by Rolipram

    PubMed Central

    Balakrishnan, Saju; Niebert, Marcus; Richter, Diethelm W.

    2016-01-01

    Rett syndrome (RTT) patients experience learning difficulties and memory loss. Analogous deficits of hippocampal plasticity are reported in mouse models of RTT. To elucidate the underlying pathophysiology, we studied long term potentiation (LTP) at the CA3 to CA1 synapses in the hippocampus in acute brain slices from WT and Mecp2-/y mice, by either activating cAMP dependent pathway or using high frequency stimulation, by means of patch clamp. We have observed that, the NMDA channel current characteristics remain unchanged in the Mecp2-/y mice. The adenylyl cyclase (AC) agonist forskolin evoked a long lasting potentiation of evoked EPSCs in WT CA1 neurons, but only minimally enhanced the EPSCs in the Mecp2-/y mice. This weaker potentiation in Mecp2-/y mice was ameliorated by application of phosphodiesterase 4 inhibitor rolipram. The hyperpolarization activated cyclic nucleotide gated channel current (Ih) was potentiated to similar extent by forskolin in both phenotypes. Multiple tetanus induced cAMP-dependent plasticity was also impaired in the Mecp2-/y mice, and was also partially rescued by rolipram. Western blot analysis of CA region of Mecp2-/y mice hippocampus revealed more than twofold up-regulation of protein kinase A (PKA) regulatory subunits, while the expression of the catalytic subunit remained unchanged. We hypothesize that the overexpressed PKA regulatory subunits buffer cAMP and restrict the PKA mediated phosphorylation of target proteins necessary for LTP. Blocking the degradation of cAMP, thereby saturating the regulatory subunits alleviated this defect. PMID:26869885

  16. Rescue of Cyclic AMP Mediated Long Term Potentiation Impairment in the Hippocampus of Mecp2 Knockout (Mecp2(-/y) ) Mice by Rolipram.

    PubMed

    Balakrishnan, Saju; Niebert, Marcus; Richter, Diethelm W

    2016-01-01

    Rett syndrome (RTT) patients experience learning difficulties and memory loss. Analogous deficits of hippocampal plasticity are reported in mouse models of RTT. To elucidate the underlying pathophysiology, we studied long term potentiation (LTP) at the CA3 to CA1 synapses in the hippocampus in acute brain slices from WT and Mecp2(-/y) mice, by either activating cAMP dependent pathway or using high frequency stimulation, by means of patch clamp. We have observed that, the NMDA channel current characteristics remain unchanged in the Mecp2(-/y) mice. The adenylyl cyclase (AC) agonist forskolin evoked a long lasting potentiation of evoked EPSCs in WT CA1 neurons, but only minimally enhanced the EPSCs in the Mecp2(-/y) mice. This weaker potentiation in Mecp2 (-/) (y) mice was ameliorated by application of phosphodiesterase 4 inhibitor rolipram. The hyperpolarization activated cyclic nucleotide gated channel current (I h) was potentiated to similar extent by forskolin in both phenotypes. Multiple tetanus induced cAMP-dependent plasticity was also impaired in the Mecp2 (-/) (y) mice, and was also partially rescued by rolipram. Western blot analysis of CA region of Mecp2 (-/) (y) mice hippocampus revealed more than twofold up-regulation of protein kinase A (PKA) regulatory subunits, while the expression of the catalytic subunit remained unchanged. We hypothesize that the overexpressed PKA regulatory subunits buffer cAMP and restrict the PKA mediated phosphorylation of target proteins necessary for LTP. Blocking the degradation of cAMP, thereby saturating the regulatory subunits alleviated this defect. PMID:26869885

  17. The effect of dose on 2,3,7,8-TCDD tissue distribution, metabolism and elimination in CYP1A2 (-/-) knockout and C57BL/6N parental strains of mice

    SciTech Connect

    Hakk, Heldur; Diliberto, Janet J.; Birnbaum, Linda S.

    2009-11-15

    Numerous metabolism studies have demonstrated that the toxic contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is poorly metabolized. A hallmark feature of TCDD exposure is induction of hepatic CYP1A2 and subsequent sequestration leading to high liver-to-fat concentration ratios. This study was initiated to determine whether TCDD was inherently poorly metabolized or unavailable for metabolism because of sequestration to CYP1A2. [{sup 3}H]TCDD was administered as a single, oral dose (0.1 and 10 mug/kg) to 12 male C57BL/6N mice or 12 CYP1A2 (-/-) mice. At 96 h, less than 5% of the dose was eliminated in the urine of all groups, and TCDD detected in urine was bound to mouse major urinary protein (mMUP). Feces were the major elimination pathway (24-31% of dose), and fecal extracts and non-extractables were quantitated by HPLC for metabolites. No great differences in urinary or fecal elimination (% dose) were observed between the high and low dose treatments. TCDD concentrations were the highest in adipose tissue for CYP1A2 knockout mice but in liver for C57BL/6N mice supporting the role of hepatic CYP1A2 in the sequestration of TCDD. Overall metabolism between parental and knockout strains showed no statistical differences at either the high or low doses. The data suggested that metabolism of TCDD is inherently slow, due principally to CYP1A1, and that hepatic CYP1A2 is not an active participant in the metabolism of TCDD in male mice. Rather, CYP1A2 governs the pharmacokinetics of TCDD by making it unavailable for hepatic CYP1A1 through sequestration and attenuating extrahepatic tissue disposition.

  18. Single-dose ethanol administration downregulates expression of cytochrome p450 2E1 mRNA in aldehyde dehydrogenase 2 knockout mice.

    PubMed

    Matsumoto, Akiko; Kawamoto, Toshihiro; Horita, Mikako; Takahashi, Tatsuya; Isse, Toyohi; Oyama, Tsunehiro; Ichiba, Masayoshi

    2007-12-01

    The polymorphism of aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2, is very common in East Asian origin. Acetaldehyde, an intermediate metabolite of ethanol, is metabolized very slowly in people with ALDH2*2 because the mutant ALDH2 protein lacks the activity of acetaldehyde metabolism. On the other hand, it is well established that one of the cytochrome P450 enzymes, CYP2E1, is an activator of carcinogens (e.g., nitorosamines) and a generator of oxidative stress, and it is shown that CYP2E1 was induced by ethanol via gene transcriptional regulation. In the present study, to examine the consequences of ALDH2 polymorphism on transcriptional regulation of CYP2E1 in liver tissue, Aldh2+/+ and Aldh2-/- mice were orally administered 5 g/kg body weight of ethanol and the levels of CYP2E1 mRNA in liver tissue then analyzed. The level of CYP2E1 mRNA 12h after the ethanol administration tended to be higher than the 0-h group in Aldh2+/+ mice, however, it was significantly lower than the 0-h group in Aldh2-/- mice. These findings suggest that single-dose ethanol administration downregulates the expression of cytochrome p450 2E1 mRNA in the presence of inactive ALDH2. PMID:17980998

  19. 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

  20. BEHAVIORAL AND AUTONOMIC THERMOREGULATION IN MICE EXPOSED TO MICROWAVE RADIATION

    EPA Science Inventory

    Preferred ambient temperature (T) and breathing rate were measured in free-moving mice exposed to 2,450-MHz microwaves. A waveguide-exposure system was imposed with a longitudinal temperature gradient that permitted mice to select their preferred T. Breathing rate was determined ...

  1. 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

  2. Functional consequences of hippocampal neuronal ectopia in the apolipoprotein E receptor-2 knockout mouse

    PubMed Central

    Fish, Kenneth. N.; Krucker, Thomas

    2008-01-01

    Little is known about the impact ectopically located neurons have on the functional connectivity of local circuits. The ApoER2 knockout mouse has subtle cytoarchitectural disruptions, altered prepulse inhibition, and memory abnormalities. We evaluated this mouse mutant as a model to study the role ectopic neurons play in the manifestation of symptoms associated with brain diseases. We found that ectopic CA1 pyramidal and inhibitory neurons in the ApoER2 knockout hippocampus are organized into two distinct stratum pyramidale layers. In vitro analyses found that ApoER2 is not required for neurons to reach maturity in regards to dendritic arborization and synaptic structure density, and electrophysiological testing determined that neurons in both strata pyramidale are integrated into the hippocampal network. However, the presence of these two layers alters the spatiotemporal pattern of hippocampal activity, which may explain why ApoER2 knockout mice have selective cognitive dysfunctions that are revealed only under challenging conditions. PMID:18778775

  3. 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...

  4. REPRODUCTIVE DEVELOPMENT IN MALE DEER MICE EXPOSED TO AGGRESSIVE BEHAVIOR

    EPA Science Inventory

    Male deer mice (Peromyscus maniculatus bairdii) were reared in a long photoperiod and housed individually from 3 weeks of age until they were killed 2, 4, or 6 weeks later. Males that were exposed to aggressive females for 2 min, three times per week, were of normal body weight a...

  5. Erythrocytes from ozone-exposed mice exhibit decreased deformability

    SciTech Connect

    Morgan, D.L.; Dorsey, A.F.; Menzel, D.B.

    1985-02-01

    Injury from short-term exposure to ozone (O/sub 3/) was detected by a simple test of red blood cell (RBC) filterability. This test measures changes in the ability of the RBC to deform--as occurs during passage through small capillaries. Male CD-1 mice were exposed to 1.0, 0.7, or 0.3 ppm O/sub 3/ for 4 hr, and blood samples were obtained by heart puncture. RBCs were suspended in Tris-HCl buffer, pH 7.4, containing 10 mg/dl glucose. After incubation in air for up to 6 hr, the time required for 2 ml RBC suspension to pass through a 3-micron-pore-size polycarbonate filter was determined. A significant increase in the 6-hr filtration time for O/sub 3/-exposed (1.0 ppm) mice over unexposed mice and a lack of protection by vitamin E were shown. The increases in RBC filtration times for O/sub 3/-exposed mice appeared to be dose related. Ozone exposure (1.0 ppm) caused a significant increase in the hematocrit of both vitamin E-deficient and -supplemented mice. Vitamin E supplementation appeared to partially prevent this increase in hematocrit. Measurement of lipid peroxidation by the thiobarbituric acid (TBA) test revealed no detectable levels of TBA-reactive material in RBC from O/sub 3/-exposed mice. These results suggest that measurement of RBC filterability may be feasible as a clinical test for short-term injury from exposure to oxidant gases.

  6. Acute and delayed thermoregulatory response of mice exposed to brevetoxin.

    PubMed

    Gordon, C J; Kimm-Brinson, K L; Padnos, B; Ramsdell, J S

    2001-09-01

    Thermal dysthesia, characterized by a painful sensation of warm and cool surfaces, is one of many ailments in humans exposed to various marine algal toxins such as brevetoxin (PbTx). There is no animal model to study thermal dysthesia and little is known of the mechanism of action. There is also little known on the acute and delayed thermoregulatory effects of PbTx. In this study, we developed a behavioral system to assess the possible development of thermal dysthesia in mice exposed to PbTx. Female mice were implanted with radiotransmitters to monitor core temperature (Tc) and motor activity (MA). In one experiment, mice were dosed with the control vehicle or 180 microg/kg PbTx and placed on a floor temperature gradient to measure the selected foot temperature (SFT) while air temperature was kept constant. PbTx-treated mice underwent a 10 degrees C reduction in SFT concomitant with a 3 degrees C reduction in Tc within 30 min after exposure. In another study, Tc and MA were monitored in mice maintained in their home cages after dosing with 180 microg/kg PbTx. Tc but not MA increased for 2-5 days after exposure. SFT was unaffected by PbTx when tested 1-12 days after exposure. However, PbTx-treated mice underwent an increase in Tc when placed in the temperature gradient for up to 12 days after exposure. This suggests that PbTx augments the stress-induced hyperthermia from being placed in a novel environment. Overall, acute PbTx exposure leads to a regulated reduction in Tc as characterized by a preference for cooler SFTs and a reduced Tc. Thermal dysthesia was not apparent, but the exaggerated hyperthermic response with a normal SFT in the temperature gradient may suggest an altered processing of thermal stimuli in mice treated with PbTx. PMID:11384725

  7. 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

  8. Differential Cytotoxicity but Augmented IFN-γ Secretion by NK Cells after Interaction with Monocytes from Humans, and Those from Wild Type and Myeloid-Specific COX-2 Knockout Mice

    PubMed Central

    Tseng, Han-Ching; Arasteh, Aida; Kaur, Kawaljit; Kozlowska, Anna; Topchyan, Paytsar; Jewett, Anahid

    2015-01-01

    The list of genes, which augment NK cell function when knocked out in neighboring cells is increasing, and may point to the fundamental function of NK cells targeting cells with diminished capability to differentiate optimally since NK cells are able to target less differentiated cells, and aid in their differentiation. In this paper, we aimed at understanding the effect of monocytes from targeted knockout of COX-2 in myeloid cells (Cox-2flox/flox;LysMCre/+) and from control littermates (Cox-2flox/flox;LysM+/+) on ex vivo function of NK cells. Furthermore, we compared the effect of monocytes treated with and without lipopolysaccharide (LPS) on NK cells from mice and humans. NK cells purified from Cox-2flox/flox;LysMCre/+ mice had heightened cytotoxic activity when compared to those obtained from control littermates. In addition, NK cells cultured with autologous Cox-2flox/flox;LysMCre/+ monocytes and DCs, mouse embryonic fibroblasts from global knockout COX-2, but not with knockout of COX-2 in T cells, had increased cytotoxic function as well as augmented IFN-γ secretion when compared to NK cells from control littermates cultured with monocytes. LPS inhibited NK cell cytotoxicity while increasing IFN-γ secretion when cultured in the presence of monocytes from either Cox-2flox/flox;LysMCre/+ or control littermates. In contrast to mice, NK cells from humans when cultured with monocytes lost cytotoxic function and gained ability to secrete large amounts of IFN-γ, a process, which we had previously coined as “split anergy.” Similar to mice, LPS potentiated the loss of human NK cell cytotoxicity while increasing IFN-γ secretion in the presence of monocytes. Greater loss of cytotoxicity and larger secretion of IFN-γ in NK cells induced by gene knockout cells may be important for the greater need of these cells for differentiation. PMID:26106386

  9. Memory deficit in Swiss mice exposed to tannery effluent.

    PubMed

    Rabelo, Letícia Martins; Costa E Silva, Bianca; de Almeida, Sabrina Ferreira; da Silva, Wellington Alves Mizael; de Oliveira Mendes, Bruna; Guimarães, Abraão Tiago Batista; da Silva, Anderson Rodrigo; da Silva Castro, André Luis; de Lima Rodrigues, Aline Sueli; Malafaia, Guilherme

    2016-01-01

    Although it is known that tannery effluents constitute highly toxic pollutants whose effects in humans represent public health problems in several countries, studies involving experimental mammalian models are rare. In this context, the objective of the present study was to assess the effect of the exposure to tannery effluent on the memory of male and female Swiss mice. Animals of each sex were distributed into two experimental groups: the control group, in which the animals received only drinking water and the effluent group, in which the mice received 1% of gross tannery effluent diluted in water. The animals were exposed to the effluent by gavage, oral dosing, for 15days, ensuring the administration of 0.1mL of liquid (water or effluent)/10g of body weight/day. On the 14th and 15th experimental days the animals were submitted to the object recognition test. It was observed that the new object recognition indices calculated for the animals exposed to the effluent (males and females) were significantly lower than those obtained with the control group. The exposure to tannery effluent caused memory deficit in Swiss mice in a similar way for both sexes, reinforcing previous findings that these pollutants affect the central nervous system. It contributes to the knowledge in the area by attesting harmful effects to the cognition of such animals. PMID:27063058

  10. Embryo- and fetotoxicity of chromium in pregestationally exposed mice

    SciTech Connect

    Junaid, M.; Murthy, R.C.; Saxena, D.K.

    1996-10-01

    Chromium, an essential element in the human body required for proper carbohydrate, protein, and fat metabolism, is reported to impair gestational development of offspring of workers chronically exposed to this metal in the work place. Workers in chromium based industries can be exposed to concentrations two orders of magnitude higher than the general population. Among the general population, residents living near chromate production sites may be exposed to high levels of chromium (VI) in air or to elevated levels (40 - 50,000 ppm) of chromium in effluents. Shmitova reported afterbirth and puerperal hemorrhages in women industrially exposed to this metal and observed high chromium levels in blood and urine of pregnant women and in fetal and cord blood. Chromium readily passes the placental barrier and reaches the growing fetus. Exposure of mice to chromium during various gestational periods resulted in embryo and fetotoxic effects. This study looks at the role of body chromium accumulated pregestationally on embryo and fetal development and its subsequent transfer to feto-placental sites. 25 refs., 3 tabs.

  11. Generation of a New Model Rat: Nrf2 Knockout Rats Are Sensitive to Aflatoxin B1 Toxicity.

    PubMed

    Taguchi, Keiko; Takaku, Misaki; Egner, Patricia A; Morita, Masanobu; Kaneko, Takehito; Mashimo, Tomoji; Kensler, Thomas W; Yamamoto, Masayuki

    2016-07-01

    THE TRANSCRIPTION FACTOR NRF2: (NF-E2-related-factor 2) REGULATES A BATTERY OF ANTIOXIDATIVE STRESS-RESPONSE GENES AND DETOXICATION GENES, AND NRF2 KNOCKOUT LINES OF MICE HAVE BEEN CONTRIBUTING CRITICALLY TO THE CLARIFICATION OF ROLES THAT NRF2 PLAYS FOR CELL PROTECTION HOWEVER, THERE ARE APPARENT LIMITATIONS IN USE OF THE MOUSE MODELS FOR INSTANCE, RATS EXHIBIT MORE SUITABLE FEATURES FOR TOXICOLOGICAL OR PHYSIOLOGICAL EXAMINATIONS THAN MICE IN THIS STUDY, WE GENERATED 2 LINES OF NRF2 KNOCKOUT RATS BY USING A GENOME EDITING TECHNOLOGY; 1 LINE HARBORS A 7-BP DELETION Δ7 AND THE OTHER LINE HARBORS A 1-BP INSERTION +1 IN THE NRF2 GENE IN THE LIVERS OF RATS HOMOZYGOUSLY DELETING THE NRF2 GENE, AN ACTIVATOR OF NRF2 SIGNALING, CDDO-IM, COULD NOT INDUCE EXPRESSION OF REPRESENTATIVE NRF2 TARGET GENES TO EXAMINE ALTERED TOXICOLOGICAL RESPONSE, WE TREATED THE NRF2 KNOCKOUT RATS WITH AFLATOXIN B1 AFB1, A CARCINOGENIC MYCOTOXIN THAT ELICITS GENE MUTATIONS THROUGH BINDING OF ITS METABOLITES TO DNA AND FOR WHICH THE RAT HAS BEEN PROPOSED AS A REASONABLE SURROGATE FOR HUMAN TOXICITY INDEED, IN THE NRF2 KNOCKOUT RAT LIVERS THE ENZYMES OF THE AFB1 DETOXICATION PATHWAY WERE SIGNIFICANTLY DOWNREGULATED SINGLE DOSE ADMINISTRATION OF AFB1 INCREASED HEPATOTOXICITY AND BINDING OF AFB1-N7-GUANINE TO HEPATIC DNA IN NRF2 KNOCKOUT RATS COMPARED WITH WILD-TYPE NRF2 KNOCKOUT RATS REPEATEDLY TREATED WITH AFB1 WERE PRONE TO LETHALITY AND CDDO-IM WAS NO LONGER PROTECTIVE THESE RESULTS DEMONSTRATE THAT NRF2 KNOCKOUT RATS ARE QUITE SENSITIVE TO AFB1 TOXICITIES AND THIS RAT GENOTYPE EMERGES AS A NEW MODEL ANIMAL IN TOXICOLOGY. PMID:27071940

  12. Neurobehavioral changes in mice exposed to fast neutrons in utero.

    PubMed

    Ishida, Yuka; Ohmachi, Yasushi; Takai, Nobuhiko; Hiraoka, Takeshi; Ogiu, Toshiaki; Nishikawa, Tetsu; Nishimura, Yoshikazu; Shimada, Yoshiya

    2011-01-01

    Epidemiological studies have revealed that radiation causes brain development abnormalities in atomic bomb survivors exposed in utero. Rat and mouse studies have also shown that prenatal exposure to low-linear energy transfer radiation induces developmental brain anomalies. Because the effects of prenatal irradiation on adult behavior patterns remain largely unknown, the present study investigated the effects of neutron exposure in utero on postnatal behavior patterns in mice. [C57BL/6J × C3H/He] hybrid (B6C3F1) mice were exposed to cyclotron-derived fast neutrons with peak energy of 10 MeV (0.02-0.2 Gy) or Cs-137 gamma-rays (0.2-1.5 Gy) on embryonic day 13.5. At 5.5-8 months of age, the neurobehavior of male offspring was examined by Rota-rod treadmill and locomotor activity. The accumulation of radio-labeled drug at muscarinic acetylcholine and serotonin receptors in mice from control and neutron-irradiated groups was determined by the tracer method. Locomotor activity during the dark period increased in the 0.02 Gy neutron-irradiated group. Furthermore, at 5.5 months of age, tracer binding in vivo to the muscarinic acetylcholine increased and to the serotonin receptors decreased in the 0.02 Gy neutron-irradiated group. In conclusion, the present study reveals that a certain "low-dose window" may exist for radiation-induced changes in neurobehavior and binding to neurotransmitter receptors, because there was correlation in neurobehavior and binding to neurotransmitter receptors in the 0.02 Gy neutron-irradiated group though there was not correlation in the neutron-irradiated groups more than 0.05 Gy. PMID:21422737

  13. Inducibility of aryl hydrocarbon hydroxylase in BALB/c/ki mice exposed to urban air pollution.

    PubMed

    Mostardi, R A; Ely, D L; Liebelt, A; Grossman, S; Fu, M M

    1981-05-01

    In two separate experiments BALB/c/ki mice were exposed to urban air pollution. Mice exposed to clean air served as controls. In both experiments there were no obvious quantitative or qualitative differences in lung or liver tissue examined by light microscopy. In both experiments higher aryl hydrocarbon hydroxylase activities and higher trace metal concentrations were observed in the mice exposed to polluted urban air. These data are interpreted in terms of health hazards of urban air pollutants. PMID:7265310

  14. Electrophoresis pattern of serum from mice exposed to different concentrations of sulfur dioxide

    NASA Technical Reports Server (NTRS)

    Singh, J.

    1977-01-01

    Three day old mice were continuously exposed to sulphur dioxide concentrations at 0ppm, 0.05ppm, 0.15ppm and 1ppm for eight weeks. At the end of the experiment, blood samples were collected and centrifuged for electrophoresis studies of the serum in 5 percent acrylamide gel. The length of bands of different serum proteins from the SO2 exposed mice was at a variance as compared with the length of bands from the control exposed mice and alpha-1 band seems to be missing from the serum of SO2 exposed mice.

  15. Immunological studies on mice exposed subacutely to methyl isocyanate

    SciTech Connect

    Tucker, A.N.; Bucher, J.R.; Germolec, D.R.; Silver, M.T.; Vore, S.J.; Luster, M.I.

    1987-06-01

    The immunotoxicity of methyl isocyanate (MIC) was evaluated in female B6C3F1 mice exposed via inhalation to 0, 1, or 3 ppm for 6 hr per day on 4 consecutive days. The antibody response to sheep erythrocytes and natural killer cell activity were found to be unaffected by MIC exposure. Although lymphoproliferative responses to mitogens were moderately suppressed by MIC, the differences were not statistically significant. The response of splenic lymphocytes to allogeneic leukocytes in a mixed leukocyte response (MLR) was suppressed in a dose-related fashion and was significantly different from the control response at the 3 ppm level. This effect was thought to be secondary and a result of general toxicity rather than a direct effect of MIC on the immune system. Furthermore, resistance to the infectious agents Listeria monocytogenes, mouse malaria parasite, and influenza virus, or to transplantable tumor cells was not compromised by MIC exposure. Thus, the immune system does not appear to be a primary target for MIC toxicity.

  16. SYSTEMS FOR EXPOSING MICE TO 2,450-MHZ ELECTROMAGNETIC FIELDS

    EPA Science Inventory

    Two systems for exposing mice to 2,450-MHz electromagnetic fields are described. In a waveguide system, four mice were placed in a Styrofoam cage and exposed dorsally to circularly polarized electromagnetic fields. The temperature and humidity in the mouse holder were kept consta...

  17. Changes in delayed hypersensitivity reaction in mice exposed to O/sub 3/

    SciTech Connect

    Fujimaki, H.; Shiraishi, F.; Ashikawa, T.; Murakami, M.

    1987-06-01

    BALB/c mice were continuously exposed to 0.8 ppm O/sub 3/ for 1, 3, 7, and 14 days. Ozone exposure suppressed the delayed hypersensitivity (DH) reaction to sheep red blood cells (SRBC). The maximum effect was seen after 7 days of exposure. To estimate the suppression of the DH reaction by O/sub 3/ exposure, the numbers of lymphocytes in thymus and blood of exposed mice were compared with those of control mice. A decrease in the numbers of lymphocytes in both thymus and blood was observed in O/sub 3/-exposed mice. The percentage of T and B lymphocytes in blood of exposed mice was the same as that in blood of control mice. These results suggest that 0.8 ppm O/sub 3/ exposure affects the T lymphocytes required for DH reactions.

  18. Dominant lethal mutation test in male mice exposed to 900MHz radiofrequency fields.

    PubMed

    Zhu, Shunxing; Zhang, Jie; Liu, Chun; He, Qina; Vijayalaxmi; Prihoda, Thomas J; Tong, Jian; Cao, Yi

    2015-10-01

    Adult male ICR mice were exposed to continuous wave 900MHz radiofrequency fields (RF) at 1.6mW/cm(2) power intensity (whole body average specific absorption rate of 0.731W/kg) for 4 hour/day for 15 days. At the end of exposure, each mouse was caged with 3 mature virgin female mice for mating. After 7 days, each male mouse was transferred to a fresh cage and mated with a second batch of 3 females. This process was repeated for a total of 4 consecutive weeks. Sham exposed male mice and those subjected to an acute 2Gy γ-irradiation (GR) were handled similarly and used as un-exposed and positive controls, respectively. All females were sacrificed on the 18th day of gestation and presumptive mating and, the contents in their uteri were examined. The overall observations during the 4 weeks of mating indicated that the un-exposed female mice mated to RF-exposed male mice showed no significant differences in the percentage of pregnancies, total implants, live implants and dead implants when compared with those mated with sham-exposed mice. In contrast, female mice mated with GR-exposed males showed a consistent pattern of significant differences in the above indices in each and all 4 weeks of mating. Thus, the data indicated an absence of mutagenic potential of RF exposure in the germ cells of male mice. PMID:26433262

  19. 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 ...

  20. Immunization of mice with Trypanosoma rhodesiense exposed to ultraviolet irradiation

    SciTech Connect

    Charoenvit, Y.; Campbell, G.H.

    1981-11-01

    Exposure time of Trypanosoma rhodesiense as short as 1 minute to ultraviolet (uv) light prevents the organisms from causing infection. Live trypanosome challenge of mice immunized with uv-irradiated trypanosomes results in sterile immunity. This allows a method for the induction of protective immunity to experimental trypanosomiasis which can be performed in most laboratories using uv germicidal lamps found in sterile hoods.

  1. RAG1/2 knockout pigs with severe combined immunodeficiency.

    PubMed

    Huang, Jiao; Guo, Xiaogang; Fan, Nana; Song, Jun; Zhao, Bentian; Ouyang, Zhen; Liu, Zhaoming; Zhao, Yu; Yan, Quanmei; Yi, Xiaoling; Schambach, Axel; Frampton, Jon; Esteban, Miguel A; Yang, Dongshan; Yang, Huaqiang; Lai, Liangxue

    2014-08-01

    Pigs share many physiological, biochemical, and anatomical similarities with humans and have emerged as valuable large animal models for biomedical research. Considering the advantages in immune system resemblance, suitable size, and longevity for clinical practical and monitoring purpose, SCID pigs bearing dysfunctional RAG could serve as important experimental tools for regenerative medicine, allograft and xenograft transplantation, and reconstitution experiments related to the immune system. In this study, we report the generation and phenotypic characterization of RAG1 and RAG2 knockout pigs using transcription activator-like effector nucleases. Porcine fetal fibroblasts were genetically engineered using transcription activator-like effector nucleases and then used to provide donor nuclei for somatic cell nuclear transfer. We obtained 27 live cloned piglets; among these piglets, 9 were targeted with biallelic mutations in RAG1, 3 were targeted with biallelic mutations in RAG2, and 10 were targeted with a monoallelic mutation in RAG2. Piglets with biallelic mutations in either RAG1 or RAG2 exhibited hypoplasia of immune organs, failed to perform V(D)J rearrangement, and lost mature B and T cells. These immunodeficient RAG1/2 knockout pigs are promising tools for biomedical and translational research. PMID:24973446

  2. Increased Myeloid Cell Production and Lung Bacterial Clearance in Mice Exposed to Cigarette Smoke.

    PubMed

    Basilico, Paola; Cremona, Tiziana P; Oevermann, Anna; Piersigilli, Alessandra; Benarafa, Charaf

    2016-03-01

    Pneumonia is a leading cause of hospitalization in patients with chronic obstructive pulmonary disease (COPD). Although most patients with COPD are smokers, the effects of cigarette smoke exposure on clearance of lung bacterial pathogens and on immune and inflammatory responses are incompletely defined. Here, clearance of Streptococcus pneumoniae and Pseudomonas aeruginosa and associated immune responses were examined in mice exposed to cigarette smoke or after smoking cessation. Mice exposed to cigarette smoke for 6 weeks or 4 months demonstrated decreased lung bacterial burden compared with air-exposed mice when infected 16 to 24 hours after exposure. When infection was performed after smoke cessation, bacterial clearance kinetics of mice previously exposed to smoke reversed to levels comparable to those of control mice, suggesting that the observed defects were not dependent on adaptive immunological memory to bacterial determinants found in smoke. Comparing cytokine levels and myeloid cell production before infection in mice exposed to cigarette smoke with mice never exposed or after smoke cessation revealed that reduced bacterial burden was most strongly associated with higher levels of IL-1β and granulocyte-macrophage colony-stimulating factor in the lungs and with increased neutrophil reserve and monocyte turnover in the bone marrow. Using Serpinb1a-deficient mice with reduced neutrophil numbers and treatment with granulocyte colony-stimulating factor showed that increased neutrophil numbers contribute only in part to the effect of smoke on infection. Our findings indicate that cigarette smoke induces a temporary and reversible increase in clearance of lung pathogens, which correlates with local inflammation and increased myeloid cell output from the bone marrow. PMID:26273827

  3. Adaptive Response in Mice Exposed to 900 MHz Radiofrequency Fields: Primary DNA Damage

    PubMed Central

    Zhou, Zhen; Zhang, Jie; Tong, Jian; Cao, Yi

    2012-01-01

    The phenomenon of adaptive response (AR) in animal and human cells exposed to ionizing radiation is well documented in scientific literature. We have examined whether such AR could be induced in mice exposed to non-ionizing radiofrequency fields (RF) used for wireless communications. Mice were pre-exposed to 900 MHz RF at 120 µW/cm2 power density for 4 hours/day for 1, 3, 5, 7 and 14 days and then subjected to an acute dose of 3 Gy γ-radiation. The primary DNA damage in the form of alkali labile base damage and single strand breaks in the DNA of peripheral blood leukocytes was determined using the alkaline comet assay. The results indicated that the extent of damage in mice which were pre-exposed to RF for 1 day and then subjected to γ-radiation was similar and not significantly different from those exposed to γ-radiation alone. However, mice which were pre-exposed to RF for 3, 5, 7 and 14 days showed progressively decreased damage and was significantly different from those exposed to γ-radiation alone. Thus, the data indicated that RF pre-exposure is capable of inducing AR and suggested that the pre-exposure for more than 4 hours for 1 day is necessary to elicit such AR. PMID:22389679

  4. 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. PMID:26163175

  5. Curcumin improves liver damage in male mice exposed to nicotine

    PubMed Central

    Salahshoor, Mohammadreza; Mohamadian, Sabah; Kakabaraei, Seyran; Roshankhah, Shiva; Jalili, Cyrus

    2015-01-01

    The color of turmeric (薑黃 jiāng huáng) is because of a substance called curcumin. It has different pharmacological effects, such as antioxidant and anti-inflammatory properties. Nicotine is a major pharmacologically active substance in cigarette smoke. It is mainly metabolized in the liver and causes devastating effects. This study was designed to evaluate the protective role of curcumin against nicotine on the liver in mice. Forty-eight mice were equally divided into eight groups; control (normal saline), nicotine (2.5 mg/kg), curcumin (10, 30, and 60 mg/kg) and curcumin plus nicotine-treated groups. Curcumin, nicotine, and curcumin plus nicotine (once a day) were intraperitoneally injected for 4 weeks. The liver weight and histology, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and serum nitric oxide levels have been studied. The results indicated that nicotine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein, liver enzymes level, and blood serum nitric oxide level compared with the saline group (p < 0.05). However, curcumin and curcumin plus nicotine administration substantially increased liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes, and nitric oxide levels in all groups compared with the nicotine group (p < 0.05). Curcumin demonstrated its protective effect against nicotine-induced liver toxicity. PMID:27114942

  6. Curcumin improves liver damage in male mice exposed to nicotine.

    PubMed

    Salahshoor, Mohammadreza; Mohamadian, Sabah; Kakabaraei, Seyran; Roshankhah, Shiva; Jalili, Cyrus

    2016-04-01

    The color of turmeric ( jiāng huáng) is because of a substance called curcumin. It has different pharmacological effects, such as antioxidant and anti-inflammatory properties. Nicotine is a major pharmacologically active substance in cigarette smoke. It is mainly metabolized in the liver and causes devastating effects. This study was designed to evaluate the protective role of curcumin against nicotine on the liver in mice. Forty-eight mice were equally divided into eight groups; control (normal saline), nicotine (2.5 mg/kg), curcumin (10, 30, and 60 mg/kg) and curcumin plus nicotine-treated groups. Curcumin, nicotine, and curcumin plus nicotine (once a day) were intraperitoneally injected for 4 weeks. The liver weight and histology, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and serum nitric oxide levels have been studied. The results indicated that nicotine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein, liver enzymes level, and blood serum nitric oxide level compared with the saline group (p < 0.05). However, curcumin and curcumin plus nicotine administration substantially increased liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes, and nitric oxide levels in all groups compared with the nicotine group (p < 0.05). Curcumin demonstrated its protective effect against nicotine-induced liver toxicity. PMID:27114942

  7. Automated Measurement of Pulmonary Emphysema and Small Airway Remodeling in Cigarette Smoke-exposed Mice

    PubMed Central

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

    2015-01-01

    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. PMID:25651034

  8. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet

    PubMed Central

    Kesby, James P.; Kim, Jane J.; Scadeng, Miriam; Woods, Gina; Kado, Deborah M.; Olefsky, Jerrold M.; Jeste, Dilip V.; Achim, Cristian L.; Semenova, Svetlana

    2015-01-01

    Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions. PMID:26448649

  9. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

    PubMed

    Kesby, James P; Kim, Jane J; Scadeng, Miriam; Woods, Gina; Kado, Deborah M; Olefsky, Jerrold M; Jeste, Dilip V; Achim, Cristian L; Semenova, Svetlana

    2015-01-01

    Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions. PMID:26448649

  10. Tiotropium Attenuates Virus-Induced Pulmonary Inflammation in Cigarette Smoke-Exposed Mice.

    PubMed

    Bucher, Hannes; Duechs, Matthias J; Tilp, Cornelia; Jung, Birgit; Erb, Klaus J

    2016-06-01

    Viral infections trigger exacerbations in chronic obstructive pulmonary disease (COPD), and tiotropium, a M3 receptor antagonist, reduces exacerbations in patients by unknown mechanisms. In this report, we investigated whether tiotropium has anti-inflammatory effects in mice exposed to cigarette smoke (CS) and infected with influenza virus A/PR/8/34 (H1N1) or respiratory syncytial virus (RSV) and compared these effects with those of steroid fluticasone and PDE4-inhibitor roflumilast. Mice were exposed to CS; infected with H1N1 or RSV; and treated with tiotropium, fluticasone, or roflumilast. The amount of cells and cytokine levels in the airways, lung function, and viral load was determined. NCI-H292 cells were infected with H1N1 or RSV and treated with the drugs. In CS/H1N1-exposed mice, tiotropium reduced neutrophil and macrophage numbers and levels of interleukin-6 (IL-6) and interferon-γ (IFN-γ) in the airways and improved lung function. In contrast, fluticasone increased the loss of body weight; failed to reduce neutrophil or macrophage numbers; increased IL-6, KC, and tumor necrosis factor-α (TNF-α) in the lungs; and worsened lung function. Treatment with roflumilast reduced macrophage numbers, IL-6, and KC in the lungs but had no effect on neutrophil numbers or lung function. In CS/RSV-exposed mice, treatment with tiotropium, but not fluticasone or roflumilast, reduced neutrophil numbers and IL-6 and TNF-α levels in the lungs. Viral load of H1N1 and RSV was significantly elevated in CS/virus-exposed mice and NCI-H292 cells after fluticasone treatment, whereas tiotropium and roflumilast had no effect. In conclusion, tiotropium has anti-inflammatory effects on CS/virus-induced inflammation in mice that are superior to the effects of roflumilast and fluticasone. This finding might help to explain the observed reduction of exacerbation rates in COPD patients. PMID:27016458

  11. Tiotropium Attenuates Virus-Induced Pulmonary Inflammation in Cigarette Smoke–Exposed Mice

    PubMed Central

    Bucher, Hannes; Duechs, Matthias J.; Tilp, Cornelia; Jung, Birgit

    2016-01-01

    Viral infections trigger exacerbations in chronic obstructive pulmonary disease (COPD), and tiotropium, a M3 receptor antagonist, reduces exacerbations in patients by unknown mechanisms. In this report, we investigated whether tiotropium has anti-inflammatory effects in mice exposed to cigarette smoke (CS) and infected with influenza virus A/PR/8/34 (H1N1) or respiratory syncytial virus (RSV) and compared these effects with those of steroid fluticasone and PDE4-inhibitor roflumilast. Mice were exposed to CS; infected with H1N1 or RSV; and treated with tiotropium, fluticasone, or roflumilast. The amount of cells and cytokine levels in the airways, lung function, and viral load was determined. NCI-H292 cells were infected with H1N1 or RSV and treated with the drugs. In CS/H1N1-exposed mice, tiotropium reduced neutrophil and macrophage numbers and levels of interleukin-6 (IL-6) and interferon-γ (IFN-γ) in the airways and improved lung function. In contrast, fluticasone increased the loss of body weight; failed to reduce neutrophil or macrophage numbers; increased IL-6, KC, and tumor necrosis factor-α (TNF-α) in the lungs; and worsened lung function. Treatment with roflumilast reduced macrophage numbers, IL-6, and KC in the lungs but had no effect on neutrophil numbers or lung function. In CS/RSV-exposed mice, treatment with tiotropium, but not fluticasone or roflumilast, reduced neutrophil numbers and IL-6 and TNF-α levels in the lungs. Viral load of H1N1 and RSV was significantly elevated in CS/virus-exposed mice and NCI-H292 cells after fluticasone treatment, whereas tiotropium and roflumilast had no effect. In conclusion, tiotropium has anti-inflammatory effects on CS/virus-induced inflammation in mice that are superior to the effects of roflumilast and fluticasone. This finding might help to explain the observed reduction of exacerbation rates in COPD patients. PMID:27016458

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

    SciTech Connect

    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 demonstrate 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.

  13. Iron and copper accumulation in the brain of coxsackievirus-infected mice exposed to cadmium

    SciTech Connect

    Ilbaeck, N.-G. . E-mail: nils-gunnar.ilback@slv.se; Lindh, U.; Minqin, R.; Friman, G.; Watt, F.

    2006-11-15

    Cadmium (Cd) is a potentially toxic metal widely distributed in the environment and known to cause adverse health effects in humans. During coxsackievirus infection, the concentrations of essential and nonessential trace elements (e.g., iron (Fe), copper (Cu), and Cd) change in different target organs of the infection. Fe and Cu are recognized cofactors in host defence reactions, and Fe is known to be associated with certain pathological conditions of the brain. However, whether nonessential trace elements could influence the balance of essential trace elements in the brain is unknown. In this study the brain Fe, Cu, and Cd contents were measured through inductively coupled plasma mass spectrometry and their distributions determined by nuclear microscopy in the early phase (day 3) of coxsackievirus B3 (CB3) infection in nonexposed and in Cd-exposed female Balb/c mice. In CB3 infection the brain is a well-known target that has not been studied with regard to trace element balance. The brain concentration of Cu compared with that of noninfected control mice was increased by 9% (P<0.05) in infected mice not exposed to Cd and by 10% (not significant) in infected Cd-exposed mice. A similar response was seen for Fe, which in infected Cd-exposed mice, compared to noninfected control mice, tended to increase by 16%. Cu showed an even tissue distribution, whereas Fe was distributed in focal deposits. Changes in Cd concentration in the brain of infected mice were less consistent but evenly distributed. Further studies are needed to define whether the accumulation and distribution of trace elements in the brain have an impact on brain function.

  14. CIRCULATING ANTIBODY RESPONSE OF MICE EXPOSED TO 9-GHZ PULSED MICROWAVE RADIATION

    EPA Science Inventory

    Female CD-1 mice immunized against the bacterium Streptococcus pneumoniae type III were exposed to 9-GHz pulsed microwaves (pulse repetition rate 970-1.000, pulse width 1.0 micro seconds, peak power 1 W/cm2) at an average incident power density of 1 mW/sq.cm. (calculated SAR = 0....

  15. Tularemia among Free-Ranging Mice without Infection of Exposed Humans, Switzerland, 2012

    PubMed Central

    Origgi, Francesco C.; König, Barbara; Lindholm, Anna K.; Mayor, Désirée

    2015-01-01

    The animals primarily infected by Francisella tularensis are rapidly consumed by scavengers, hindering ecologic investigation of the bacterium. We describe a 2012 natural tularemia epizootic among house mice in Switzerland and the assessment of infection of exposed humans. The humans were not infected, but the epizootic coincided with increased reports of human cases in the area. PMID:25531919

  16. 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...

  17. 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...

  18. Postexposure aerosolized heparin reduces lung injury in chlorine-exposed mice

    PubMed Central

    Zarogiannis, Sotirios G.; Wagener, Brant M.; Basappa, Susanna; Doran, Stephen; Rodriguez, Cilina A.; Jurkuvenaite, Asta; Pittet, Jean Francois

    2014-01-01

    Chlorine (Cl2) is a highly reactive oxidant gas that, when inhaled, may cause acute lung injury culminating in death from respiratory failure. In this study, we tested the hypothesis that exposure of mice to Cl2 causes intra-alveolar and systemic activation of the coagulation cascade that plays an important role in development of lung injury. C57Bl/6 mice were exposed to Cl2 (400 for 30 min or 600 ppm for 45 min) in environmental chambers and then returned to room air for 1 or 6 h. Native coagulation (NATEM) parameters such as blood clotting time and clot formation time were measured in whole blood by the viscoelastic technique. D-dimers and thrombin-anti-thrombin complexes were measured in both plasma and bronchoalveolar lavage fluid (BALF) by ELISA. Our results indicate that mice exposed to Cl2 gas had significantly increased clotting time, clot formation time, and D-dimers compared with controls. The thrombin-anti-thrombin complexes were also increased in the BALF of Cl2 exposed animals. To test whether increased coagulation contributed to the development of acute lung injury, mice exposed to Cl2 and returned to room air were treated with aerosolized heparin or vehicle for 20 min. Aerosolized heparin significantly reduced protein levels and the number of inflammatory cells in the BALF at 6 h postexposure. These findings highlight the importance of coagulation abnormities in the development of Cl2-induced lung injury. PMID:25038191

  19. 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...

  20. [Genetic effects in mice exposed to the 10-km area around the Chernobyl Atomic Energy Station].

    PubMed

    Pomerantseva, M D; Chekhovich, A V; Ramaiĭa, L K; Shevchenko, V A; Shaks, A I; Lobaneva, N V

    1990-10-01

    Mice (CBAxC57BL) F of both sexes were exposed within the 10 km zone of Chernobyl nuclear power station. Genetic damage of phone chronic effect of increased radiation in exposed adult mice and in the course of embryogenesis was studied. The total absorbed radiation doses in testes varied from 1.85 to 0.42 Gy in embryos and from 3.4 to 2.7 Gy in adult males. Increase of dominant lethal mutations (DLM) and abnormal sperm heads (ASH) was only observed right after the end of exposure of adult males. The yield of reciprocal translocations (RT) in these males was relatively low. Among the males exposed at the stage of early embryogenesis, 4 heterozygotes for RT were revealed. In other males of this group the RT yield was low. PMID:2283055

  1. 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. PMID:24012645

  2. Disruption of cerebellar microzonal organization in GluD2 (GluRδ2) knockout mouse

    PubMed Central

    Hashizume, Miki; Miyazaki, Taisuke; Sakimura, Kenji; Watanabe, Masahiko; Kitamura, Kazuo; Kano, Masanobu

    2013-01-01

    Cerebellar cortex has an elaborate rostrocaudal organization comprised of numerous microzones. Purkinje cells (PCs) in the same microzone show synchronous activity of complex spikes (CSs) evoked by excitatory inputs from climbing fibers (CFs) that arise from neurons in the inferior olive (IO). The synchronous CS activity is considered to depend on electrical coupling among IO neurons and anatomical organization of the olivo-cerebellar projection. To determine how the CF–PC wiring contributes to the formation of microzone, we examined the synchronous CS activities between neighboring PCs in the glutamate receptor δ2 knockout (GluD2 KO) mouse in which exuberant surplus CFs make ectopic innervations onto distal dendrites of PCs. We performed in vivo two-photon calcium imaging for PC populations to detect CF inputs. Neighboring PCs in GluD2 KO mice showed higher synchrony of calcium transients than those in wild-type (control) mice. Moreover, the synchrony in GluD2 KO mice hardly declined with mediolateral separation between PCs up to ~200 μm, which was in marked contrast to the falloff of the synchrony in control mice. The enhanced synchrony was only partially affected by the blockade of gap junctional coupling. On the other hand, transverse CF collaterals in GluD2 KO mice extended beyond the border of microzone and formed locally clustered ectopic synapses onto dendrites of neighboring PCs. Furthermore, PCs in GluD2 KO mice exhibited clustered firing (Cf), the characteristic CF response that was not found in PCs of wild-type mice. Importantly, Cf was often associated with localized calcium transients in distal dendrites of PCs, which are likely to contribute to the enhanced synchrony of calcium signals in GluD2 KO mice. Thus, our results indicate that CF signals in GluD2 KO mice propagate across multiple microzones, and that proper formation of longitudinal olivo-cerebellar projection is essential for the spatiotemporal organization of CS activity in the

  3. Anti-apoptotic role of retinoic acid in the inner ear of noise-exposed mice

    SciTech Connect

    Ahn, Joong Ho; Kang, Hun Hee; Kim, Young-Jin; Chung, Jong Woo . E-mail: jwchung@amc.seoul.kr

    2005-09-23

    Exposure to loud noise can induce temporary or permanent hearing loss, and acoustic trauma is the major cause of hearing impairment in industrial nations. However, the mechanisms underlying the death of hair cells after acoustic trauma remain unclear. In addition to its involvement in cellular stress and apoptosis, the c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, is involved in cell survival, transformation, embryonic morphogenesis, and differentiation. JNK is primarily activated by various environmental stresses including noise, and the phenotypic result appears be to cell death. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A that regulates a wide range of biological processes, including cell proliferation, differentiation, and morphogenesis. We evaluated the role of ATRA in preserving hearing in mice exposed to noise that can induce permanent hearing loss. Mice fed with ATRA before and during 3 consecutive days of noise exposure had a more preserved hearing threshold than mice fed sesame oil or saline. Histological and TUNEL staining of the cochlea showed significantly enhanced preservation of the organ of Corti, including outer hair cells and relatively low apoptotic nuclei, in mice-fed ATRA than in mice-fed sesame oil or saline. Phospho-JNK immunohistochemistry showed that ATRA inhibited the activation of JNK. These results suggest that ATRA has an anti-apoptotic effect on cochleae exposed to noise.

  4. Influence of conditioned psychological stress on immunological recovery in mice exposed to low-dose x irradiation

    SciTech Connect

    Sato, K.; Flood, J.F.; Makinodan, T.

    1984-05-01

    A study was initiated to determine the effects of psychological stress on the immune response in BALB/c mice recovering from exposure to a low dose of ionizing radiation. Mice were first subjected to conditioning training for 12 days, then exposed to 200 R, subjected to psychological stress for 14 days, and assessed for peak anti-sheep RBC response. The seven treatment groups included two unirradiated groups and five irradiated groups. Mice exposed to 200 R and then subjected to conditioned psychological stress responded less vigorously to antigenic stimulation than those of the other irradiated groups. The psychological stress imposed upon these mice did not influence the antibody-forming capacity of unirradiated mice. These results indicate that a psychological stress which did not affect the immunological activity of unirradiated mice can curtail the immunological recovery of mice exposed to low doses of ionizing radiation.

  5. Specific Accumulation of Lipid Droplets in Hepatocyte Nuclei of PFOA-exposed BALB/c Mice

    NASA Astrophysics Data System (ADS)

    Wang, Ling; Wang, Yu; Liang, Yong; Li, Jia; Liu, Yuchen; Zhang, Jie; Zhang, Aiqian; Fu, Jianjie; Jiang, Guibin

    2013-07-01

    Lipid droplets (LDs), which are important storage structures for neutral lipids and organelles of diverse functions, participate in various cellular activities. In this study, BALB/c mice, fed a regular or a high-fat diet, were exposed to the synthetic perfluorinated compound, perfluorooctanoic acid (PFOA). PFOA-exposed mice had altered serum lipid and lipoprotein levels, and hydropic degeneration or ballooning degeneration of hepatocytes. Moreover, we report for the first time that LDs accumulate in hepatic nuclei after PFOA exposure. As PFOA resembles fatty acids (FA) in its structure, this chemical may interfere with the transportation and metabolism of FA as well as LDs in the cell. This abnormal localization of LDs in the nucleus may be related to the cause of PFOA toxicity.

  6. Influences of Diabetes on Hearing Recovery in Noise-Exposed Mice

    PubMed Central

    Yang, Chan Joo; Lee, Ji-Won

    2015-01-01

    Background and Objectives Many studies have reported an association between diabetes and hearing loss. However, these reports were mainly abstractive correlations between common hearing loss and the incidence of diabetes. Therefore, we evaluated the impact of diabetes on the occurrence of and recovery from noise-induced hearing loss. Materials and Methods We used 5-week-old C57BLKS/J-m wild type (+/+) and C57BLKS/J-db/db male mice as the control and diabetic groups, respectively. In one set of experiments, the hearing levels of control and diabetic mice were measured weekly for 7 weeks. In a second set of experiments, control and diabetic mice were exposed to broadband white noise of 110 dB SPL for 3 hours; hearing levels were analyzed before and immediately after exposure, 1, 3, and 5 days, and 1, 2, 3, and 4 weeks after the noise exposure. Results The hearing levels of the control group were better than those of the diabetic group at each weekly revision for 7 weeks at all auditory brainstem response frequencies (4, 8, 16, and 32 kHz). After noise exposure, both groups of mice showed an immediate increase in the hearing level threshold at all frequencies. Subsequent threshold recovery was seen in both groups with no difference in the hearing level recovery rates between the two groups. Conclusions Hearing level with aging becomes significantly impaired earlier in diabetic mice but hearing recovery after noise exposure is similar between diabetic and control mice. PMID:26771012

  7. In vivo estimation of pigmentation in ultraviolet-exposed hairless mice.

    PubMed

    Hansen, A B; Bech-Thomsen, N; Wulf, H C

    1995-02-01

    A new in vivo method of visual scoring of pigmentation in hairless hr/hr mice with a C3H/Tif background is described. The mice were placed under a bank of 6 Philips TL08 fluorescent ultraviolet A (UVA) tubes in a dark room, and the pigmentation of the skin was compared with a Kodak Gray Scale with 20 different shades from white to black. The radiation from the tubes changed both the color of the back of the mouse and the gray scale into purple hues. The purple color of the back of each mouse could then be classified as one of 20 shades on the gray scale. An experiment was conducted exposing 3 groups of 20 mice to different doses of UV radiation from Philips TL01 tubes. One group of 20 mice was not irradiated and served as control. The pigmentation of each mouse was scored by one investigator every 2-3 weeks. After a few weeks of exposure a clear distinction between the groups was seen. To evaluate the inter- and intrapersonal variation of the method, 30 mice with various degrees of pigmentation were scored independently and blindly by two investigators. This was done twice during the study with a few days' interval. No interpersonal difference was found, but one investigator scored differently the first and second time by only 0.5 points. The described method provides a reproducible in vivo method, with very good discrimination, for estimation of pigmentation in hairless mice. PMID:7654561

  8. Aortic smooth muscle cell alterations in mice systemically exposed to arsenic.

    PubMed

    Chen, Shih-Chieh; Huang, Shin-Yin; Lin, Wen-Ting; Yang, Rei-Cheng; Yu, Hsin-Su

    2016-05-01

    Previous epidemiological studies showed that chronic arsenic exposure is related to increased cardiovascular disease incidence. The detailed biochemical mechanisms by which arsenic exerts its effects remain unknown. Vascular disease progression is characterized by smooth muscle cell (SMC) phenotypic switching, vessel wall reorganization, and platelet-derived growth factor (PDGF) production. The objective of this study was to examine early biochemical and structural changes in the aortas of ICR mice systemically exposed to arsenic. Animals were fed sodium arsenite (20 mg/kg) via gavage 5 days/week or Milli-Q water only (control) for 8 weeks. Aortic proteins were subjected to two-dimensional (2-D) differential gel electrophoresis and proteomic studies. Two 2-D gel protein spots were identified as the same protein, smooth muscle (SM)22α, using proteomics. SM22α and Rho kinase 2 gene and protein expression were significantly decreased in the aortic tissue of arsenic-exposed mice compared with that of control mice. No atherosclerotic lesion formation or tissue injury was detected in the aortic wall of either the arsenic-fed or the control group. However, the percent (%) SMC area of the aortic wall was significantly decreased in arsenic-fed mice compared with that in control mice. Additionally, the expression levels of PDGF-BB and early growth response-1 (Egr-1) were significantly higher in the arsenic group than that in the control group. These findings reveal biochemical alterations of SM22α, PDGF, and Egr-1 in conjunction with decreased SMC area in the aortic wall of arsenic-fed mice. Arsenic may initiate aortic SMC alterations that subsequently lead to vascular dysfunction. PMID:26135927

  9. Expression of calmodulin-related genes in lead-exposed mice

    PubMed Central

    Liu, Xiao-Lin; Zhou, Xie-Lai; Jiang, Su-Jun; Yuan, Hong

    2015-01-01

    The toxic metal lead is a widespread environmental polutant that can adversely affect human health. However, the underlying mechanisms of lead-induced toxicity are still largely unknown. The mechanism of lead toxicity was presumed to involve cross reaction between Pb2+ and Ca2+ with calmodulin dependent systems. The aim of the present study was thus to identify differential expression of calmodulin-related genes in the spleen of lead-exposed mice. We performed microarray analysis to identify differentially expressed genes. RNAs from spleen tissue of lead exposed animals (n=6) and controls (n=6) were converted to labeled cRNA and hybridized to Illumina mouse WG-6_v2_Bead Chip. Expression profiles were analyzed using Illumina BeadStudio Application. Real-time RT-PCR was conducted to validate the microarray data. By microarray analysis 5 calmodulin-related genes (MAP2K6, CAMKK2, CXCR4, PHKA2, MYLK) were found to be differently expressed in lead exposed compared with control mice (p<0.05). The results of Real-time RT-PCR showed that MAP2K6 and CAMKK2 were up-regulated and CXCR4 was down-regulated in lead exposure, but there were no significant differences in PHKA2 and MYLK expression between the lead exposed and control group. These results show that lead exposure produced significant changes in expression of a variety of genes in the spleen and can affect calmodulin-related gene expression. PMID:27486376

  10. Impaired acquisition of swimming navigation in adult mice exposed prenatally to oxazepam.

    PubMed

    Dell'Omo, G; Wolfer, D; Alleva, E; Lipp, H P

    1993-01-01

    Prenatally administered oxazepam (OX) impairs adult radial maze performance in mice, possibly by permanent hippocampal changes. CDI mice were tested in swimming navigation, a sensitive indicator for hippocampal damage. Ten males and ten females were exposed to OX on fetal days 12-16 by maternal administration PO of 30 mg/kg/day and fostered at birth to untreated dams, while control mice received vehicle solution. All mice were tested at 8-9 weeks for ability to find a submerged platform in a fixed location (acquisition: 18 trials, 6 trials per day) and for capacity to re-orient towards a new platform position (reversal: 12 trials, 6 trials per day). OX mice showed a slight but significant impairment of swimming navigation during the initial part of training, as indicated by longer swimming paths during the fourth and fifth trial (day 1), an impairment due both to delayed habituation to the novel stressfull condition and acquisition of platform climbing but unrelated to navigational abilities. No treatment-dependent differences were observed in the reversal phase. During reversal, both OX and control females spent significantly more time in swimming across the location of the old platform. Unrelated to navigational performance, females showed a slightly but significantly higher swimming speed than males. Due to the absence of any navigational impairment, data suggest that prenatal exposure to oxazepam exerts long-term influence on adult learning capacities primarily through interaction with brain systems located outside the hippocampus. PMID:7870931

  11. Neurobehavioral phenotype of C57BL/6J mice prenatally and neonatally exposed to cigarette smoke

    PubMed Central

    Amos-Kroohs, Robyn M.; Williams, Michael T.; Braun, Amanda A.; Graham, Devon L; Webb, Cynthia L.; Birtles, Todd S.; Greene, Robert M.; Vorhees, Charles V.; Pisano, M. Michele

    2013-01-01

    Although maternal cigarette smoking during pregnancy is a well-documented risk factor for a variety of adverse pregnancy outcomes, how prenatal cigarette smoke exposure affects postnatal neurobehavioral/cognitive development remains poorly defined. In order to investigate the cause of an altered behavioral phenotype, mice developmentally exposed to a paradigm of ‘active’ maternal cigarette smoke is needed. Accordingly, cigarette smoke exposed (CSE) and air-exposed C57BL/6J mice were treated for 6 h per day in paired inhalation chambers throughout gestation and lactation and were tested for neurobehavioral effects while controlling for litter effects. CSE mice exhibited less than normal anxiety in the elevated zero maze, transient hypoactivity during a 1 h locomotor activity test, had longer latencies on the last day of cued Morris water maze testing, impaired hidden platform learning in the Morris water maze during acquisition, reversal, and shift trials, and impaired retention for platform location on probe trials after reversal but not after acquisition or shift. CSE mice also showed a sexually dimorphic response in central zone locomotion to a methamphetamine challenge (males under-responded and females over-responded), and showed reduced anxiety in the light-dark test by spending more time on the light side. No differences on tests of marble burying, acoustic startle response with prepulse inhibition, Cincinnati water maze, matching-to-sample Morris water maze, conditioned fear, forced swim, or MK-801-induced locomotor activation were found. Collectively, the data indicate that developmental cigarette smoke exposure induces subnormal anxiety in a novel environment, impairs spatial learning and reference memory while sparing other behaviors (route-based learning, fear conditioning, and forced swim immobility). The findings add support to mounting evidence that developmental cigarette smoke exposure has long-term adverse effects on brain function. PMID

  12. Neurobehavioral phenotype of C57BL/6J mice prenatally and neonatally exposed to cigarette smoke.

    PubMed

    Amos-Kroohs, Robyn M; Williams, Michael T; Braun, Amanda A; Graham, Devon L; Webb, Cynthia L; Birtles, Todd S; Greene, Robert M; Vorhees, Charles V; Pisano, M Michele

    2013-01-01

    Although maternal cigarette smoking during pregnancy is a well-documented risk factor for a variety of adverse pregnancy outcomes, how prenatal cigarette smoke exposure affects postnatal neurobehavioral/cognitive development remains poorly defined. In order to investigate the cause of an altered behavioral phenotype, mice developmentally exposed to a paradigm of 'active' maternal cigarette smoke is needed. Accordingly, cigarette smoke exposed (CSE) and air-exposed C57BL/6J mice were treated for 6h per day in paired inhalation chambers throughout gestation and lactation and were tested for neurobehavioral effects while controlling for litter effects. CSE mice exhibited less than normal anxiety in the elevated zero maze, transient hypoactivity during a 1h locomotor activity test, had longer latencies on the last day of cued Morris water maze testing, impaired hidden platform learning in the Morris water maze during acquisition, reversal, and shift trials, and impaired retention for platform location on probe trials after reversal but not after acquisition or shift. CSE mice also showed a sexually dimorphic response in central zone locomotion to a methamphetamine challenge (males under-responded and females over-responded), and showed reduced anxiety in the light-dark test by spending more time on the light side. No differences on tests of marble burying, acoustic startle response with prepulse inhibition, Cincinnati water maze, matching-to-sample Morris water maze, conditioned fear, forced swim, or MK-801-induced locomotor activation were found. Collectively, the data indicate that developmental cigarette smoke exposure induces subnormal anxiety in a novel environment, impairs spatial learning and reference memory while sparing other behaviors (route-based learning, fear conditioning, and forced swim immobility). The findings add support to mounting evidence that developmental cigarette smoke exposure has long-term adverse effects on brain function. PMID:23314114

  13. Fetal loss in mice exposed to magnetic fields during early pregnancy

    SciTech Connect

    Svedenstaal, B.M.; Johanson, K.J.

    1995-12-01

    The effects of low-frequency magnetic fields (MFs) on early pregnancy were studied in CBA/S mice. The magnetic field was a 20 kHz, 15 {micro}T sawtooth. Pregnant females were divided into four groups, two control groups and two exposed groups. One group was exposed to MFs continuously from day 1 postconception (pc) until day 5.5 pc, and the other group was exposed continuously until day 7 pc. All animals were sacrificed on day 19 pc, the day before partus, and their uterine contents were analyzed. No significant increase in the resorption (early fetal death) rate was found in the exposed animals compared to the sham controls. In the group exposed during days 1.0--5.5 pc, the body weight and length of the living fetuses were significantly decreased. Except on day 3 pc (progesterone) and day 13 pc (calcium) in the treated groups, there were no significant differences in progesterone and calcium levels in peripheral blood. Implantation occurred on the same day in MF-treated and control animals.

  14. Time-lapse analysis of tangential migration in Sema6A and PlexinA2 knockouts.

    PubMed

    Renaud, Julie; Chédotal, Alain

    2014-11-01

    In the developing cerebellum, granule cells migrate tangentially in the external granule cell layer and then radially and inward, across the molecular layer and Purkinje cell layer. We showed previously that the transmembrane semaphorin Sema6A and its receptor PlexinA2 control the ability of migrating granule cells to switch from one mode of migration to the other. In both Sema6A and PlexinA2 knockouts, a large number of granule cells remain in the molecular layer, a defect that is most likely due to abnormal nuclear translocation. We show here that the lack of Sema6A or PlexinA2 preferentially much more severely perturbs the migration of later-born granule cells than early-born ones. We also use a cerebellum slice model system and electroporation to perform time-lapse analysis of granule cell migration in wild-type mice, Sema6A and PlexinA2 knockouts. This study reveals that defects of tangential migration can be detected in bipolar granule cells before the initiation of radial migration. Our results also directly confirm that the absence of Sema6A does not perturb radial migration. PMID:25284064

  15. Data on megakaryocytes in the bone marrow of mice exposed to formaldehyde.

    PubMed

    Zhang, Yuchao; McHale, Cliona M; Liu, Xudong; Yang, Xu; Ding, Shumao; Zhang, Luoping

    2016-03-01

    Previously, we reported that occupational exposure to formaldehyde (FA) exposure in factory workers reduced platelet counts, http://dx.doi.org/10.1158/1055-9965.EPI-09-0762[1], while exposure in mice increased platelet counts http://dx.doi.org/10.1371/journal.pone.0074974[2]. Bone marrow megakaryocyte (MK) numbers were also increased in exposed mice, as determined qualitatively. The data presented here are from a quantitative evaluation of MK numbers in the bone marrow histopathological slides from the previous FA exposure experiments in mice. Bone marrow slides were prepared using a single 5 μm section of femur from 2 mice randomly selected from each exposure group (n=9) treated with 0, 0.5 and 3.0 mg/m(3) FA by nose-only inhalation. MKs were systemically counted and average MK frequency was calculated as the total MK per slide divided by the number of fields evaluated. Data are presented visually as microscopy views and graphically as MK frequency. PMID:26937474

  16. Data on megakaryocytes in the bone marrow of mice exposed to formaldehyde

    PubMed Central

    Zhang, Yuchao; McHale, Cliona M.; Liu, Xudong; Yang, Xu; Ding, Shumao; Zhang, Luoping

    2016-01-01

    Previously, we reported that occupational exposure to formaldehyde (FA) exposure in factory workers reduced platelet counts, http://dx.doi.org/10.1158/1055-9965.EPI-09-0762[1], while exposure in mice increased platelet counts http://dx.doi.org/10.1371/journal.pone.0074974[2]. Bone marrow megakaryocyte (MK) numbers were also increased in exposed mice, as determined qualitatively. The data presented here are from a quantitative evaluation of MK numbers in the bone marrow histopathological slides from the previous FA exposure experiments in mice. Bone marrow slides were prepared using a single 5 μm section of femur from 2 mice randomly selected from each exposure group (n=9) treated with 0, 0.5 and 3.0 mg/m3 FA by nose-only inhalation. MKs were systemically counted and average MK frequency was calculated as the total MK per slide divided by the number of fields evaluated. Data are presented visually as microscopy views and graphically as MK frequency. PMID:26937474

  17. DNA replication and unscheduled DNA synthesis in lungs of mice exposed to cigarette smoke

    SciTech Connect

    Rasmussen, R.E.; Boyd, C.H.; Dansie, D.R.; Kouri, R.E.; Henry, C.J.

    1981-07-01

    Mice of the hybrid strain BC3F1/Cum (C57BL/Cum X C3H/AnfCum) were chronically exposed to measured amounts of machine-generated whole Kentucky reference 2A1 cigarette smoke. DNA replication and unscheduled DNA synthesis (UDS) were measured in lung tissue in vitro using a short-term organ culture method. Within one week of beginning smoke exposure, DNA replicative activity, as indicated by incorporation of (3H)-thymidine into total lung DNA, was increased more than two-fold over sham-exposed controls and remained elevated as long as smoke exposure was continued. Treatment of lung tissues in vitro with either the lung carcinogen 4-nitroquinoline-1-oxide or methylmethane sulfonate stimulated UDS, measured as incorporation of (3H)thymidine into lung DNA in the presence of hydroxyurea, presumably as the result of DNA repair activity. Until the 10th to 12th week of smoke exposure, at which time the accumulated deposition of total particulate material in the lung was approximately 40 mg, the level of UDS stimulated by the alkylating chemicals declined to approximately 50% of that seen in lung tissue from sham-exposed control mice. If the mice were removed from smoke exposure, DNA replicative activity returned to normal levels within one week, but the UDS response to DNA damage remained depressed up to five months after ending smoke exposure. The results show that both transient and apparently permanent changes are produced in mouse lung as the result of exposure to cigarette smoke. The role of these changes in lung neoplasia is under investigation.

  18. 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

  19. Arginases I and II in lungs of ovalbumin-sensitized mice exposed to ovalbumin: Sources and consequences

    SciTech Connect

    Kenyon, Nicholas J.; Bratt, Jennifer M.; Linderholm, Angela L.; Last, Michael S.; Last, Jerold A.

    2008-08-01

    Arginase gene expression in the lung has been linked to asthma both in clinical studies of human patients and in the well-studied mouse model of ovalbumin-induced airway inflammation. Arginase is thought to regulate NO levels in the lung by its ability to divert arginine, the substrate for nitric oxide synthases that produce citrulline and NO, into an alternative metabolic pathway producing ornithine and urea. In the present study arginase I and arginase II concentrations were measured in isolated microdissected airway preparations from sensitized Balb/c mice exposed to ovalbumin aerosol. We found that arginase II was constitutively expressed in the airways of normal mice, whereas arginase I was undetectable in normal airways, while its expression was increased in airways of mice exposed to ovalbumin. The expression of arginase I strongly correlated with the presence of lung inflammation, as quantified by differential cell counts in lung lavage, suggesting that most, or all, of the arginase I in lungs of mice exposed to ovalbumin is present in the inflammatory cells rather than in the airway epithelium. There was also a significant correlation between increased expression of arginase I in the isolated airways and decreased lung compliance. On the other hand, while we found arginase II expression to also be significantly increased in airways from mice exposed to ovalbumin as compared with normal airways, the relative increase was much less than that observed for arginase I, suggesting that there was a smaller contribution of inflammatory cells to the arginase II content of the airways in mice exposed to ovalbumin. There was no apparent correlation between the content of arginase in isolated airways and exhaled NO concentration in the expired air from mice exposed to ovalbumin. However, there was a correlation between exhaled NO concentration from mice exposed to ovalbumin and the lymphocyte content of the lung lavage. The concentration of arginine found in isolated

  20. Arginase I and II in Lungs of Ovalbumin-Sensitized Mice Exposed to Ovalbumin: Sources and consequences

    PubMed Central

    Kenyon, Nicholas J.; Bratt, Jennifer M.; Linderholm, Angela L.; Last, Michael S.; Last, Jerold A.

    2008-01-01

    Arginase gene expression in the lung has been linked to asthma both in clinical studies of human patients and in the well-studied mouse model of ovalbumin-induced airway inflammation. Arginase is thought to regulate NO levels in the lung by its ability to divert arginine, the substrate for nitric oxide synthases that produce citrulline and NO, into an alternative metabolic pathway producing ornithine and urea. In the present study arginase I and arginase II concentrations were measured in isolated microdissected airway preparations from sensitized Balb/c mice exposed to ovalbumin aerosol. We found that arginase II was constitutively expressed in the airways of normal mice, whereas arginase I was undetectable in normal airways, while its expression was increased in airways of mice exposed to ovalbumin. The expression of arginase I strongly correlated with the presence of lung inflammation, as quantified by differential cell counts in lung lavage, suggesting that most, or all, of the arginase I in lungs of mice exposed to ovalbumin is present in the inflammatory cells rather than in the airway epithelium. There was also a significant correlation between increased expression of arginase I in the isolated airways and decreased lung compliance. On the other hand, while we found arginase II expression to also be significantly increased in airways from mice exposed to ovalbumin as compared with normal airways, the relative increase was much less than that observed for arginase I, suggesting that there was a smaller contribution of inflammatory cells to the arginase II content of the airways in mice exposed to ovalbumin. There was no apparent correlation between the content of arginase in isolated airways and exhaled NO concentration in the expired air from mice exposed to ovalbumin. However, there was a correlation between exhaled NO concentration from mice exposed to ovalbumin and the lymphocyte content of the lung lavage. The concentration of arginine found in isolated

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

    PubMed Central

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

    2016-01-01

    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 × 104.5 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. PMID:26877172

  2. The oxygen consuming systems of the liver of mice exposed to simulated high altitude

    NASA Astrophysics Data System (ADS)

    Rivera, K.; Aguilar, R.; Burgos, C.; Alvarez, J.

    1981-12-01

    Altitude hypoxia does not induce any changes in the enzymatic systems related to oxygen consumption in guinea pigs native of the Peruvian high altitudes. The biochemical changes frequently found in high altitude animals are the result of exposure to the low temperature of this environment rather than to hypoxia. In the present work, mice were chronically exposed to hypobaric hypoxia and maintained at equal temperature as the sea level control group, and measurements of enzymatic activities of the three major oxygen consuming systems of the liver were carried out, i.e., mitochondria, microsomes and peroxisomes. The results obtained have confirmed that hypoxia has no apparent influence on these enzymatic systems.

  3. 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.

  4. Altered host resistance to Listeria monocytogenes in mice exposed to 1-chloroacetophenone (CN) vapours

    SciTech Connect

    Kumar, P.; Kumar, P.; Zachariah, K.; Rai, G.P.; Vijayraghavan, R. )

    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. This may be attributed to immunotoxic effects of CN on T-cells mediated macrophage functions.

  5. Modulation of neurological related allergic reaction in mice exposed to low-level toluene

    SciTech Connect

    Tin-Tin-Win-Shwe; Yamamoto, Shoji; Nakajima, Daisuke; Furuyama, Akiko; Fukushima, Atsushi; Ahmed, Sohel; Goto, Sumio; Fujimaki, Hidekazu . E-mail: fujimaki@nies.go.jp

    2007-07-01

    The contributing role of indoor air pollution to the development of allergic disease has become increasingly evident in public health problems. It has been reported that extensive communication exists between neurons and immune cells, and neurotrophins are molecules potentially responsible for regulating and controlling this neuroimmune crosstalk. The adverse effects of volatile organic compounds which are main indoor pollutants on induction or augmentation of neuroimmune interaction have not been fully characterized yet. To investigate the effects of low-level toluene inhalation on the airway inflammatory responses, male C3H mice were exposed to filtered air (control), 9 ppm, and 90 ppm toluene for 30 min by nose-only inhalation on Days 0, 1, 2, 7, 14, 21, and 28. Some groups of mice were injected with ovalbumin intraperitoneally before starting exposure schedule and these mice were then challenged with aerosolized ovalbumin as booster dose. For analysis of airway inflammation, bronchoalveolar lavage (BAL) fluid were collected to determine inflammatory cell influx and lung tissue and blood samples were collected to determine cytokine and neurotrophin mRNA and protein expressions and plasma antibody titers using real-time RT-PCR and ELISA methods respectively. Exposure of the ovalbumin-immunized mice to low-level toluene resulted in (1) increased inflammatory cells infiltration in BAL fluid; (2) increased IL-5 mRNA, decreased nerve growth factor receptor tropomyosin-related kinase A and brain-derived neurotrophic factor mRNAs in lung; and (3) increased IgE and IgG{sub 1} antibodies and nerve growth factor content in the plasma. These findings suggest that low-level toluene exposure aggravates the airway inflammatory responses in ovalbumin-immunized mice by modulating neuroimmune crosstalk.

  6. Alterations in Skeletal Muscle Oxidative Phenotype in Mice Exposed to 3 Weeks of Normobaric Hypoxia.

    PubMed

    Slot, Ilse G M; Schols, Annemie M W J; de Theije, Chiel C; Snepvangers, Frank J M; Gosker, Harry R

    2016-02-01

    Skeletal muscle of patients with chronic respiratory failure is prone to loss of muscle mass and oxidative phenotype. Tissue hypoxia has been associated with cachexia and emphysema in humans. Experimental research on the role of hypoxia in loss of muscle oxidative phenotype, however, has yielded inconsistent results. Animal studies are frequently performed in young animals, which may hinder translation to generally older aged patients. Therefore, in this study, we tested the hypothesis that hypoxia induces loss of skeletal muscle oxidative phenotype in a model of aged (52 weeks) mice exposed to 3 weeks of hypoxia. Additional groups of young (4 weeks) and adult (12 weeks) mice were included to examine age effects. To verify hypoxia-induced cachexia, fat pad and muscle weights as well as muscle fiber cross-sectional areas were determined. Muscle oxidative phenotype was assessed by expression and activity of markers of mitochondrial metabolism and fiber-type distribution. A profound loss of muscle and fat was indeed accompanied by a slightly lower expression of markers of muscle oxidative capacity in the aged hypoxic mice. In contrast, hypoxia-associated changes of fiber-type composition were more prominent in the young mice. The differential response of the muscle of young, adult, and aged mice to hypoxia suggests that age matters and that the aged mouse is a better model for translation of findings to elderly patients with chronic respiratory disease. Furthermore, the findings warrant further mechanistic research into putative accelerating effects of hypoxia-induced loss of oxidative phenotype on the cachexia process in chronic respiratory disease. PMID:26129845

  7. Fecundity of F/sub 1/ male mice exposed to lead acetate in-utero

    SciTech Connect

    Figgs, L.W.

    1983-01-01

    Four studies were performed to examine the reproductive capacity of male mice exposed to lead in-utero. These studies concerned the fecundity/fertility, sperm and semen analysis, scanning electron microscopic (SEM) analysis of the testis, and the analysis of seminiferous tubule cell populations for chromosomal aberrations. The fecundity study revealed that male mice exposed to lead acetate in-utero showed a significant reduction in the following parameters for the F/sub 2/ litters they produced. There was a significant reduction in the number of pups produced per litter, the number of females per litter, the number of pups weaned per litter, and the percent survival of those pups. Sperm and semen analysis revealed a decrease in sperm numbers and motility. It was concluded that lead acertate exposure in-utero resulted in a decrease in reproductive capacity which was evidenced by the reduction in certain fecundity parameters pups weaned per litter, etc. It was concluded that lead acetate causes a mutation or functional change in the stem cell population of the embryonic gonad that resulted in a slowed transition from spermatocyte to spermatid during spermatogenesis in the adult. This slowed transition may have been translated into decreased sperm production, a decrease in x-bearing sperm, and genetic changes that caused decreased numbers of pups and decreased survivorship of the pups in those litters. This was not demonstrated by microscopic analysis of the sperm and testis but was suggested by an analysis of a sample population of cells from the seminiferous tubules.

  8. Dendritic cells inversely regulate airway inflammation in cigarette smoke-exposed mice.

    PubMed

    Givi, Masoumeh Ezzati; Akbari, Peyman; Boon, Louis; Puzovic, Vladimir S; Bezemer, Gillina F G; Ricciardolo, Fabio L M; Folkerts, Gert; Redegeld, Frank A; Mortaz, Esmaeil

    2016-01-01

    The recruitment and activation of inflammatory cells into the respiratory system is considered a crucial feature in the pathophysiology of chronic obstructive pulmonary disease (COPD). Because dendritic cells (DCs) have a pivotal role in the onset and regulation of immune responses, we investigated the effect of modulating DC subsets on airway inflammation by acute cigarette smoke (CS) exposure. CS-exposed mice (5 days) were treated with fms-like tyrosine kinase 3 ligand (Flt3L) and 120g8 antibody to increase total DC numbers and deplete plasmacytoid DCs (pDCs), respectively. Flt3L treatment decreased the number of inflammatory cells in the bronchoalveolar lavage (BALF) of the smoke-exposed mice and increased these in lung tissue. DC modulation reduced IL-17 and increased IL-10 levels, which may be responsible for the suppression of the BALF cells. Furthermore, depletion of pDCs led to increased infiltration of alveolar macrophages while restricting the presence of CD103(+) DCs. This study suggests that DC subsets may differentially and compartment-dependent influence the inflammation induced by CS. pDC may play a role in preventing the pathogenesis of CS by inhibiting the alveolar macrophage migration to lung and increasing CD103(+) DCs at inflammatory sites to avoid extensive lung tissue damage. PMID:26475733

  9. Impaired Lipid and Glucose Homeostasis in Hexabromocyclododecane-Exposed Mice Fed a High-Fat Diet

    PubMed Central

    Koike, Eiko; Win-Shwe, Tin-Tin; Yamamoto, Megumi; Takano, Hirohisa

    2014-01-01

    Background: Hexabromocyclododecane (HBCD) is an additive flame retardant used in the textile industry and in polystyrene foam manufacturing. Because of its lipophilicity and persistency, HBCD accumulates in adipose tissue and thus has the potential of causing metabolic disorders through disruption of lipid and glucose homeostasis. However, the association between HBCD and obesity remains unclear. Objectives: We investigated whether exposure to HBCD contributes to initiation and progression of obesity and related metabolic dysfunction in mice fed a normal diet (ND) or a high-fat diet (HFD). Methods: Male C57BL/6J mice were fed a HFD (62.2 kcal% fat) or a ND and treated orally with HBCD (0, 1.75, 35, or 700 μg/kg body weight) weekly from 6 to 20 weeks of age. We examined body weight, liver weight, blood biochemistry, histopathological changes, and gene expression profiles in the liver and adipose tissue. Results: In HFD-fed mice, body and liver weight were markedly increased in mice treated with the high (700 μg/kg) and medium (35 μg/kg) doses of HBCD compared with vehicle. This effect was more prominent in the high-dose group. These increases were paralleled by increases in random blood glucose and insulin levels and enhancement of microvesicular steatosis and macrophage accumulation in adipose tissue. HBCD-treated HFD-fed mice also had increased mRNA levels of Pparg (peroxisome proliferator-activated receptor-γ) in the liver and decreased mRNA levels of Glut4 (glucose transporter 4) in adipose tissue compared with vehicle-treated HFD-fed mice. Conclusions: Our findings suggest that HBCD may contribute to enhancement of diet-induced body weight gain and metabolic dysfunction through disruption of lipid and glucose homeostasis, resulting in accelerated progression of obesity. Citation: Yanagisawa R, Koike E, Win-Shwe TT, Yamamoto M, Takano H. 2014. Impaired lipid and glucose homeostasis in hexabromocyclododecane-exposed mice fed a high-fat diet. Environ Health

  10. Alteration of cytokine profiles in mice exposed to chronic low-dose ionizing radiation

    SciTech Connect

    Shin, Suk Chul; Lee, Kyung-Mi; Kang, Yu Mi; Kim, Kwanghee; Kim, Cha Soon; Yang, Kwang Hee; Jin, Young-Woo; Kim, Chong Soon; Kim, Hee Sun

    2010-07-09

    While a high-dose of ionizing radiation is generally harmful and causes damage to living organisms, a low-dose of radiation has been shown to be beneficial in a variety of animal models. To understand the basis for the effect of low-dose radiation in vivo, we examined the cellular and immunological changes evoked in mice exposed to low-dose radiation at very low (0.7 mGy/h) and low (3.95 mGy/h) dose rate for the total dose of 0.2 and 2 Gy, respectively. Mice exposed to low-dose radiation, either at very low- or low-dose rate, demonstrated normal range of body weight and complete blood counts. Likewise, the number and percentage of peripheral lymphocyte populations, CD4{sup +} T, CD8{sup +} T, B, or NK cells, stayed unchanged following irradiation. Nonetheless, the sera from these mice exhibited elevated levels of IL-3, IL-4, leptin, MCP-1, MCP-5, MIP-1{alpha}, thrombopoietin, and VEGF along with slight reduction of IL-12p70, IL-13, IL-17, and IFN-{gamma}. This pattern of cytokine release suggests the stimulation of innate immunity facilitating myeloid differentiation and activation while suppressing pro-inflammatory responses and promoting differentiation of naive T cells into T-helper 2, not T-helper 1, types. Collectively, our data highlight the subtle changes of cytokine milieu by chronic low-dose {gamma}-radiation, which may be associated with the functional benefits observed in various experimental models.

  11. Regional and splenic lymphocyte proliferative responses of mice exposed to normal or irradiated Schistosoma mansoni cercariae

    SciTech Connect

    Lewis, F.A.; Wilson, E.M.

    1982-05-01

    Developing larvae of Schistosoma mansoni migrate through various tissues en route to the liver and mesenteric veins of their definitive host. Regional (lymph node) and systemic (spleen) blastogenic responses to cercarial, adult and egg antigens were measured in CBA/J mice at various times after exposure to normal or irradiated S. mansoni cercariae. Among the separate lymph node groups studied were those draining the tail, thoracic region, intestines, head and neck, and the pelvis. Blastogenic responses were assayed by a micromethod requiring 10(5) cells in 20 microliter volumes per culture. Up to 5 weeks post-cercarial exposure the pattern of responses in lymphoid tissues of infected mice coincided with the migratory route of the parasites. Following oviposition, cellular reactivity was pronounced in all lymph node groups. The reactivity of mice exposed to irradiated cercariae followed a pattern suggestive of a sustained antigenic stimulus only in the nodes draining the tail and lungs. Splenic (systemic) reactivity was roughly comparable between the two exposure groups. These data show the independence and vast differences in the host regional responses following normal or irradiated cercarial exposure.

  12. Cytokine expression in mice exposed to diesel exhaust particles by inhalation. Role of tumor necrosis factor

    PubMed Central

    Saber, Anne T; Jacobsen, Nicklas R; Bornholdt, Jette; Kjær, Sanna L; Dybdahl, Marianne; Risom, Lotte; Loft, Steffen; Vogel, Ulla; Wallin, Håkan

    2006-01-01

    Background Particulate air pollution has been associated with lung and cardiovascular disease, for which lung inflammation may be a driving mechanism. The pro-inflammatory cytokine, tumor necrosis factor (TNF) has been suggested to have a key-role in particle-induced inflammation. We studied the time course of gene expression of inflammatory markers in the lungs of wild type mice and Tnf-/- mice after exposure to diesel exhaust particles (DEPs). Mice were exposed to either a single or multiple doses of DEP by inhalation. We measured the mRNA level of the cytokines Tnf and interleukin-6 (Il-6) and the chemokines, monocyte chemoattractant protein (Mcp-1), macrophage inflammatory protein-2 (Mip-2) and keratinocyte derived chemokine (Kc) in the lung tissue at different time points after exposure. Results Tnf mRNA expression levels increased late after DEP-inhalation, whereas the expression levels of Il-6, Mcp-1 and Kc increased early. The expression of Mip-2 was independent of TNF if the dose was above a certain level. The expression levels of the cytokines Kc, Mcp-1 and Il-6, were increased in the absence of TNF. Conclusion Our data demonstrate that Tnf is not important in early DEP induced inflammation and rather exerts negative influence on Mcp-1 and Kc mRNA levels. This suggests that other signalling pathways are important, a candidate being one involving Mcp-1. PMID:16504008

  13. Inhibition of lung tumor development by berry extracts in mice exposed to cigarette smoke.

    PubMed

    Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta; Kratchanova, Maria; Denev, Petko; Kratchanov, Christo; Polasa, Kalpagam; D'Agostini, Francesco; Steele, Vernon E; De Flora, Silvio

    2012-11-01

    Cigarette smoke (CS) and dietary factors play a major role in cancer epidemiology. At the same time, however, the diet is the richest source of anticancer agents. Berries possess a broad array of health protective properties and were found to attenuate the yield of tumors induced by individual carcinogens in the rodent digestive tract and mammary gland but failed to prevent lung tumors induced by typical CS components in mice. We exposed whole-body Swiss ICR mice to mainstream CS, starting at birth and continuing daily for 4 months. Aqueous extracts of black chokeberry and strawberry were given as the only source of drinking water, starting after weaning and continuing for 7 months, thus mimicking an intervention in current smokers. In the absence of berries, CS caused a loss of body weight, induced early cytogenetical damage in circulating erythrocytes and histopathological alterations in lung (emphysema, blood vessel proliferation, alveolar epithelial hyperplasia and adenomas), liver (parenchymal degeneration) and urinary bladder (epithelial hyperplasia). Both berry extracts inhibited the CS-related body weight loss, cytogenetical damage, liver degeneration, pulmonary emphysema and lung adenomas. Protective effects were more pronounced in female mice, which may be ascribed to modulation by berry components of the metabolism of estrogens implicated in lung carcinogenesis. Interestingly, both the carcinogen and the chemopreventive agents tested are complex mixtures that contain a multitude of components working through composite mechanisms. PMID:22328465

  14. Aerosolized bovine lactoferrin reduces lung injury and fibrosis in mice exposed to hyperoxia.

    PubMed

    Chen, Hsiao-Ling; Yen, Chih-Ching; Wang, Shih-Ming; Tsai, Tung-Chou; Lai, Zi-Lun; Sun, Jheng-Yue; Lin, Willei; Hsu, Wu-Huei; Chen, Chuan-Mu

    2014-10-01

    This study investigated the ability of aerosolized bovine lactoferrin (bLF) to protect the lungs from injury induced by chronic hyperoxia. Female CD-1 mice were exposed to hyperoxia (FiO2 = 80 %) for 7 days to induce lung injury and fibrosis. The therapeutic effects of bLF, administered via an aerosol delivery system, on the chronic lung injury induced by this period of hyperoxia were measured by bronchoalveolar lavage, lung histology, cell apoptosis, and inflammatory cytokines in the lung tissues. After exposure to hyperoxia for 7 days, the survival of the mice was significantly decreased to 20 %. The protective effects of bLF against hyperoxia were further confirmed by significant reductions in lung edema, total cell numbers in bronchoalveolar lavage fluid, inflammatory cytokines (IL-1β and IL-6), pulmonary fibrosis, and apoptotic DNA fragmentation. The aerosolized bLF protected the mice from oxygen toxicity and increased the survival fraction to 66.7 % in the hyperoxic model. The results support the use of an aerosol therapy with bLF in intensive care units to reduce oxidative injury in patients with severe hypoxemic respiratory failure or chronic obstructive pulmonary disease. PMID:24842100

  15. Ethanol and acetaldehyde differentially alter extracellular dopamine and serotonin in Aldh2-knockout mouse dorsal striatum: A reverse microdialysis study.

    PubMed

    Jamal, Mostofa; Ameno, Kiyoshi; Miki, Takanori; Tanaka, Naoko; Ito, Asuka; Ono, Junichiro; Takakura, Ayaka; Kumihashi, Mitsuru; Kinoshita, Hiroshi

    2016-01-01

    Dopamine (DA) and serotonin (5-HT) seem to be involved in several of the effects of ethanol (EtOH). Acetaldehyde (AcH), especially in the brain, induces effects that mimic those of EtOH. The purpose of this study was to investigate the effects of local perfusion of EtOH and AcH on extracellular DA and 5-HT in the dorsal striatum of Aldh2-knockout (Aldh2-KO) and wild-type (WT) mice. Aldh2-KO mice were used as a model of aldehyde dehydrogenase 2 deficiency in humans to examine the effects of AcH. Mice were perfused with Ringer's solution (control), EtOH (100, 200, or 500mM) and AcH (100, 200, or 500μM) into the dorsal striatum. Dialysate samples were collected every 5min, and then analyzed with HPLC coupled to an ECD. We found that local perfusion with 500mM EtOH increased extracellular levels of DA (p<0.05) in both Aldh2-KO and WT mice, while 5-HT levels remain unchanged. EtOH at a dose of 200mM also increased DA in WT mice, but this was limited to a 30-40-min time-point. In contrast, perfusion with 200 and 500μM AcH decreased both DA and 5-HT (p<0.05) in Aldh2-KO mice, but this decrease was not found in WT mice at any AcH dose, indicating an effect of AcH on DA and 5-HT levels. There were no genotype effects on the basal levels of DA and 5-HT. These results indicate that high EtOH can stimulate DA, whereas high AcH can depress both DA and 5-HT in the dorsal striatum of mice. PMID:26711020

  16. Decreased fertility in mice exposed to environmental air pollution in the city of Sao Paulo.

    PubMed

    Mohallem, Soraya Vecci; de Araújo Lobo, Débora Jã; Pesquero, Célia Regina; Assunção, João Vicente; de Andre, Paulo Afonso; Saldiva, Paulo Hilário Nascimento; Dolhnikoff, Marisa

    2005-06-01

    It has largely been shown that air pollution can affect human health. Effects on human fertility have been shown mainly in males by a decrease in semen quality. Few studies have focused on the environmental effects on female fertility. The aim of the present study was to analyze the effects of air pollution in the city of Sao Paulo on mouse female fertility. Four groups of female Balb/c mice were placed in two chambers 10 days (newborn) or 10 weeks (adults) after birth. Mice were maintained in the chambers 24 h a day, 7 days a week, for 4 months. The first chamber received air that had passed through an air filter (clean chamber) and the second received ambient air (polluted chamber). We measured PM10 and NO2 inside both chambers. Mice belonging to the adult groups were bred to male mice after living for 3 months inside the chambers. The newborn groups mated after reaching reproductive age (12 weeks). After 19 days of pregnancy the numbers of live-born pups, reabsorptions, fetal deaths, corpora lutea, and implantation failures were determined. PM10 and NO2 concentrations in the clean chamber were 50% and 77.5% lower than in the polluted chamber, respectively. Differences in fertility parameters between groups were observed only in animals exposed to air pollution at an early age (10 days after birth). We observed a higher number of live-born pups per animal in the clean chamber than per animal from the polluted chamber (median=6.0 and 4.0, respectively; P=0.037). There was a higher incidence of implantation failures in the polluted group than in the clean group (median=3.5 and 2.0, respectively; P=0.048). There were no significant differences in the other reproductive parameters between groups. These results support the concept that female reproductive health represents a target of air pollutants. PMID:15820725

  17. Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens

    PubMed Central

    Fox, J G; Feng, Y; Theve, E J; Raczynski, A R; Fiala, J L A; Doernte, A L; Williams, M; McFaline, J L; Essigmann, J M; Schauer, D B; Tannenbaum, S R; Dedon, P C; Weinman, S A; Lemon, S M; Fry, R C; Rogers, A B

    2013-01-01

    Background and aims Hepatocellular carcinoma (HCC) frequently results from synergism between chemical and infectious liver carcinogens. Worldwide, the highest incidence of HCC is in regions endemic for the foodborne contaminant aflatoxin B1 (AFB1) and hepatitis B virus (HBV) infection. Recently, gut microbes have been implicated in multisystemic diseases including obesity and diabetes. Here, the hypothesis that specific intestinal bacteria promote liver cancer was tested in chemical and viral transgenic mouse models. Methods Helicobacter-free C3H/HeN mice were inoculated with AFB1 and/or Helicobacter hepaticus. The incidence, multiplicity and surface area of liver tumours were quantitated at 40 weeks. Molecular pathways involved in tumourigenesis were analysed by microarray, quantitative real-time PCR, liquid chromatography/mass spectrometry, ELISA, western blot and immunohistochemistry. In a separate experiment, C57BL/6 FL-N/35 mice harbouring a full-length hepatitis C virus (HCV) transgene were crossed with C3H/HeN mice and cancer rates compared between offspring with and without H hepaticus. Results Intestinal colonisation by H hepaticus was sufficient to promote aflatoxin- and HCV transgene-induced HCC. Neither bacterial translocation to the liver nor induction of hepatitis was necessary. From its preferred niche in the intestinal mucus layer, H hepaticus activated nuclear factor-κB (NF-κB)-regulated networks associated with innate and T helper 1 (Th1)-type adaptive immunity both in the lower bowel and liver. Biomarkers indicative of tumour progression included hepatocyte turnover, Wnt/β-catenin activation and oxidative injury with decreased phagocytic clearance of damaged cells. Conclusions Enteric microbiota define HCC risk in mice exposed to carcinogenic chemicals or hepatitis virus transgenes. These results have implications for human liver cancer risk assessment and prevention. PMID:19850960

  18. Metabolomics in Lung Inflammation: A High Resolution 1H NMR Study of Mice Exposed to Silica Dust

    PubMed Central

    Hu, Jian Zhi; Rommereim, Donald N.; Minard, Kevin R.; Woodstock, Angie; Harrer, Bruce J.; Wind, Robert A.; Phipps, Richard P.; Sime, Patricia J.

    2010-01-01

    Here we report the first 1H NMR metabolomics studies on excised lungs and bronchoalveolar lavage fluid (BALF) from mice exposed to crystalline silica. High resolution 1H NMR metabolic profiling on intact excised lungs was performed using slow magic angle sample spinning (slow-MAS) 1H PASS (phase altered spinning sidebands) at a sample spinning rate of 80 Hz. Metabolic profiling on BALF was completed using fast magic angle spinning at 2kHz. Major findings are that the relative concentrations of choline, phosphocholine (PC) and glycerophosphocholine(GPC) were statistically significantly increased in silica-exposed mice compared to sham controls, indicating an altered membrane choline phospholipids metabolism (MCPM). The relative concentrations of glycogen/glucose, lactate and creatine were also statistically significantly increased in mice exposed to silica dust, suggesting that cellular energy pathways were affected by silica dust. Elevated levels of glycine, lysine, glutamate, proline and 4-hydroxyproline were also increased in exposed mice, suggesting the activation of a collagen pathway. Furthermore, metabolic profiles in mice exposed to silica dust were found to be spatially heterogeneous, in consistent with regional inflammation revealed by in vivo magnetic resonance imaging (MRI). PMID:20020862

  19. 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

  20. Effects of Low Doses of Bisphenol A on the Metabolome of Perinatally Exposed CD-1 Mice

    PubMed Central

    Cabaton, Nicolas J.; Canlet, Cécile; Wadia, Perinaaz R.; Tremblay-Franco, Marie; Gautier, Roselyne; Molina, Jérôme; Sonnenschein, Carlos; Cravedi, Jean-Pierre; Rubin, Beverly S.; Soto, Ana M.

    2013-01-01

    Background: Bisphenol A (BPA) is a well-known endocrine disruptor used to manufacture polycarbonate plastics and epoxy resins. Exposure of pregnant rodents to low doses of BPA results in pleiotropic effects in their offspring. Objective: We used metabolomics—a method for determining metabolic changes in response to nutritional, pharmacological, or toxic stimuli—to examine metabolic shifts induced in vivo by perinatal exposure to low doses of BPA in CD-1 mice. Methods: Male offspring born to pregnant CD-1 mice that were exposed to vehicle or to 0.025, 0.25, or 25 µg BPA/kg body weight/day, from gestation day 8 through day 16 of lactation, were examined on postnatal day (PND) 2 or PND21. Aqueous extracts of newborns (PND2, whole animal) and of livers, brains, and serum samples from PND21 pups were submitted to 1H nuclear magnetic resonance spectroscopy. Data were analyzed using partial least squares discriminant analysis. Results: Examination of endogenous metabolic fingerprints revealed remarkable discrimination in whole extracts of the four PND2 newborn treatment groups, strongly suggesting changes in the global metabolism. Furthermore, statistical analyses of liver, serum, and brain samples collected on PND21 successfully discriminated among treatment groups. Variations in glucose, pyruvate, some amino acids, and neurotransmitters (γ-aminobutyric acid and glutamate) were identified. Conclusions: Low doses of BPA disrupt global metabolism, including energy metabolism and brain function, in perinatally exposed CD-1 mouse pups. Metabolomics can be used to highlight the effects of low doses of endocrine disruptors by linking perinatal exposure to changes in global metabolism. PMID:23425943

  1. Hydrogen sulfide alleviates cardiac contractile dysfunction in an Akt2-knockout murine model of insulin resistance: role of mitochondrial injury and apoptosis

    PubMed Central

    Hu, Nan; Dong, Maolong

    2014-01-01

    Hydrogen sulfide (H2S) is a toxic gas now being recognized as an endogenous signaling molecule in multiple organ systems, in particular, the cardiovascular system. H2S is known to regulate cardiac function and protect against ischemic injury. However, little information is available regarding the effect of H2S on cardiac function in insulin resistance. This study was designed to examine the impact of H2S supplementation on cardiac function using an Akt2 knockout model of insulin resistance. Wild-type and Akt2 knockout mice were treated with NaHS (50 μM·kg−1·day−1 ip for 10 days) prior to evaluation of echocardiographic, cardiomyocyte contractile, and intracellular Ca2+ properties, apoptosis, and mitochondrial damage. Our results revealed that Akt2 ablation led to overtly enlarged ventricular end-systolic diameter, reduced myocardial and cardiomyocyte contractile function, and disrupted intracellular Ca2+ homeostasis and apoptosis, the effects of which were ameliorated by H2S. Furthermore, Akt2 knockout displayed upregulated apoptotic protein markers (Bax, caspase-3, caspase-9, and caspace-12) and mitochondrial damage (reduced aconitase activity and NAD+, elevated cytochrome-c release from mitochondria) along with reduced phosphorylation of PTEN, Akt, and GSK3β in the absence of changes in pan protein expression, the effects of which were abolished or significantly ameliorated by H2S treatment. In vitro data revealed that H2S-induced beneficial effect against Akt2 ablation was obliterated by mitochondrial uncoupling. Taken together, our findings suggest the H2S may reconcile Akt2 knockout-induced myocardial contractile defect and intracellular Ca2+ mishandling, possibly via attenuation of mitochondrial injury and apoptosis. PMID:24622975

  2. Prophylactic efficacy of Coriandrum sativum (Coriander) on testis of lead-exposed mice.

    PubMed

    Sharma, Veena; Kansal, Leena; Sharma, Arti

    2010-09-01

    Lead poisoning is a worldwide health problem, and its treatment is under investigation. The aim of this study was to access the efficacy of Coriandrum sativum (coriander) in reducing lead-induced changes in mice testis. Animal exposed to lead nitrate showed significant decrease in testicular SOD, CAT, GSH, total protein, and tissue lead level. This was accompanied by simultaneous increase in the activities of LPO, AST, ALT, ACP, ALP, and cholesterol level. Serum testosterone level and sperm density were suppressed in lead-treated group compared with the control. These influences of lead were prevented by concurrent daily administration of C. sativum extracts to some extent. Treating albino mice with lead-induced various histological changes in the testis and treatment with coriander led to an improvement in the histological testis picture. The results thus led us to conclude that administration of C. sativum significantly protects against lead-induced oxidative stress. Further work need to be done to isolate and purify the active principle involved in the antioxidant activity of this plant. PMID:19902160

  3. DNA damage in bone marrow and blood cells of mice exposed to municipal sludge leachates.

    PubMed

    Tewari, Anamika; Dhawan, Alok; Gupta, Shrawan Kumar

    2006-05-01

    Leachates of municipal solid waste from unsecured disposal sites contaminate sources of potable water and affect human health. In the present study, we have used the Comet assay to evaluate the DNA damage in mice exposed to municipal sludge leachates. Ten percent leachates were prepared from municipal sludge obtained from two different disposal drains. Male Swiss albino mice were treated daily with 0.1-0.4 ml of the leachates by oral gavage for 15 days, and the DNA damage was evaluated in bone marrow and blood using Olive tail moment, % tail DNA, and tail length as measures of DNA damage. Physicochemical and metal analysis of the leachates detected the presence of cadmium, chromium, copper, nickel, lead, and zinc, as well as elevated concentrations of sulfate and nitrate. Both of the leachates produced significant dose-responsive increases in DNA damage in both mouse tissues. There were no significant differences in the responses for any of the Comet endpoints between tissues (for the same leachate sample) or between leachate samples (for the same tissue). The results of this study indicate that municipal waste leachates produce DNA damage in vivo. PMID:16470523

  4. Time course of pulmonary burden in mice exposed to residual oil fly ash

    PubMed Central

    Carvalho, Giovanna Marcella Cavalcante; Nagato, Lilian Katiê da Silva; Fagundes, Sheila da Silva; dos Santos, Flávia Brandão; Calheiros, Andrea Surrage; Malm, Olaf; Bozza, Patricia Torres; Saldiva, Paulo Hilário N.; Faffe, Débora Souza; Rocco, Patricia Rieken Macedo; Zin, Walter Araujo

    2014-01-01

    Residual oil fly ash (ROFA) is a common pollutant in areas where oil is burned. This particulate matter (PM) with a broad distribution of particle diameters can be inhaled by human beings and putatively damage their respiratory system. Although some studies deal with cultured cells, animals, and even epidemiological issues, so far a comprehensive analysis of respiratory outcomes as a function of the time elapsed after exposure to a low dose of ROFA is wanted. Thus, we aimed to investigate the time course of mechanical, histological, and inflammatory lung changes, as well as neutrophils in the blood, in mice exposed to ROFA until 5 days after exposure. BALB/c mice (25 ± 5 g) were randomly divided into 7 groups and intranasally instilled with either 10 μL of sterile saline solution (0.9% NaCl, CTRL) or ROFA (0.2 μg in 10 μL of saline solution). Pulmonary mechanics, histology (normal and collapsed alveoli, mononuclear and polymorphonuclear cells, and ultrastructure), neutrophils (in blood and bronchoalveolar lavage fluid) were determined at 6 h in CTRL and at 6, 24, 48, 72, 96, and 120 h after ROFA exposure. ROFA contained metal elements, especially iron, polycyclic aromatic hydrocarbons (PAHs), and organochlorines. Lung resistive pressure augmented early (6 h) in the course of lung injury and other mechanical, histological and inflammatory parameters increased at 24 h, returning to control values at 120 h. Blood neutrophilia was present only at 24 and 48 h after exposure. Swelling of endothelial cells with adherent neutrophils was detected after ROFA instillation. No neutrophils were present in the lavage fluid. In conclusion, the exposure to ROFA, even in low doses, induced early changes in pulmonary mechanics, lung histology and accumulation of neutrophils in blood of mice that lasted for 4 days and disappeared spontaneously. PMID:25309454

  5. Time course of pulmonary burden in mice exposed to residual oil fly ash.

    PubMed

    Carvalho, Giovanna Marcella Cavalcante; Nagato, Lilian Katiê da Silva; Fagundes, Sheila da Silva; Dos Santos, Flávia Brandão; Calheiros, Andrea Surrage; Malm, Olaf; Bozza, Patricia Torres; Saldiva, Paulo Hilário N; Faffe, Débora Souza; Rocco, Patricia Rieken Macedo; Zin, Walter Araujo

    2014-01-01

    Residual oil fly ash (ROFA) is a common pollutant in areas where oil is burned. This particulate matter (PM) with a broad distribution of particle diameters can be inhaled by human beings and putatively damage their respiratory system. Although some studies deal with cultured cells, animals, and even epidemiological issues, so far a comprehensive analysis of respiratory outcomes as a function of the time elapsed after exposure to a low dose of ROFA is wanted. Thus, we aimed to investigate the time course of mechanical, histological, and inflammatory lung changes, as well as neutrophils in the blood, in mice exposed to ROFA until 5 days after exposure. BALB/c mice (25 ± 5 g) were randomly divided into 7 groups and intranasally instilled with either 10 μL of sterile saline solution (0.9% NaCl, CTRL) or ROFA (0.2 μg in 10 μL of saline solution). Pulmonary mechanics, histology (normal and collapsed alveoli, mononuclear and polymorphonuclear cells, and ultrastructure), neutrophils (in blood and bronchoalveolar lavage fluid) were determined at 6 h in CTRL and at 6, 24, 48, 72, 96, and 120 h after ROFA exposure. ROFA contained metal elements, especially iron, polycyclic aromatic hydrocarbons (PAHs), and organochlorines. Lung resistive pressure augmented early (6 h) in the course of lung injury and other mechanical, histological and inflammatory parameters increased at 24 h, returning to control values at 120 h. Blood neutrophilia was present only at 24 and 48 h after exposure. Swelling of endothelial cells with adherent neutrophils was detected after ROFA instillation. No neutrophils were present in the lavage fluid. In conclusion, the exposure to ROFA, even in low doses, induced early changes in pulmonary mechanics, lung histology and accumulation of neutrophils in blood of mice that lasted for 4 days and disappeared spontaneously. PMID:25309454

  6. Frontal Cortex Transcriptome Analysis of Mice Exposed to Electronic Cigarettes During Early Life Stages.

    PubMed

    Lauterstein, Dana E; Tijerina, Pamella B; Corbett, Kevin; Akgol Oksuz, Betul; Shen, Steven S; Gordon, Terry; Klein, Catherine B; Zelikoff, Judith T

    2016-01-01

    Electronic cigarettes (e-cigarettes), battery-powered devices containing nicotine, glycerin, propylene glycol, flavorings, and other substances, are increasing in popularity. They pose a potential threat to the developing brain, as nicotine is a known neurotoxicant. We hypothesized that exposure to e-cigarettes during early life stages induce changes in central nervous system (CNS) transcriptome associated with adverse neurobiological outcomes and long-term disease states. To test the hypothesis, pregnant C57BL/6 mice were exposed daily (via whole body inhalation) throughout gestation (3 h/day; 5 days/week) to aerosols produced from e-cigarettes either with nicotine (13-16 mg/mL) or without nicotine; following birth, pups and dams were exposed together to e-cigarette aerosols throughout lactation beginning at postnatal day (PND) 4-6 and using the same exposure conditions employed during gestational exposure. Following exposure, frontal cortex recovered from ~one-month-old male and female offspring were excised and analyzed for gene expression by RNA Sequencing (RNA-Seq). Comparisons between the treatment groups revealed that e-cigarette constituents other than nicotine might be partly responsible for the observed biological effects. Transcriptome alterations in both offspring sexes and treatment groups were all significantly associated with downstream adverse neurobiological outcomes. Results from this study demonstrate that e-cigarette exposure during early life alters CNS development potentially leading to chronic neuropathology. PMID:27077873

  7. Frontal Cortex Transcriptome Analysis of Mice Exposed to Electronic Cigarettes During Early Life Stages

    PubMed Central

    Lauterstein, Dana E.; Tijerina, Pamella B.; Corbett, Kevin; Akgol Oksuz, Betul; Shen, Steven S.; Gordon, Terry; Klein, Catherine B.; Zelikoff, Judith T.

    2016-01-01

    Electronic cigarettes (e-cigarettes), battery-powered devices containing nicotine, glycerin, propylene glycol, flavorings, and other substances, are increasing in popularity. They pose a potential threat to the developing brain, as nicotine is a known neurotoxicant. We hypothesized that exposure to e-cigarettes during early life stages induce changes in central nervous system (CNS) transcriptome associated with adverse neurobiological outcomes and long-term disease states. To test the hypothesis, pregnant C57BL/6 mice were exposed daily (via whole body inhalation) throughout gestation (3 h/day; 5 days/week) to aerosols produced from e-cigarettes either with nicotine (13–16 mg/mL) or without nicotine; following birth, pups and dams were exposed together to e-cigarette aerosols throughout lactation beginning at postnatal day (PND) 4–6 and using the same exposure conditions employed during gestational exposure. Following exposure, frontal cortex recovered from ~one-month-old male and female offspring were excised and analyzed for gene expression by RNA Sequencing (RNA-Seq). Comparisons between the treatment groups revealed that e-cigarette constituents other than nicotine might be partly responsible for the observed biological effects. Transcriptome alterations in both offspring sexes and treatment groups were all significantly associated with downstream adverse neurobiological outcomes. Results from this study demonstrate that e-cigarette exposure during early life alters CNS development potentially leading to chronic neuropathology. PMID:27077873

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

    SciTech Connect

    Blossom, Sarah J.; Cooney, Craig A.; Melnyk, Stepan B.; Rau, Jenny L.; Swearingen, Christopher J.; Wessinger, William D.

    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 of 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

  9. Sexual maturation and fertility of male and female mice exposed prenatally and postnatally to trivalent and hexavalent chromium compounds.

    PubMed

    Al-Hamood, M H; Elbetieha, A; Bataineh, H

    1998-01-01

    The reproductive toxicity of trivalent and hexavalent chromium compounds was investigated in male and female mice exposed to 1000 ppm chromium chloride and potassium dichromate via their mother during gestational and lactational periods. Fertility was reduced in male offspring exposed to either trivalent or hexavalent chromium compounds. Body weights and weights of testes, seminal vesicles and preputial glands were reduced in trivalent-exposed male offspring. The exposure of female mice offspring to trivalent and hexavalent chromium compounds delayed sexual maturation. Fertility was reduced in female offspring exposed to either trivalent or hexavalent chromium compounds. The exposure of female mice to hexavalent chromium compound reduced the number of implantations and viable fetuses respectively. Body weight and weights of ovaries and uteri were reduced in trivalent-exposed female offspring. The results indicate that under our experimental conditions, the exposure of male and female mice offspring to either trivalent or hexavalent chromium compounds during gestational and lactational periods impair reproductive functions and fertility in adulthood. PMID:9801270

  10. Sex- and Tissue-Specific Methylome Changes in Brains of Mice Perinatally Exposed to Lead

    PubMed Central

    Sánchez-Martín, Francisco Javier; Lindquist, Diana M.; Landero-Figueroa, Julio; Zhang, Xiang; Chen, Jing; Cecil, Kim M.; Medvedovic, Mario; Puga, Alvaro

    2014-01-01

    Changes in DNA methylation and subsequent changes in gene expression regulation are the hallmarks of age- and tissue-dependent epigenetic drift and plasticity resulting from the combinatorial integration of genetic determinants and environmental cues. To determine whether perinatal lead exposure caused persistent DNA methylation changes in target tissues, we exposed mouse dams to 0, 3 or 30 ppm of lead acetate in drinking water for a period extending from 2 months prior to mating, through gestation, until weaning of pups at postnatal day-21, and analyzed whole-genome DNA methylation in brain cortex and hippocampus of 2-month old exposed and unexposed progeny. Lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males. These regions mapped to Rn4.5s, Sfi1, and Rn45s loci in mouse chromosomes 2, 11 and 17, respectively. At a conservative fdr<0.001, 1,623 additional CpG sites were differentially methylated in female hippocampus, corresponding to 117 unique genes. Sixty of these genes were tested for mRNA expression and showed a trend towards negative correlation between mRNA expression and methylation in exposed females but not males. No statistically significant methylome changes were detected in male hippocampus or in cortex of either sex. We conclude that exposure to lead during embryonic life, a time when the organism is most sensitive to environmental cues, appears to have a sex- and tissue-specific effect on DNA methylation that may produce pathological or physiological deviations from the epigenetic plasticity operative in unexposed mice. PMID:25530354

  11. T-cell activation in pulmonary lymph nodes of mice exposed to ozone

    SciTech Connect

    Dziedzic, D.; White, H.J.

    1985-12-01

    Groups of Cd-1 female mice were exposed to ozone at 0.3, 0.5, and 0.7 ppm, 20 hr per day, 7 days per week for 1-28 days. The effect of ozone exposure on lymphoid cells was determined by studying mediastinal lymph nodes at various times of exposure. It was found that lymphocyte numbers underwent a dose-dependent, four-phased change:cellular depletion (Days 1-2), followed by rapid hyperplasia (Days 3-4), incremental cell number reduction (Days 5-7), and a subsequent subacute phase of elevated lymphocyte numbers (Days 8-28). Using tritiated thymidine it was determined that cells underwent a rapid burst of division by Day 3 of exposure and that mitosis subsequently declined to near baseline values by 2 weeks of exposure. Autoradiographic analysis of histologic sections revealed that the paracortical T-cell areas of the nodes were particularly involved. In addition to the increase in thymidine uptake, several morphologic changes were evident in affected cells. By comparison, the B cells from ozone-exposed animals were virtually unaffected with respect to cell division or morphological alterations. Prior treatment of ozone-exposed animals with a monoclonal antibody that is cytotoxic for T cells eliminated the hyperplastic response. Immunologic aspects of T-cell reactivity were studied. T-cell responsiveness to mitogenic stimulation with concanavalin A showed little alteration during the first days of exposure; however, by Day 14 an increase in reactivity was observed. This change indicated that functional lymphocyte stimulation occurred during ozone exposure.

  12. 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...

  13. Modulation of pulmonary inflammatory responses and antimicrobial defenses in mice exposed to diesel exhaust.

    PubMed

    Gowdy, Kymberly; Krantz, Quentin T; Daniels, Mary; Linak, William P; Jaspers, Ilona; Gilmour, M Ian

    2008-06-15

    Diesel exhaust (DE) is a major component of urban air pollution and has been shown to increase the severity of infectious and allergic lung disease. The purpose of this study was to evaluate the effects of DE exposure on pulmonary inflammation, mediator production and antimicrobial defenses in an exposure model that had previously been shown to increase susceptibility to influenza. BALB/c mice were exposed to filtered air, or to DE diluted to yield 0.5 or 2 mg/m(3) of diesel exhaust particles (DEP) for 4 h per day for 1 or 5 days. Immediately and 18 h after one or five diesel exposures mice were euthanized to assess both immediate and delayed effects. DE exposure for 5 days at either concentration caused higher neutrophil numbers and lesion scoring compared to air controls. Intracellular adhesion molecule-1 (ICAM-1), which recruits inflammatory cells and is an entry site for rhinoviruses was increased immediately after 1 or 5 days of DE exposure. Several inflammatory and immune cytokines (TNF-alpha, MIP-2, IL-6, IFN-gamma, and IL-13) were also upregulated at various time points and concentrations. In contrast, clara cell secretory protein (CCSP), surfactant protein A (SP-A), and surfactant protein D (SP-D) which are important host defense molecules, were significantly decreased at both the message and protein level with DE exposure. We conclude that exposure to moderate and high occupational levels of DE caused an increase in lung injury and inflammation, and a decrease in host defense molecules, which could result in increased susceptibility to respiratory pathogens. PMID:18343473

  14. Modulation of pulmonary inflammatory responses and antimicrobial defenses in mice exposed to diesel exhaust

    SciTech Connect

    Gowdy, Kymberly; Krantz, Quentin T.; Daniels, Mary; Linak, William P.; Jaspers, Ilona; Gilmour, M. Ian

    2008-06-15

    Diesel exhaust (DE) is a major component of urban air pollution and has been shown to increase the severity of infectious and allergic lung disease. The purpose of this study was to evaluate the effects of DE exposure on pulmonary inflammation, mediator production and antimicrobial defenses in an exposure model that had previously been shown to increase susceptibility to influenza. BALB/c mice were exposed to filtered air, or to DE diluted to yield 0.5 or 2 mg/m{sup 3} of diesel exhaust particles (DEP) for 4 h per day for 1 or 5 days. Immediately and 18 h after one or five diesel exposures mice were euthanized to assess both immediate and delayed effects. DE exposure for 5 days at either concentration caused higher neutrophil numbers and lesion scoring compared to air controls. Intracellular adhesion molecule-1 (ICAM-1), which recruits inflammatory cells and is an entry site for rhinoviruses was increased immediately after 1 or 5 days of DE exposure. Several inflammatory and immune cytokines (TNF-{alpha}, MIP-2, IL-6, IFN-{gamma}, and IL-13) were also upregulated at various time points and concentrations. In contrast, clara cell secretory protein (CCSP), surfactant protein A (SP-A), and surfactant protein D (SP-D) which are important host defense molecules, were significantly decreased at both the message and protein level with DE exposure. We conclude that exposure to moderate and high occupational levels of DE caused an increase in lung injury and inflammation, and a decrease in host defense molecules, which could result in increased susceptibility to respiratory pathogens.

  15. Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice.

    PubMed

    Ha, Michael A; Smith, Gregory J; Cichocki, Joseph A; Fan, Lu; Liu, Yi-Shiuan; Caceres, Ana I; Jordt, Sven Eric; Morris, John B

    2015-01-01

    Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone) and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol's effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8), the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may promote smoking

  16. Menthol Attenuates Respiratory Irritation and Elevates Blood Cotinine in Cigarette Smoke Exposed Mice

    PubMed Central

    Ha, Michael A.; Smith, Gregory J.; Cichocki, Joseph A.; Fan, Lu; Liu, Yi-Shiuan; Caceres, Ana I.; Jordt, Sven Eric; Morris, John B.

    2015-01-01

    Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone) and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol’s effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8), the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may promote smoking

  17. Protective Effect of Porcine Cerebral Hydrolysate Peptides on Learning and Memory Deficits and Oxidative Stress in Lead-Exposed Mice.

    PubMed

    Zou, Ye; Feng, Weiwei; Wang, Wei; Chen, Yao; Zhou, Zhaoxiang; Li, Qian; Zhao, Ting; Mao, Guanghua; Wu, Xiangyang; Yang, Liuqing

    2015-12-01

    In this study, lead acetate solution and porcine cerebral hydrolysate peptides (PCHPs) were administered to developing mice. Porcine cerebral protein pretreated by ultrasound was hydrolyzed with alcalase, and 11 peptide fragments were obtained by Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of PCHPs. Our data showed that PCHPs significantly decreased Pb2+-induced spontaneous locomotor activity, latencies to reach the platform, and the time in target quadrant. It also decreased the accumulation of lead in the blood and brain of Pb2+-exposed developing mice. Co-administration of PCHPs and dimercaptosuccinic acid (DMSA) did not only reduce the accumulation of lead in blood but also increased the absorption of zinc and iron in Pb2+-exposed mice. Administration of PCHPs individually significantly enhanced hematopoietic parameters compared with the Pb2+-exposed group. PCHPs significantly reduced the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) but increased glutathione (GSH) content and anti-oxidant enzymes and nitric oxide synthase (NOS) activities in Pb2+-exposed brain. Our findings suggest that PCHPs have the ability to protect against Pb2+-exposed learning and memory deficits and oxidative damage. PMID:25956150

  18. Cardiovascular protection by ezetimibe and influence on oxidative stress in mice exposed to intermittent hypoxia.

    PubMed

    Kato, Ryuji; Nishioka, Satoshi; Nomura, Atsuo; Ijiri, Yoshio; Miyamura, Masatoshi; Ukimura, Akira; Okada, Yoshikatsu; Kitaura, Yasushi; Hayashi, Tetsuya

    2015-10-15

    Ezetimibe is as an inhibitor of NPC1L1 protein, which has a key role in cholesterol absorption. The aim of this study was to evaluate the influence of ezetimibe on the plasma lipid profile, atherosclerotic lesions, and cardiomyocyte ultrastructure in an animal model of atherosclerosis with intermittent hypoxia. Apolipoprotein E-knockout mice received a high-fat diet for 30 days. Then animals were exposed to intermittent hypoxia for 10 days or were maintained under normoxic conditions. In the ezetimibe group, ezetimibe (5 mg/kg/day) was added to the diet. Under normoxic conditions, the total cholesterol level was significantly lower in the ezetimibe group (63.6±6.6 mg/dl) than in the control group (116.3±16.9 mg/dl, P<0.001). Intermittent hypoxia accelerated atherosclerosis associated with increased superoxide production, which also caused degeneration of cardiomyocytes, mitochondrial abnormalities, and interstitial fibrosis. Compared with the control group, the ezetimibe group showed significantly less advanced atherosclerotic lesions and lower superoxide production in the thoracic aorta, as well as reduced oxidative stress, preservation of cardiomyocyte ultrastructure, and reduced interstitial fibrosis in the left ventricular myocardium. In conclusion, ezetimibe not only reduces total cholesterol, but also prevents the development of atherosclerosis and cardiovascular events due to intermittent hypoxia at least partly through suppression of oxidative stress. PMID:26276396

  19. Hepatic Transcriptome Responses in Mice (Mus musculus) Exposed to the Nafion Membrane and Its Combustion Products

    PubMed Central

    Feng, Mingbao; Qu, Ruijuan; Habteselassie, Mussie; Wu, Jun; Yang, Shaogui; Sun, Ping; Huang, Qingguo; Wang, Zunyao

    2015-01-01

    Nafion 117 membrane (N117), an important polymer electrolyte membrane (PEM), has been widely used for numerous chemical technologies. Despite its increasing production and use, the toxicity data for N117 and its combustion products remain lacking. Toxicity studies are necessary to avoid problems related to waste disposal in landfills and incineration that may arise. In this study, we investigated the histopathological alterations, oxidative stress biomarker responses, and transcriptome profiles in the liver of male mice exposed to N117 and its combustion products for 24 days. An ion-chromatography system and liquid chromatography system coupled to a hybrid quadrupole time-of-flight mass spectrometry were used to analyze the chemical compositions of these combustion products. The transcriptomics analysis identified several significantly altered molecular pathways, including the metabolism of xenobiotics, carbohydrates and lipids; signal transduction; cellular processes; immune system; and signaling molecules and interaction. These studies provide preliminary data for the potential toxicity of N117 and its combustion products on living organisms and may fill the information gaps in the toxicity databases for the currently used PEMs. PMID:26057616

  20. Influence of sexual dimorphism on pulmonary inflammatory response in adult mice exposed to chloroform.

    PubMed

    de Oliveira, Túlio Henrique Versiani; Campos, Keila Karine Duarte; Soares, Nícia Pedreira; Pena, Karina Braga; Lima, Wanderson Geraldo; Bezerra, Frank Silva

    2015-01-01

    Chloroform is an organic solvent used as an intermediate in the synthesis of various fluorocarbons. Despite its widespread use in industry and agriculture, exposure to chloroform can cause illnesses such as cancer, especially in the liver and kidneys. The aim of the study was to analyze the effects of chloroform on redox imbalance and pulmonary inflammatory response in adult C57BL/6 mice. Forty animals were divided into 4 groups (N = 10): female (FCG) and male (MCG) controls, and females (FEG) and males (MEG) exposed to chloroform (7.0 ppm) 3 times/d for 20 minutes for 5 days. Total and differential cell counts, oxidative damage analysis, and protein carbonyl and antioxidant enzyme catalase (CAT) activity measurements were performed. Morphometric analyses included alveolar area (Aa) and volume density of alveolar septa (Vv) measurements. Compared to FCG and MCG, inflammatory cell influx, oxidative damage to lipids and proteins, and CAT activity were higher in FEG and MEG, respectively. Oxidative damage and enzyme CAT activity were higher in FEG than in FCG. The Aa was higher in FEG and MEG than in FCG and MCG, respectively. The Vv was lower in FEG and MEG than in FCG and MCG, respectively. This study highlights the risks of occupational chloroform exposure at low concentrations and the intensity of oxidative damage related to gender. The results validate a model of acute exposure that provides cellular and biochemical data through short-term exposure to chloroform. PMID:25870144

  1. Hepatic gene expression analysis of mice exposed to raw water from Meiliang Bay, Lake Taihu, China.

    PubMed

    Wu, Bing; Liu, Su; Cheng, Shupei; Zhang, Yan; Zhang, Xuxiang

    2013-12-01

    Lake water is a micro-polluted water system, and characterization of its toxicity remains difficult. Microarray-based determination of altered gene expression might be an alterative approach. We chose raw water from Meiliang Bay, Lake Taihu, China as the target water. Male mice were exposed to the lake water for 90 days. Total hepatic RNA was applied to interrogate the Affymetrix Mouse Genome 430A 2.0 array. Gene ontology analysis, pathway analysis and gene network analysis were used to identify biological effects of differently expressed genes. The results showed that the expressions of 170 genes were altered. Nine biological processes and nine biological pathways were significantly perturbed (P ≤ 0.01), mainly linked to the regulation of cell processes, DNA repair, chromatin modification, oxidative reduction and carbohydrate metabolism. Important genes, such as Prkca, Pik3r1, Fgfr1 and Zbtb16, were identified by gene network analysis. This study provided excellent insights into early toxicological effects related to raw Lake Taihu water, and illustrated that the toxicogenomic approach might be a useful tool to evaluate potential environmental health effects of raw lake water. PMID:22899542

  2. Enhanced oxidative stress in the skin of vitamin E deficient mice exposed to semisynthetic metal working fluids.

    PubMed

    Shvedova, Anna A; Kisin, Elena; Murray, Ashley; Smith, Charlotte; Castranova, Vincent; Kommineni, Choudari

    2002-07-01

    Metal working fluids (MWFs) are widely used in industry for metal cutting, drilling, shaping, lubricating, and milling. Many occupational health concerns have arisen for workers exposed to MWFs. It has been reported earlier that occupational exposure to MWFs causes allergic and irritant contact dermatitis. Previously, we have shown that dermal exposure of female and male B6C3F1 mice to 5% MWFs for 3 months resulted in accumulation of mast cells and elevation of histamine in the skin. Topical exposure to MWFs also resulted in elevated oxidative stress in the liver of both sexes and the testes in males. The goal of this study was to evaluate whether preexisting oxidative stress in the skin exacerbated mast cell influx after MWFs treatment. Oxidative stress in the skin of B6C3F1 mice was generated by dietary vitamin E deprivation. Mice were given vitamin E deficient (5-10 i.v./kg of vitamin E) or basal (50 i.v./kg of vitamin E) diets for 34 weeks. Topical treatment with MWFs (100 microl, 30%) started after 18 weeks of alimentary vitamin E deprivation. Histology of the skin after 16 weeks of exposure to MWFs revealed a 53% increase in mast cell accumulation in vitamin E deficient diets compared to mice given a vitamin E sufficient diet. Total antioxidant reserve in skin of vitamin E deprived mice treated with MWFs was decreased by 66% as compared to those mice given a vitamin E sufficient diet. GSH and protein thiols in the dermis of vitamin E deprived mice exposed to MWFs were also decreased 39 and 42%, respectively, as compared to mice given basal diet. This study clearly delineates the role of oxidative stress in enhancing mast cell accumulation caused by topical exposure to MWFs. PMID:12062937

  3. Comparison of Serum Bisphenol A Concentrations in Mice Exposed to Bisphenol A through the Diet versus Oral Bolus Exposure

    PubMed Central

    Sieli, Paizlee T.; Jašarevic´, Eldin; Warzak, Denise A.; Mao, Jiude; Ellersieck, Mark R.; Liao, Chunyang; Kannan, Kurunthachalam; Collet, Séverine H.; Toutain, Pierre-Louis; vom Saal, Frederick S.

    2011-01-01

    Background: Bisphenol A (BPA) is a widely produced endocrine-disrupting chemical. Diet is a primary route of exposure, but internal exposure (serum concentrations) in animals and humans has been measured only after single oral bolus administration. Objective: We compared serum concentrations of BPA over a 24-hr period after oral bolus administration or ad libitum feeding in mice and assessed for buildup with dietary exposure. Methods: Adult female mice were administered [dimethyl-d6]-BPA (BPA-d6) as a single oral bolus (20 mg/kg body weight) or fed a diet containing 100 mg BPA-d6/kg feed weight ad libitum for 1 week. Serum concentrations were analyzed using isotope dilution liquid chromatography coupled with electrospray tandem mass spectrometry and compared between exposure groups over the first 23 hr and after 7 days of dietary exposure. Results: Maximum concentration (Cmax) for BPA-d6 during the first 24 hr was reached at 1 hr and 6 hr for oral bolus and diet groups, respectively. Relative BPA-d6 bioavailability (unconjugated BPA-d6) was higher in diet-exposed mice than in the bolus group despite a relative lower absorption, a phenomenon consistent with an inhibitory effect of food on first-pass hepatic metabolism. In mice with ongoing dietary exposure, unconjugated BPA-d6 was higher on day 7 than on day 1. Conclusions: This is the first report of serum BPA concentrations in an animal model exposed to this chemical via the diet. Although bolus administration of BPA-d6 led to peak concentrations within 1 hr, Cmax for diet-exposed mice was delayed for several hours. However, bolus administration underestimates bioavailable serum BPA concentrations in animals—and presumably humans—than would result from dietary exposure. Exposure via diet is a more natural continuous exposure route than oral bolus exposure and is thus a better predictor of BPA concentrations in chronically exposed animals and humans. PMID:21642047

  4. Expression Profiling Reveals Novel Hypoxic Biomarkers in Peripheral Blood of Adult Mice Exposed to Chronic Hypoxia

    PubMed Central

    Zeiger, Ulrike; Khurana, Tejvir S.

    2012-01-01

    Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO) mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX), exposed for two weeks to normobaric chronic hypoxia (CH) or two weeks of CH followed by two weeks of normoxic recovery (REC). Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off), 230 genes were identified and separated into four distinct temporal categories. Class I) contained 1 transcript up-regulated in both CH and REC; Class II) contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III) contained 9 transcripts down-regulated both in CH and REC; Class IV) contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1) by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia. PMID:22629407

  5. Expression profiling reveals novel hypoxic biomarkers in peripheral blood of adult mice exposed to chronic hypoxia.

    PubMed

    Mosqueira, Matias; Willmann, Gabriel; Zeiger, Ulrike; Khurana, Tejvir S

    2012-01-01

    Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO) mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX), exposed for two weeks to normobaric chronic hypoxia (CH) or two weeks of CH followed by two weeks of normoxic recovery (REC). Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off), 230 genes were identified and separated into four distinct temporal categories. Class I) contained 1 transcript up-regulated in both CH and REC; Class II) contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III) contained 9 transcripts down-regulated both in CH and REC; Class IV) contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1) by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia. PMID:22629407

  6. 7-Alkylguanine adduct levels in urine, lungs and liver of mice exposed to styrene by inhalation

    SciTech Connect

    Vodicka, Pavel Erik . E-mail: pvodicka@biomed.cas.cz; Linhart, Igor; Novak, Jan; Koskinen, Mikko; Vodickova, Ludmila; Hemminki, Kari

    2006-01-15

    This study describes urinary excretion of two nucleobase adducts derived from styrene 7,8-oxide (SO), i.e., 7-(2-hydroxy-1-phenylethyl)guanine (N7{alpha}G) and 7-(2-hydroxy-2-phenylethyl)guanine (N7{beta}G), as well as a formation of N7-SO-guanine adducts in lungs and liver of two month old male NMRI mice exposed to styrene by inhalation in a 3-week subacute study. Strikingly higher excretion of both isomeric nucleobase adducts in the first day of exposure was recorded, while the daily excretion of nucleobase adducts in following time intervals reached the steady-state level at 4.32 + 1.14 and 6.91 + 1.17 pmol/animal for lower and higher styrene exposure, respectively. {beta}-SO-guanine DNA adducts in lungs increased with exposure in a linear way (F = 13.7 for linearity and 0.17 for non-linearity, respectively), reaching at the 21st day the level of 23.0 adducts/10{sup 8} normal nucleotides, i.e., 0.74 fmol/{mu}g DNA of 7-alkylguanine DNA adducts for the concentration of 1500 mg/m{sup 3}, while no 7-SO-guanine DNA adducts were detected in the liver after 21 days of inhalation exposure to both of styrene concentrations. A comparison of 7-alkylguanines excreted in urine with 7-SO-guanines in lungs (after correction for depurination and for missing {alpha}-isomers) revealed that persisting 7-SO-guanine DNA adducts in lungs account for about 0.5% of the total alkylation at N7 of guanine. The total styrene-specific 7-guanine alkylation accounts for about 1.0 x 10{sup -5}% of the total styrene uptake, while N1-adenine alkylation contributes to this percentage only negligibly.

  7. Immunological function in mice exposed to JP-8 jet fuel in utero.

    PubMed

    Keil, Deborah E; Warren, D Alan; Jenny, Matthew J; EuDaly, Jackie G; Smythe, Joshua; Peden-Adams, Margie M

    2003-12-01

    Immunological parameters, host resistance, and thyroid hormones were evaluated in F1 mice exposed in utero to jet propulsion fuel-8 (JP-8). C57BL/6 pregnant dams (mated with C3H/HeJ males) were gavaged daily on gestation days 6-15 with JP-8 in a vehicle of olive oil at 0, 1000, or 2000 mg/kg. At weaning (3 weeks of age), no significant differences were observed in body, liver, spleen, or thymus weight, splenic and thymic cellularity, splenic CD4/CD8 lymphocyte subpopulations, or T-cell proliferation. Yet, lymphocytic proliferative responses to B-cell mitogens were suppressed in the 2000 mg/kg treatment group. In addition, thymic CD4-/CD8+ cells were significantly increased. By adulthood (8 weeks of age), lymphocyte proliferative responses and the alteration in thymic CD4-/CD8+ cells had returned to normal. However, splenic weight and thymic cellularity were altered, and the IgM plaque forming cell response was suppressed by 46% and 81% in the 1000 and 2000 mg/kg treatment groups, respectively. Furthermore, a 38% decrease was detected in the total T4 serum hormone level at 2000 mg/kg. In F1 adults, no significant alterations were observed in natural killer cell activity, T-cell lymphocyte proliferation, bone marrow cellularity and proliferative responses, complete blood counts, peritoneal and splenic cellularity, liver, kidney, or thymus weight, macrophage phagocytosis or nitric oxide production, splenic CD4/CD8 lymphocyte subpopulations, or total T3 serum hormone levels. Host resistance models in treated F1 adults demonstrated that immunological responses were normal after challenge with Listeria monocytogenes, but heightened susceptibility to B16F10 tumor challenge was seen at both treatment levels. This study demonstrates that prenatal exposure to JP-8 can target the developing murine fetus and result in impaired immune function and altered T4 levels in adulthood. PMID:14514957

  8. 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

  9. Alteration of the immune response to Mycobacterium bovis BCG in mice exposed chronically to low doses of UV radiation.

    PubMed

    Jeevan, A; Kripke, M L

    1990-10-01

    BALB/c mice were exposed on shaved dorsal skin to 1 minimal erythemal dose (MED) of UVB radiation (2.25 kJ/m2) from a bank of six FS-40 sunlamps three times per week. The total number of irradiations ranged from 1 to 27. At regular intervals, groups of mice were injected in the left hind foot pad with 1 x 10(6) live mycobacteria (Mycobacterium bovis BCG) 3 days after the last UVB exposure. The mice were tested 21 and 42 days after infection for a delayed type hypersensitivity (DTH) response to the purified protein derivative (PPD) of tubercle bacilli by injecting PPD into the right hind foot pad and measuring the foot pad swelling 24 hr later. The course of infection was followed by assessing the number of bacterial colony forming units in the lymph node draining the site of BCG infection and the spleen. Mice exposed from 1 to 15 times to 1 MED of UV radiation showed a significant suppression in their DTH response to PPD compared with the unirradiated mice. At the same time, the number of bacterial colony-forming units in the lymph node and spleen of the UV-irradiated mice was greater than in control mice. With continued exposure to UVB, however, the DTH response recovered to a normal level, and there was no longer an increase in the number of viable bacteria in the lymphoid organs. These results indicate that early in the course of chronic UV irradiation, mice were impaired in their ability to mount a DTH response to BCG and to clear these bacteria from their lymphoid organs; later the mice recovered from these effects of UV, with continued treatment. A dose-response study using single doses of UV radiation indicated that a dose of 2.7 kJ/m2 suppressed the DTH response by 50%. Thus, exposure of mice to a single or multiple low doses of UV radiation prior to infection can interfere with systemic immunity to mycobacteria. PMID:2204482

  10. Antioxidant and micronutrient-rich milk formula reduces lead poisoning and related oxidative damage in lead-exposed mice.

    PubMed

    Zhang, Yu; Li, Qingqing; Liu, Xiaojie; Zhu, Hui; Song, Aihua; Jiao, Jingjing

    2013-07-01

    Lead poisoning is a global environmental disease that induces lifelong adverse health effects. The effect of a milk formula consisting of antioxidant of bamboo leaves (AOB), vitamin C (Vc), calcium lactate (CaLac), ferrous sulfate (FeSO₄) and zinc sulfate (ZnSO₄) on the reduction of lead and lead-induced oxidative damage in lead-exposed mice was studied. The lead-reducing effect of milk formula was investigated via a 7-week toxicokinetics study and a tissue distribution level examination. The ameliorating effect of milk formula on lead-induced oxidative damage was investigated. Results demonstrated current milk formula could effectively reduce blood lead levels (BLLs) and lead distribution levels of liver, kidneys, thighbones and brain in mice based on metal ion-mediated antagonism and chelation mechanisms. This milk formula could not only protect lead-susceptible tissues against lead poisoning, but also maintain normal absorption and distribution of essential elements in vivo. Meanwhile, current milk formula could prevent the reduction of δ-aminolevulinic acid dehydratase (δ-ALAD) activity and enhancement of free erythrocyte protoporphyrins (FEP) levels in blood erythrocytes of mice. Also, this formula could indirectly protect blood cell membranes against lead-induced lipid peroxidation. We conclude that current optimized milk formula effectively reduces lead poisoning and lead-induced in vivo oxidative damage in lead-exposed mice. PMID:23537597

  11. Oxidative stress in the lung of mice exposed to cigarette smoke either early in life or in adulthood.

    PubMed

    Micale, Rosanna T; La Maestra, Sebastiano; Maestra, Sebastiano La; Di Pietro, Angela; Pietro, Angela Di; Visalli, Giuseppa; Baluce, Barbara; Balansky, Roumen; Steele, Vernon E; De Flora, Silvio

    2013-05-01

    Birth and early life stages are critical periods characterized by severe alterations of the redox balance and by "physiological" genomic changes in lung cells, which may be responsible for cancer and other diseases in adulthood. Oxidative stress is a major mechanism accounting for the carcinogenicity of cigarette smoke (CS), which becomes more potently carcinogenic in mice when exposure starts at birth and continues early in life. We compared herewith a variety of end-points related to oxidative stress, mitochondrial alterations, and cell turnover in the lung of Swiss H mice, either sham-exposed or CS-exposed for 4 weeks, starting either at birth or at 4 months of age. The results showed that the physiological levels of certain end-points are affected by age. In fact, the baseline proportion of hypodiploid cells and the mitochondrial potential and mass were higher in adults, whereas 8-hydroxy-2'-deoxyguanosine (8-oxo-dGuo) levels, the proportion of necrotic cells, and the extent of autophagy were higher early in life. Adult mice were more responsive to CS by increasing the proportion of necrotic cells and of cells in S/G2 phase, whereas young mice maintained a high extent of autophagy, exhibited a greater increase of lipid peroxidation products and 8-oxo-dGuo levels, and had a higher frequency of micronucleated cells. In addition, exposure to CS affected the mitochondrial potential/mass, especially in young mice. In conclusion, these data provide evidence that oxidative stress and the resulting DNA damage provide a major contribution to the high susceptibility of mice to CS early in life. PMID:23423711

  12. Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin.

    PubMed

    Anisimov, Vladimir N; Popovich, Irina G; Zabezhinski, Mark A; Egormin, Peter A; Yurova, Maria N; Semenchenko, Anna V; Tyndyk, Margarita L; Panchenko, Andrey V; Trashkov, Alexandr P; Vasiliev, Andrey G; Khaitsev, Nikolai V

    2015-01-01

    The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone--IGF-1--insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (+20%, P < 0.05) and slightly increased the maximum life span (+3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (-9.1% and -13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice. PMID:25483062

  13. Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

    PubMed Central

    Xu, Hong; Xian, Jian; Vire, Emmanuelle; McKinney, Steven; Wong, Jason; Wei, Vivien; Tong, Rebecca; Kouzarides, Tony; Caldas, Carlos; Aparicio, Samuel

    2016-01-01

    BRCA2 mutations are significantly associated with early onset breast cancer, and the tumour suppressing function of BRCA2 has been attributed to its involvement in homologous recombination [1]-mediated DNA repair. In order to identify additional functions of BRCA2, we generated BRCA2-knockout HCT116 human colorectal carcinoma cells. Using genome-wide microarray analyses, we have discovered a link between the loss of BRCA2 and the up-regulation of a subset of interferon (IFN)-related genes, including APOBEC3F and APOBEC3G. The over-expression of IFN-related genes was confirmed in different human BRCA2−/− and mouse Brca2−/− tumour cell lines, and was independent of either senescence or apoptosis. In isogenic wild type BRCA2 cells, we observed over-expression of IFN-related genes after treatment with DNA-damaging agents, and following ionizing radiation. Cells with endogenous DNA damage because of defective BRCA1 or RAD51 also exhibited over-expression of IFN-related genes. Transcriptional activity of the IFN-stimulated response element (ISRE) was increased in BRCA2 knockout cells, and the expression of BRCA2 greatly decreased IFN-α stimulated ISRE reporter activity, suggesting that BRCA2 directly represses the expression of IFN-related genes through the ISRE. Finally, the colony forming capacity of BRCA2 knockout cells was significantly reduced in the presence of either IFN-β or IFN-γ, suggesting that IFNs may have potential as therapeutic agents in cancer cells with BRCA2 mutations. PMID:25043256

  14. FACTORS THAT INFLUENCE THE SUPPRESSION OF PULMONARY ANTIBACTERIAL DEFENSES IN MICE EXPOSED TO OZONE

    EPA Science Inventory

    Exposure to ozone (03) has been shown to increase susceptibility of mice to bacterial infection; however the underlying mechanism has not been well elucidated. his study investigated the effect Of 03 exposure on the ability of mice to combat an infectious challenge of Streptococc...

  15. EVALUATION OF HOST RESISTANCE AND IMMUNE FUNCTION IN CADMIUM-EXPOSED MICE (JOURNAL VERSION)

    EPA Science Inventory

    Adult female B6C3F1 mice received distilled water only or water containing 10, 50, or 250 ppm of cadmium chloride (CdCl2) for 90 days. On Day 91 mice also received a primary challenge with various infectious agents. There was no change in body weight gain, organ weights, or in hu...

  16. 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

  17. Sunscreens prevent local and systemic immunosuppression of contact hypersensitivity in mice exposed to solar-simulated ultraviolet radiation.

    PubMed

    Roberts, L K; Beasley, D G

    1997-06-01

    Ultraviolet (UV) irradiation causes the immunosuppression of contact hypersensitivity (CH) responses in animals and humans. There are conflicting reports regarding the effectiveness of sunscreens in preventing UV-induced suppression of both local-type CH (induced by the application of the contact sensitizer directly to UV-exposed skin) and systemic-type CH (induced by the application of the contact sensitizer to an unirradiated skin site 3 days after UV exposure). The purposes of this study were as follows: 1. to derive solar simulator UV dose-response curves for the induction of local and systemic CH suppression in C3H mice; 2. to establish minimum immune suppression doses (MISDs) for local and systemic CH; 3. to determine the local and systemic immune protection capacity of two commercial sunscreen lotions with labeled sun protection factors (SPFs) of 4 and 8. Dose-response curves for the induction of local and systemic CH suppression were derived by exposing groups of mice to a range of full-spectrum UV doses (0.37-21.4 kJ m-2) on two consecutive days delivered from a filtered 1000 W xenon arc lamp solar simulator. The MISDs, defined as the lowest dose tested to cause approximately 50% suppression of the normal CH response, were obtained from the dose-response curves. Although the local and systemic immunosuppression dose-response curves were not statistically different, the MISD for local suppression of CH (1.35 kJ m-2) was about fivefold lower than that for systemic CH suppression (6.76 kJ m-2). The MISD was used as the endpoint to determine sunscreen immune protection levels. Both sunscreens, applied at 2 mg cm-2, provided immune protection against the induction of local and systemic CH suppression in mice exposed to an effective UV dose of 1 MISD given through the sunscreen, i.e. 4 MISD to SPF 4 sunscreen-protected mice and 8 MISD to SPF 8 sunscreen-protected mice mounted CH responses that were significantly greater than those elicited in unprotected mice

  18. Marked rapid alterations in nocturnal pineal serotonin metabolism in mice and rats exposed to weak intermittent magnetic fields

    SciTech Connect

    Lerchl, A.; Nonaka, K.O.; Stokkan, K.A.; Reiter, R.J. )

    1990-05-31

    Adult AMES mice and male Sprague Dawley rats were exposed to an artificial magnetic field, generated by Helmholtz coils. 3.5 hours after the onset of darkness the coils were activated for one hour resulting in an inversion of the horizontal component of the earth's magnetic field. The coils were activated and deactivated at 5 min intervals during the 1 hour exposure period. In both mice and rats, the levels of serotonin in the pineal were markedly increased by the exposure. In rats, an increase of pineal 5-hydroxyindole acetic acid and a decrease of the activity of the pineal enzyme serotonin-N-acetyltransferase also was observed. However, pineal and serum melatonin levels were not altered. The results indicate that the metabolism of serotonin in the pineal is quickly affected by the exposure of animals to a magnetic field.

  19. Nitric Oxide Synthase Enzymes in the Airways of Mice Exposed to Ovalbumin: NOS2 Expression Is NOS3 Dependent

    PubMed Central

    Bratt, Jennifer M.; Williams, Keisha; Rabowsky, Michelle F.; Last, Michael S.; Franzi, Lisa M.; Last, Jerold A.; Kenyon, Nicholas J.

    2010-01-01

    Objectives and Design. The function of the airway nitric oxide synthase (NOS) isoforms and the lung cell types responsible for its production are not fully understood. We hypothesized that NO homeostasis in the airway is important to control inflammation, which requires upregulation, of NOS2 protein expression by an NOS3-dependent mechanism. Materials or Subjects. Mice from a C57BL/6 wild-type, NOS1−/−, NOS2−/−, and NOS3−/− genotypes were used. All mice strains were systemically sensitized and exposed to filtered air or ovalbumin (OVA) aerosol for two weeks to create a subchronic model of allergen-induced airway inflammation. Methods. We measured lung function, lung lavage inflammatory and airway epithelial goblet cell count, exhaled NO, nitrate and nitrite concentration, and airway NOS1, NOS2, and NOS3 protein content. Results. Deletion of NOS1 or NOS3 increases NOS2 protein present in the airway epithelium and smooth muscle of air-exposed animals. Exposure to allergen significantly reduced the expression of NOS2 protein in the airway epithelium and smooth muscle of the NOS3−/− strain only. This reduction in NOS2 expression was not due to the replacement of epithelial cells with goblet cells as remaining epithelial cells did not express NOS2. NOS1−/− animals had significantly reduced goblet cell metaplasia compared to C57Bl/6 wt, NOS2−/−, and NOS3−/− allergen-exposed mice. Conclusion. The airway epithelial and smooth muscle cells maintain a stable airway NO concentration under noninflammatory conditions. This “homeostatic” mechanism is unable to distinguish between NOS derived from the different constitutive NOS isoforms. NOS3 is essential for the expression of NOS2 under inflammatory conditions, while NOS1 expression contributes to allergen-induced goblet cell metaplasia. PMID:20953358

  20. Anxiety-like behaviour in mice exposed to tannery wastewater: The effect of photoelectrooxidation treatment.

    PubMed

    Siqueira, Ionara Rodrigues; Vanzella, Cláudia; Bianchetti, Paula; Rodrigues, Marco Antonio Siqueira; Stülp, Simone

    2011-01-01

    The leather industry is a major producer of wastewaters and releases large quantities of many different chemical agents used in hide processing into the environment. Since the central nervous system is sensitive to many different contaminants, our aim was to investigate the neurobehavioral effects of exposure of mice to tannery effluents using animal models of depression and anxiety, namely forced swim and elevated plus-maze. In order to propose a clean technology for the treatment of this effluent, we also investigated the exposure of mice to effluents treated by photoelectrooxidation process (PEO). Adult male Swiss albino mice (CF1 strain) were given free access to water bottles containing an effluent treated by a tannery (non-PEO) or PEO-treated tannery wastewater (0.1 and 1% in drinking water). Exposure to tannery wastewater induced behavioural changes in the mice in elevated plus-maze. Exposure to non-PEO 1% decreased the percentage of time spent in the open arms, indicating anxiety-like behaviour. Exposure to tannery wastewater did not alter immobility time in the forced swim test, suggesting that tannery effluents did not induce depression-like behaviour in the mice. These behavioural data suggest that non-PEO tannery effluent has an anxiogenic effect, whereas PEO-treated tannery effluents do not alter anxiety levels. PMID:21664271

  1. LETHALITY IN MICE AND RATS EXPOSED TO 2450 MHZ CIRCULARLY POLARIZED MICROWAVES AS A FUNCTION OF EXPOSURE DURATION AND ENVIRONMENTAL FACTORS

    EPA Science Inventory

    Adult male CD-1 mice and CD rats were used to determine LD50/24 hr of lethality from exposure to 2450-MHz circularly-polarized microwaves. Groups of sixteen mice or six rats were exposed in each of 32 combinations of nominal power density (10, 25, 50 or 75 mW/sq. cm.), exposure d...

  2. Neurochemical effects of a 20 kHz magnetic field on the central nervous system in prenatally exposed mice

    SciTech Connect

    Dimberg, Y.

    1995-09-01

    C57/B1 mice were exposed during pregnancy (gestation days 0--19) to a 20 kHz magnetic field (MF). The asymmetric sawtooth-waveform magnetic field in the exposed racks had a flux density of 15 {micro}T (peak to peak). After 19 days, the exposure was terminated, and the mice were housed individually under normal laboratory conditions. On postnatal day (PD) 1, PD21, and PD308, various neurochemical markers in the brains of the offspring were investigated and the brains weighed. No significant difference was found in the whole brain weight at PD1 or PD21 between exposed offspring and control animals. However, on PD308, a significant decrease in weight of the whole brain was detected in exposed animals. No significant differences were found in the weight of cortex, hippocampus, septum, or cerebellum on nay of the sampling occasions, nor were any significant differences detected in protein-, DNA-level, nerve growth factor (NGF), acetylcholine esterase- (AChE), or 2{prime},3{prime}-cyclic nucleotide 3{prime}-phosphodiesterase- (CNP; marker for oligodendrocytes) activities on PD21 in cerebellum. Cortex showed a more complex pattern of response to MF: MF treatment resulted in a decrease in DNA level and increases in the activities of CNP, AChE, and NGF protein. On PD308, the amount of DNA was significantly reduced in MF-treated cerebellum and CNP activity was still enhanced in MF-treated cortex compared to controls. Most of the effect of MF treatment during the embryonic period were similar to those induced by ionizing radiation but much weaker. However, the duration of the exposure required to elucidate the response of different markers to MF seems to be greater and effects appear later during development compared to responses to ionizing radiation.

  3. Quantitation and localization of intracellular redox active metals by X-ray fluorescence microscopy in cortical neurons derived from APP and APLP2 knockout tissue

    DOE PAGESBeta

    Ciccotosto, Giuseppe D.; James, Simon A.; Altissimo, Matteo; Paterson, David; Vogt, Stefan; Lai, Barry; de Jonge, Martin D.; Howard, Daryl L.; Bush, Ashley I.; Cappai, Roberto

    2014-10-01

    The amyloid precursor protein (APP) gene family includes APP and the amyloid precursor-like proteins, APLP1 and APLP2. These proteins contain metal binding sites for copper, zinc and iron and are known to have physiological roles in modulating the metal homeostasis in brain cells. Here we report the application of X-ray fluorescence microscopy (XFM) to investigate the subcellular distribution patterns of the metal ions Cu, Zn, Fe, and Ca in individual neurons derived from APP and APLP2 knockout mice brains to further define their role in metal homeostasis. These studies add to the growing body of data that the APP familymore » of proteins are metalloproteins that have shared as well as distinct effects on metals. As we continue to delineate the cellular effects of the APP family of proteins it is important to consider how metals are involved in their actions.« less

  4. Quantitation and localization of intracellular redox active metals by X-ray fluorescence microscopy in cortical neurons derived from APP and APLP2 knockout tissue

    SciTech Connect

    Ciccotosto, Giuseppe D.; James, Simon A.; Altissimo, Matteo; Paterson, David; Vogt, Stefan; Lai, Barry; de Jonge, Martin D.; Howard, Daryl L.; Bush, Ashley I.; Cappai, Roberto

    2014-10-01

    The amyloid precursor protein (APP) gene family includes APP and the amyloid precursor-like proteins, APLP1 and APLP2. These proteins contain metal binding sites for copper, zinc and iron and are known to have physiological roles in modulating the metal homeostasis in brain cells. Here we report the application of X-ray fluorescence microscopy (XFM) to investigate the subcellular distribution patterns of the metal ions Cu, Zn, Fe, and Ca in individual neurons derived from APP and APLP2 knockout mice brains to further define their role in metal homeostasis. These studies add to the growing body of data that the APP family of proteins are metalloproteins that have shared as well as distinct effects on metals. As we continue to delineate the cellular effects of the APP family of proteins it is important to consider how metals are involved in their actions.

  5. Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin

    PubMed Central

    Anisimov, Vladimir N; Popovich, Irina G; Zabezhinski, Mark A; Egormin, Peter A; Yurova, Maria N; Semenchenko, Anna V; Tyndyk, Margarita L; Panchenko, Andrey V; Trashkov, Alexandr P; Vasiliev, Andrey G; Khaitsev, Nikolai V

    2015-01-01

    The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone – IGF-1 – insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (+20%, P < 0.05) and slightly increased the maximum life span (+3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (−9.1% and −13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice. PMID:25483062

  6. Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin

    PubMed Central

    Anisimov, Vladimir N; Popovich, Irina G; Zabezhinski, Mark A; Egormin, Peter A; Yurova, Maria N; Semenchenko, Anna V; Tyndyk, Margarita L; Panchenko, Andrey V; Trashkov, Alexandr P; Vasiliev, Andrey G; Khaitsev, Nikolai V

    2015-01-01

    The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone – IGF-1 – insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (+20%, P < 0.05) and slightly increased the maximum life span (+3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (−9.1% and −13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice.

  7. GENE PROFILING IN WILD TYPE AND PPARÁ NULL MICE EXPOSED TO PFOA

    EPA Science Inventory

    Perflurooctanoic acid (PFOA) is a perfluoroalkyl acid used in a variety of commercial applications. Concerns have been raised because PFOA is ubiquitous in the environment and can be detected in human tissues. PFOA is a rodent carcinogen and a developmental toxicant in mice. W...

  8. EVALUATION OF IMMUNE FUNCTION IN MICE EXPOSED TO ORDRAM (TRADE NAME)

    EPA Science Inventory

    The potential effects that the thiocarbamate herbicide Ordram has on the immune system of mice was evaluated following 12 days of acute dosing by oral gavage. Dosages of Ordram ranging from 20 to 320 mg/kg/day had no consistent significant effects on a variety of immune parameter...

  9. ENHANCED MORTALITY AND LIVER DAMAGE IN VIRUS-INFECTED MICE EXPOSED TO PARAXYLENE

    EPA Science Inventory

    This study assessed effects of p-xylene exposure on mice concurrently infected with murine cytomegalovirus (MCMV). ossible effects included: enhanced infection due to p-xylene induced immune suppression; increased p-xylene toxicity due to viral suppression of cytochrome P-450 (P-...

  10. [Redistribution of immune defence in male mice exposed by female scent].

    PubMed

    Litvinova, E A; Garms, A I; Zaĭdman, A M; Korel', A V; Gerlinskaia, L A; Moshkin, M P

    2009-01-01

    Since scent marks of mice are harbored by parasites, their sniffing during olfactory search of the mating partner leads to increase of the infection risk. A hypothesis that sexual signals can induce, along with the reproductive behavior, non-specific immune defense against respiratory infections is tested in the present paper. It was found in the experiments on outbred ICR mice that the scent of soiled bedding from cages with mature females stimulated leukocyte intervention to the upper air-ways. Migration of the white blood cells to lung tissue was accompanied with a more prominent immune and endocrine responeses to intranasal application of the bacterial lipopolysacharide (LPS). In particular, LPS administration to male mice treated by female scent was resulted in much greater amount of leukocyte aggregations in the peribronchial areas than that was found in the males kept isolated from the female signals. The female scent also enhanced adrenocortical response to LPS administration, which was coincided with statistically significant increase of IL-1beta concentration in hypothalamus. So, chemical signals of the mature female induce travel of white blood cells to the upper air-waya in the scent treated male mice. It can increase resistance to respiratory infections, on the one hand, and aggravates stress response to inhalation of the bacterial compounds, on the other hand. PMID:19326854

  11. EFFECTS OF PERFLUOROOCTANOIC ACID (PFOA) ON MICE EXPOSED IN UTERO AT SPECIFIC GESTATIONAL STAGES

    EPA Science Inventory

    Perfluorooctanoic acid is developmentally toxic resulting in embryonic and postnatal deaths and growth retardation. Previous studies showed that dosing mice from gestation day (GD)2-18 with 5 mg PFOA/kg body weight impacts the growth and development of the fetus and newborns. The...

  12. HOST RESISTANCE TO MURINE MALARIA IN MICE EXPOSED TO THE ADENOSINE TEAMINASE INHIBITOR, 2'-DEOXYCOFORMYCIN

    EPA Science Inventory

    Resistance to infection with the nonlethal rodent malaria parasite Plasmodium yoelii 17XNL is mediated by humoral, T-cell and accessory cell activity. he purpose of this study was to profile host resistance to infection with this organism in mice xposed to 2'-deoxycoformycin (2dC...

  13. Altered sperm chromatin structure in mice exposed to sodium fluoride through drinking water.

    PubMed

    Sun, Zilong; Niu, Ruiyan; Wang, Bin; Wang, Jundong

    2014-06-01

    This study investigated the effects of sodium fluoride (NaF) on sperm abnormality, sperm chromatin structure, protamine 1 and protamine 2 (P1 and P2) mRNA expression, and histones expression in sperm in male mice. NaF was orally administrated to male mice at 30, 70, and 150 mg/l for 49 days (more than one spermatogenic cycle). Sperm head and tail abnormalities were significantly enhanced at middle and high doses. Similarly, sperm chromatin structure was also adversely affected by NaF exposure, indicating DNA integrity damage. Furthermore, middle and high NaF significantly reduced the mRNA expressions of P1 and P2, and P1/P2 ratio, whereas the sperm histones level was increased, suggesting the abnormal histone-protamine replacement. Therefore, we concluded that the mechanism by which F induced mice sperm abnormality and DNA integrity damage may involved in the alterations in P1, P2, and histones expression in sperm of mice. PMID:22865829

  14. IMMUNE FUNCTION IN MICE EXPOSED TO THE ADENOSINE DEAMINASE INHIBITOR 2'-DEOXYCOFORMYCIN DURING IMMUNE SYSTEM DEVELOPMENT

    EPA Science Inventory

    Pregnant mice were administered 2'-deoxycoformycin (2dCF), a potent inhibitor of adensoine deaminase activity, by intraperitoneal injection on day 7 or 15 of gestation or from day 8-12 or 14-18 of gestation. A total dose of 0, 0.5 or 2.0 micrograms 2dCF/g of maternal body weight ...

  15. NICOTINE EFFECTS ON THE ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.

    EPA Science Inventory

    Considerable research has shown long-lasting effects of early exposure in experimental animals to nicotine. Anatoxin-a is produced by cyanobacteria and has been shown to be a potent nicotinic agonist. This experiment evaluated the motor activity of adult mice, and their respons...

  16. Riboflavin supplementation improves energy metabolism in mice exposed to acute hypoxia.

    PubMed

    Wang, Y P; Wei, J Y; Yang, J J; Gao, W N; Wu, J Q; Guo, C J

    2014-01-01

    This study investigated the effects of riboflavin on energy metabolism in hypoxic mice. Kunming mice were fed diets containing riboflavin at doses of 6, 12, 24 and 48 mg/kg, respectively for 2 weeks before exposure to a simulated altitude of 6000 m for 8 h. Changes of riboflavin status and energy metabolism were assessed biochemically. Simultaneously, a (1)H nuclear magnetic resonance (NMR) based metabolomic technique was used to track the changes of plasma metabolic profiling. It was found that the content of hepatic riboflavin was decreased and erythrocyte glutathione activation coefficient was elevated significantly under hypoxic condition. Meanwhile, increased plasma pyruvate, lactate, beta-hydroxybutyrate and urea, as well as decreased plasma carnitine were observed. Riboflavin supplementation improved riboflavin status remarkably in hypoxic mice and decreased plasma levels of pyruvate, free fatty acids and beta-hydroxybutyrate significantly. Plasma carnitine was increased in response to riboflavin supplementation. Results obtained from (1)H NMR analysis were basically in line with the data from biochemical assays and remarkable changes in plasma taurine, choline and some other metabolites were also indicated. It was concluded that riboflavin requirement was increased under acute hypoxic condition and riboflavin supplementation was effective in improving energy metabolism in hypoxic mice. PMID:24564599

  17. An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD

    SciTech Connect

    Mustafa, A.; Holladay, S.D.; Goff, M.; Witonsky, S.G.; Kerr, R.; Reilly, C.M.; Sponenberg, D.P.; Gogal, R.M.

    2008-10-01

    Developmental exposure of mice to the environmental contaminant and AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes persistent postnatal suppression of T cell-mediated immune responses. The extent to which prenatal TCDD may induce or exacerbate postnatal autoimmune disease remains unknown. In the present study, time-pregnant high affinity AhR C57BL/6 mice received a single oral administration of 0, 2.5, or 5 {mu}g/kg TCDD on gestation day (gd) 12. Offspring of these mice (n = 5/gender/treatment) were evaluated at 24 weeks-of-age and showed considerable immune dysregulation that was often gender-specific. Decreased thymic weight and percentages of CD4{sup +}CD8{sup +} thymocytes, and increased CD4{sup +}CD8{sup -} thymocytes, were present in the female but not male offspring. Males but not females showed decreased CD4{sup -}CD8{sup +} T cells, and increased V{beta}3{sup +} and V{beta}17a{sup +} T cells, in the spleen. Males but not females also showed increased percentages of bone marrow CD24{sup -}B220{sup +} B cell progenitors. Antibody titers to dsDNA, ssDNA and cardiolipin displayed increasing trends in both male and female mice, reaching significance for anti-dsDNA in both genders and for ssDNA in males at 5 {mu}g/kg TCDD. Immunofluorescent staining of IgG and C3 deposition in kidney glomeruli increased in both genders of prenatal TCDD-exposed mice, suggestive of early stages of autoimmune glomerulonephritis. Collectively, these results show that exposure to TCDD during immune system development causes persistent humoral immune dysregulation as well as altered cell-mediated responses, and induces an adult profile of changes suggestive of increased risk for autoimmune disease.

  18. Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation

    PubMed Central

    Rithidech, Kanokporn Noy; Udomtanakunchai, Chatchanok; Honikel, Louise; Whorton, Elbert

    2013-01-01

    It is clear that high-dose radiation is harmful. However, despite extensive research, assessment of potential health-risks associated with exposure to low-dose radiation (at doses below or equal to 0.1 Gy) is still challenging. Recently, we reported that 0.05 Gy of 137Cs gamma rays (the existing limit for radiation-exposure in the workplace) was incapable of inducing significant in vivo genomic instability (measured by the presence of late-occurring chromosomal damage at 6 months post-irradiation) in bone marrow (BM) cells of two mouse strains, one with constitutively high and one with intermediate levels of the repair enzyme DNA-dependent protein-kinase catalytic-subunit (DNA-PKcs). In this study, we present evidence for a lack of genomic instability in BM cells of the severely combined-immunodeficiency (SCID/J) mouse (which has an extremely low-level of DNA-PKcs activity) exposed whole-body to low-dose radiation (0.05 Gy). Together with our previous report, the data indicate that low-dose radiation (0.05 Gy) is incapable of inducing genomic instability in vivo (regardless of the levels of DNA-PKcs activity of the exposed mice), yet higher doses of radiation (0.1 and 1 Gy) do induce genomic instability in mice with intermediate and extremely low-levels of DNA-PKcs activity (indicating an important role of DNA-PKcs in DNA repair). PMID:23549227

  19. Acceleration of atherogenesis in ApoE−/− mice exposed to acute or low-dose-rate ionizing radiation

    PubMed Central

    Mancuso, Mariateresa; Pasquali, Emanuela; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Pannicelli, Alessandro; Giardullo, Paola; Pazzaglia, Simonetta; Tapio, Soile; Atkinson, Michael J.; Saran, Anna

    2015-01-01

    There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE−/− mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE−/− females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response. PMID:26359350

  20. Acceleration of atherogenesis in ApoE-/- mice exposed to acute or low-dose-rate ionizing radiation.

    PubMed

    Mancuso, Mariateresa; Pasquali, Emanuela; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Pannicelli, Alessandro; Giardullo, Paola; Pazzaglia, Simonetta; Tapio, Soile; Atkinson, Michael J; Saran, Anna

    2015-10-13

    There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE-/- mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE-/- females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response. PMID:26359350

  1. Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation.

    PubMed

    Banda, Malathi; McKim, Karen L; Haber, Lynne T; MacGregor, Judith A; Gollapudi, B Bhaskar; Parsons, Barbara L

    2015-08-01

    This study investigated whether Kras mutation is an early event in the development of lung tumors induced by inhalation of particulate vanadium pentoxide (VP) aerosols. A National Toxicology Program tumor bioassay of inhaled particulate VP aerosols established that VP-induced alveolar/bronchiolar carcinomas of the B6C3F1 mouse lung carried Kras mutations at a higher frequency than observed in spontaneous mouse lung tumors. Therefore, this study sought to: (1) characterize any Kras mutational response with respect to VP exposure concentration, and (2) investigate the possibility that amplification of preexisting Kras mutation is an early event in VP-induced mouse lung tumorigenesis. Male Big Blue B6C3F1 mice (6 mice/group) were exposed to aerosolized particulate VP by inhalation, 6h/day, 5 days/week for 4 or 8 weeks, using VP exposure concentrations of 0, 0.1, and 1 mg/m(3). The levels of two different Kras codon 12 mutations [GGT → GAT (G12D) and GGT → GTT (G12V)] were measured in lung DNAs by Allele-specific Competitive Blocker PCR (ACB-PCR). For both exposure concentrations (0.1 and 1.0mg/m(3)) and both time points (4 and 8 weeks), the mutant fractions observed in VP-exposed mice were not significantly different from the concurrent controls. Given that 8 weeks of inhalation of a tumorigenic concentration of particulate aerosols of VP did not result in a significant change in levels of lung Kras mutation, the data do not support either a direct genotoxic effect of VP on Kras or early amplification of preexisting mutation as being involved in the genesis of VP-induced mouse lung tumors under the exposure conditions used. Rather, the data suggest that accumulation of Kras mutation occurs later with chronic VP exposure and is likely not an early event in VP-induced mouse lung carcinogenesis. PMID:26232258

  2. Effects of COX inhibitors on neurodegeneration and survival in mice exposed to the marine neurotoxin domoic acid.

    PubMed

    Ryan, James C; Cross, Cheryl A; Van Dolah, Frances M

    2011-01-01

    The marine neurotoxin domoic acid (DA) is a rigid analogue of the neurotransmitter glutamate and a potent agonist of kainate subtype glutamate receptors. Persistent activation of these receptor subtypes results in rapid excitotoxicity, calcium-dependent cell death, and neuronal degeneration in regions of the brain where glutamatergic pathways are concentrated. Previous work has shown that DA promotes the expression of inflammatory genes in the brain, such as cyclooxygenase 2 (COX2). To investigate the impact of inflammation on the development of neurodegeneration, and ultimately survival following DA administration, we used selective (L745337, Merck) and non-selective (acetylsalicylic acid (ASA)) COX inhibitors in DA exposed mice. Adult male ICR mice were given a regime of either ASA or L23547 both before and after a single LD50 dose of DA. Mice were observed immediately after toxin introduction and then sacrificed at 2 days post exposure. Our lower dose of L23547 increased survival and was most effective at decreasing neuronal degeneration in the CA1 and CA3 regions of the hippocampus, areas especially sensitive to DA excitotoxicity. This study shows that COX2 plays a role in DA induced neurodegeneration and death, and that inhibitors may be of value for treatment in human and wildlife DA exposure. PMID:20934488

  3. Modulation by metformin of molecular and histopathological alterations in the lung of cigarette smoke-exposed mice.

    PubMed

    Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; Micale, Rosanna T; La Maestra, Sebastiano; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

    2014-06-01

    The anti-diabetic drug metformin is endowed with anti-cancer properties. Epidemiological and experimental studies, however, did not provide univocal results regarding its role in pulmonary carcinogenesis. We used Swiss H mice of both genders in order to detect early molecular alterations and tumors induced by mainstream cigarette smoke. Based on a subchronic toxicity study, oral metformin was used at a dose of 800 mg/kg diet, which is 3.2 times higher than the therapeutic dose in humans. Exposure of mice to smoke for 4 months, starting at birth, induced a systemic clastogenic damage, formation of DNA adducts, oxidative DNA damage, and extensive downregulation of microRNAs in lung after 10 weeks. Preneoplastic lesions were detectable after 7.5 months in both lung and urinary tract along with lung tumors, both benign and malignant. Modulation by metformin of 42 of 1281 pulmonary microRNAs in smoke-free mice highlighted a variety of mechanisms, including modulation of AMPK, stress response, inflammation, NFκB, Tlr9, Tgf, p53, cell cycle, apoptosis, antioxidant pathways, Ras, Myc, Dicer, angiogenesis, stem cell recruitment, and angiogenesis. In smoke-exposed mice, metformin considerably decreased DNA adduct levels and oxidative DNA damage, and normalized the expression of several microRNAs. It did not prevent smoke-induced lung tumors but inhibited preneoplastic lesions in both lung and kidney. In conclusion, metformin was able to protect the mouse lung from smoke-induced DNA and microRNA alterations and to inhibit preneoplastic lesions in lung and kidney but failed to prevent lung adenomas and malignant tumors induced by this complex mixture. PMID:24683044

  4. Modulation by metformin of molecular and histopathological alterations in the lung of cigarette smoke-exposed mice

    PubMed Central

    Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; Micale, Rosanna T; La Maestra, Sebastiano; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

    2014-01-01

    The anti-diabetic drug metformin is endowed with anti-cancer properties. Epidemiological and experimental studies, however, did not provide univocal results regarding its role in pulmonary carcinogenesis. We used Swiss H mice of both genders in order to detect early molecular alterations and tumors induced by mainstream cigarette smoke. Based on a subchronic toxicity study, oral metformin was used at a dose of 800 mg/kg diet, which is 3.2 times higher than the therapeutic dose in humans. Exposure of mice to smoke for 4 months, starting at birth, induced a systemic clastogenic damage, formation of DNA adducts, oxidative DNA damage, and extensive downregulation of microRNAs in lung after 10 weeks. Preneoplastic lesions were detectable after 7.5 months in both lung and urinary tract along with lung tumors, both benign and malignant. Modulation by metformin of 42 of 1281 pulmonary microRNAs in smoke-free mice highlighted a variety of mechanisms, including modulation of AMPK, stress response, inflammation, NFκB, Tlr9, Tgf, p53, cell cycle, apoptosis, antioxidant pathways, Ras, Myc, Dicer, angiogenesis, stem cell recruitment, and angiogenesis. In smoke-exposed mice, metformin considerably decreased DNA adduct levels and oxidative DNA damage, and normalized the expression of several microRNAs. It did not prevent smoke-induced lung tumors but inhibited preneoplastic lesions in both lung and kidney. In conclusion, metformin was able to protect the mouse lung from smoke-induced DNA and microRNA alterations and to inhibit preneoplastic lesions in lung and kidney but failed to prevent lung adenomas and malignant tumors induced by this complex mixture. PMID:24683044

  5. Functions of mononuclear phagocytes in mice exposed to diethylstilbestrol: a model of aberrant macrophage development.

    PubMed

    Dean, J H; Lauer, L D; Murray, M J; Luster, M I; Neptun, D; Adams, D O

    1986-10-15

    Administration of the synthetic estrogen diethylstilbestrol (DES) lowers the systemic resistance of mice to challenge with either tumor cells or the facultative intracellular parasite Listeria monocytogenes. To assess the potential role of impaired mononuclear phagocyte system (MPS) function in this depression of host resistance, we addressed the question of systemic perturbations of the MPS induced by administration of DES. A panel of objective quantitative markers which have been previously shown to identify and characterize macrophages in the several stages of development of activation was employed. DES perturbed the resident population of peritoneal macrophages by increasing their number approximately twofold and by enhancing their competence for phagocytosis, cytostasis of tumor cells, and secretion of plasminogen activator. When we examined the competence of the MPS in DES-treated mice to respond to challenge with activating stimuli, we found that DES systemically suppressed the development of macrophages, in response to either pyran copolymer or BCG, to develop tumoricidal function and to gain competence for secretion of reactive oxygen intermediates such as H2O2. Since these data suggested that DES inhibited the development of macrophages from a precursor stage (i.e., responsive macrophages) to activated macrophages in vivo, we tested this possibility directly by applying known activating signals in vitro to responsive macrophages. Responsive macrophages from DES-treated mice did not become activated in response to the application of two known potent activating signals (i.e., MAF + LPS). Taken together, the data indicate that DES systemically perturbs the MPS and does so by enhancing development of the early stages of maturation and suppressing subsequent development. PMID:3802203

  6. Gender Dependent Evaluation of Autism like Behavior in Mice Exposed to Prenatal Zinc Deficiency

    PubMed Central

    Grabrucker, Stefanie; Boeckers, Tobias M.; Grabrucker, Andreas M.

    2016-01-01

    Zinc deficiency has recently been linked to the etiology of autism spectrum disorders (ASD) as environmental risk factor. With an estimated 17% of the world population being at risk of zinc deficiency, especially zinc deficiency during pregnancy might be a common occurrence, also in industrialized nations. On molecular level, zinc deficiency has been shown to affect a signaling pathway at glutamatergic synapses that has previously been identified through genetic mutations in ASD patients, the Neurexin-Neuroligin-Shank pathway, via altering zinc binding Shank family members. In particular, prenatal zinc deficient but not acute zinc deficient animals have been reported to display autism like behavior in some behavioral tests. However, a full behavioral analysis of a possible autism like behavior has been lacking so far. Here, we performed an extensive behavioral phenotyping of mice born from mothers with mild zinc deficiency during all trimesters of pregnancy. Prenatal zinc deficient animals were investigated as adults and gender differences were assessed. Our results show that prenatal zinc deficient mice display increased anxiety, deficits in nest building and various social interaction paradigm, as well as mild alterations in ultrasonic vocalizations. A gender specific analysis revealed only few sex specific differences. Taken together, given that similar behavioral abnormalities as reported here are frequently observed in ASD mouse models, we conclude that prenatal zinc deficient animals even without specific genetic susceptibility for ASD, already show some features of ASD like behavior. PMID:26973485

  7. [Cytogenetic investigations of bone marrow cells from mice exposed onboard biosatellite "Bion-M1"].

    PubMed

    Dorozhkina, O V; Ivanov, A A

    2015-01-01

    The results of studying the mitotic activities and chromosomal aberrations in bone marrow cells from C57/BL6N mice with the help of the anaphase technique in 12 hours after completion of the 30-day "Bion-M1" mission and ground-based experiment using flight equipment are presented. A statistically reliable decline of the mitotic activity (0.74%) was found in cells taken from the space flown animals. In the ground-based experiment, a statistically reliable downward trend in proliferative activity (1.37%) was revealed after the comparison with groups of vivarium control (1.46-1.53%). In both experiments mice increased the number of initial mitotic phases (prophase + metaphase) relative to the sum of anaphases and telophases. The number of aberrant mitoses grew reliably in the group of flight animals by 29.7%, whereas in the ground-based experiment an upward trend was insignificant as their number increased up to 2.3% only. In the vivarium controls aberrant mitoses constituted 1.75-1.8%. An increase in chromosomal aberrations was largely due to such abnormalities as fragments. These findings seem to have been a result of summation of the effects of radiation and other stressful factors in space flight. PMID:25958465

  8. Toxicity of Lunar Dust in Lungs Assessed by Examining Biomarkers in Exposed Mice

    NASA Technical Reports Server (NTRS)

    Lam, C.-W.; James, J. T.; Zeidler-Erdely, P. C.; Castranova, V.; Young, S. H.; Quan, C. L.; Khan-Mayberry, N.; Taylor, L. A.

    2010-01-01

    NASA is contemplating to build an outpost on the Moon for prolonged human habitation and research. The lunar surface is covered by a layer of soil, of which the finest portion is highly reactive dust. Dust samples of respirable sizes were aerodynamically isolated from two lunar soil samples of different maturities (cosmic exposure ages) collected during the Apollo 16 mission. The lunar dust samples, TiO2, or quartz, suspended in normal saline were given to groups of 5 C57 male mice by intrapharyngeal aspiration at 0. 1, 0.3, or 1.0 mg/mouse. Because lunar dust aggregates rapidly in aqueous media, some tests were conducted with dusts suspended in Survanta/saline (1:1). The mice were euthanized 7 or 30 days later, and their lungs were lavaged to assess the presence of toxicity biomarkers in bronchioalveolar lavage fluids. The overall results showed that the two lunar dust samples were similar in toxicity, they were more toxic than T102 , but less toxic than quartz. This preliminary study is a part of the large study to obtain data for setting exposure limits for astronauts living on the Moon

  9. Gender Dependent Evaluation of Autism like Behavior in Mice Exposed to Prenatal Zinc Deficiency.

    PubMed

    Grabrucker, Stefanie; Boeckers, Tobias M; Grabrucker, Andreas M

    2016-01-01

    Zinc deficiency has recently been linked to the etiology of autism spectrum disorders (ASD) as environmental risk factor. With an estimated 17% of the world population being at risk of zinc deficiency, especially zinc deficiency during pregnancy might be a common occurrence, also in industrialized nations. On molecular level, zinc deficiency has been shown to affect a signaling pathway at glutamatergic synapses that has previously been identified through genetic mutations in ASD patients, the Neurexin-Neuroligin-Shank pathway, via altering zinc binding Shank family members. In particular, prenatal zinc deficient but not acute zinc deficient animals have been reported to display autism like behavior in some behavioral tests. However, a full behavioral analysis of a possible autism like behavior has been lacking so far. Here, we performed an extensive behavioral phenotyping of mice born from mothers with mild zinc deficiency during all trimesters of pregnancy. Prenatal zinc deficient animals were investigated as adults and gender differences were assessed. Our results show that prenatal zinc deficient mice display increased anxiety, deficits in nest building and various social interaction paradigm, as well as mild alterations in ultrasonic vocalizations. A gender specific analysis revealed only few sex specific differences. Taken together, given that similar behavioral abnormalities as reported here are frequently observed in ASD mouse models, we conclude that prenatal zinc deficient animals even without specific genetic susceptibility for ASD, already show some features of ASD like behavior. PMID:26973485

  10. Dose-related growth deficits in LS but not SS mice prenatally exposed to alcohol.

    PubMed

    Gilliam, D M; Kotch, L E

    1996-01-01

    Genetically based alcohol sensitivity may influence the severity of alcohol-related birth defects. To examine this question, measures of growth and survival were examined in offspring of the alcohol sensitive Long-Sleep (LS) and alcohol-resistant Short-Sleep (SS) mouse lines following prenatal ethanol exposure. Pregnant LS and SS mice received an ethanol dose of either 6 or 8 g/kg/day from days 7 through 18 of pregnancy. Control groups received a maltose-dextran solution made isocaloric to the 8 g/kg/day dose. Ethanol and maltose-dextrin solutions were administered as split doses, 6 h apart, via gavage. Nonintubated lab chow control groups were also included for both mouse lines. Offspring were fostered at birth to lactating mice of an outbred stock. Pregnancy was longer for ethanol-treated LS dams compared to maltose-dextrin and lab chow LS control groups, whereas pregnancy length for ethanol-treated SS dams was similar to SS controls. Prenatal ethanol exposure resulted in dose-related growth deficits in LS but not in SS litters. Line differences in postnatal growth deficits in response to prenatal alcohol exposure suggest maternal or fetal alcohol sensitivity influence alcohol-related birth defects. PMID:8837934

  11. An α4β1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice

    PubMed Central

    Kenyon, Nicholas J.; Liu, Ruiwu; O’Roark, Erin M.; Huang, Wenzhe; Peng, Li; Lam, Kit S.

    2008-01-01

    Inhibition of the α4 subunit of both the α4β1 and α4β7 integrins has shown promise in decreasing airway inflammation and airway hyperresponsiveness in various animal models. We hypothesized that a novel, high-affinity α4β1 antagonist (LLP2A) would decrease the migration of eosinophils to the lung and ameliorate the airway hyperresponsiveness in a mouse model of ovalbumin-induced airway inflammation. To test this hypothesis, we administered LLP2A, or scrambled LLP2A (a negative control), prior to exposure of sensitized BALB/c mice to ovalbumin aerosol. We can partially prevent, or reverse, the airway inflammatory response, but not airways hyperresponsiveness, by treatment of mice with LLP2A, a synthetic peptidomimetic α4β1 antagonist LLP2A. Specifically engineered, PEGylated (PEG) formulations of this antagonist further reduce the airway inflammatory response to ovalbumin lbumin, presumably by improving the circulating half-life of the drug. PMID:19103195

  12. Effect of roflumilast on inflammatory cells in the lungs of cigarette smoke-exposed mice

    PubMed Central

    Martorana, Piero A; Lunghi, Benedetta; Lucattelli, Monica; De Cunto, Giovanna; Beume, Rolf; Lungarella, Giuseppe

    2008-01-01

    Background We reported that roflumilast, a phosphodiesterase 4 inhibitor, given orally at 5 mg/kg to mice prevented the development of emphysema in a chronic model of cigarette smoke exposure, while at 1 mg/kg was ineffective. Here we investigated the effects of roflumilast on the volume density (VV) of the inflammatory cells present in the lungs after chronic cigarette smoke exposure. Methods Slides were obtained from blocks of the previous study and VV was assessed immunohistochemically and by point counting using a grid with 48 points, a 20× objective and a computer screen for a final magnification of 580×. Neutrophils were marked with myeloperoxidase antibody, macrophages with Mac-3, dendritic cells with fascin, B-lymphocytes with B220, CD4+ T-cells with CD4+ antibody, and CD8+T-cells with CD8-α. The significance of the differences was calculated using one-way analysis of variance. Results Chronic smoke exposure increased neutrophil VV by 97%, macrophage by 107%, dendritic cell by 217%, B-lymphocyte by 436%, CD4+ by 524%, and CD8+ by 417%. The higher dose of roflumilast prevented the increase in neutrophil VV by 78%, macrophage by 82%, dendritic cell by 48%, B-lymphocyte by 100%, CD4+ by 98% and CD8+ VV by 88%. The lower dose of roflumilast did not prevent the increase in neutrophil, macrophage and B-cell VV but prevented dendritic cells by 42%, CD4+ by 55%, and CD8+ by 91%. Conclusion These results indicate (i) chronic exposure to cigarette smoke in mice results in a significant recruitment into the lung of inflammatory cells of both the innate and adaptive immune system; (ii) roflumilast at the higher dose exerts a protective effect against the recruitment of all these cells and at the lower dose against the recruitment of dendritic cells and T-lymphocytes; (iii) these findings underline the role of innate immunity in the development of pulmonary emphysema and (iiii) support previous results indicating that the inflammatory cells of the adaptive immune

  13. Cytogenetic effects in bone marrow cells of mice exposed on the biosatellite "BION-M1"

    NASA Astrophysics Data System (ADS)

    Dorozhkina, Olga; Ivanov, Alexander

    In studies of cytogenetic damage in blood lymphocytes of astronauts, conducted in recent years, have shown an increase in the frequency of chromosomal damage bound, as believe, with influence on an organism of astronauts of space radiation (B.S. Fedorenko, G.P. Snigireva, 2004). However, in recent years published evidence that both acute and chronic stress induce chromosomal aberrations and modified genome sensitivity to mutagens of different nature, including to ionizing radiation (F.I. Ingel et al, 2005 ). This question is especially actual for space biology and medicine due to a number of specific features of space flights, when the interaction of factors more pronounced than in normal terrestrial conditions. In experiment "BION - M1" by anaphase method was determined level of chromosomal aberrations in bone marrow cells of tibia of mice. Flight duration biosatellite "BION - M1" was 30 days in Earth orbit. Euthanasia of experimental animals was carried out at intervals of 15-20 minutes by method of cervical dislocation after 12 hours from the moment of landing satellite. Level of chromosomal aberrations in vivarium-housed control mice was 1,75 ± 0,6% and 1,8 ± 0,45%, while the mitotic index 1,46 ± 0,09% and 1,53 ± 0,05%. Differences are not significant. The maintenance of animals in experiment with the onboard equipment (ground experiment) led to some increase in aberrant mitoses (2,3 ± 0,4%) and to decrease in a mitotic index (1,37 ± 0,02%). In the flight experiment "BION - M1" statistically significant increase of level of chromosomal aberrations (29,7 ± 4,18%) and a decrease in the mitotic index (0,74 ± 0,07%). Since the mouse is a suitable experimental model , also had several ground experiments on research of combined effect of irradiation and other stress factors specific to space flight, with marked tendency to increase the level of aberrant mitoses under the combined action of radiation and stress exposure group housing male mice. Statistically

  14. Altered immunological response in mice subjected to stress and exposed to fungal spores

    NASA Technical Reports Server (NTRS)

    Kurup, Viswanath P.; Choi, Hongyung; Kumar, Anoopa; Murali, Pazhayannur S.; Mishra, S. K.; Pierson, Duane L.

    1992-01-01

    Space flight and related factors such as stress appear to have an adverse effect on astronauts' immune systems. The presence of potentially pathogenic microbes including several genera of fungi reported from spacecraft environment may be a cause of concern in such situations. In order to study the role of such organisms in causing opportunistic or allergic diseases in crewmembers, we have tried to develop an animal model. BALB/c mice were suspended upside down for varying periods of time to induce stress, and their lymphocyte functions were evaluated. These studies indicate that the stress resulted in lowered mitogen induced lymphocyte stimulation as represented by 3H-thymidine uptake. We have also studied the ability of these animals to respond to Aspergillus fumigatus spores. The results of the study clearly demonstrate a definite down-regulation in T-cell proliferation and a higher incidence of infection with A. fumigatus.

  15. [Scanning electron microscopic study of films of the loose connective tissue of mice exposed to DMBA].

    PubMed

    Ol'shevskaia, L V

    1979-01-01

    Under examination by scanning electron microscopy were film samples of the subcutaneous connective tissue. The surface of the films from intact mice was even and smooth, fibroblasts have a spread pattern. Following the saline injection the film was even, collagen fibres, differing in the character of surface and the size of diameter, were readily seen. The collagen fibres formed a multilayer system with a definite orientation inside the layer. After DMBA injection the film surface would get uneven and tuberous, the fibroblast body rising over the film surface, thus the orientation of fibres and all strata was disturbed. There was a spacial rearrangement of all tissue components. It is suggested that carcinogenic agents affecting the relationship between tissue components could interfere the contact inhibition of cell division and result in the development of focal cell proliferates. PMID:113934

  16. Differential proteome and gene expression for testis of mice exposed to carbon ion radiation

    NASA Astrophysics Data System (ADS)

    Zhang, Hong; Li, Hongyan

    Objective To investigate the effect and mechanism of high linear energy transfer (LET) carbon ion irradiation (CIR) on reproduction in the testis of male Swiss Webster mice, and assess the risk associated with space environment. Methods Male mice underwent whole-body irradiation with CIR (0.5, 1 and 4Gy), and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF) analysis was used to determine the alteration in protein expression in 2-DE (two-dimensional gel electrophoresis) gels of testes caused by irradiation after 7, 14 days. Results 15 differentially expressed proteins, such as glucose-regulated protein(GRP78), aconitate hydratase-mitochondrial precursor (ACO), pyruvate kinase isozymes M1/M2 (PKM1/M2), glutathione-S-transferaseA3 (GSTA3), glutathione S-transferase Pi 1 (GSTP1), Cu/Zn super-oxide dismutase (SOD1), Peptidyl-prolyl cis-trans isomerase (Pin1) and Heat shock 70 kDa protein 4L (HSPa4L), were identified and these proteins were mainly involved in energy supply, the endoplasmic reticulum, cell proliferation, cell cycle, antioxidant capacity and mitochondrial respiration, which play important roles in the inhibition of testicular function in response to CIR. Furthermore, we confirmed the relationship between transcription of mRNA and the abundance of proteins. Conclusion The findings of the present study demonstrated that these proteins may lead to new insights into the molecular mechanism of CIR toxicity, and suggested that the gene expression response to CIR involves diverse regulatory mechanisms from transcription of mRNA to the formation of functional proteins. These data also may provide a scientific basis for protecting astronauts and space traveler’s health and safety.

  17. Toxicity of Lunar Dust in Lungs Assessed by Examining Biomarkers in Exposed Mice

    NASA Technical Reports Server (NTRS)

    Lam, C.-W.; James, J. T.; Zeidler-Erdely, P. C.; Castranova, V.; Young, S. H.; Quan, C. L.; Khan-Mayberry, N.; Taylor, L. A.

    2009-01-01

    NASA plans to build an outpost on the Moon for prolonged human habitation and research. The lunar surface is covered by a layer of soil, of which the finest portion is highly reactive dust. NASA has invited NIOSH to collaboratively investigate the toxicity of lunar dust. Dust samples of respirable sizes were aerodynamically isolated from two lunar soil samples of different maturities (cosmic exposure ages) collected during the Apollo 16 mission. The lunar dust samples, titanium dioxide, or quartz, suspended in normal saline or in Survanta (a bovine lung surfactant), were given to groups of 5 mice (C-57 male) by intrapharyngeal aspiration at 1, 0.3, or 0.1 mg/mouse. The mice were euthanized 7 or 30 days later, and their lungs were lavaged to assess the toxicity biomarkers in bronchioalveolar lavage fluids. The acellular fractions were assayed for total proteins, lactate dehydrogenase activities, and cytokines; the cellular portions were assessed for total cell counts and cell differentials. Results from the high-dose groups showed that lunar dust, suspended in saline, was more toxic than TiO 2, but less toxic than quartz. Lunar dust particles aggregate and settle out rapidly in water or saline, but not in Survanta. Lunar dust suspended in Survanta manifested greater toxicity than lunar dust in saline. The increase in toxicity presumably was due to that Survanta gave a better particle dispersion in the lungs. The two lunar dust samples showed similar toxicity. The overall results showed that lunar dust is more toxic than TiO 2 but less toxic than quartz.

  18. Toxicogenomic analysis of mainstream tobacco smoke-exposed mice reveals repression of plasminogen activator inhibitor-1 gene in heart.

    PubMed

    Halappanavar, Sabina; Stampfli, Martin R; Berndt-Weis, Lynn; Williams, Andrew; Douglas, George R; Yauk, Carole L

    2009-01-01

    Tobacco smoking is associated with cardiovascular pathology. However, the molecular mechanisms of tobacco smoke exposure that lead to initiation or exacerbation of cardiovascular disease are unclear. In this study, the effects of mainstream tobacco smoke (MTS) on global transcription in the heart were investigated. Male C57B1/CBA mice were exposed to MTS from 2 cigarettes daily, 5 days/wk for 6 or 12 wk. Mice were sacrificed immediately, or 6 wk following the last cigarette. High-density DNA microarrays were used to characterize global gene expression changes in whole heart. Fifteen genes were significantly differentially expressed following exposure to MTS. Among these genes, cytochrome P-450 1A1 (Cyp1A1) was upregulated by 12-fold, and Serpine-1 (plasminogen activator inhibitor-1, PAI-1) was downregulated by 1.7-fold. Concomitant increase in Cyp1A1 protein levels and decrease in total and active PAI-1 protein was observed in tissue extracts by Western blot assay and enzyme-linked immunosorbent assay (ELISA), respectively. Observed changes were transient and were partially reversed during break periods. Thus, gene expression profiling of heart tissue revealed a novel cardiovascular mechanism operating in response to MTS. Our results suggest a potential role for PAI-1 in MTS-induced cardiovascular pathology. PMID:18925475

  19. Generation and characterization of RAG2 knockout pigs as animal model for severe combined immunodeficiency.

    PubMed

    Suzuki, Shunichi; Iwamoto, Masaki; Hashimoto, Michiko; Suzuki, Misae; Nakai, Michiko; Fuchimoto, Daiichiro; Sembon, Shoichiro; Eguchi-Ogawa, Tomoko; Uenishi, Hirohide; Onishi, Akira

    2016-10-01

    Pigs with severe combined immunodeficiency (SCID) are versatile animal models for human medical research because of their biological similarities to humans, suitable body size, and longevity for practical research. SCID pigs with defined mutation(s) can be an invaluable tool for research on porcine immunity. In this study, we produced RAG2-knockout pigs via somatic cell nuclear transfer and analyzed their phenotype. The V(D)J recombination processes were confirmed as being inactivated. They consistently lacked mature T and B cells but had substantial numbers of cells considered to be T- or B-cell progenitors as well as NK cells. They also lacked thymic medulla and lymphoid aggregations in the spleen, mesenteric lymph nodes, and ileal Peyer's patches. We showed more severe immunological defects in the RAG2 and IL2RG double-knockout pig through this study. Thus, SCID pigs could be promising animal models not only for translational medical research but also for immunological studies of pigs themselves. PMID:27496741

  20. Testicular effects of 3-nitro-1,2,4-triazol-5-one (NTO) in mice when exposed orally.

    PubMed

    Mullins, Anna B; Despain, Kenneth E; Wallace, Shannon M; Honnold, Cary L; May Lent, Emily

    2016-02-01

    3-Nitro-1,2,4-triazol-5-one (NTO) is currently being investigated in the development of insensitive munitions. Rats orally exposed to NTO have demonstrated testicular toxicity in both subacute and subchronic studies; however, toxicity has not been verified in mice. Also, previous studies have not demonstrated the nature of NTO-induced testicular toxicity due to the prolonged dosing regimen utilized and effects of maturation depletion. In this study, a time-course design was used and the earliest pathological changes in testes of adult BALB/c mice orally dosed with NTO in corn oil suspensions at 0, 500 or 1000 mg/kg-day NTO for 1, 3, 7 or 14 d were evaluated. The earliest NTO-induced testicular changes occurred in the 1000 mg/kg-day group at day 7 and the 500 mg/kg-day group at day 14 as evident by the presence of bi- and multinucleated giant cells (MNGCs) of almost all spermatids in an isolated stage II-III tubule/step 2-3 and a stage IX tubule/step 9 in the 1000 and 500 mg/kg-day groups, respectively. Testicular toxicity was characterized by degeneration and the presence of bi- and MNGCs of spermatids (stages II-III and IX), which progressed to additional germ cell degeneration as dosing duration increased. Occasional step 16 spermatid retention was also noted in stage XII and I tubules in the day 14, 1000 mg/kg-day group. These data indicate that NTO is a testicular toxicant in mice and that spermatids are the most sensitive cell. The presence of retained spermatids warrants further investigation regarding NTO's role as a direct Sertoli cell toxicant. PMID:26804465

  1. Proteome alterations in cortex of mice exposed to fluoride and lead.

    PubMed

    Niu, Ruiyan; Zhang, Yuliang; Liu, Shuangling; Liu, Fengyu; Sun, Zilong; Wang, Jundong

    2015-03-01

    Both fluoride and lead can cross the blood-brain barrier and produce toxic effects on the central neural system, resulting in low learning and memory abilities, especially in children. In order to identify the proteomic pattern in the cortex of young animals, from the beginning of fertilization to the age of postnatal day 56, pregnant female mice and pups were administrated with 150 mg sodium fluoride/L and/or 300 mg lead acetate/L in their drinking water. Two-dimensional electrophoresis (2-DE) combined with mass spectrometry (MS) was applied to identify differently expressed protein spots. Results showed that there were eight proteins in the cortex that significantly changed, whose biological functions were involved in (1) energy metabolism (Ndufs1, Atp5h, Atp6v1b2), (2) cytoskeleton (Spna2, Tuba1a, Tubb2a), (3) glycation repair (Hdhd2), and (4) cell stress response (Hspa8). Based on the previous and current studies, ATPase, Spna2, and Hspa8 were shared by fluoride and lead both as common target molecules. PMID:25529766

  2. Differential Transcriptional Changes in Mice Exposed to Chemically Distinct Diesel Samples

    PubMed Central

    Stevens, Tina; Hester, Susan; Gilmour, M. Ian

    2010-01-01

    Epidemiological studies have linked exposure to ambient particulate matter (PM) with increased asthmatic symptoms. Diesel exhaust particles (DEP) are a predominant source of vehicle derived ambient PM, and experimental studies have demonstrated that they may have adjuvant potential when given with an antigen. We previously compared 3 DEP samples: N-DEP, A-DEP, and C-DEP in a murine ovalbumin (OVA) mucosal sensitization model and reported the adjuvant activity to be: C-DEP ≈ A-DEP > N-DEP. The present study analyzed gene expression changes from the lungs of these mice. Transcription profiling demonstrated that all the DEP samples altered cytokine and toll-like receptor pathways regardless of type, with or without antigen sensitization. Further analysis of DEP exposure with OVA showed that all DEP treatments altered networks involved in immune and inflammatory responses. The A- and C-DEP/OVA treatments induced differential expression of apoptosis pathways in association with stronger adjuvant responses, while expression of cell cycle control and DNA damage pathways were also altered in the C-DEP/OVA treatment. This comprehensive approach using gene expression analysis to examine changes at a pathway level provides detailed information on events occurring in the lung after DEP exposure, and confirms that the most bioactive sample induced many more individual genes and changes in immunoregulatory and homeostatic pathways. PMID:27458330

  3. Brain barrier properties and cerebral blood flow in neonatal mice exposed to cerebral hypoxia-ischemia

    PubMed Central

    Ek, C Joakim; D'Angelo, Barbara; Baburamani, Ana A; Lehner, Christine; Leverin, Anna-Lena; Smith, Peter LP; Nilsson, Holger; Svedin, Pernilla; Hagberg, Henrik; Mallard, Carina

    2015-01-01

    Insults to the developing brain often result in irreparable damage resulting in long-term deficits in motor and cognitive functions. The only treatment today for hypoxic-ischemic encephalopathy (HIE) in newborns is hypothermia, which has limited clinical benefit. We have studied changes to the blood–brain barriers (BBB) as well as regional cerebral blood flow (rCBF) in a neonatal model of HIE to further understand the underlying pathologic mechanisms. Nine-day old mice pups, brain roughly equivalent to the near-term human fetus, were subjected to hypoxia-ischemia. Hypoxia-ischemia increased BBB permeability to small and large molecules within hours after the insult, which normalized in the following days. The opening of the BBB was associated with changes to BBB protein expression whereas gene transcript levels were increased showing direct molecular damage to the BBB but also suggesting compensatory mechanisms. Brain pathology was closely related to reductions in rCBF during the hypoxia as well as the areas with compromised BBB showing that these are intimately linked. The transient opening of the BBB after the insult is likely to contribute to the pathology but at the same time provides an opportunity for therapeutics to better reach the infarcted areas in the brain. PMID:25627141

  4. Toxicogenomic analysis of placenta samples from mice exposed to different doses of BPA

    PubMed Central

    Tait, Sabrina; Tassinari, Roberta; Maranghi, Francesca; Mantovani, Alberto

    2015-01-01

    Bisphenol A (BPA), a widespread Endocrine Disrupter mainly used in food contact plastics, may induce adverse effects especially on susceptible lifestages, first of all pregnancy. The present study considered placental development as a potential target of BPA and investigated potential differences in the modes of action of two doses of BPA by a toxicogenomic approach. Pregnant CD-1 mice were administered with vehicle, 0.5 (BPA05) or 50 mg/kg (BPA50) body weight (bw)/die of BPA, from gestational day (GD) 1 to GD11. At GD12 dams were sacrificed and transcriptomic analysis was performed on placenta samples. Histological, histomorphometrical and immunohistochemical analyses were also performed to phenotypically anchor transcriptional changes associated with BPA exposure. The interpretation and description of the overall data are included in a manuscript under revision [1]. Here we describe the experimental design and the analysis performed on the gene expression data which are publicly available through the Gene Expression Omnibus (GEO) database with accession number GSE63852. PMID:26484192

  5. Persistence of chromosome aberrations in mice acutely exposed to 56Fe+26 ions.

    PubMed

    Tucker, James D; Marples, Brian; Ramsey, Marilyn J; Lutze-Mann, Louise H

    2004-06-01

    Space exploration has the potential to yield exciting and significant discoveries, but it also brings with it many risks for flight crews. Among the less well studied of these are health effects from space radiation, which includes the highly charged, energetic particles of elements with high atomic numbers that constitute the galactic cosmic rays. In this study, we demonstrated that 1 Gy iron ions acutely administered to mice in vivo resulted in highly complex chromosome damage. We found that all types of aberrations, including dicentrics as well as translocations, insertions and acentric fragments, disappear rapidly with time after exposure, probably as a result of the death of heavily damaged cells, i.e. cells with multiple and/or complex aberrations. In addition, numerous cells have apparently simple exchanges as their only aberrations, and these cells appear to survive longer than heavily damaged cells. Eight weeks after exposure, the frequency of cells showing cytogenetic damage was reduced to less than 20% of the levels evident at 1 week, with little further decline apparent over an additional 8 weeks. These results indicate that exposure to 1 Gy iron ions produces heavily damaged cells, a small fraction of which appear to be capable of surviving for relatively long periods. The health effects of exposure to high-LET radiation in humans on prolonged space flights should remain a matter of concern. PMID:15161355

  6. Metabolomic and lipidomic analysis of serum from mice exposed to an internal emitter, cesium-137, using a shotgun LC-MS(E) approach.

    PubMed

    Goudarzi, Maryam; Weber, Waylon M; Mak, Tytus D; Chung, Juijung; Doyle-Eisele, Melanie; Melo, Dunstana R; Brenner, David J; Guilmette, Raymond A; Fornace, Albert J

    2015-01-01

    In this study ultra performance liquid chromatography (UPLC) coupled to time-of-flight mass spectrometry in the MS(E) mode was used for rapid and comprehensive analysis of metabolites in the serum of mice exposed to internal exposure by Cesium-137 ((137)Cs). The effects of exposure to (137)Cs were studied at several time points after injection of (137)CsCl in mice. Over 1800 spectral features were detected in the serum of mice in positive and negative electrospray ionization modes combined. Detailed statistical analysis revealed that several metabolites associated with amino acid metabolism, fatty acid metabolism, and the TCA cycle were significantly perturbed in the serum of (137)Cs-exposed mice compared with that of control mice. While metabolites associated with the TCA cycle and glycolysis increased in their serum abundances, fatty acids such as linoleic acid and palmitic acid were detected at lower levels in serum after (137)Cs exposure. Furthermore, phosphatidylcholines (PCs) were among the most perturbed ions in the serum of (137)Cs-exposed mice. This is the first study on the effects of exposure by an internal emitter in serum using a UPLC-MS(E) approach. The results have put forth a panel of metabolites, which may serve as potential serum markers to (137)Cs exposure. PMID:25333951

  7. Metabolomic and Lipidomic Analysis of Serum from Mice Exposed to an Internal Emitter, Cesium-137, Using a Shotgun LC–MSE Approach

    PubMed Central

    2015-01-01

    In this study ultra performance liquid chromatography (UPLC) coupled to time-of-flight mass spectrometry in the MSE mode was used for rapid and comprehensive analysis of metabolites in the serum of mice exposed to internal exposure by Cesium-137 (137Cs). The effects of exposure to 137Cs were studied at several time points after injection of 137CsCl in mice. Over 1800 spectral features were detected in the serum of mice in positive and negative electrospray ionization modes combined. Detailed statistical analysis revealed that several metabolites associated with amino acid metabolism, fatty acid metabolism, and the TCA cycle were significantly perturbed in the serum of 137Cs-exposed mice compared with that of control mice. While metabolites associated with the TCA cycle and glycolysis increased in their serum abundances, fatty acids such as linoleic acid and palmitic acid were detected at lower levels in serum after 137Cs exposure. Furthermore, phosphatidylcholines (PCs) were among the most perturbed ions in the serum of 137Cs-exposed mice. This is the first study on the effects of exposure by an internal emitter in serum using a UPLC–MSE approach. The results have put forth a panel of metabolites, which may serve as potential serum markers to 137Cs exposure. PMID:25333951

  8. The anti-fatty liver effects of garlic oil on acute ethanol-exposed mice.

    PubMed

    Zeng, Tao; Guo, Fang-Fang; Zhang, Cui-Li; Zhao, Sheng; Dou, Dan-Dan; Gao, Xu-Cong; Xie, Ke-Qin

    2008-11-25

    The protective effects of single dose of garlic oil (GO) on acute ethanol-induced fatty liver were investigated. Mice were treated with ethanol (4.8 g/kg bw) to induce acute fatty liver. The liver index, the serum and hepatic triglyceride (TG) levels and the histological changes were examined to evaluate the protective effects. Hepatic malondialdehyde (MDA), glutathione (GSH) levels and superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST) activities were determined for the antioxidant capacity assay. Acute ethanol exposure resulted in the enlargement of the liver index and the increase of the serum and hepatic TG levels (P<0.01), which were dramatically attenuated by GO pretreatment in a dose-dependent manner (P<0.01). GO treatment (simultaneously with ethanol exposure) exhibited similar effects to those of pretreatment, while no obviously protective effects were displayed when it was used at 2h after ethanol intake. Histological changes were paralleled to these indices. Beside this, GO dramatically prolonged the drunken time and shortened the waking time, and these effects were superior to those of silymarin and tea polyphenol. In addition, GO dose-dependently suppressed the elevation of MDA levels, restored the GSH levels and enhanced the SOD, GR and GST activities. Compared with the ethanol group, the MDA levels decreased by 14.2% (P<0.05), 29.9% and 32.8% (P<0.01) in GO groups 50, 100 and 200 mg/kg, respectively. The GST activity increased by 9.97%, 19.94% (P<0.05) and 42.12% (P<0.01) of the ethanol group in GO groups 50, 100 and 200 mg/kg, respectively, while the GR activity increased by 28.57% (P<0.05), 37.97% (P<0.01), 50.45% (P<0.01) of the ethanol group in GO groups 50, 100 and 200 mg/kg, respectively. These data indicated that single dose of GO possessed ability to prevent acute ethanol-induced fatty liver, but may lose its capacity when used after ethanol exposure. The protective effects

  9. Gene expression profiling in spleens of deoxynivalenol-exposed mice: immediate early genes as primary targets.

    PubMed

    Kinser, Shawn; Jia, Qunshan; Li, Maioxing; Laughter, Ashley; Cornwell, Paul; Corton, J Christopher; Pestka, James

    2004-09-24

    Exposure to the trichothecene mycotoxin deoxynivalenol (DON) alters immune functions in vitro and in vivo. To gain further insight into DON's immunotoxic effects, microarrays were used to determine how acute exposure to this mycotoxin modulates gene expression profiles in murine spleen. B6C3F1 mice were treated orally with 25mg/kg body weight DON, and 2h later spleens were collected for macroarray analysis. Following normalization using a local linear regression model, expression of 116 out of 1176 genes was significantly altered compared to average expression levels in all treatment groups. When genes were arranged into an ontology tree to facilitate comparison of expression profiles between treatment groups, DON was found primarily to modulate genes associated with immunity, inflammation, and chemotaxis. Real-time polymerase chain reaction was used to confirm modulation for selected genes. DON was found to induce the cytokines interleukin (IL)-1alpha, IL-1beta, IL-6 and IL-11. In analogous fashion, DON upregulated expression of the chemokines macrophage inhibitory protein-2 (MIP-2), cytokine-induced chemoattractant protein-1 (CINC-1), monocyte chemoattractant protein (MCP)-1, MCP-3, and cytokine-responsive gene-2 (CRG-2). c-Fos, Fra-, c-Jun, and JunB, components of the activator protein-1 (AP-1) transcription factor complex, were induced by DON as well as another transcription factor, NR4A1. Four hydrolases were found to be upregulated by DON, including mitogen-activated protein kinase phosphatase 1 (MKP1), catalytic subunit beta isoform (CnAbeta), protein tyrosine phosphatase receptor type J (Ptprj), and protein tyrosine phosphatase nonreceptor type 8 (Ptpn8), whereas three other hydrolases, microsomal epoxide hydrolase (Eph) 1, histidine triad nucleotide binding protein (Hint), and proteosome subunit beta type 8 (Psmb8) were significantly decreased by the toxin. Finally, cysteine-rich protein 61 (CRP61) and heat-shock protein 40 (Hsp40), genes associated with

  10. 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 Central

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

    2012-01-01

    The role of the histamine H3 receptor (H3R) 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 H3R agonist (methimepip), and exposed to an open-field. In the second one, Balb/c mice were treated with H3R 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 H3R 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 H3R antagonist/inverse agonist) induced entry into the arms of the maze, indicative of lack of anxiolytic effects. PMID:22811660

  11. Utility of a novel Oatp1b2 knockout mouse model for evaluating the role of Oatp1b2 in the hepatic uptake of model compounds.

    PubMed

    Chen, Cuiping; Stock, Jeffery L; Liu, Xingrong; Shi, Jilin; Van Deusen, Jeffrey W; DiMattia, Debra A; Dullea, Robert G; de Morais, Sonia M

    2008-09-01

    We generated the organic anion transporting polypeptide (Oatp) 1b2 knockout (KO) mouse model and assessed its utility to study hepatic uptake using model compounds: cerivastatin, lovastatin acid, pravastatin, simvastatin acid, rifampicin, and rifamycin SV. A selective panel of liver cytochromes P450 (P450s) (Cyp3a11, Cyp3a13, Cyp3a16, Cyp2c29, and Cyp2c39) and transporters [Oatp1b2, Oatp1a1, Oatp1a4, Oatp1a5; organic anion transporter (Oat) 1, Oat2, Oat3; multidrug resistance gene 1 (Mdr1) a, Mdr1b; bile salt export pump, multidrug resistance associated protein (Mrp) 2, Mrp3; breast cancer resistance protein] were measured by reverse transcription-polymerase chain reaction in both KO and wild-type (WT) male mice. Male KO and WT mice received each model compound s.c. at 3 mg/kg. Blood and liver samples were obtained at 0, 0.5, and 2 h postdose and analyzed using liquid chromatography/tandem mass spectrometry. Liver/plasma concentration ratio (K(p,liver)) was calculated. Student's t test was used to compare the mRNA and K(p,liver) between the KO and WT mice. A similar mRNA expression was observed between the KO and WT for the selected P450s and transporters except for Oatp1b2, for which the level was negligible in the KO but prominent in the WT mice with P < 0.0001. The in vivo results showed a differential effect of Oatp1b2 on hepatic uptake of the model compounds, indicating that Oatp1b2 plays a more significant role in the hepatobiliary disposition of rifampicin and lovastatin than the other compounds tested. This study suggests the Oatp1b2 mouse as a useful in vivo tool to understand drug targeting and disposition in the liver. PMID:18556442

  12. 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...

  13. CD28 in thymocyte development and peripheral T cell activation in mice exposed to suspended particulate matter

    SciTech Connect

    Drela, Nadzieja . E-mail: ndrela@biol.uw.edu.pl; Zesko, Izabela; Jakubowska, Martyna; Biernacka, Marzena

    2006-09-01

    The CD28:B7 signaling pathway is very important for the activity of mature peripheral T lymphocytes and thymocyte development. The proper development of thymocytes into mature single positive CD4{sup +}and CD8{sup +} T cells is crucial for almost all immune functions. In naturally occurring conditions, T cells maturation in the thymus is influenced by environmental agents. The expression of CD28 and the distribution of CD28{sup low/high} thymocytes have been examined at various stages of thymocyte development in BALB/c mice exposed to air-suspended particulate matter (ASM). Acute exposure to ASM resulted in the decrease of CD28 expression in the total thymocyte population. The increase of the percentage of CD28{sup low} and the decrease of CD28{sup high} thymocytes were observed, which may account for the acceleration of thymocyte development under the conditions of elevated risk resulting from the exposure of animals to environmental xenobiotics. ASM exposure resulted in the increase of the level of proliferation of lymph node T cells induced by anti-CD3 and anti-CD28 monoclonal antibodies activation despite normal expression of CD28 molecule. In contrast, the level of proliferation of spleen T cells was lowered or normal dependently of the concentration of stimuli used for activation. Results of these studies demonstrate that acute exposure of mice to ASM can result in the progression of two contrasting processes in the immune system: upregulation of thymocyte development, which contributes to the maintenance of peripheral T cell pool, and over-activation of lymph node lymphocytes, which may lead to uncontrolled immunostimulation.

  14. DNA damage and apoptosis of endometrial cells cause loss of the early embryo in mice exposed to carbon disulfide

    SciTech Connect

    Zhang, Bingzhen; Shen, Chunzi; Yang, Liu; Li, Chunhui; Yi, Anji; Wang, Zhiping

    2013-12-01

    Carbon disulfide (CS{sub 2}) may lead to spontaneous abortion and very early pregnancy loss in women exposed in the workplace, but the mechanism remains unclear. We designed an animal model in which gestating Kunming strain mice were exposed to CS{sub 2} via i.p. on gestational day 4 (GD4). We found that the number of implanted blastocysts on GD8 was significantly reduced by each dose of 0.1 LD{sub 50} (157.85 mg/kg), 0.2 LD{sub 50} (315.7 mg/kg) and 0.4 LD{sub 50} (631.4 mg/kg). In addition, both the level of DNA damage and apoptosis rates of endometrial cells on GD4.5 were increased, showed definite dose–response relationships, and inversely related to the number of implanted blastocysts. The expressions of mRNA and protein for the Bax and caspase-3 genes in the uterine tissues on GD4.5 were up-regulated, while the expressions of mRNA and protein for the Bcl-2 gene were dose-dependently down-regulated. Our results indicated that DNA damage and apoptosis of endometrial cells were important reasons for the loss of implanted blastocysts induced by CS{sub 2}. - Highlights: • We built an animal model of CS2 exposure during blastocyst implantation. • Endometrial cells were used in the comet assay to detect DNA damage. • CS2 exposure caused DNA damage and endometrial cell apoptosis. • DNA damage and endometrial cell apoptosis were responsible for embryo loss.

  15. Emotional Contagion is not Altered in Mice Prenatally Exposed to Poly (I:C) on Gestational Day 9

    PubMed Central

    Gonzalez-Liencres, Cristina; Juckel, Georg; Esslinger, Manuela; Wachholz, Simone; Manitz, Marie-Pierre; Brüne, Martin; Friebe, Astrid

    2016-01-01

    Prenatal immune activation has been associated with increased risk of developing schizophrenia. The polyinosinic-polycytidylic acid (Poly(I:C)) mouse model replicates some of the endophenotype characteristic of this disorder but the social deficits observed in schizophrenia patients have not been well studied in this model. Therefore we aimed to investigate social behavior, in particular emotional contagion for pain, in this mouse model. We injected pregnant mouse dams with Poly(I:C) or saline (control) on gestation day 9 (GD9) and we evaluated their offspring in the pre-pulse inhibition (PPI) test at age 50–55 days old to confirm the reliability of our model. Mice were then evaluated in an emotional contagion test immediately followed by the light/dark test to explore post-test anxiety-like behavior at 10 weeks of age. In the emotional contagion test, an observer (prenatally exposed to Poly(I:C) or to saline) witnessed a familiar wild-type (WT) mouse (demonstrator) receiving electric foot shocks. Our results replicate the sensory gating impairments in the Poly(I:C) offspring but we only observed minor group differences in the social tasks. One of the differences we found was that demonstrators deposited fewer feces in the presence of control observers than of observers prenatally exposed to Poly(I:C), which we suggest could be due to the observers’ behavior. We discuss the findings in the context of age, sex and day of prenatal injection, suggesting that Poly(I:C) on GD9 may be a valuable tool to assess other symptoms or symptom clusters of schizophrenia but perhaps not comprising the social domain. PMID:27445729

  16. Metabolomic Profiling of Urine Samples from Mice Exposed to Protons Reveals Radiation Quality and Dose Specific Differences

    PubMed Central

    Laiakis, Evagelia C.; Trani, Daniela; Moon, Bo-Hyun; Strawn, Steven J.; Fornace, Albert J.

    2015-01-01

    As space travel is expanding to include private tourism and travel beyond low-Earth orbit, so is the risk of exposure to space radiation. Galactic cosmic rays and solar particle events have the potential to expose space travelers to significant doses of radiation that can lead to increased cancer risk and other adverse health consequences. Metabolomics has the potential to assess an individual’s risk by exploring the metabolic perturbations in a biofluid or tissue. In this study, C57BL/6 mice were exposed to 0.5 and 2 Gy of 1 GeV/nucleon of protons and the levels of metabolites were evaluated in urine at 4 h after radiation exposure through liquid chromatography coupled to time-of-flight mass spectrometry. Significant differences were identified in metabolites that map to the tricarboxylic acid (TCA) cycle and fatty acid metabolism, suggesting that energy metabolism is severely impacted after exposure to protons. Additionally, various pathways of amino acid metabolism (tryptophan, tyrosine, arginine and proline and phenylalanine) were affected with potential implications for DNA damage repair and cognitive impairment. Finally, presence of products of purine and pyrimidine metabolism points to direct DNA damage or increased apoptosis. Comparison of these metabolomic data to previously published data from our laboratory with gamma radiation strongly suggests a more pronounced effect on metabolism with protons. This is the first metabolomics study with space radiation in an easily accessible biofluid such as urine that further investigates and exemplifies the biological differences at early time points after exposure to different radiation qualities. PMID:25768838

  17. Loss of Metabotropic Glutamate Receptor 5 Function on Peripheral Benzodiazepine Receptor in Mice Prenatally Exposed to LPS

    PubMed Central

    Arsenault, Dany; Coulombe, Katherine; Zhu, Aijun; Gong, Chunyu; Kil, Kun-Eek; Choi, Ji-Kyung; Poutiainen, Pekka; Brownell, Anna-Liisa

    2015-01-01

    Parental microglial induced neuroinflammation, triggered by bacterial- or viral infections, can induce neuropsychiatric disorders like schizophrenia and autism to offspring in animal models. Recent investigations suggest that microglia, the resident immune cells of the brain, provides a link between neurotransmission, immune cell activation, brain inflammation and neuronal dysfunction seen with the offspring. Relatively little is known about how reduction of brain inflammation and restoration of glial function are associated with diminution of brain degeneration and behavioral deficits in offspring. Increased mGluR5 expression and the long-lasting excitotoxic effects of the neurotoxin during brain development are associated with the glial dysfunctions. We investigated the relationship of mGluR5 and PBR and how they regulate glial function and inflammatory processes in mice prenatally exposed to LPS (120μg/kg, between gestational days 15 and 17), an inflammatory model of a psychiatric disorder. Using PET imaging, we showed that pharmacological activation of mGluR5 during 5 weeks reduced expression of classic inflammation marker PBR in many brain areas and that this molecular association was not present in LPS-exposed offspring. The post-mortem analysis revealed that the down regulation of PBR was mediated through activation of mGluR5 in astrocytes. In addition, we demonstrated that this interaction is defective in a mouse model of the psychiatric deficit offering a novel insight of mGluR5 involvement to brain related disorders and PBR related imaging studies. In conclusion, mGluR5 driven glutamatergic activity regulates astrocytic functions associated with PBR (cholesterol transport, neurosteroidogenesis, glial phenotype) during maturation and could be associated with neuropsychiatric disorders in offspring. PMID:26536027

  18. Metabolomic profiling of urine samples from mice exposed to protons reveals radiation quality and dose specific differences.

    PubMed

    Laiakis, Evagelia C; Trani, Daniela; Moon, Bo-Hyun; Strawn, Steven J; Fornace, Albert J

    2015-04-01

    As space travel is expanding to include private tourism and travel beyond low-Earth orbit, so is the risk of exposure to space radiation. Galactic cosmic rays and solar particle events have the potential to expose space travelers to significant doses of radiation that can lead to increased cancer risk and other adverse health consequences. Metabolomics has the potential to assess an individual's risk by exploring the metabolic perturbations in a biofluid or tissue. In this study, C57BL/6 mice were exposed to 0.5 and 2 Gy of 1 GeV/nucleon of protons and the levels of metabolites were evaluated in urine at 4 h after radiation exposure through liquid chromatography coupled to time-of-flight mass spectrometry. Significant differences were identified in metabolites that map to the tricarboxylic acid (TCA) cycle and fatty acid metabolism, suggesting that energy metabolism is severely impacted after exposure to protons. Additionally, various pathways of amino acid metabolism (tryptophan, tyrosine, arginine and proline and phenylalanine) were affected with potential implications for DNA damage repair and cognitive impairment. Finally, presence of products of purine and pyrimidine metabolism points to direct DNA damage or increased apoptosis. Comparison of these metabolomic data to previously published data from our laboratory with gamma radiation strongly suggests a more pronounced effect on metabolism with protons. This is the first metabolomics study with space radiation in an easily accessible biofluid such as urine that further investigates and exemplifies the biological differences at early time points after exposure to different radiation qualities. PMID:25768838

  19. Emotional Contagion is not Altered in Mice Prenatally Exposed to Poly (I:C) on Gestational Day 9.

    PubMed

    Gonzalez-Liencres, Cristina; Juckel, Georg; Esslinger, Manuela; Wachholz, Simone; Manitz, Marie-Pierre; Brüne, Martin; Friebe, Astrid

    2016-01-01

    Prenatal immune activation has been associated with increased risk of developing schizophrenia. The polyinosinic-polycytidylic acid (Poly(I:C)) mouse model replicates some of the endophenotype characteristic of this disorder but the social deficits observed in schizophrenia patients have not been well studied in this model. Therefore we aimed to investigate social behavior, in particular emotional contagion for pain, in this mouse model. We injected pregnant mouse dams with Poly(I:C) or saline (control) on gestation day 9 (GD9) and we evaluated their offspring in the pre-pulse inhibition (PPI) test at age 50-55 days old to confirm the reliability of our model. Mice were then evaluated in an emotional contagion test immediately followed by the light/dark test to explore post-test anxiety-like behavior at 10 weeks of age. In the emotional contagion test, an observer (prenatally exposed to Poly(I:C) or to saline) witnessed a familiar wild-type (WT) mouse (demonstrator) receiving electric foot shocks. Our results replicate the sensory gating impairments in the Poly(I:C) offspring but we only observed minor group differences in the social tasks. One of the differences we found was that demonstrators deposited fewer feces in the presence of control observers than of observers prenatally exposed to Poly(I:C), which we suggest could be due to the observers' behavior. We discuss the findings in the context of age, sex and day of prenatal injection, suggesting that Poly(I:C) on GD9 may be a valuable tool to assess other symptoms or symptom clusters of schizophrenia but perhaps not comprising the social domain. PMID:27445729

  20. Evaluation of micronuclei in mice bone marrow and antioxidant systems in erythrocytes exposed to α-amanitin.

    PubMed

    Marciniak, B; Lopaczyńska, D; Kowalczyk, E; Skośkiewicz, J; Witczak, M; Majczyk, M; Grabowicz, W; Ferenc, T

    2013-03-01

    α-Amanitin, the main toxic substance from mushroom species (Amanita genus), blocks the activity of RNA polymerase II (Pol II) in mammalian cells causing inhibition of transcription and subsequent synthesis of structural and enzymatic proteins. It has been postulated that α-amanitin generates the increase of reactive oxygen species (ROS) concentration. The micronucleus (MN) test was used on an animal experimental model to evaluate possible potential genotoxic effect of α-amanitin on mice bone marrow cells. At the same time the activity of antioxidant enzymes: superoxide dismutase (SOD) and catalase (CAT) as well as concentration of thiobarbituric acid reactive substance (TBARS) were investigated in the lysate of mice erythrocytes. α-Amanitin was administered intraperitoneally at the doses: 0.1, 0.15, and 0.25 mg/kg bw (LD(50) for mice) 48 h prior to sacrification. A statistically significant increase of SOD activity was observed in the hemolysate for all the investigated α-amanitin doses as compared to the negative control (p < 0.05). CAT activity for α-amanitin doses 0.1 and 0.15 mg/kg was higher in comparison to the negative control but the differences were not statistically significant (p > 0.05). However, for the dose 0.25 mg/kg the activity of CAT was statistically significantly higher (p < 0.001). All the tested α-amanitin doses decreased TBARS concentration in the hemolysate as compared to the negative control but the differences were not statistically significant (p > 0.05). A statistically significant increase of mean values of MN percent was found in polychromatic erythrocytes (PCEs) as compared to the negative control for α-amanitin dose 0.1 and 0.25 mg/kg (p < 0.05). For the dose 0.15 mg/kg the mean value of MN percent was higher but it did not demonstrate statistical significance (p > 0.1). The observed disturbances in the activity of the examined antioxidant enzymes in cells exposed in vivo to α-amanitin suggest indirect

  1. Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation

    PubMed Central

    Cortese, Rene; Khalyfa, Abdelnaby; Bao, Riyue; Andrade, Jorge; Gozal, David

    2015-01-01

    Background Sleep fragmentation during late gestation (LG-SF) is one of the major perturbations associated with sleep apnea and other sleep disorders during pregnancy. We have previously shown that LG-SF induces metabolic dysfunction in offspring mice during adulthood. Objectives To investigate the effects of late LG-SF on metabolic homeostasis in offspring and to determine the effects of LG-SF on the epigenome of visceral white adipose tissue (VWAT) in the offspring. Methods Time-pregnant mice were exposed to LG-SF or control sleep (LG-SC) conditions during the last 6 days of gestation. At 24 weeks of age, lipid profiles and metabolic parameters were assessed in the offspring. We performed large-scale DNA methylation analyses using MeDIP coupled to microarrays (MeDIP-chip) in VWAT of 24-week-old LG-SF and LG-SC offspring (n=8 mice/group). Univariate multiple-testing adjusted statistical analyses were applied to identify differentially methylated regions (DMRs) between the groups. DMRs were mapped to their corresponding genes, and tested for potential overlaps with biological pathways and gene networks. Results We detected significant increases in body weight (31.7 vs. 28.8 g; p=0.001), visceral (642.1 vs. 497.0 mg; p=0.002) and subcutaneous (293.1 vs. 250.1 mg; p=0.001) fat mass, plasma cholesterol (110.6 vs. 87.6 mg/dL; p=0.001), triglycerides (87.3 vs. 84.1 mg/dL; p=0.003) and HOMA-IR values (8.1 vs. 6.1; p=0.007) in the LG-SF group. MeDIP analyses revealed that 2148 DMRs (LG-SF vs. LG-SC; p< 0.0001, MAT algorithm). A large proportion of the DMR-associated genes have reported functions that are altered in obesity and metabolic syndrome, such as Cartpt, Akt2, Apoe, Insr1, etc. Overrepresented pathways and gene networks were related to metabolic regulation and inflammatory response. Conclusions Our findings show a major role for epigenomic regulation of pathways associated with metabolic processes and inflammatory response in VWAT. LG-SF-induced epigenetic

  2. Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin

    SciTech Connect

    Shan, Qiuli; Wang, Jing; Huang, Fengchen; Lv, Xiaowen; Ma, Min; Du, Yuguo

    2014-04-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent organic pollutants found as complex mixtures in the environment throughout the world. Therefore, humans are ubiquitously and simultaneously exposed to TCDD and PCBs. TCDD and PCBs alone have been linked to atherosclerosis. However, the effects of interactions or synergism between TCDD and PCBs on atherogenesis are unknown. We investigated the possible enhanced atherogenesis by co-exposure to TCDD and PCBs and the potential mechanism(s) involved in this enhancement. Male ApoE{sup −/−} mice were exposed to TCDD (15 μg/kg) and Aroclor1254 (55 mg/kg, a representative mixture of PCBs) alone or in combination by intraperitoneal injection four times over six weeks of duration. Our results showed that mice exposed to TCDD alone, but not Aroclor1254 alone, developed atherosclerotic lesions. Moreover, we found that atherosclerotic disease was exacerbated to the greatest extent in mice co-exposed to TCDD and Aroclor1254. The enhanced lesions correlated with several pro-atherogenic changes, including a marked increase in the accumulation of the platelet-derived chemokine PF4, and the expression of the proinflammatory cytokine MCP-1 and the critical immunity gene-RIG-I. Our data demonstrated that co-exposure to TCDD and Aroclor1254 markedly enhanced atherogenesis in ApoE{sup −/−} mice. Significantly, our observations suggest that combined exposure to TCDD and PCBs may be a greater cardiovascular health risk than previously anticipated from individual studies. - Highlights: • Augmented atherogenesis was found in ApoE{sup −/−} mice co-exposed to Aroclor1254 and TCDD. • Enhanced expression of PF4, MCP-1 and RIG-I correlated with augmented lesions. • POPs combination may be a greater cardiovascular health risk than individual POPs.

  3. Preneoplastic and neoplastic lesions in the lung, liver and urinary tract of mice exposed to environmental cigarette smoke and UV light since birth.

    PubMed

    D'Agostini, Francesco; Balansky, Roumen; Steele, Vernon E; Ganchev, Gancho; Pesce, Carlo; De Flora, Silvio

    2008-12-01

    It is difficult to reproduce the carcinogenicity of cigarette smoke (CS) in animal models. Recently, we showed that exposure of mice to mainstream CS (MCS) for 120 days, starting immediately after birth, resulted in an early and potent carcinogenic response. In parallel, we implemented studies evaluating intermediate biomarkers and tumors in mice exposed to environmental CS (ECS). To this purpose, we used 263 newborn CD-1 mice born from 27 dams. The whole-body exposure to ECS for 120 days, starting within 12 hr after birth, resulted in an early appearance of preneoplastic lesions in lung, which however tended to attenuate after discontinuing exposure. When the experiment was stopped, after 330 days, the number of lung adenomas was higher in ECS-exposed mice as compared to sham-exposed mice, but such increase was statistically significant only in mice co-exposed to smoke and halogen light mimicking solar irradiation. Moreover, exposure to ECS produced extensive histopathological changes, mainly parenchymatous degeneration, in liver. The alterations produced in both lung and liver require that exposure to ECS starts immediately after birth, no effect being observed when exposure started 8 days later. In contrast, induction by ECS of alterations in the urinary tract, such as microadenomas and adenomas in renal pelvis and kidney, papillary hyperplasia of urothelium, and urinary bladder papillomas, were unrelated to the exposure time after birth. The results obtained with ECS cannot be directly compared to those previously obtained with MCS, since the latter involved shorter daily exposures to more massive CS doses. PMID:18770867

  4. HIPPOCAMPAL SPINE-ASSOCIATED Rap-SPECIFIC GTPase-ACTIVATING PROTEIN INDUCES ENHANCEMENT OF LEARNING AND MEMORY IN POSTNATALLY HYPOXIA-EXPOSED MICE

    PubMed Central

    LU, X.-J.; CHEN, X.-Q.; WENG, J.; ZHANG, H.-Y.; PAK, D. T.; LUO, J.-H.; DU, J.-Z.

    2011-01-01

    Spine-associated Rap-specific GTPase-activating protein (SPAR) is a postsynaptic protein that forms a complex with postsynaptic density (PSD)-95 and N-methyl-D-aspartate receptors (NMDARs), and morphologically regulates dendritic spines. Mild intermittent hypoxia (IH, 16.0% O2, 4 h/day for 4 weeks) is known to markedly enhance spatial learning and memory in postnatal developing mice. Here, we report that this effect is correlated with persistent increases in SPAR expression as well as long-term potentiation (LTP) in the hippocampus of IH-exposed mice. Furthermore, an infusion of SPAR antisense oligonucleotides into the dorsal hippocampus disrupted elevation of SPAR expression, preventing enhanced hippocampal LTP in IH-exposed developing mice and also reducing LTP in normoxic mice, without altering basal synaptic transmission. In SPAR antisense-treated mice, acquisition of the Morris water maze spatial learning task was impaired, as was memory retention in probe trails following training. This study provides the first evidence that SPAR is functionally required for synaptic plasticity and contributes to the IH-induced enhancement of spatial learning and memory in postnatal developing mice. PMID:19442707

  5. Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice.

    PubMed

    Pascolo, Lorella; Zabucchi, Giuliano; Gianoncelli, Alessandra; Kourousias, George; Trevisan, Elisa; Pascotto, Ernesto; Casarsa, Claudia; Ryan, Chris; Lucattelli, Monica; Lungarella, Giuseppe; Cavarra, Eleonora; Bartalesi, Barbara; Zweyer, Marina; Cammisuli, Francesca; Melato, Mauro; Borelli, Violetta

    2016-01-22

    Human exposure to asbestos can cause a wide variety of lung diseases that are still a current major health concern, even if asbestos has been banned in many countries. It has been shown in many studies that asbestos fibers, ingested by alveolar macrophages, disrupt lung iron homeostasis by sequestering iron. Calcium can also be deposited on the fibers. The pathways along which iron and above all calcium interact with fibers are still unknown. Our aim was that of investigating if the iron accumulation induced by the inhaled asbestos fibers also involves calcium ions accumulation. Lung sections of asbestos-exposed mice were analyzed using an extremely sensitive procedure available at the synchrotron facilities, that provides morphological and chemical information based on X-ray fluorescence microspectroscopy (μ-XRF). In this study we show that (1) where conventional histochemical procedures revealed only weak deposits of iron and calcium, μ-XRF analysis is able to detect significant deposits of both iron and calcium on the inhaled asbestos fibers; (2) the extent of the deposition of these ions is proportionally directly related and (3) iron and calcium deposition on inhaled asbestos fibers is concomitant with the appearance of inflammatory and hyperplastic reactions. PMID:26602167

  6. Hepatic and Nephric NRF2 Pathway Up-Regulation, an Early Antioxidant Response, in Acute Arsenic-Exposed Mice

    PubMed Central

    Li, Jinlong; Duan, Xiaoxu; Dong, Dandan; Zhang, Yang; Li, Wei; Zhao, Lu; Nie, Huifang; Sun, Guifan; Li, Bing

    2015-01-01

    Inorganic arsenic (iAs), a proven human carcinogen, damages biological systems through multiple mechanisms, one of them being reactive oxygen species (ROS) production. NRF2 is a redox-sensitive transcription factor that positively regulates the genes of encoding antioxidant and detoxification enzymes to neutralize ROS. Although NRF2 pathway activation by iAs has been reported in various cell types, however, the experimental data in vivo are very limited and not fully elucidated in humans. The present investigation aimed to explore the hepatic and nephric NRF2 pathway upregulation in acute arsenic-exposed mice in vivo. Our results showed 10 mg/kg NaAsO2 elevated the NRF2 protein and increased the transcription of Nrf2 mRNA, as well as up-regulated NRF2 downstream targets HO-1, GST and GCLC time- and dose-dependently both in the liver and kidney. Acute NaAsO2 exposure also resulted in obvious imbalance of oxidative redox status represented by the increase of GSH and MDA, and the decrease of T-AOC. The present investigation reveals that hepatic and nephric NRF2 pathway expression is an early antioxidant defensive response upon iAs exposure. A better knowledge about the NRF2 pathway involvment in the cellular response against arsenic could help improve the strategies for reducing the cellular toxicity related to this metalloid. PMID:26473898

  7. Maternal substrate utilization programs the development of the metabolic syndrome in male mice exposed to high fat in utero.

    PubMed

    Hartil, Kirsten; Vuguin, Patricia M; Kruse, Michael; Schmuel, Esther; Fiallo, Ariana; Vargas, Carlos; Warner, Matthew J; Durand, Jorge L; Jelicks, Linda A; Charron, Maureen J

    2009-10-01

    Studies were conducted to determine whether maternal substrate utilization during pregnancy affects fetal growth and predisposes offspring to metabolic disease. Female wild-type (WT) and glucose transporter 4 heterozygous mice (G4+/-, a model of altered peripheral substrate utilization) were fed high-fat diet (HFD, 35.5% fat) or control chow (C, 9.5% fat) for 2 wk before mating, throughout pregnancy and lactation (IU/L). WT HFD females exhibited increased serum nonesterified fatty acid and lactate levels and increased hepatic mRNA expression of peroxisome proliferator-activated receptor gamma coactivator-1-beta and SREBP-1c, consistent with increased lipogenesis. G4+/- HFD females exhibited enhanced lipid clearance, and exposure to HFD did not increase hepatic gene expression. HFD independent of maternal genotype decreased fetal growth and birth weight. WT offspring were weaned onto a low-fat diet (5.6% fat). Male offspring of WT mothers exposed to HFD exhibited "catch-up" growth accompanied by increased adiposity, impaired glucose tolerance, and insulin sensitivity. In contrast, male offspring of G4+/- HFD mothers did not exhibit any characteristics of metabolic syndrome. These data suggest that differences in maternal substrate utilization influence offspring metabolic phenotype. PMID:19581843

  8. Preventive effect of phytoglycoprotein (27 kDa) on inflammatory factors at liver injury in cadmium chloride-exposed ICR mice.

    PubMed

    Lee, Jin; Lim, Kye-Taek

    2011-02-01

    Cadmium is one of the inflammation-related xenobiotics and has been regarded as a potent carcinogen. Gardenia jasminoides Ellis (GJE) has been used to cure inflammation in Korean folk medicine for a long time. The purpose of present study is the inhibitory effect of glycoprotein isolated from GJE (27 kDa) on inflammation mechanism in cadmium chloride-exposed ICR mice. We evaluated the activities of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and thiobarbituric acid-reactive substances (TBARS), activities of anti-oxidative enzymes [superoxide dismutase (SOD) and gluthathione peroxidase (GPx)], activities of c-Jun N-terminal protein kinase (JNK), heat shock protein 27 (Hsp27), activator protein (AP)-1, nuclear factor (NF)-κB and expression of inflammation-related mediators including tumor necrosis factor (TNF)-α and interleukin (IL)-6 in cadmium chloride-exposed ICR mice using immunoblot analysis, EMSA and RT-PCR. It notes that mice plasma was used to measure ALT, LDH, and TBARS after treatment with cadmium chloride alone or cadmium chloride under the pretreatment with GJE glycoprotein. Liver tissues were used to assess activities of anti-oxidant enzymes, SAPK/JNK, Hsp27, AP-1, NF-κB, TNF-α, and IL-6 in this study. The results obtained from this study revealed that GJE glycoprotein (10 mg/kg) decreased the levels of LDH, ALT and TBARS, whereas increased the activity of hepatic anti-oxidant enzymes (SOD and GPx) in cadmium chloride-exposed ICR mice. Moreover, it decreased the activity of JNK/AP-1, NF-κB, Hsp27, and pro-inflammatory cytokines (TNF-α and IL-6). Taken together, the results in this study suggest that GJE glycoprotein inhibits the expression of inflammation-related cytokines (TNF-α and IL-6) in cadmium chloride-exposed ICR mice. PMID:21268091

  9. Ultrastructural findings in the brain of fruit flies (Drosophila melanogaster) and mice exposed to high-energy particle radiation

    SciTech Connect

    D'Amelio, F.; Kraft, L.M.; D'Antoni-D'Amelio, E.; Benton, E.V.; Miquel, J.

    1984-01-01

    Effects of high energy, heavy particle (HZE) radiation were studied in the brain of the fruit fly (Drosophila melanogaster) exposed to argon (40Ar) or krypton (84Kr) ions. In the flies exposed to argon the fluence ranged from 6 X 10(4) to 8 X 10(7) particles/cm2. The insects were killed 35 days after exposure. Extensive tissue fragmentation was observed at the higher fluence employed. At fluences ranging from 5 X 10(6) (one hit/two cell bodies) to 9 X 10(4) (one hit/90 cell bodies) particles/cm2, swelling of the neuronal cytoplasm and focally fragmented membranes was observed. Marked increase of glial lamellae around nerve cell processes was seen at fluences ranging from one hit/six to one hit/135 cell bodies. In the flies irradiated with krypton, the fluences employed were 5.8 X 10(3) and 2.2 X 10(6) particles/cm2. Acute and late effects were evaluated. In the flies killed 36 hours after exposure (acute effects) to either fluence, glycogen particles were found in the neuroglial compartment. The granules were no longer present in flies killed 35 days later (late effects). From these studies it appears that the Drosophila brain is a useful model to investigate radiation damage to mature neurons, neuroglia, and therefore, to the glio-neuronal metabolic unit. In a separate study, the synaptic profiles of the neuropil in layers II-III of the frontal cerebral cortex of anesthesized adult LAFl mice were quantitatively appraised after exposure to argon (40Ar) particles. The absorbed dose ranged from 0.05 to 5 gray (Gy) plateau. It was determined that the sodium pentobarbital anesthesia per se results in a significant decrease in synaptic profile length one day after anesthetization, with return to normal values after 2-28 days. Irradiation with 0.05-5 Gy argon particles significantly inhibited the synaptic shortening effect of anesthesia at one day after exposure.

  10. [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. PMID:24989296

  11. Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The stunning complexity of the resident microbiota and the intricate pathways of microbial and host interactions provide a massive adaptive capacity for mammals. In this addendum we reflect on our recent publication on Toll-like receptor 2 deficiency related colonic mucosal epigenetic, immunologic a...

  12. A comparison of the phototumorigenic potential of 8-MOP and 5-MOP in hairless albino mice exposed to solar simulated radiation.

    PubMed

    Young, A R; Magnus, I A; Davies, A C; Smith, N P

    1983-05-01

    Hairless albino mice have been treated with topically applied 8-methoxypsoralen and 5-methoxypsoralen at two concentrations and exposed to solar simulated radiation. Both these compounds significantly increased the incidence of cutaneous tumours when compared with controls irradiated after treatment with vehicle. This effect was related to psoralen concentration and at the two concentrations investigated there was no significant difference between the compounds. PMID:6849820

  13. Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

    PubMed Central

    Yauk, Carole; Polyzos, Aris; Rowan-Carroll, Andrea; Somers, Christopher M.; Godschalk, Roger W.; Van Schooten, Frederik J.; Berndt, M. Lynn; Pogribny, Igor P.; Koturbash, Igor; Williams, Andrew; Douglas, George R.; Kovalchuk, Olga

    2008-01-01

    Particulate air pollution is widespread, yet we have little understanding of the long-term health implications associated with exposure. We investigated DNA damage, mutation, and methylation in gametes of male mice exposed to particulate air pollution in an industrial/urban environment. C57BL/CBA mice were exposed in situ to ambient air near two integrated steel mills and a major highway, alongside control mice breathing high-efficiency air particulate (HEPA) filtered ambient air. PCR analysis of an expanded simple tandem repeat (ESTR) locus revealed a 1.6-fold increase in sperm mutation frequency in mice exposed to ambient air for 10 wks, followed by a 6-wk break, compared with HEPA-filtered air, indicating that mutations were induced in spermatogonial stem cells. DNA collected after 3 or 10 wks of exposure did not exhibit increased mutation frequency. Bulky DNA adducts were below the detection threshold in testes samples, suggesting that DNA reactive chemicals do not reach the germ line and cause ESTR mutation. In contrast, DNA strand breaks were elevated at 3 and 10 wks, possibly resulting from oxidative stress arising from exposure to particles and associated airborne pollutants. Sperm DNA was hypermethylated in mice breathing ambient relative to HEPA-filtered air and this change persisted following removal from the environmental exposure. Increased germ-line DNA mutation frequencies may cause population-level changes in genetic composition and disease. Changes in methylation can have widespread repercussions for chromatin structure, gene expression and genome stability. Potential health effects warrant extensive further investigation. PMID:18195365

  14. Epigallocatechin-3-O-Gallate Protects Against Hepatic Damage and Testicular Toxicity in Male Mice Exposed to Di-(2-Ethylhexyl) Phthalate.

    PubMed

    Ge, Jian; Han, Baoyu; Hu, Huajun; Liu, Jun; Liu, Yang

    2015-07-01

    The aim of this study was to examine the effects of epigallocatechin-3-O-gallate (EGCG) on hepatic damage and testicular toxicity in male mice exposed to daily oral administration of di-(2-ethylhexyl) phthalate (DEHP). A mouse model was used to assess the effects of daily intraperitoneal EGCG injection on hepatic and testicular damage. Histological and mitochondrial membrane potential results revealed that EGCG treatment significantly arrested the progression of hepatic damage. EGCG treatment resulted in significant suppression of liver injury (i.e., reduced activities of alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). The development of DEHP-induced hepatic and testicular damage altered the testosterone concentration in mouse serum, which could affect the reproductive ability of male mice. Moreover, EGCG treatment markedly attenuated testes lesions, sperm deformity, and spermatogenic cell apoptosis. At the molecular level, hepatic CYP3A4 expression was substantially reduced by EGCG treatment in mice exposed to DEHP compounds, whereas testicular aromatase expression was increased significantly in testes. Thus, these results demonstrate that EGCG administration may protect against liver damage and reproductive toxicity in males exposed to DEHP. PMID:25789634

  15. Lung Deposition and Clearance of Inhaled Vanadium Pentoxide in Chronically Exposed F344 Rats and B6C3F1 Mice

    SciTech Connect

    Dill, Jeffrey A.; Lee, Kyeonghee M.; Mellinger, Kathleen H.; Bates, Derrick J.; Burka, Leo T.; Roycroft, Joseph H.

    2004-01-01

    Female F344 rats and B6C3F1 mice were exposed to vanadium pentoxide (V{sub 2}O{sub 5}) at concentrations of 0, 0.5, 1, or 2 mg/m{sup 3} (rats) and 0, 1, 2, or 4 mg/m{sup 3} (mice) for 6 h/day, 5 days/week (for up to 18 months), by whole-body inhalation. Lung weights and lung burdens of vanadium were determined for exposed animals after 1, 5, and 12 days and after 1, 2, 6, 12, and 18 months of V{sub 2}O{sub 5} exposure. Blood vanadium concentrations were determined at 1, 2, 6, 12, and 18 months for all animals including controls. A model that assumed a first-order deposition rate and a first-order elimination rate for vanadium was employed to fit the lung burden data. Comparisons between exposed groups indicated a progressive increase in lung weight with exposure concentration and time on exposure for both species. The vanadium lung burdens appeared to reach steady state in the lowest exposure groups (0.5 and 1 mg/m{sup 3} for rats and mice, respectively) but showed a decline in the higher exposure groups. This deposition pattern was similar between rats and mice but the maximum lung burdens were observed at different times (1 or 2 months in mice vs. 6 months in rats). The vanadium deposition rate decreased faster in mice, while the elimination half-lives of vanadium lung burdens were about six- to nine-fold shorter in mice than in rats at 1 and 2 mg/m{sup 3}. Thus, the retention of vanadium in the lungs at 18 months was lower in mice ({approx}2% retained) compared with rats (13-15% retained) at the common exposure concentrations of 1 and 2 mg/m{sup 3}. The lung burden data were approximately proportional to the exposure concentration in both species, likely due to concomitant decreases in deposition and elimination to a similar extent with increasing exposure. The area under the lung burden versus time curves and the area under the blood concentration (control-normalized) versus time curves were also proportional to exposure concentration. The progression of

  16. 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 Central

    Flegal, Matthew; Blimkie, Melinda; Roch-Lefevre, Sandrine; Gregoire, Eric; Klokov, Dmitry

    2013-01-01

    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. PMID:24317437

  17. 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

  18. 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.

  19. Reactive oxygen species- and nitric oxide-mediated lung inflammation and mitochondrial dysfunction in wild-type and iNOS-deficient mice exposed to diesel exhaust particles.

    PubMed

    Zhao, Hongwen; Ma, Joseph K; Barger, Mark W; Mercer, Robert R; Millecchia, Lyndell; Schwegler-Berry, Diane; Castranova, Vince; Ma, Jane Y

    2009-01-01

    Pulmonary responses to diesel exhaust particles (DEP) exposure are mediated through enhanced production of reactive oxygen species (ROS) and nitric oxide (NO) by alveolar macrophages (AM). The current study examined the differential roles of ROS and NO in DEP-induced lung injury using C57B/6J wild-type (WT) and inducible NO synthase knockout (iNOS KO) mice. Mice exposed by pharyngeal aspiration to DEP or carbon black particles (CB) (35 mg/kg) showed an inflammatory profile that included neutrophil infiltration, increased lactate dehydrogenase (LDH) activity, and elevated albumin content in bronchoalveolar lavage fluid (BALF) at 1, 3, and 7 d postexposure. The organic extract of DEP (DEPE) did not induce an inflammatory response. Comparing WT to iNOS KO mice, the results show that NO enhanced DEP-induced neutrophils infiltration and plasma albumin content in BALF and upregulated the production of the pro-inflammatory cytokine interleukin 12 (IL-12) by AM. DEP-exposed AM from iNOS KO mice displayed diminished production of IL-12 and, in response to ex vivo lipopolysaccharide (LPS) challenge, decreased production of IL-12 but increased production of IL-10 when compared to cells from WT mice. DEP, CB, but not DEPE, induced DNA damage and mitochondria dysfunction in AM, however, that is independent of cellular production of NO. These results demonstrate that DEP-induced immune/inflammatory responses in mice are regulated by both ROS- and NO-mediated pathways. NO did not affect ROS-mediated mitochondrial dysfunction and DNA damage but upregulated IL-12 and provided a counterbalance to the ROS-mediated adaptive stress response that downregulates IL-12 and upregulates IL-10. PMID:19267316

  20. HUMORAL AND CELL-MEDIATED IMMUNE STATUS OF MICE EXPOSED TO TRANS-1,2-DICHLORO ETHYLENE

    EPA Science Inventory

    The study assessed possible adverse immunological effects of trans-1,2-dichloroethylene (DCE) on random-bred CD-1 mice following 14 and 90 days of exposure. A 14-day range-finding study was performed on male mice by gavage at doses 1/10 and 1/100 the LD50 (210 and 21 mg/kg). No a...

  1. Survival and diseases in C57BL mice exposed to X rays or 3.1 MeV neutrons at an age of 7 or 21 days

    SciTech Connect

    Maisin, J.R.; Wambersie, A.; Gerber, G.B.; Vankerkom, J.

    1996-10-01

    Survival and causes of mortality were studied in 7- or 21-day-old male C57BL/Cnb mice exposed to 0.5, 1 or 3 Gy of 250 kVp X rays or 0.125, 0.25, 0.5 or 1 Gy of accelerator neutrons (modal energy 3.1 MeV). A total of 1287 animals were used in the experiments. Survival of irradiated animals was reduced significantly only in the mice receiving the highest doses (1 Gy neutrons, 3 Gy X rays). Mice exposed to the lowest doses (0.125 Gy neutrons, 0.5 Gy X rays) lived significantly longer than controls, apparently reflecting a reduction in non-neoplastic lung and liver diseases. All malignant tumors increased significantly from (and including) doses of 0.5 Gy neutrons and 1 Gy X rays. Hepatocellular carcinoma was the principal contributor to the increase in tumor incidence, at least after exposure to neutrons. No significant increase in hepatocellular carcinoma was seen in 21-day-old mice exposed to X rays. An increase, especially after 3 Gy X rays, was also observed for all leukemias. Controls in the present study lived significantly longer than those in our earlier studies of irradiated adult mice, making a direct comparison of the radiation-induced effects in adult and infant mice difficult. Based on percentage life shortening, it appears that exposure during infancy does not shorten total survival or survival from cancer much more than exposure of adults, although such exposure, especially to neutrons, causes more hepatocellular carcinoma. Due to the nonlinearity of the dose-effect relationships, it is difficult to calculate the RBE of neutrons. For survival time at higher does an RBE of about 3 is obtained. When the incidence of all malignant tumors and of hepatocellular cancer is fitted to a linear or a linear-quadratic function, an RBE from 5 to 8 is obtained. No RBE can be estimated for hepatocellular carcinoma in mice of an age of 21 days because exposure to X rays does not seem to cause this tumor at that age. 45 refs., 12 figs., 1 tab.

  2. 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

  3. Pronounced susceptibility to infection by Salmonella enterica serovar Typhimurium in mice chronically exposed to lead correlates with a shift to Th2-type immune responses

    SciTech Connect

    Fernandez-Cabezudo, Maria J.; Ali, Sumaya A.E.; Ullah, Azim; Hasan, Mohammed Y.; Kosanovic, Melita; Fahim, Mohamed A.; Adem, Abdu; Al-Ramadi, Basel K. . E-mail: ramadi.b@uaeu.ac.ae

    2007-02-01

    Persistent exposure to inorganic lead (Pb) is known to adversely affect the immune system. In the present study, we assessed the effect of chronic Pb exposure on susceptibility to infection by the facultative intracellular pathogen Salmonella enterica serovar Typhimurium. Mice were exposed to 10 mM Pb-acetate in drinking water for {approx} 16 weeks, resulting in a significant level of Pb in the blood (106.2 {+-} 8.9 {mu}g/dl). Pb exposure rendered mice susceptible to Salmonella infection, manifested by increased bacterial burden in target organs and heightened mortality. Flow cytometric analysis of the splenic cellular composition in normal and Pb-exposed mice revealed no gross alteration in the ratios of B and T lymphocytes or myeloid cells. Similarly, the capacity of B and T cells to upregulate the expression of activation antigens in response to mitogenic or inflammatory stimuli was not hindered by Pb exposure. Analysis of the ability of ex vivo-cultured splenocytes to secrete cytokines demonstrated a marked reduction in IFN-{gamma} and IL-12p40 production associated with Pb exposure. In contrast, secretion of IL-4 by splenocytes of Pb-treated mice was 3- to 3.6-fold higher than in normal mice. The increased capacity to produce IL-4 correlated with a shift in the in vivo anti-Salmonella antibody response from the protective IgG2a isotype to the Th2-induced IgG1 isotype. We conclude that chronic exposure to high levels of Pb results in a state of immunodeficiency which is not due to an overt cytotoxic or immunosuppressive mechanism, but rather is largely caused by a shift in immune responsiveness to Th2-type reactions.

  4. [CYSTEAMINE-INDUCED MODIFICATION OF CYTOGENETIC DAMAGES TO THE CORNEAL EPITHELIUM OF MICE EXPOSED TO CORPUSCULAR RADIATION WITH VARYING LINEAR TRANSFER ENERGIES].

    PubMed

    Vorozhtsova, S V; Bulynina, T M; Molokanov, A G; Ivanov, A A

    2015-01-01

    Cytogenetic damages to cells of the corneal epithelium were studied in mice exposed to protons (10, 25, 50 and 645 MeV), ions of boron, carbon and neon, and X-rays (180 keV) within the dose range from 25 to 750 cGy and injected with a radioprotector. Animals were subjected to a single exposure. The protective effect of β-mercaptoethylamine was tested in the experiment. The radioprotector (0.2 ml) was introduced intraperitoneally 30 minutes before exposure in 350 mI/kg dose. Control animals received the same amount of sodium chloride solution. The animals were sacrificed by cervical dislocation in 24 and 72 hrs. after exposure. It was shown that cysteamine effectively protects in vivo corneal epithelium cells of mice exposed to electromagnetic radiation or protons in a broad energy spectrum (10 to 645 MeV), and to a broad range of radiation doses (25 to 750 cGy), as judged from levels of aberrant mitosis and mitotic activity. The radioprotector exhibited the highest effectiveness in animals exposed to the doses of 50 to 300 cGy. These findings prove that cysteamine may potentially be used for pharmacological protection from protons. The radioprotector failed to prevent chromosomal aberrations after exposure to heavy charged particles of boron, carbon and neon, which implies the need to design radioprotectors against this type of corpuscular radiation specifically. PMID:26292425

  5. Modulation by aspirin and naproxen of nucleotide alterations and tumors in the lung of mice exposed to environmental cigarette smoke since birth.

    PubMed

    La Maestra, Sebastiano; D'Agostini, Francesco; Izzotti, Alberto; Micale, Rosanna T; Mastracci, Luca; Camoirano, Anna; Balansky, Roumen; Trosko, James E; Steele, Vernon E; De Flora, Silvio

    2015-12-01

    Chemoprevention provides an important strategy for cancer control in passive smokers. Due to the crucial role played by smoke-related chronic inflammation in lung carcinogenesis, of special interest are extensively used pharmacological agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs). We evaluated the ability of aspirin and naproxen, inhibitors of both cyclooxygenase-1 and cyclooxygenase -2, to modulate environmental cigarette smoke (ECS)-induced lung carcinogenesis in A/J mice of both genders. Based on a subchronic toxicity study in 180 postweaning mice, we used 1600 mg/kg diet aspirin and 320 mg/kg diet naproxen. In the tumor chemoprevention study, using 320 mice, exposure to ECS started soon after birth and administration of NSAIDs started after weaning. At 10 weeks of life, the NSAIDs did not affect the presence of occult blood in feces. As assessed in a subset of 40 mice, bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine levels were considerably increased in ECS-exposed mice and, irrespective of gender, both NSAIDs remarkably inhibited these nucleotide alterations. After exposure for 4 months followed by 5 months in filtered air, ECS induced a significant increase in the yield of surface lung tumors, the 43.7% of which were adenomas and the 56.3% were adenocarcinomas. Oct-4 (octamer-binding transcription factor 4), a marker of cell stemness, was detected in some adenocarcinoma cells. The NAIDs attenuated the yield of lung tumors, but prevention of ECS-induced lung adenomas was statistically significant only in female mice treated with aspirin, which supports a role for estrogens in ECS-related lung carcinogenesis and highlights the antiestrogenic properties of NSAIDs. PMID:26464196

  6. Nrf2 Knockout Attenuates the Anti-Inflammatory Effects of Phenethyl Isothiocyanate and Curcumin

    PubMed Central

    2015-01-01

    The role of phytochemicals in preventive and therapeutic medicine is a major area of scientific research. Several studies have illustrated the mechanistic roles of phytochemicals in Nrf2 transcriptional activation. The present study aims to examine the importance of the transcription factor Nrf2 by treating peritoneal macrophages from Nrf2+/+ and Nrf2–/– mice ex vivo with phenethyl isothiocyanate (PEITC) and curcumin (CUR). The peritoneal macrophages were pretreated with the drugs and challenged with lipopolysaccharides (LPSs) alone and in combination with PEITC or CUR to assess their anti-inflammatory and antioxidative effects based on gene and protein expression in the treated cells. LPS treatment resulted in an increase in the expression of inflammatory markers such as cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in both Nrf2+/+ and Nrf2–/– macrophages, detected by quantitative polymerase chain reaction (qPCR). Nrf2+/+ macrophages treated with PEITC and CUR exhibited a significant decrease in the expression of these anti-inflammatory genes along with an increase in the expression of hemeoxygenase-1 (HO-1), which is an antioxidative stress gene downstream of the Nrf2 transcription factor battery. Although there was no significant decrease in the expression of the anti-inflammatory genes or an increase in HO-1 expression in Nrf2–/– macrophages treated with either PEITC or CUR, there was a significant decrease in the protein expression of COX-2 and an increase in the expression of HO-1 in Nrf2+/+ macrophages treated with PEITC compared to that with CUR treatment. No significant changes were observed in the macrophages from knockout animals. Additionally, there was a significant decrease in LPS-induced IL-6 and TNF-α production following PEITC treatment compared with that following CUR in Nrf2+/+ macrophages, whereas no change was observed in the macrophages from knockout

  7. Biomedical Analyses of Mice Body Hair Exposed to Long-term Space Flight as a Compliment of Human Research

    NASA Astrophysics Data System (ADS)

    Mukai, Chiaki

    Introduction: To understand the effect of space environment characterized by microgravity and radiation on protein and mineral metabolisms is important for developing the countermeasures to the adverse effects happening on the astronauts who stay long-term in space. Thus JAXA has started a human research to study the effects of long-term exposure in space flight on gene expression and mineral metabolism by analyzing astronaut's hair grown in space since December 2009 (Experiment nicknamed "HAIR"). Ten human subjects who are the crew of the International Space Station (ISS) will be expected to complete this experiment. Thanks to the tissue sharing program of space-flown mice which is presented and organized by AGI(Italian Space Agency), we can also have an opportunity to analyze rodents samples which will greatly compliment human hair experiment by enable us to conduct more detailed analysis with the expansion of skin analysis which is not include in human experiment. The purpose of this flown-mice experiment is to study the effects of long-term exposure to space environment such as microgravity and space radiation on mineral and protein metabolism, the biological responses to the stress levels, and the initial process of skin carcinogenesis by analyzing hair shaft, its root cells, and skin. Approach and Method In this experiment, we analyzed hair shaft, hair root and skin. Hair samples with skin were taken from 3-month space-flown mice and ground-control mice in the AGI's tissue sharing program in 2009. The sample numbers of space-flown mice and control-mice were three and six, respectively. And they were at the Mice Drawer System (MDS) in ISS and in the laboratory of Geneva University. For the hair shaft, the mineral balance is investi-gated by energy dispersive X-ray spectroscopy (SEM-EDX). For hair root, the extracted RNA undergoes DNA microarray analysis, and will be further examined particular interests of gene-expression by real time Reverse Transcription

  8. Altered gene expression and spine density in nucleus accumbens of adolescent and adult male mice exposed to emotional and physical stress.

    PubMed

    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 stress (ES) or physical stress (PS) 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 35) or adult (8-week-old) mice were exposed to ES or PS using a witness social defeat paradigm. Then, 24 h 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 extracellular signal-related kinase 2 (ERK2), reduced transcription of ΔFosB and had no effect on cAMP response element-binding protein (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

  9. Evidence for humoral immunodepression in NO/sub 2/-exposed mice: influence of food restriction and stress

    SciTech Connect

    Azoulay-Dupuis, E.; Bouley, G.; Moreau, J.; Muffat-Joly, M.; Pocidalo, J.J.

    1987-04-01

    The effects of food restriction or 20 ppm NO/sub 2/ exposure on humoral immunity were investigated in normal and adrenalectomized C/sub 57/B1/6 mice. The thymic and splenic weights of sham-operated mice were similarly diminished after 4 days of NO/sub 2/ exposure or 4 days of food depletion. The responses of corresponding adrenalectomized mice were less depressed. Undernutrition induced lymphoid organ involution and corticosteroids were partly involved. Plaque-forming cells (PFC) per spleen and per 10/sup 6/ cells were markedly depressed after 4 days of NO/sub 2/ exposure, but less so after food deprivation. The same significant suppression of PFC was observed in adrenalectomized groups. Depression of humoral immunity was independent of stress-induced endogenous steroids. Moreover, NO/sub 2/ had a specific effect on humoral immunodepression, food restriction being an associated factor.

  10. DOES RESPONSE EVALUATION OF GENE EXPRESSION PROFILES IN THE SKIN OF K6/ODC MICE EXPOSED TO SODIUM ARSENITE

    EPA Science Inventory

    Abstract - Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, gene expression profiles were characterized fro...

  11. DETECTION OF EARLY GENE EXPRESSION CHANGES BY DIFFERENTIAL DISPLAY IN THE LIVERS OF MICE EXPOSED TO DICHLOROACETIC ACID

    EPA Science Inventory

    Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated the hepatocarcinogenicity of DCA in mice when administered in drinking water. The mechanism of DCA carcinogenicity is not clear and we speculate that changes...

  12. NICOTINE EFFECTS ON THE MOTOR ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.

    EPA Science Inventory

    Several studies in the literature have shown that exposure of mice and rats to nicotine early in development alters its effects when the rodents are subsequently challenged with nicotine. Anatoxin-a is a nicotinic agonist produced by several genera of cyanobacteria, and has caus...

  13. Protective role of diet supplements Spirulina and Tamarind fruit pulp on kidney in sodium fluoride exposed Swiss albino mice: Histological and biochemical indices.

    PubMed

    Yadav, N; Sharma, Shweta; Sharma, K p; Pandey, A; Pareek, P; Sharma, Subhasini

    2016-01-01

    Fluoride toxicity through potable water, particularly ground water, is not uncommon in countries such as India, China, Iran, Iraq, Turkey, parts of Africa and Afghanistan. Kidney being the main organ involved in fluoride removal, it accumulates considerable amount of fluoride. Here, we report toxic effects of oral exposure of Swiss albino mice to fluoride (sub-acute: 190 mg/kg body wt. for 7 days; and sub-chronic: 94 mg/kg body wt. for 90 days) and recovery of sub-chronic fluoride exposed mice after 90 days of sodium fluoride (NaF) withdrawal. The role of diet supplements (Spirulina and tamarind fruit pulp @ 230 mg/kg body wt. independently as well as in combination) in amelioration of fluoride toxicity has also been screened. Compared with controls, feed intake decreased from 3-43%, body wt. 4-18%, and kidney wt. 5-12% in treated mice (except diet supplement groups of sub-chronic exposure) while their water intake increased from 4-43%. Histopathological changes in the cortical region of kidney in fluoride treated mice were as follows: dilation of bowman's capsule and thickening of its parietal and visceral layer; alterations in glomeruli size and their sclerotization; increase in bowman's space; proliferation of mesangial cells; reduction in podocyte counts; and dilation of proximal and distal tubules. Fluoride exposure altered tissue biochemistry (protein, acid phosphatase and alkaline phosphatase content) and increased urea (23-58%) and creatinine content (14-127%) in the serum. Sub-acute exposure was found more toxic. The diet modulation not only reduced fluoride toxicity but also led to better recovery of treated mice after withdrawal, especially in combination. PMID:26891552

  14. Long-term preservation of cone photoreceptors and visual acuity in rd10 mutant mice exposed to continuous environmental enrichment

    PubMed Central

    Strettoi, Enrica

    2014-01-01

    Purpose In human patients and animal models of retinitis pigmentosa (RP), a gradual loss of rod photoreceptors and decline in scotopic vision are the primary manifestations of the disease. Secondary death of cones and gradual, regressive remodeling of the inner retina follow and progress at different speeds according to the underlying genetic defect. In any case, the final outcome is near-blindness without a conclusive cure yet. We recently reported that environmental enrichment (EE), an experimental manipulation based on exposure to enhanced motor, sensory, and social stimulation, when started at birth, exerts clear beneficial effects on a mouse model of RP, by slowing vision loss. The purpose of this study was to investigate in the same mouse the long-term effects of chronic exposure to an EE and assess the outcome of this manipulation on cone survival, inner retinal preservation, and visual behavior. Methods Two groups of rd10 mutant mice were maintained in an EE or standard (ST) laboratory conditions up to 1 year of age. Then, retinal preservation was assessed with immunocytochemistry, confocal microscopy examination, cone counts, and electron microscopy of the photoreceptor layer, while visual acuity was tested behaviorally with a Prusky water maze. Results rd10 mice are a model of autosomal recessive RP with a typical rod-cone, center to the periphery pattern of photoreceptor degeneration. They carry a mutation of the rod-specific phosphodiesterase gene and undergo rod death that peaks at around P24, while cone electroretinogram (ERG) is extinct by P60. We previously showed that early exposure to an EE efficiently delays photoreceptor degeneration in these mutants, extending the time window of cone viability and cone-mediated vision well beyond the phase of maximum rod death. Here we find that a maintained EE can delay the degeneration of cones even in the long term. Confocal and electron microscopy examination of the retinas of the rd10 EE and ST mice at 1

  15. Strain Specific Induction of Pyometra and Differences in Immune Responsiveness in Mice Exposed to 17α-Ethinyl Estradiol or the Endocrine Disrupting Chemical Bisphenol A

    PubMed Central

    Kendziorski, Jessica A.; Kendig, Eric L.; Gear, Robin L.; Belcher, Scott M.

    2012-01-01

    Pyometra is an inflammatory disease of the uterus that can be caused by chronic exposure to estrogens. It is unknown whether weakly estrogenic endocrine disruptors can cause pyometra. We investigated whether dietary exposures to the estrogenic endocrine disruptor bisphenol A (BPA) induced pyometra. Pyometra did not occur in CD1 mice exposed to different dietary doses of BPA ranging from 4.1 to >4000 µg/kg/day or 17α-ethinyl estradiol (EE; 1.2 to >150 µg/kg/day). In the C57BL/6 strain, pyometra occurred in the 15 µg/kg/day EE and 33 µg/kg/day BPA treatment groups. At the effective concentration of BPA, histological analysis revealed pathological alterations of uterine morphology associated with a >5.3-fold increase in macrophage numbers in non-pyometra uteri of C57BL/6 mice exposed to BPA. These results suggest that BPA enhances immune responsiveness of the uterus and that heightened responsiveness in C57BL/6 females is related to increased susceptibility to pyometra. PMID:22429997

  16. Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

    PubMed

    Macrì, Simone; Ceci, Chiara; Onori, Martina Proietti; Invernizzi, Roberto William; Bartolini, Erika; Altabella, Luisa; Canese, Rossella; Imperi, Monica; Orefici, Graziella; Creti, Roberta; Margarit, Immaculada; Magliozzi, Roberta; Laviola, Giovanni

    2015-01-01

    Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities. PMID:26304458

  17. Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon

    PubMed Central

    Macrì, Simone; Ceci, Chiara; Onori, Martina Proietti; Invernizzi, Roberto William; Bartolini, Erika; Altabella, Luisa; Canese, Rossella; Imperi, Monica; Orefici, Graziella; Creti, Roberta; Margarit, Immaculada; Magliozzi, Roberta; Laviola, Giovanni

    2015-01-01

    Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities. PMID:26304458

  18. Ciguatoxin reduces regenerative capacity of axotomized peripheral neurons and delays functional recovery in pre-exposed mice after peripheral nerve injury.

    PubMed

    Au, Ngan Pan Bennett; Kumar, Gajendra; Asthana, Pallavi; Tin, Chung; Mak, Yim Ling; Chan, Leo Lai; Lam, Paul Kwan Sing; Ma, Chi Him Eddie

    2016-01-01

    Ciguatera fish poisoning (CFP) results from consumption of tropical reef fish containing ciguatoxins (CTXs). Pacific (P)-CTX-1 is among the most potent known CTXs and the predominant source of CFP in the endemic region responsible for the majority of neurological symptoms in patients. Chronic and persistent neurological symptoms occur in some CFP patients, which often result in incomplete functional recovery for years. However, the direct effects of exposure to CTXs remain largely unknown. In present study, we exposed mice to CTX purified from ciguatera fish sourced from the Pacific region. P-CTX-1 was detected in peripheral nerves within hours and persisted for two months after exposure. P-CTX-1 inhibited axonal regrowth from axotomized peripheral neurons in culture. P-CTX-1 exposure reduced motor function in mice within the first two weeks of exposure before returning to baseline levels. These pre-exposed animals exhibited delayed sensory and motor functional recovery, and irreversible motor deficits after peripheral nerve injury in which formation of functional synapses was impaired. These findings are consistent with reduced muscle function, as assessed by electromyography recordings. Our study provides strong evidence that the persistence of P-CTX-1 in peripheral nerves reduces the intrinsic growth capacity of peripheral neurons, resulting in delayed functional recovery after injury. PMID:27229176

  19. Ciguatoxin reduces regenerative capacity of axotomized peripheral neurons and delays functional recovery in pre-exposed mice after peripheral nerve injury

    PubMed Central

    Au, Ngan Pan Bennett; Kumar, Gajendra; Asthana, Pallavi; Tin, Chung; Mak, Yim Ling; Chan, Leo Lai; Lam, Paul Kwan Sing; Ma, Chi Him Eddie

    2016-01-01

    Ciguatera fish poisoning (CFP) results from consumption of tropical reef fish containing ciguatoxins (CTXs). Pacific (P)-CTX-1 is among the most potent known CTXs and the predominant source of CFP in the endemic region responsible for the majority of neurological symptoms in patients. Chronic and persistent neurological symptoms occur in some CFP patients, which often result in incomplete functional recovery for years. However, the direct effects of exposure to CTXs remain largely unknown. In present study, we exposed mice to CTX purified from ciguatera fish sourced from the Pacific region. P-CTX-1 was detected in peripheral nerves within hours and persisted for two months after exposure. P-CTX-1 inhibited axonal regrowth from axotomized peripheral neurons in culture. P-CTX-1 exposure reduced motor function in mice within the first two weeks of exposure before returning to baseline levels. These pre-exposed animals exhibited delayed sensory and motor functional recovery, and irreversible motor deficits after peripheral nerve injury in which formation of functional synapses was impaired. These findings are consistent with reduced muscle function, as assessed by electromyography recordings. Our study provides strong evidence that the persistence of P-CTX-1 in peripheral nerves reduces the intrinsic growth capacity of peripheral neurons, resulting in delayed functional recovery after injury. PMID:27229176

  20. Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

    PubMed Central

    Wang, Hong; Sethi, Gautam; Loke, Weng-Keong; Sim, Meng-Kwoon

    2015-01-01

    ACE inhibitors and ARBs (angiotensin receptor blockers) have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I), an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy) attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p.) that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia), and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA-I. DAA-I completely

  1. Chronic central serotonin depletion attenuates ventilation and body temperature in young but not adult Tph2 knockout rats.

    PubMed

    Kaplan, Kara; Echert, Ashley E; Massat, Ben; Puissant, Madeleine M; Palygin, Oleg; Geurts, Aron M; Hodges, Matthew R

    2016-05-01

    Genetic deletion of brain serotonin (5-HT) neurons in mice leads to ventilatory deficits and increased neonatal mortality during development. However, it is unclear if the loss of the 5-HT neurons or the loss of the neurochemical 5-HT led to the observed physiologic deficits. Herein, we generated a mutant rat model with constitutive central nervous system (CNS) 5-HT depletion by mutation of the tryptophan hydroxylase 2 (Tph2) gene in dark agouti (DA(Tph2-/-)) rats. DA(Tph2-/-) rats lacked TPH immunoreactivity and brain 5-HT but retain dopa decarboxylase-expressing raphe neurons. Mutant rats were also smaller, had relatively high mortality (∼50%), and compared with controls had reduced room air ventilation and body temperatures at specific postnatal ages. In adult rats, breathing at rest and hypoxic and hypercapnic chemoreflexes were unaltered in adult male and female DA(Tph2-/-) rats. Body temperature was also maintained in adult DA(Tph2-/-) rats exposed to 4°C, indicating unaltered ventilatory and/or thermoregulatory control mechanisms. Finally, DA(Tph2-/-) rats treated with the 5-HT precursor 5-hydroxytryptophan (5-HTP) partially restored CNS 5-HT and showed increased ventilation (P < 0.05) at a developmental age when it was otherwise attenuated in the mutants. We conclude that constitutive CNS production of 5-HT is critically important to fundamental homeostatic control systems for breathing and temperature during postnatal development in the rat. PMID:26869713

  2. Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

    PubMed

    Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-05-01

    We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model. PMID:25870909

  3. Artificial daylight photodynamic therapy with "non-inflammatory" doses of hexyl aminolevulinate only marginally delays SCC development in UV-exposed hairless mice.

    PubMed

    Togsverd-Bo, Katrine; Lerche, Catharina M; Philipsen, Peter A; Hædersdal, Merete; Wulf, Hans Christian

    2013-12-01

    Photodynamic therapy (PDT) is effective for actinic keratoses, but is associated with pain and post-treatment inflammation. Daylight-mediated PDT and PpIX-precursors at low concentrations reduce pain and inflammation intensity. The objective was to evaluate the effect of repeated low-concentration PDT combined with artificial daylight on SCC development. Mice (n = 265) were exposed to simulated solar UV-irradiation (UVR) 3 times weekly mimicking "summer-dose"-exposure (3 SED). Selected groups of mice received a "winter-dose"-exposure (0.6 SED) for the first 90 days. PDT was delivered with 0.1%, 0.05% and 0.02% hexyl aminolevulinate (HAL) cream and artificial daylight for 2.5 hours (6 J cm(-2)) in different treatment regimes (1-3 times weekly, 45-days intervals, days 1-180 and from day 180 onwards). The primary end-point was the time to first SCC (1 mm diameter). 0.1% HAL-PDT given 3 times weekly slightly delayed SCC development and induced minimal inflammation. In winter- and summer UVR-treatment regimes, 0.1% HAL PDT delayed the time to first SCC compared to control UVR and placebo-PDT when mice were PDT-treated on days 1-180 (median 213 vs. 199 days, p = 0.011) and from day 180 onwards (median 218 vs. 199 days, p = 0.006). PDT with 0.05% and 0.02% HAL did not influence SCC development (medians 206 days, p = ns). In summer UVR-exposed mice, 0.1% HAL-PDT marginally postponed the time to first SCC compared to control UVR (median 160 days) when treatments were given 3 times weekly for 180 days (median 166, p = 0.01), but not for 90 days (median 161, p = 0.112). In conclusion, repeated low-concentration HAL-PDT combined with artificial daylight is well-tolerated, but only marginally delays SCC development in mice. PMID:24064675

  4. Late-occurring chromosome aberrations and global DNA methylation in hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon ((28)Si) ions.

    PubMed

    Rithidech, Kanokporn Noy; Honikel, Louise M; Reungpathanaphong, Paiboon; Tungjai, Montree; Jangiam, Witawat; Whorton, Elbert B

    2015-11-01

    Although myeloid leukemia (ML) is one of the major health concerns from exposure to space radiation, the risk prediction for developing ML is unsatisfactory. To increase the reliability of predicting ML risk, a much improved understanding of space radiation-induced changes in the target cells, i.e. hematopoietic stem/progenitor cells (HSPCs), is important. We focused on the in vivo induction of late-occurring damage in HSPCs of mice exposed to (28)Si ions since such damage is associated with radiation-induced genomic instability (a key event of carcinogenesis). We gave adult male CBA/CaJ mice, known to be sensitive to radiation-induced ML, a whole-body exposure (2 fractionated exposures, 15 days apart, that totaled each selected dose, delivered at the dose-rate of 1 cGy/min) to various doses of 300 MeV/n (28)Si ions, i.e. 0 (sham controls), 0.1, 0.25, or 0.5 Gy. At 6 months post-irradiation, we collected bone marrow cells from each mouse (five mice per treatment-group) for obtaining the myeloid-lineage of HSPC-derived clones for analyses. We measured the frequencies of late-occurring chromosome aberrations (CAs), using the genome-wide multicolor fluorescence in situ hybridization method. The measurement of CAs was coupled with the characterization of the global DNA methylation patterns, i.e. 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5 hmC). A dose-dependent increase in the frequencies of CAs was detected (Analysis of Variance or ANOVA, p<0.01), indicating the induction of genomic instability after exposure of mice to 300 MeV/n (28)Si ions. Slight increases in the levels of 5 mC were observed in all treatment groups, as compared to the sham-control level. In contrast, there was a significant reduction in levels of 5 hmC (ANOVA, p<0.01). Since these endpoints were evaluated in the same mouse, our data suggested for the first time a link between a reduction in 5 hmC and genomic instability in HSPC-derived myeloid colonies of CBA/CaJ mice exposed to 300 Me

  5. Kinetics of Neutrophils in Mice Exposed to Radiation and/or Granulocyte Colony-Stimulating Factor Treatment

    PubMed Central

    Romero-Weaver, A. L.; Wan, X. S.; Diffenderfer, E. S.; Lin, L.; Kennedy, A. R.

    2014-01-01

    Astronauts have the potential to develop the hematopoietic syndrome as a result of exposure to radiation from a solar particle event (SPE) during exploration class missions. This syndrome is characterized by a reduction in the number of circulating blood cells (cytopenias). In the present study the effects of SPE-like proton and γ radiation on the kinetics of circulating neutrophils were evaluated during a one-month time period using mice as a model system. The results revealed that exposure to a 2 Gy dose of either SPE-like proton or γ radiation significantly decreased the number of circulating neutrophils, with two nadirs observed on day 4 and day 16 postirradiation. Low circulating neutrophil count (neutropenia) is particularly important because it can increase the risk of astronauts developing infections, which can compromise the success of the mission. Thus, two granulocyte colony-stimulating factors (G-CSFs), filgrastim and pegfilgrastim were evaluated as countermeasures for this endpoint. Both forms of G-CSF significantly increased neutrophil counts in irradiated mice, however, the effect of pegfilgrastim was more potent and lasted longer than filgrastim. Using the expression of CD11b, CD18 and the production of reactive oxygen species (ROS) as markers of neutrophil activation, it was determined that the neutrophils in the irradiated mice treated with pegfilgrastim were physiologically active. Thus, these results suggest that pegfilgrastim could be a potential countermeasure for the reduced number of circulating neutrophils in irradiated animals. PMID:23829559

  6. Effect of tea (Camellia sinensis) and olive (Olea europaea L.) leaves extracts on male mice exposed to diazinon.

    PubMed

    Al-Attar, Atef M; Abu Zeid, Isam M

    2013-01-01

    The present study was aimed to evaluate the effects of tea and olive leaves extracts and their combination in male mice intoxicated with a sublethal concentration of diazinon. Exposure of mice to 6.5 mg/kg body weight of diazinon for seven weeks resulted in statistical increases of serum alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, alkaline phosphatase, creatine kinase, creatinine, glucose, triglycerides, and cholesterol, while the value of serum total protein was declined. Treating diazinon-intoxicated mice with tea and olive leaves extracts or their combination significantly attenuated the severe alterations in these hematobiochemical parameters. Moreover, the results indicated that the supplementation with combination of tea and olive leaves extracts led to more attenuation effect against diazinon toxicity. Additionally, these new findings suggest that the effect of tea and olive leaves extracts and their combination against toxicity of diazinon may be due to antioxidant properties of their chemical constituents. Finally, the present study indicated that the extracts of tea and olive leaves and their combination can be considered as promising therapeutic agents against hepatotoxicity, cardiotoxicity, nephrotoxicity, and metabolic disorders induced by diazinon and maybe by other toxicants and pathogenic factors. PMID:23691503

  7. Epimedium flavonoids ameliorate neuropathological changes and increases IGF-1 expression in C57BL/6 mice exposed to cuprizone.

    PubMed

    Liang, Mengru; Chen, Yongyan; Zhang, Li; Li, Lin; Chen, Guangliang; Yin, Linlin

    2015-03-01

    The cuprizone (CPZ)-induced toxic demyelinating model, characterized by the degeneration of oligodendrocytes, has been utilized to study multiple sclerosis-related lesions. The present study was designed to determine the effect of epimedium flavonoids (EF), the main component extracted from Epimedium sagittatum, on CPZ-induced neuropathological changes in the corpus callosum of C57BL/6 mice. Once we determined an EF-based protective effect on the corpus callosum, we sought to explore the underlying mechanism of this protection. To induce demyelination, 8-week-old mice were fed with 0.2% CPZ for a maximum period of 6 weeks. EF treatment for a period of 3 weeks effectively decreased the breakdown of myelin, OL loss, and oligodendrocyte precursor cell accumulation in CPZ-fed mice. In addition, EF administration significantly increased the cortical expression level of insulin-like growth factor 1 (IGF-1). This study provides the first in vivo evidence of EF-based protection against CPZ-induced neuropathological changes. Furthermore, our study suggests that upregulated IGF-1 may play a role in this protection. PMID:25663299

  8. Topical AC-11 abates actinic keratoses and early squamous cell cancers in hairless mice exposed to Ultraviolet A (UVA) radiation.

    PubMed

    Mentor, Julian M; Etemadi, Amir; Patta, Abrienne M; Scheinfeld, Noah

    2015-04-01

    AC-11 is an aqueous extract of the botanical, Uncaria tomentosa, which has a variety of effects that enhance DNA repair and down regulate inflammation. AC-11 is essentially free of oxindole alkaloids (< 0.05%, w/w) but contains more than 8% carboxy alkyl esters (CAEs) as their active ingredients. Three groups of 10 outbred SK-1 hairless or SK-II hairless strains of mice each were treated with AC-11 at 0.5%, 1.5%, and 3.0% in a non-irritating, dye-free, perfume-free, and fragrance-free vanishing cream vehicle. Ten mice used vehicle only and 10 were untreated. Each concentration of AC-11 and was applied daily to the backs of the mice prior to exposure to a 1,600-watt solar simulator used in this work (Solar Light Co. Philadelphia, PA) emitting (mainly Ultraviolet A (UVA) and B (UVB) radiation) duration of the experimental period with UVB wavelengths was filtered out with a 1.0 cm Schott WG 345 filter. AC-11 with a peak absorption at 200nm does act as a sun block. We tested for and focused on clinical appearance of mice and histological appearance of tumors in mice rather than metrics of radiation generated inflammation. Tumor progression scores were assigned as follows: 4+ = extensive tumor development; 3+ = early malignancies (raised palpable plaques)(early squamous cell cancers) 2+ = firm scaling, palpable keratosis (actinic keratoses); 1+ = light scaling with erythema. Following a total cumulative dose of 738 J/cm2, 85.7% all of the irradiated control animals, which did not receive AC-11 had precancerous actinic keratosis (AK)-type lesions (2+) (64.3% versus 42.9%) or early squamous cell carcinoma (SCC) (3+) (21.4% vs. 4.8%), in comparison with 47.7 % of AC-11-treated animals. There were no significant differences between the AC-11 groups. Three months after cessation of exposure to UVA radiation, the lesions in all but three of the 14 animals which were treated with AC-11 that were still evaluable irradiated with UVA radiation progressed to papillomas and frank

  9. Effects of Dietary Antioxidant Supplementation on the Development of Malignant Lymphoma and Other Neoplastic Lesions in Mice Exposed to Proton or Iron-Ion Radiation

    PubMed Central

    Kennedy, Ann R.; Davis, James G.; Carlton, William; Ware, Jeffrey H.

    2013-01-01

    Malignancy is considered to be a particular risk associated with exposure to the types of ionizing radiation encountered during extended space flight. In the present study, two dietary preparations were evaluated for their ability to prevent carcinogenesis in CBA mice exposed to different forms of space radiation: protons and highly energetic heavy particles (HZE particles). One preparation contained a mixture of antioxidant agents. The other contained the soybean-derived Bowman-Birk protease inhibitor (BBI), used in the form of BBI Concentrate (BBIC). The major finding was that there was a reduced risk of developing malignant lymphoma in animals exposed to space radiation and maintained on diets containing the antioxidant formulation or BBIC compared to the irradiated animals maintained on the control diet. In addition, the two different dietary countermeasures also reduced the yields of a variety of different rare tumor types observed in the animals exposed to space radiation. These results suggest that dietary supplements could be useful in the prevention of malignancies and other neoplastic lesions developing from exposure to space radiation. PMID:18494549

  10. 1H NMR Metabolomics Study of Spleen from C57BL/6 Mice Exposed to Gamma Radiation

    PubMed Central

    Xiao, X; Hu, M; Liu, M; Hu, JZ

    2016-01-01

    Due to the potential risk of accidental exposure to gamma radiation, it’s critical to identify the biomarkers of radiation exposed creatures. In the present study, NMR based metabolomics combined with multivariate data analysis to evaluate the metabolites changed in the C57BL/6 mouse spleen after 4 days whole body exposure to 3.0 Gy and 7.8 Gy gamma radiations. Principal component analysis (PCA) and orthogonal projection to latent structures analysis (OPLS) are employed for classification and identification potential biomarkers associated with gamma irradiation. Two different strategies for NMR spectral data reduction (i.e., spectral binning and spectral deconvolution) are combined with normalize to constant sum and unit weight before multivariate data analysis, respectively. The combination of spectral deconvolution and normalization to unit weight is the best way for identifying discriminatory metabolites between the irradiation and control groups. Normalized to the constant sum may achieve some pseudo biomarkers. PCA and OPLS results shown that the exposed groups can be well separated from the control group. Leucine, 2-aminobutyrate, valine, lactate, arginine, glutathione, 2-oxoglutarate, creatine, tyrosine, phenylalanine, π-methylhistidine, taurine, myoinositol, glycerol and uracil are significantly elevated while ADP is decreased significantly. These significantly changed metabolites are associated with multiple metabolic pathways and may be potential biomarkers in the spleen exposed to gamma irradiation. PMID:27019763

  11. Defensive Effect of Lansoprazole in Dementia of AD Type in Mice Exposed to Streptozotocin and Cholesterol Enriched Diet

    PubMed Central

    Sodhi, Rupinder K.; Singh, Nirmal

    2013-01-01

    The present study investigates the potential of lansoprazole (a proton pump inhibitor and agonist of liver x receptors) in experimental dementia of AD type. Streptozotocin [STZ, 3 mg/kg, injected intracerebroventricular (i.c.v), and high fat diet (HFD, administered for 90 days)] were used to induce dementia in separate groups of Swiss mice. Morris water maze (MWM) test was performed to assess learning and memory of the animals. A battery of biochemical and histopathological studies were also performed. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and HFD produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH levels. Further, the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. Lansoprazole treatment significantly attenuated STZ and HFD -induced memory deficits, biochemical and histopathological alterations. It also prevented HFD-induced rise in the cholesterol level. Therefore, the findings demonstrate potential of lansoprazole in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory effects. Moreover, both cholesterol-dependent as well as cholesterol-independent effects of lansoprazole appear to play a role. In addition study indicates the role of liver x receptors in dementia. PMID:23936214

  12. INTERPRETATION OF THE CANCER RESPONSE TO POTENTIAL RENTAL CARCINOGENS IN THE TSC2 KNOCKOUT (EKER) RAT IS DEPENDENT ON LENGTH OF TREATMENT.

    EPA Science Inventory

    INTERPRETATION OF THE CANCER RESPONSE TO POTENTIAL RENAL CARCINOGENS IN THE TSC2 KNOCKOUT (EKER) RAT IS DEPENDENT ON LENGTH OF TREATMENT.

    Genetically increasing the function of oncogenes or knocking out the function of a tumor supressor gene has dramatically increased the...

  13. CDRI-08 Attenuates REST/NRSF-Mediated Expression of NMDAR1 Gene in PBDE-209-Exposed Mice Brain

    PubMed Central

    Verma, Priya; Gupta, Rajaneesh K.; Gandhi, Behrose S.; Singh, Poonam

    2015-01-01

    CDRI-08 is a standardized bacoside enriched ethanolic extract of Bacopa monnieri, a nootropic plant. We reported that CDRI-08 attenuated oxidative stress and memory impairment in mice, induced by a flame retardant, PBDE-209. In order to explore the mechanism, present study was designed to examine the role of CDRI-08 on the expression of NMDAR1 (NR1) and the binding of REST/NRSF to NR1 promoter against postnatal exposure of PBDE-209. Male mice pups were orally supplemented with CDRI-08 at the doses of 40, 80, or 120 mg/kg along with PBDE-209 (20 mg/kg) during PND 3–10 and frontal cortex and hippocampus were collected at PND 11 and 60 to study the expression and regulation of NR1 by RT-PCR and electrophoretic mobility shift assay, respectively. The findings showed upregulated expression of NR1 and decreased binding of REST/NRSF to NR1 promoter after postnatal exposure of PBDE-209. Interestingly, supplementation with CDRI-08 significantly restored the expression of NR1 and binding of REST/NRSF to NR1 promoter near to the control value at the dose of 120 mg/kg. In conclusion, the results suggest that CDRI-08 possibly acts on glutamatergic system through expression and regulation of NR1 and may restore memory, impaired by PBDE-209 as reported in our previous study. PMID:26413122

  14. Construction of Vapor Chambers Used to Expose Mice to Alcohol During the Equivalent of all Three Trimesters of Human Development

    PubMed Central

    Morton, Russell A.; Diaz, Marvin R.; Topper, Lauren A.; Valenzuela, C. Fernando

    2014-01-01

    Exposure to alcohol during development can result in a constellation of morphological and behavioral abnormalities that are collectively known as Fetal Alcohol Spectrum Disorders (FASDs). At the most severe end of the spectrum is Fetal Alcohol Syndrome (FAS), characterized by growth retardation, craniofacial dysmorphology, and neurobehavioral deficits. Studies with animal models, including rodents, have elucidated many molecular and cellular mechanisms involved in the pathophysiology of FASDs. Ethanol administration to pregnant rodents has been used to model human exposure during the first and second trimesters of pregnancy. Third trimester ethanol consumption in humans has been modeled using neonatal rodents. However, few rodent studies have characterized the effect of ethanol exposure during the equivalent to all three trimesters of human pregnancy, a pattern of exposure that is common in pregnant women. Here, we show how to build vapor chambers from readily obtainable materials that can each accommodate up to six standard mouse cages. We describe a vapor chamber paradigm that can be used to model exposure to ethanol, with minimal handling, during all three trimesters. Our studies demonstrate that pregnant dams developed significant metabolic tolerance to ethanol. However, neonatal mice did not develop metabolic tolerance and the number of fetuses, fetus weight, placenta weight, number of pups/litter, number of dead pups/litter, and pup weight were not significantly affected by ethanol exposure. An important advantage of this paradigm is its applicability to studies with genetically-modified mice. Additionally, this paradigm minimizes handling of animals, a major confound in fetal alcohol research. PMID:25046568

  15. Construction of vapor chambers used to expose mice to alcohol during the equivalent of all three trimesters of human development.

    PubMed

    Morton, Russell A; Diaz, Marvin R; Topper, Lauren A; Valenzuela, C Fernando

    2014-01-01

    Exposure to alcohol during development can result in a constellation of morphological and behavioral abnormalities that are collectively known as Fetal Alcohol Spectrum Disorders (FASDs). At the most severe end of the spectrum is Fetal Alcohol Syndrome (FAS), characterized by growth retardation, craniofacial dysmorphology, and neurobehavioral deficits. Studies with animal models, including rodents, have elucidated many molecular and cellular mechanisms involved in the pathophysiology of FASDs. Ethanol administration to pregnant rodents has been used to model human exposure during the first and second trimesters of pregnancy. Third trimester ethanol consumption in humans has been modeled using neonatal rodents. However, few rodent studies have characterized the effect of ethanol exposure during the equivalent to all three trimesters of human pregnancy, a pattern of exposure that is common in pregnant women. Here, we show how to build vapor chambers from readily obtainable materials that can each accommodate up to six standard mouse cages. We describe a vapor chamber paradigm that can be used to model exposure to ethanol, with minimal handling, during all three trimesters. Our studies demonstrate that pregnant dams developed significant metabolic tolerance to ethanol. However, neonatal mice did not develop metabolic tolerance and the number of fetuses, fetus weight, placenta weight, number of pups/litter, number of dead pups/litter, and pup weight were not significantly affected by ethanol exposure. An important advantage of this paradigm is its applicability to studies with genetically-modified mice. Additionally, this paradigm minimizes handling of animals, a major confound in fetal alcohol research. PMID:25046568

  16. Induction of Chronic Inflammation and Altered Levels of DNA Hydroxymethylation in Somatic and Germinal Tissues of CBA/CaJ Mice Exposed to (48)Ti Ions.

    PubMed

    Rithidech, Kanokporn Noy; Jangiam, Witawat; Tungjai, Montree; Gordon, Chris; Honikel, Louise; Whorton, Elbert B

    2016-01-01

    Although the lung is one of the target organs at risk for cancer induction from exposure to heavy ions found in space, information is insufficient on cellular/molecular responses linked to increased cancer risk. Knowledge of such events may aid in the development of new preventive measures. Furthermore, although it is known that germinal cells are sensitive to X- or γ-rays, there is little information on the effects of heavy ions on germinal cells. Our goal was to investigate in vivo effects of 1 GeV/n (48)Ti ions (one of the important heavy ions found in the space environment) on somatic (lung) and germinal (testis) tissues collected at various times after a whole body irradiation of CBA/CaJ mice (0, 0.1, 0.25, or 0.5 Gy, delivered at 1 cGy/min). We hypothesized that (48)Ti-ion-exposure induced damage in both tissues. Lung tissue was collected from each mouse from each treatment group at 1 week, 1 month, and 6 months postirradiation. For the testis, we collected samples at 6 months postirradiation. Hence, only late-occurring effects of (48)Ti ions in the testis were studied. There were five mice per treatment group at each harvest time. We investigated inflammatory responses after exposure to (48)Ti ions by measuring the levels of activated nuclear factor kappa B and selected pro-inflammatory cytokines in both tissues of the same mouse. These measurements were coupled with the quantitation of the levels of global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Our data clearly showed the induction of chronic inflammation in both tissues of exposed mice. A dose-dependent reduction in global 5hmC was found in the lung at all time-points and in testes collected at 6 months postirradiation. In contrast, significant increases in global 5mC were found only in lung and testes collected at 6 months postirradiation from mice exposed to 0.5 Gy of 1 GeV/n (48)Ti ions. Overall, our data showed that (48)Ti ions may create health risks in both

  17. Induction of Chronic Inflammation and Altered Levels of DNA Hydroxymethylation in Somatic and Germinal Tissues of CBA/CaJ Mice Exposed to 48Ti Ions

    PubMed Central

    Rithidech, Kanokporn Noy; Jangiam, Witawat; Tungjai, Montree; Gordon, Chris; Honikel, Louise; Whorton, Elbert B.

    2016-01-01

    Although the lung is one of the target organs at risk for cancer induction from exposure to heavy ions found in space, information is insufficient on cellular/molecular responses linked to increased cancer risk. Knowledge of such events may aid in the development of new preventive measures. Furthermore, although it is known that germinal cells are sensitive to X- or γ-rays, there is little information on the effects of heavy ions on germinal cells. Our goal was to investigate in vivo effects of 1 GeV/n 48Ti ions (one of the important heavy ions found in the space environment) on somatic (lung) and germinal (testis) tissues collected at various times after a whole body irradiation of CBA/CaJ mice (0, 0.1, 0.25, or 0.5 Gy, delivered at 1 cGy/min). We hypothesized that 48Ti-ion-exposure induced damage in both tissues. Lung tissue was collected from each mouse from each treatment group at 1 week, 1 month, and 6 months postirradiation. For the testis, we collected samples at 6 months postirradiation. Hence, only late-occurring effects of 48Ti ions in the testis were studied. There were five mice per treatment group at each harvest time. We investigated inflammatory responses after exposure to 48Ti ions by measuring the levels of activated nuclear factor kappa B and selected pro-inflammatory cytokines in both tissues of the same mouse. These measurements were coupled with the quantitation of the levels of global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Our data clearly showed the induction of chronic inflammation in both tissues of exposed mice. A dose-dependent reduction in global 5hmC was found in the lung at all time-points and in testes collected at 6 months postirradiation. In contrast, significant increases in global 5mC were found only in lung and testes collected at 6 months postirradiation from mice exposed to 0.5 Gy of 1 GeV/n 48Ti ions. Overall, our data showed that 48Ti ions may create health risks in both lung and

  18. Piper betle induces phase I & II genes through Nrf2/ARE signaling pathway in mouse embryonic fibroblasts derived from wild type and Nrf2 knockout cells

    PubMed Central

    2014-01-01

    Background Nuclear factor-erythroid 2 p45 related factor 2 (Nrf2) is a primary transcription factor, protecting cells from oxidative stress by regulating a number of antioxidants and phase II detoxifying enzymes. Dietary components such as sulforaphane in broccoli and quercetin in onions have been shown to be inducers of Nrf2. Piper betle (PB) grows well in tropical climate and the leaves are used in a number of traditional remedies for the treatment of stomach ailments and infections among Asians. The aim of this study was to elucidate the effect of Piper betle (PB) leaves extract in Nrf2 signaling pathway by using 2 types of cells; mouse embryonic fibroblasts (MEFs) derived from wild-type (WT) and Nrf2 knockout (N0) mice. Methods WT and N0 cells were treated with 5 and 10 μg/ml of PB for 10 and 12-h for the determination of nuclear translocation of Nrf2 protein. Luciferase reporter gene activity was performed to evaluate the antioxidant response element (ARE)-induction by PB. Real-time PCR and Western blot were conducted on both WT and N0 cells after PB treatment for the determination of antioxidant enzymes [superoxide dismutase (SOD1) and heme-oxygenase (HO-1)], phase I oxidoreductase enzymes [NAD(P)H: quinone oxidoreductase (NQO1)] and phase II detoxifying enzyme [glutathione S-transferase (GST)]. Results Nuclear translocation of Nrf2 by PB in WT cells was better after 10 h incubation compared to 12 h. Real time PCR and Western blot analysis showed increased expressions of Nrf2, NQO1 and GSTA1 genes with corresponding increases in glutathione, NQO1 and HO-1 proteins in WT cells. Reporter gene ARE was stimulated by PB as shown by ARE/luciferase assay. Interestingly, PB induced SOD1 gene and protein expressions in N0 cells but not in WT cells. Conclusion The results of this study confirmed that PB activated Nrf2-ARE signaling pathway which subsequently induced some phase I oxidoreductase, phase II detoxifying and antioxidant genes expression via ARE reporter

  19. Slight respiratory irritation but not inflammation in mice exposed to (1-->3)-beta-D-glucan aerosols.

    PubMed Central

    Korpi, A; Kasanen, J-P; Kosma, V-M; Rylander, R; Pasanen, A-L

    2003-01-01

    Airway irritation effects after single and repeated inhalation exposures to aerosols of beta-glucan (grifolan) were investigated in mice. In addition, the effects on serum total immunoglobulin E (IgE) production and histopathological inflammation in the respiratory tract were studied. The beta-glucan aerosols provoked slight sensory irritation in the airways, but the response was not concentration dependent at the levels studied. Slight pulmonary irritation was observed after repeated exposures. No effect was found on the serum total IgE levels, and no signs of inflammation were seen in the airways 6 h after the final exposure. The results suggest that, irrespective of previous fungal sensitization of the animals, inhaled beta-glucan may cause symptoms of respiratory tract irritation but without apparent inflammation. Respiratory tract irritation reported after inhalation of fungi may not be entirely attributed to beta-glucan. PMID:12857597

  20. Patchy deletion of Bmpr1a potentiates proximal pulmonary artery remodeling in mice exposed to chronic hypoxia

    PubMed Central

    Vanderpool, Rebecca R.; El-Bizri, Nesrine; Rabinovitch, Marlene; Chesler, Naomi C

    2012-01-01

    Reduced vascular expression of bone morphogenetic type IA receptor (Bmpr1a) has been found in patients with pulmonary arterial hypertension (PAH). Our previous studies in mice with patchy deletion of Bmpr1a in vascular smooth muscle cells and cardiac myocytes showed decreased distal vascular remodeling despite a similar severity of hypoxic pulmonary hypertension (HPH). We speculate increased stiffness from ectopic deposition of collagen in proximal pulmonary arteries (PAs) might account for HPH. Pulsatile pressure-flow relationships were measured in isolated, ventilated, perfused lungs of SM22α;TRE-Cre;R26R;Bmpr1aflox/flox (KO) mice and wild-type (WT) littermates following 21 days (hypoxia) and 0 days (control) of chronic hypoxia. Pulmonary vascular impedance, which yields insight into proximal and distal arterial remodeling, was calculated. Reduced Bmpr1a expression had no effect on input impedance Z0 (P=0.52) or characteristic impedance ZC (P=0.18) under control conditions; it also had no effect on the decrease in Z0 via acute rho kinase inhibition. However, following chronic hypoxia, reduced Bmpr1a expression increased ZC (P<0.001) without affecting Z0 (P=0.72). These results demonstrate that Bmpr1a deficiency does not significantly alter the hemodynamic function of the distal vasculature or its response to chronic hypoxia but larger, more proximal arteries are affected. In particular, reduced Bmpr1a expression likely decreased dilatation and increased stiffening in response to hypoxia, probably by collagen accumulation. Increased PA stiffness can have a significant impact on right ventricular function. This study illustrates for the first time how proximal pulmonary artery changes in the absence of distal pulmonary artery changes contribute to pulmonary hypertension. PMID:22314711

  1. Detection of differential DNA methylation in repetitive DNA of mice and humans perinatally exposed to bisphenol A

    PubMed Central

    Faulk, Christopher; Kim, Jung H.; Anderson, Olivia S.; Nahar, Muna S.; Jones, Tamara R.; Sartor, Maureen A.; Dolinoy, Dana C.

    2016-01-01

    ABSTRACT Developmental exposure to bisphenol A (BPA) has been shown to induce changes in DNA methylation in both mouse and human genic regions; however, the response in repetitive elements and transposons has not been explored. Here we present novel methodology to combine genomic DNA enrichment with RepeatMasker analysis on next-generation sequencing data to determine the effect of perinatal BPA exposure on repetitive DNA at the class, family, subfamily, and individual insertion level in both mouse and human samples. Mice were treated during gestation and lactation to BPA in chow at 0, 50, or 50,000 ng/g levels and total BPA was measured in stratified human fetal liver tissue samples as low (non-detect to 0.83 ng/g), medium (3.5 to 5.79 ng/g), or high (35.44 to 96.76 ng/g). Transposon methylation changes were evident in human classes, families, and subfamilies, with the medium group exhibiting hypomethylation compared to both high and low BPA groups. Mouse repeat classes, families, and subfamilies did not respond to BPA with significantly detectable differential DNA methylation. In human samples, 1251 individual transposon loci were detected as differentially methylated by BPA exposure, but only 19 were detected in mice. Of note, this approach recapitulated the discovery of a previously known mouse environmentally labile metastable epiallele, CabpIAP. Thus, by querying repetitive DNA in both mouse and humans, we report the first known transposons in humans that respond to perinatal BPA exposure. PMID:27267941

  2. Detection of differential DNA methylation in repetitive DNA of mice and humans perinatally exposed to bisphenol A.

    PubMed

    Faulk, Christopher; Kim, Jung H; Anderson, Olivia S; Nahar, Muna S; Jones, Tamara R; Sartor, Maureen A; Dolinoy, Dana C

    2016-07-01

    Developmental exposure to bisphenol A (BPA) has been shown to induce changes in DNA methylation in both mouse and human genic regions; however, the response in repetitive elements and transposons has not been explored. Here we present novel methodology to combine genomic DNA enrichment with RepeatMasker analysis on next-generation sequencing data to determine the effect of perinatal BPA exposure on repetitive DNA at the class, family, subfamily, and individual insertion level in both mouse and human samples. Mice were treated during gestation and lactation to BPA in chow at 0, 50, or 50,000 ng/g levels and total BPA was measured in stratified human fetal liver tissue samples as low (non-detect to 0.83 ng/g), medium (3.5 to 5.79 ng/g), or high (35.44 to 96.76 ng/g). Transposon methylation changes were evident in human classes, families, and subfamilies, with the medium group exhibiting hypomethylation compared to both high and low BPA groups. Mouse repeat classes, families, and subfamilies did not respond to BPA with significantly detectable differential DNA methylation. In human samples, 1251 individual transposon loci were detected as differentially methylated by BPA exposure, but only 19 were detected in mice. Of note, this approach recapitulated the discovery of a previously known mouse environmentally labile metastable epiallele, Cabp(IAP). Thus, by querying repetitive DNA in both mouse and humans, we report the first known transposons in humans that respond to perinatal BPA exposure. PMID:27267941

  3. Pulmonary inflammation and tumor induction in lung tumor susceptible A/J and resistant C57BL/6J mice exposed to welding fume

    PubMed Central

    Zeidler-Erdely, Patti C; Kashon, Michael L; Battelli, Lori A; Young, Shih-Houng; Erdely, Aaron; Roberts, Jenny R; Reynolds, Steven H; Antonini, James M

    2008-01-01

    Background Welding fume has been categorized as "possibly carcinogenic" to humans. Our objectives were to characterize the lung response to carcinogenic and non-carcinogenic metal-containing welding fumes and to determine if these fumes caused increased lung tumorigenicity in A/J mice, a lung tumor susceptible strain. We exposed male A/J and C57BL/6J, a lung tumor resistant strain, by pharyngeal aspiration four times (once every 3 days) to 85 μg of gas metal arc-mild steel (GMA-MS), GMA-stainless steel (SS), or manual metal arc-SS (MMA-SS) fume, or to 25.5 μg soluble hexavalent chromium (S-Cr). Shams were exposed to saline vehicle. Bronchoalveolar lavage (BAL) was done at 2, 7, and 28 days post-exposure. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 48 and 78 weeks post-exposure. Results BAL revealed notable strain-dependent differences with regards to the degree and resolution of the inflammatory response after exposure to the fumes. At 48 weeks, carcinogenic metal-containing GMA-SS fume caused the greatest increase in tumor multiplicity and incidence, but this was not different from sham. By 78 weeks, tumor incidence in the GMA-SS group versus sham approached significance (p = 0.057). A significant increase in perivascular/peribronchial lymphoid infiltrates for the GMA-SS group versus sham and an increased persistence of this fume in lung cells compared to the other welding fumes was found. Conclusion The increased persistence of GMA-SS fume in combination with its metal composition may trigger a chronic, but mild, inflammatory state in the lung possibly enhancing tumorigenesis in this susceptible mouse strain. PMID:18778475

  4. Metabolic Outcome of Female Mice Exposed to a Mixture of Low-Dose Pollutants in a Diet-Induced Obesity Model

    PubMed Central

    Naville, Danielle; Labaronne, Emmanuel; Vega, Nathalie; Pinteur, Claudie; Canet-Soulas, Emmanuelle; Vidal, Hubert; Le Magueresse-Battistoni, Brigitte

    2015-01-01

    Pollutants are suspected to contribute to the etiology of obesity and related metabolic disorders. Apart from occupational exposure which concerns a subset of chemicals, humans are mostly exposed to a large variety of chemicals, all life-long and at low doses. Food ingestion is a major route of exposure and it is suggested that pollutants have a worsened impact when combined with a high-fat diet. In the experimental studies described herein, we aimed to add further evidence on the metabolic impact of food pollutants using a recently set up model in which mice are life-long fed a high-fat/high-sucrose diet (HFSD) with/without common food pollutants shown to exhibit metabolic disrupting activities. Specifically, this mixture comprised bisphenol A, dioxin, polychlorobiphenyl PCB153, and phthalate and was added in HFSD at doses resulting in mice exposure at the Tolerable Daily Intake dose range for each pollutant. We herein focused on the 7-week-old females which exhibited early signs of obesity upon HFSD feeding. We observed no signs of toxicity and no additional weight gain following exposure to the mixture but alleviated HFSD-induced glucose intolerance in the absence of alteration of gluconeogenesis and steatosis. It suggested that the observed metabolic improvement was more likely due to effects on muscle and/or adipose tissues rather than on the liver. Consistently, female mice exhibited enhanced lean/fat mass ratio and skeletal muscle insulin sensitivity. Moreover, expression levels of inflammatory markers were reduced in adipose tissue at 7 but enhanced at 12 weeks of age in agreement with the inverse alterations of glucose tolerance observed at these ages upon pollutant exposure in the HFSD-fed females. Collectively, these data suggest apparent biphasic effects of pollutants upon HFSD feeding along with obesity development. These effects were not observed in males and may depend on interactions between diet and pollutants. PMID:25909471

  5. The neuropsychopharmacological effects of Catha edulis in mice offspring born to mothers exposed during pregnancy and lactation.

    PubMed

    Bedada, Worku; Engidawork, Ephrem

    2010-02-01

    Chewing fresh leaves of the khat plant (Catha edulis Forsk) is a deep rooted and widespread habit in East Africa and the Middle East. Although a body of knowledge exists about the adverse effects of khat during pregnancy, data are sparse with regard to the consequences of long-term exposure during pregnancy and lactation. The present work, therefore, was initiated to evaluate the neuropsychopharmacological effects of Catha edulis exposure during pregnancy and lactation in mice at postnatal day 28. To this effect, a lyophilized extract of khat (100 mg/kg, K100 and 200 mg/kg, K200), amphetamine (1 mg/kg, positive control, AMP), and a similar volume of 2% v/v Tween-80 in distilled water (negative control, CONT) were administered daily to pregnant mice from gestational day 6 until weaning. Neuropsychopharmacological measurements were done by making use of a battery of neurobehavioural and cognitive tests. Moreover, toxicity to liver and kidney was also evaluated by determining biochemical markers for possible tissue damage. K200 produced significant motor in-coordination and emotional instability; as revealed by impairment in both cliff avoidance (p < 0.01) and forelimb grip strength (p < 0.001), as well as by an increase in stereotyped behaviour such as grooming (p < 0.05), and in the percent of time spent in open arms (p < 0.05). On the other hand, K100 had an effect only on grip strength where a decrement was noted (p < 0.01). A different pattern emerged with AMP whilst it increased duration of sniffing (p < 0.05), neither grip strength nor the time spent in the open arm was affected compared with CONT. Increased latency to reach the goal box and the number of wrong decisions (p < 0.05) in both the learning and the recall tests was observed with K200 and AMP. By contrast, both doses of khat and AMP equally affected performance in the Y-maze (p < 0.05). Alterations in the biochemical indices of liver and kidney function were also noted with AMP and K200. These

  6. Antidepressant-like effects and memory enhancement of a herbal formula in mice exposed to chronic mild stress.

    PubMed

    Sun, Xiu-Ping; Li, Si-Di; Shi, Zhe; Li, Teng-Fei; Pan, Rui-Le; Chang, Qi; Qin, Chuan; Liu, Xin-Min

    2013-12-01

    Shen Yuan Gan (SYG) is a Chinese herbal prescription composed of total saponins of Panax ginseng and total oligosaccharide esters of Polygala tenuifolia (2:1). Our previous studies have demonstrated that SYG has antidepressant-like effects in various mouse models of behavioral depression. The present study aimed to test whether SYG affected chronic mild stress (CMS)-induced depression and cognitive impairment in mice. We found that a 5-week CMS schedule induced significant degradation of the coat state, decreased sucrose intake in the sucrose-preference test, and increased the latency to feed in the noveltysuppressed feeding test. All of these CMS-induced changes were ameliorated by SYG (100 and 200 mg/kg) and fluoxetine (10 mg/kg). In addition, SYG restored the decreased monoamine neurotransmitter concentrations (serotonin, dopamine, norepinephrine and acetylcholine) induced by CMS in the prefrontal cortex. Interestingly, SYG ameliorated CMS-induced cognitive impairment in the step-through test, and increased the acetylcholine level in the prefrontal cortex. These results suggest that SYG has an antidepressant-like action and enhances cognition by modulating the serotonin, dopamine, norepinephrine, and acetylcholine levels in the prefrontal cortex. PMID:24132797

  7. Lead induces similar gene expression changes in brains of gestationally exposed adult mice and in neurons differentiated from mouse embryonic stem cells.

    PubMed

    Sánchez-Martín, Francisco Javier; Fan, Yunxia; Lindquist, Diana M; Xia, Ying; Puga, Alvaro

    2013-01-01

    Exposure to environmental toxicants during embryonic life causes changes in the expression of developmental genes that may last for a lifetime and adversely affect the exposed individual. Developmental exposure to lead (Pb), an ubiquitous environmental contaminant, causes deficits in cognitive functions and IQ, behavioral effects, and attention deficit hyperactivity disorder (ADHD). Long-term effects observed after early life exposure to Pb include reduction of gray matter, alteration of myelin structure, and increment of criminal behavior in adults. Despite growing research interest, the molecular mechanisms responsible for the effects of lead in the central nervous system are still largely unknown. To study the molecular changes due to Pb exposure during neurodevelopment, we exposed mice to Pb in utero and examined the expression of neural markers, neurotrophins, transcription factors and glutamate-related genes in hippocampus, cortex, and thalamus at postnatal day 60. We found that hippocampus was the area where gene expression changes due to Pb exposure were more pronounced. To recapitulate gestational Pb exposure in vitro, we differentiated mouse embryonic stem cells (ESC) into neurons and treated ESC-derived neurons with Pb for the length of the differentiation process. These neurons expressed the characteristic neuronal markers Tubb3, Syp, Gap43, Hud, Ngn1, Vglut1 (a marker of glutamatergic neurons), and all the glutamate receptor subunits, but not the glial marker Gafp. Importantly, several of the changes observed in Pb-exposed mouse brains in vivo were also observed in Pb-treated ESC-derived neurons, including those affecting expression of Ngn1, Bdnf exon IV, Grin1, Grin2D, Grik5, Gria4, and Grm6. We conclude that our ESC-derived model of toxicant exposure during neural differentiation promises to be a useful model to analyze mechanisms of neurotoxicity induced by Pb and other environmental agents. PMID:24260418

  8. Lead Induces Similar Gene Expression Changes in Brains of Gestationally Exposed Adult Mice and in Neurons Differentiated from Mouse Embryonic Stem Cells

    PubMed Central

    Sánchez-Martín, Francisco Javier; Fan, Yunxia; Lindquist, Diana M.; Xia, Ying; Puga, Alvaro

    2013-01-01

    Exposure to environmental toxicants during embryonic life causes changes in the expression of developmental genes that may last for a lifetime and adversely affect the exposed individual. Developmental exposure to lead (Pb), an ubiquitous environmental contaminant, causes deficits in cognitive functions and IQ, behavioral effects, and attention deficit hyperactivity disorder (ADHD). Long-term effects observed after early life exposure to Pb include reduction of gray matter, alteration of myelin structure, and increment of criminal behavior in adults. Despite growing research interest, the molecular mechanisms responsible for the effects of lead in the central nervous system are still largely unknown. To study the molecular changes due to Pb exposure during neurodevelopment, we exposed mice to Pb in utero and examined the expression of neural markers, neurotrophins, transcription factors and glutamate-related genes in hippocampus, cortex, and thalamus at postnatal day 60. We found that hippocampus was the area where gene expression changes due to Pb exposure were more pronounced. To recapitulate gestational Pb exposure in vitro, we differentiated mouse embryonic stem cells (ESC) into neurons and treated ESC-derived neurons with Pb for the length of the differentiation process. These neurons expressed the characteristic neuronal markers Tubb3, Syp, Gap43, Hud, Ngn1, Vglut1 (a marker of glutamatergic neurons), and all the glutamate receptor subunits, but not the glial marker Gafp. Importantly, several of the changes observed in Pb-exposed mouse brains in vivo were also observed in Pb-treated ESC-derived neurons, including those affecting expression of Ngn1, Bdnf exon IV, Grin1, Grin2D, Grik5, Gria4, and Grm6. We conclude that our ESC-derived model of toxicant exposure during neural differentiation promises to be a useful model to analyze mechanisms of neurotoxicity induced by Pb and other environmental agents. PMID:24260418

  9. Evaluation of Gene, Protein and Neurotrophin Expression in the Brain of Mice Exposed to Space Environment for 91 Days

    PubMed Central

    Santucci, Daniela; Kawano, Fuminori; Ohira, Takashi; Terada, Masahiro; Nakai, Naoya; Francia, Nadia; Alleva, Enrico; Aloe, Luigi; Ochiai, Toshimasa; Cancedda, Ranieri; Goto, Katsumasa; Ohira, Yoshinobu

    2012-01-01

    Effects of 3-month exposure to microgravity environment on the expression of genes and proteins in mouse brain were studied. Moreover, responses of neurobiological parameters, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), were also evaluated in the cerebellum, hippocampus, cortex, and adrenal glands. Spaceflight-related changes in gene and protein expression were observed. Biological processes of the up-regulated genes were related to the immune response, metabolic process, and/or inflammatory response. Changes of cellular components involving in microsome and vesicular fraction were also noted. Molecular function categories were related to various enzyme activities. The biological processes in the down-regulated genes were related to various metabolic and catabolic processes. Cellular components were related to cytoplasm and mitochondrion. The down-regulated molecular functions were related to catalytic and oxidoreductase activities. Up-regulation of 28 proteins was seen following spaceflight vs. those in ground control. These proteins were related to mitochondrial metabolism, synthesis and hydrolysis of ATP, calcium/calmodulin metabolism, nervous system, and transport of proteins and/or amino acids. Down-regulated proteins were related to mitochondrial metabolism. Expression of NGF in hippocampus, cortex, and adrenal gland of wild type animal tended to decrease following spaceflight. As for pleiotrophin transgenic mice, spaceflight-related reduction of NGF occured only in adrenal gland. Consistent trends between various portions of brain and adrenal gland were not observed in the responses of BDNF to spaceflight. Although exposure to real microgravity influenced the expression of a number of genes and proteins in the brain that have been shown to be involved in a wide spectrum of biological function, it is still unclear how the functional properties of brain were influenced by 3-month exposure to microgravity. PMID:22808101

  10. Oxidative stress, inflammation, and DNA damage in multiple organs of mice acutely exposed to amorphous silica nanoparticles

    PubMed Central

    Nemmar, Abderrahim; Yuvaraju, Priya; Beegam, Sumaya; Yasin, Javed; Kazzam, Elsadig E; Ali, Badreldin H

    2016-01-01

    The use of amorphous silica (SiO2) in biopharmaceutical and industrial fields can lead to human exposure by injection, skin penetration, ingestion, or inhalation. However, the in vivo acute toxicity of amorphous SiO2 nanoparticles (SiNPs) on multiple organs and the mechanisms underlying these effects are not well understood. Presently, we investigated the acute (24 hours) effects of intraperitoneally administered 50 nm SiNPs (0.25 mg/kg) on systemic toxicity, oxidative stress, inflammation, and DNA damage in the lung, heart, liver, kidney, and brain of mice. Lipid peroxidation was significantly increased by SiNPs in the lung, liver, kidney, and brain, but was not changed in the heart. Similarly, superoxide dismutase and catalase activities were significantly affected by SiNPs in all organs studied. While the concentration of tumor necrosis factor α was insignificantly increased in the liver and brain, its increase was statistically significant in the lung, heart, and kidney. SiNPs induced a significant elevation in pulmonary and renal interleukin 6 and interleukin-1 beta in the lung, liver, and brain. Moreover, SiNPs caused a significant increase in DNA damage, assessed by comet assay, in all the organs studied. SiNPs caused leukocytosis and increased the plasma activities of lactate dehydrogenase, creatine kinase, alanine aminotranferase, and aspartate aminotransferase. These results indicate that acute systemic exposure to SiNPs causes oxidative stress, inflammation, and DNA damage in several major organs, and highlight the need for thorough evaluation of SiNPs before they can be safely used in human beings. PMID:27022259

  11. Increased nitration and carbonylation of proteins in MRL +/+ mice exposed to trichloroethene: Potential role of protein oxidation in autoimmunity

    SciTech Connect

    Wang Gangduo; Wang Jianling; Ma Huaxian; Khan, M. Firoze

    2009-06-01

    Even though reactive oxygen and nitrogen species (RONS) are implicated as mediators of autoimmune diseases (ADs), little is known about contribution of protein oxidation (carbonylation and nitration) in the pathogenesis of such diseases. The focus of this study was, therefore, to establish a link between protein oxidation and induction and/or exacerbation of autoimmunity. To achieve this, female MRL +/+ mice were treated with trichloroethene (TCE), an environmental contaminant known to induce autoimmune response, for 6 or 12 weeks (10 mmol/kg, i.p., every 4{sup th} day). TCE treatment resulted in significantly increased formation of nitrotyrosine (NT) and induction of iNOS in the serum at both 6 and 12 weeks of treatment, but the response was greater at 12 weeks. Likewise, TCE treatment led to greater NT formation, and iNOS protein and mRNA expression in the livers and kidneys. Moreover, TCE treatment also caused significant increases ({approx}3 fold) in serum protein carbonyls (a marker of protein oxidation) at both 6 and 12 weeks. Significantly increased protein carbonyls were also observed in the livers and kidneys (2.1 and 1.3 fold, respectively) at 6 weeks, and to a greater extent at 12 weeks (3.5 and 2.1 fold, respectively) following TCE treatment. The increases in TCE-induced protein oxidation (carbonylation and nitration) were associated with significant increases in Th1 specific cytokine (IL-2, IFN-{gamma}) release into splenocyte cultures. These results suggest an association between protein oxidation and induction/exacerbation of autoimmune response. The results present a potential mechanism by which oxidatively modified proteins could contribute to TCE-induced autoimmune response and necessitates further investigations for clearly establishing the role of protein oxidation in the pathogenesis of ADs.

  12. Microglia are less pro-inflammatory than myeloid infiltrates in the hippocampus of mice exposed to status epilepticus.

    PubMed

    Vinet, Jonathan; Vainchtein, Ilia D; Spano, Carlotta; Giordano, Carmela; Bordini, Domenico; Curia, Giulia; Dominici, Massimo; Boddeke, Hendrikus W G M; Eggen, Bart J L; Biagini, Giuseppe

    2016-08-01

    Activated microglia, astrogliosis, expression of pro-inflammatory cytokines, blood brain barrier (BBB) leakage and peripheral immune cell infiltration are features of mesial temporal lobe epilepsy. Numerous studies correlated the expression of pro-inflammatory cytokines with the activated morphology of microglia, attributing them a pro-epileptogenic role. However, microglia and myeloid cells such as macrophages have always been difficult to distinguish due to an overlap in expressed cell surface molecules. Thus, the detrimental role in epilepsy that is attributed to microglia might be shared with myeloid infiltrates. Here, we used a FACS-based approach to discriminate between microglia and myeloid infiltrates isolated from the hippocampus 24 h and 96 h after status epilepticus (SE) in pilocarpine-treated CD1 mice. We observed that microglia do not express MHCII whereas myeloid infiltrates express high levels of MHCII and CD40 96 h after SE. This antigen-presenting cell phenotype correlated with the presence of CD4(pos) T cells. Moreover, microglia only expressed TNFα 24 h after SE while myeloid infiltrates expressed high levels of IL-1β and TNFα. Immunofluorescence showed that astrocytes but not microglia expressed IL-1β. Myeloid infiltrates also expressed matrix metalloproteinase (MMP)-9 and 12 while microglia only expressed MMP-12, suggesting the involvement of both cell types in the BBB leakage that follows SE. Finally, both cell types expressed the phagocytosis receptor Axl, pointing to phagocytosis of apoptotic cells as one of the main functions of microglia. Our data suggests that, during early epileptogenesis, microglia from the hippocampus remain rather immune supressed whereas myeloid infiltrates display a strong inflammatory profile. GLIA 2016 GLIA 2016;64:1350-1362. PMID:27246930

  13. Evaluation of gene, protein and neurotrophin expression in the brain of mice exposed to space environment for 91 days.

    PubMed

    Santucci, Daniela; Kawano, Fuminori; Ohira, Takashi; Terada, Masahiro; Nakai, Naoya; Francia, Nadia; Alleva, Enrico; Aloe, Luigi; Ochiai, Toshimasa; Cancedda, Ranieri; Goto, Katsumasa; Ohira, Yoshinobu

    2012-01-01

    Effects of 3-month exposure to microgravity environment on the expression of genes and proteins in mouse brain were studied. Moreover, responses of neurobiological parameters, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), were also evaluated in the cerebellum, hippocampus, cortex, and adrenal glands. Spaceflight-related changes in gene and protein expression were observed. Biological processes of the up-regulated genes were related to the immune response, metabolic process, and/or inflammatory response. Changes of cellular components involving in microsome and vesicular fraction were also noted. Molecular function categories were related to various enzyme activities. The biological processes in the down-regulated genes were related to various metabolic and catabolic processes. Cellular components were related to cytoplasm and mitochondrion. The down-regulated molecular functions were related to catalytic and oxidoreductase activities. Up-regulation of 28 proteins was seen following spaceflight vs. those in ground control. These proteins were related to mitochondrial metabolism, synthesis and hydrolysis of ATP, calcium/calmodulin metabolism, nervous system, and transport of proteins and/or amino acids. Down-regulated proteins were related to mitochondrial metabolism. Expression of NGF in hippocampus, cortex, and adrenal gland of wild type animal tended to decrease following spaceflight. As for pleiotrophin transgenic mice, spaceflight-related reduction of NGF occurred only in adrenal gland. Consistent trends between various portions of brain and adrenal gland were not observed in the responses of BDNF to spaceflight. Although exposure to real microgravity influenced the expression of a number of genes and proteins in the brain that have been shown to be involved in a wide spectrum of biological function, it is still unclear how the functional properties of brain were influenced by 3-month exposure to microgravity. PMID:22808101

  14. Hepatic immunophenotyping for streptozotocin-induced hyperglycemia in mice

    PubMed Central

    Lee, Young-Sun; Eun, Hyuk Soo; Kim, So Yeon; Jeong, Jong-Min; Seo, Wonhyo; Byun, Jin-Seok; Jeong, Won-Il; Yi, Hyon-Seung

    2016-01-01

    Emerging evidence revealed that diabetes induces abnormal immune responses that result in serious complications in organs. However, the effect of hyperglycemia on hepatic immunity remains obscure. We evaluated the population and function of hepatic immune cells in streptozotocin (STZ)-induced hyperglycemic mice. CC chemokine receptor 2 (CCR2)-knockout mice and mice with a depletion of regulatory T cells (DEREG) were used to investigate the migration and role of regulatory T cells (Tregs) in hyperglycemic mice. The inflammatory cytokines and hepatic transaminase levels were significantly increased in the hyperglycemic mice. The population and number of infiltrating monocytes, granulocytes, and Tregs were enhanced in the livers of the hyperglycemic mice. Hepatic monocytes other than macrophages showed the increased expression of inflammatory cytokines and chemokines in the hyperglycemic mice. The CCR2 knockout and DEREG chimeric mice exhibited increased populations of activated T cells and neutrophils compared to the WT chimeric mice, which promoted hepatic inflammation in the hyperglycemic mice. The migration of CCR2 knockout Tregs into the liver was significantly reduced compared to the WT Tregs. We demonstrated that hyperglycemia contributes to increase in infiltrating monocytes and Tregs, which are associated with hepatic immune dysfunction in mice. CCR2-mediated migration of Tregs regulates hyperglycemia-induced hepatic inflammation. PMID:27464894

  15. Hepatic immunophenotyping for streptozotocin-induced hyperglycemia in mice.

    PubMed

    Lee, Young-Sun; Eun, Hyuk Soo; Kim, So Yeon; Jeong, Jong-Min; Seo, Wonhyo; Byun, Jin-Seok; Jeong, Won-Il; Yi, Hyon-Seung

    2016-01-01

    Emerging evidence revealed that diabetes induces abnormal immune responses that result in serious complications in organs. However, the effect of hyperglycemia on hepatic immunity remains obscure. We evaluated the population and function of hepatic immune cells in streptozotocin (STZ)-induced hyperglycemic mice. CC chemokine receptor 2 (CCR2)-knockout mice and mice with a depletion of regulatory T cells (DEREG) were used to investigate the migration and role of regulatory T cells (Tregs) in hyperglycemic mice. The inflammatory cytokines and hepatic transaminase levels were significantly increased in the hyperglycemic mice. The population and number of infiltrating monocytes, granulocytes, and Tregs were enhanced in the livers of the hyperglycemic mice. Hepatic monocytes other than macrophages showed the increased expression of inflammatory cytokines and chemokines in the hyperglycemic mice. The CCR2 knockout and DEREG chimeric mice exhibited increased populations of activated T cells and neutrophils compared to the WT chimeric mice, which promoted hepatic inflammation in the hyperglycemic mice. The migration of CCR2 knockout Tregs into the liver was significantly reduced compared to the WT Tregs. We demonstrated that hyperglycemia contributes to increase in infiltrating monocytes and Tregs, which are associated with hepatic immune dysfunction in mice. CCR2-mediated migration of Tregs regulates hyperglycemia-induced hepatic inflammation. PMID:27464894

  16. Toxicological responses in SW mice exposed to inhaled pyrolysates of polymer/tobacco mixtures and blended tobacco.

    PubMed

    Werley, Michael S; Lee, K Monika; Lemus-Olalde, Ranulfo

    2009-12-01

    Modern cigarette manufacturing is highly automated and produces millions of cigarettes per day. The potential for small inclusions of non-cigarette materials such as wood, cardboard packaging, plastic, and other materials exists as a result of bulk handling and high-speed processing of tobacco. Many non-tobacco inclusions such as wood, paper, and cardboard would be expected to yield similar pyrolysis products as a burning cigarette. The aircraft industry has developed an extensive literature on the pyrolysis products of plastics, however, that have been reported to yield toxic by-products upon burning, by-products that have been lethal in animals and humans upon acute exposure under some exposure conditions. Some of these smoke constituents have also been reported in cigarette smoke. Five synthetic polymers, nylon 6, acrylonitrile-butadiene-styrene (ABS), nylon 12, nylon 6,6, and acrylonitrile-butadiene (AB), and the natural polymer wool were evaluated by adding them to tobacco at a 3, 10, and 30% inclusion level and then pyrolyzing the mixture. The validated smoke generation and exposure system have been described previously. We used the DIN 53-436 tube furnace and nose-only exposure chamber in combination to conduct exposures in Swiss-Webster mice. Potentially useful biological endpoints for predicting hazards in humans included sensory irritation and pulmonary irritation, respiratory function, clinical signs, body weights, bronchoalveolar lavage (BAL) fluid analysis, carboxyhemoglogin, blood cyanide concentrations, and histopathology of the respiratory tract. Chemical analysis of selected smoke constituents in the test atmosphere was also performed in order to compare the toxicological responses with exposure to the test atmospheres. Under the conditions of these studies, biological responses considered relevant and useful for prediction of effects in humans were found for sensory irritation, body weights, BAL fluid analysis, and histopathology of the nose

  17. STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control.

    PubMed

    Toth, Karoly; Lee, Sang R; Ying, Baoling; Spencer, Jacqueline F; Tollefson, Ann E; Sagartz, John E; Kong, Il-Keun; Wang, Zhongde; Wold, William S M

    2015-08-01

    Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as animal models. PMID

  18. Claudin-2 Knockout by TALEN-Mediated Gene Targeting in MDCK Cells: Claudin-2 Independently Determines the Leaky Property of Tight Junctions in MDCK Cells

    PubMed Central

    Tokuda, Shinsaku; Furuse, Mikio

    2015-01-01

    Tight junctions (TJs) regulate the movements of substances through the paracellular pathway, and claudins are major determinants of TJ permeability. Claudin-2 forms high conductive cation pores in TJs. The suppression of claudin-2 expression by RNA interference in Madin-Darby canine kidney (MDCK) II cells (a low-resistance strain of MDCK cells) was shown to induce a three-fold increase in transepithelial electrical resistance (TER), which, however, was still lower than in high-resistance strains of MDCK cells. Because RNA interference-mediated knockdown is not complete and only reduces gene function, we considered the possibility that the remaining claudin-2 expression in the knockdown study caused the lower TER in claudin-2 knockdown cells. Therefore, we investigated the effects of claudin-2 knockout in MDCK II cells by establishing claudin-2 knockout clones using transcription activator-like effector nucleases (TALENs), a recently developed genome editing method for gene knockout. Surprisingly, claudin-2 knockout increased TER by more than 50-fold in MDCK II cells, and TER values in these cells (3000–4000 Ω·cm2) were comparable to those in the high-resistance strains of MDCK cells. Claudin-2 re-expression restored the TER of claudin-2 knockout cells dependent upon claudin-2 protein levels. In addition, we investigated the localization of claudin-1, -2, -3, -4, and -7 at TJs between control MDCK cells and their respective knockout cells using their TALENs. Claudin-2 and -7 were less efficiently localized at TJs between control and their knockout cells. Our results indicate that claudin-2 independently determines the ‘leaky’ property of TJs in MDCK II cells and suggest the importance of knockout analysis in cultured cells. PMID:25781928

  19. STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control

    PubMed Central

    Spencer, Jacqueline F.; Tollefson, Ann E.; Sagartz, John E.; Kong, Il-Keun; Wang, Zhongde; Wold, William S. M.

    2015-01-01

    Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as animal models. PMID

  20. Tandem repeats of the extracellular domain of Matrix 2 influenza protein exposed in Brucella lumazine synthase decameric carrier molecule induce protection in mice.

    PubMed

    Alvarez, Paula; Zylberman, Vanesa; Ghersi, Giselle; Boado, Lorena; Palacios, Carlos; Goldbaum, Fernando; Mattion, Nora

    2013-01-21

    The antigenic variation of influenza virus represents a major prevention problem. However, the ectodomain of the protein Matrix 2 (M2e) is nearly invariant in all human influenza A strains and has been considered as a promising candidate for a broadly protective vaccine because antibodies to M2e are protective in animal models. In this work we evaluated the possible use of Brucella abortus lumazine synthase protein (BLS), a highly immunogenic decameric protein, as a carrier of the M2e peptide. Chimeric proteins generated by the fusion of one or four in tandem copies of M2e to BLS were efficiently expressed in Escherichia coli and assembled in decameric subunits similarly to the wild type BLS enzyme, as demonstrated by the comparative circular dichroism spectra and size exclusion chromatography and static light scattering analysis. The M2e peptides were stably exposed at the ten N-terminal ends of each BLS molecule. Immunization of mice with purified chimeras carrying only one M2e (BLS-M2e) copy elicited a significant humoral immune response with the addition of different adjuvants. The fusion of four in tandem copies of the M2e peptide (BLS-4M2e) resulted in similar levels of humoral immune response but in the absence of adjuvant. Survival of mice challenged with live influenza virus was 100% after vaccination with BLS-4M2e adjuvanted with Iscomatrix(®) (P<0.001) and 80% when adjuvanted with alum (P<0.01), while the chimera alone protected 60% of the animals (P<0.05). The approach described in this study is intended as a contribution to the generation of universal influenza immunogens, through a simple production and purification process and using safe carriers that might eventually avoid the use of strong adjuvants. PMID:23246552

  1. On the effect of minocycline on the depressive-like behavior of mice repeatedly exposed to malathion: interaction between nitric oxide and cholinergic system.

    PubMed

    Saeedi Saravi, Seyed Soheil; Amirkhanloo, Roya; Arefidoust, Alireza; Yaftian, Rahele; Saeedi Saravi, Seyed Sobhan; Shokrzadeh, Mohammad; Dehpour, Ahmad Reza

    2016-06-01

    This study was performed to investigate the antidepressant-like effect of minocycline in mice exposed to organophosphate pesticide malathion and possible involvement of nitric oxide/cGMP pathway in this paradigm. Mice were administered specific doses of malathion once daily for 7 consecutive days. After induction of depression, different doses of minocycline were daily injected alone or combined with non-specific NOS inhibitor, L-NAME, specific inducible NOS inhibitor, AG, NO precursor, L-arginine, and PDE5I, sildenafil. After locomotion assessment in open-field test, immobility times were recorded in the FST and TST. Moreover, hippocampal nitrite concentrations and acetylcholinesterase activity were measured. The results showed that repeated exposure to malathion induces depressive-like behavior at dose of 250 mg/kg. Minocycline (160 mg/kg) significantly reduced immobility times in FST and TST (P < 0.001). Combination of sub-effective doses of minocycline (80 mg/kg) with either L-NAME (3 mg/kg) or AG (25 mg/kg) significantly exerted a robust antidepressant-like effect in FST and TST (P < 0.001). Furthermore, minocycline at the same dose which has antidepressant-like effect, significantly reduced hippocampal nitrite concentration. The investigation indicates the essential role for NO/cGMP pathway in malathion-induced depressive-like behavior and antidepressant-like effect of minocycline. Moreover, the interaction between nitrergic and cholinergic systems are suggested to be involved in malathion-induced depression. PMID:26581675

  2. Resveratrol Suppresses Cytokine Production Linked to FcεRI-MAPK Activation in IgE-Antigen Complex-Exposed Basophilic Mast Cells and Mice.

    PubMed

    Han, Seon-Young; Choi, Yean-Jung; Kang, Min-Kyung; Park, Jung Han Yoon; Kang, Young-Hee

    2015-01-01

    A complicated interplay between resident mast cells and other recruited inflammatory cells contributes to the development and progression of allergic inflammation entailing the promotion of T helper 2 (Th2) cytokine responses. The current study examined whether resveratrol suppressed the production of inflammatory Th2 cytokines in cultured rat basophilic leukemia RBL-2H3 cells. Cells pre-treated with resveratrol nontoxic at 1–25 μM were sensitized with anti-dinitrophenyl (anti-DNP), and subsequently stimulated by dinitrophenyl-human serum albumin (DNP–HSA) antigen. Resveratrol dose-dependently diminished the secretion of interleukin (IL)-3, IL-4, IL-13 as well as tumor necrosis factor (TNF)-α by the antigen stimulation from sensitized cells. It was found that resveratrol mitigated the phosphorylation of p38 MAPK, ERK, and JNK elevated in mast cells exposed to Fc epsilon receptor I (FcεRI)-mediated immunoglobulin E (IgE)-antigen complex. The FcεRI aggregation was highly enhanced on the surface of mast cells following the HSA stimulation, which was retarded by treatment with 1–25 μM resveratrol. The IgE-receptor engagement rapidly induced tyrosine phosphorylation of c-Src-related focal adhesion protein paxillin involved in the cytoskeleton rearrangement. The FcεRI-mediated rapid activation of c-Src and paxillin was attenuated in a dose-dependent manner. In addition, the paxillin activation entailed p38 MAPK and ERK-responsive signaling, but the JNK activation was less involved. Consistently, oral administration of resveratrol reduced the tissue level of phosphorylated paxillin in the dorsal skin of DNP–HSA-challenged mice. The other tyrosine kinase Tyk2-STAT1 signaling was activated in the dorsal epidermis of antigen-exposed mice, which was associated with allergic inflammation. These results showed that resveratrol inhibited Th2 cytokines- and paxillin-linked allergic responses dependent upon MAPK signaling. Therefore, resveratrol may possess the

  3. Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation.

    PubMed

    Kovalchuk, Olga; Burke, Paula; Besplug, Jill; Slovack, Mark; Filkowski, Jody; Pogribny, Igor

    2004-04-14

    The biological and genetic effects of chronic low-dose radiation (LDR) exposure and its relationship to carcinogenesis have received a lot of attention in the recent years. For example, radiation-induced genome instability, which is thought to be a precursor of tumorogenesis, was shown to have a transgenerational nature. This indicates a possible involvement of epigenetic mechanisms in LDR-induced genome instability. Genomic DNA methylation is one of the most important epigenetic mechanisms. Existing data on radiation effects on DNA methylation patterns is limited, and no one has specifically studied the effects of the LDR. We report the first study of the effects of whole-body LDR exposure on global genome methylation in muscle and liver tissues of male and female mice. In parallel, we evaluated changes in promoter methylation and expression of the tumor suppressor gene p16(INKa) and DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT). We observed different patterns of radiation-induced global genome DNA methylation in the liver and muscle of exposed males and females. We also found sex and tissue-specific differences in p16(INKa) promoter methylation upon LDR exposure. In male liver tissue, p16(INKa) promoter methylation was more pronounced than in female tissue. In contrast, no significant radiation-induced changes in p16(INKa) promoter methylation were noted in the muscle tissue of exposed males and females. Radiation also did not significantly affect methylation status of MGMT promoter. We also observed substantial sex differences in acute and chronic radiation-induced expression of p16(INKa) and MGMT genes. Another important outcome of our study was the fact that chronic low-dose radiation exposure proved to be a more potent inducer of epigenetic effects than the acute exposure. This supports previous findings that chronic exposure leads to greater genome destabilization than acute exposure. PMID:15063138

  4. Effects of β-glucan polysaccharide revealed by the dominant lethal assay and micronucleus assays, and reproductive performance of male mice exposed to cyclophosphamide.

    PubMed

    Oliveira, Rodrigo Juliano; Pesarini, João Renato; Sparça Salles, Maria José; Nakamura Kanno, Tatiane Yumi; Dos Santos Lourenço, Ana Carolina; da Silva Leite, Véssia; da Silva, Ariane Fernanda; Matiazi, Hevenilton José; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2014-03-01

    β-glucan is a well-known polysaccharide for its chemopreventive effect. This study aimed to evaluate the chemopreventive ability of β-glucan in somatic and germ cells through the dominant lethal and micronucleus assays, and its influence on the reproductive performance of male mice exposed to cyclophosphamide. The results indicate that β-glucan is capable of preventing changes in DNA in both germ cells and somatic ones. Changes in germ cells were evaluated by the dominant lethal assay and showed damage reduction percentages of 46.46% and 43.79% for the doses of 100 and 150 mg/kg. For the somatic changes, evaluated by micronucleus assay in peripheral blood cells in the first week of treatment, damage reduction percentages from 80.63-116.32% were found. In the fifth and sixth weeks, the percentage ranged from 10.20-52.54% and -0.95-62.35%, respectively. Besides the chemopreventive efficiency it appears that the β-glucan, when combined with cyclophosphamide, is able to improve the reproductive performance of males verified by the significant reduction in rates of post-implantation losses and reabsorption in the mating of nulliparous females with males treated with cyclophosphamide. PMID:24688298

  5. Effects of β-glucan polysaccharide revealed by the dominant lethal assay and micronucleus assays, and reproductive performance of male mice exposed to cyclophosphamide

    PubMed Central

    Oliveira, Rodrigo Juliano; Pesarini, João Renato; Sparça Salles, Maria José; Nakamura Kanno, Tatiane Yumi; dos Santos Lourenço, Ana Carolina; da Silva Leite, Véssia; da Silva, Ariane Fernanda; Matiazi, Hevenilton José; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2014-01-01

    β-glucan is a well-known polysaccharide for its chemopreventive effect. This study aimed to evaluate the chemopreventive ability of β-glucan in somatic and germ cells through the dominant lethal and micronucleus assays, and its influence on the reproductive performance of male mice exposed to cyclophosphamide. The results indicate that β-glucan is capable of preventing changes in DNA in both germ cells and somatic ones. Changes in germ cells were evaluated by the dominant lethal assay and showed damage reduction percentages of 46.46% and 43.79% for the doses of 100 and 150 mg/kg. For the somatic changes, evaluated by micronucleus assay in peripheral blood cells in the first week of treatment, damage reduction percentages from 80.63–116.32% were found. In the fifth and sixth weeks, the percentage ranged from 10.20–52.54% and −0.95–62.35%, respectively. Besides the chemopreventive efficiency it appears that the β-glucan, when combined with cyclophosphamide, is able to improve the reproductive performance of males verified by the significant reduction in rates of post-implantation losses and reabsorption in the mating of nulliparous females with males treated with cyclophosphamide. PMID:24688298

  6. Absolute quantification of superoxide dismutase in cytosol and mitochondria of mice hepatic cells exposed to mercury by a novel metallomic approach.

    PubMed

    García-Sevillano, M A; García-Barrera, T; Navarro, F; Gómez-Ariza, J L

    2014-09-01

    In the last years, the development of new methods for analyzing accurate and precise individual metalloproteins is of increasing importance, since numerous metalloproteins are excellent biomarkers of oxidative stress and diseases. In that way, methods based on the use of post column isotopic dilution analysis (IDA) or enriched protein standards are required to obtain a sufficient degree of accuracy, precision and high limits of detection. This paper reports the identification and absolute quantification of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) in cytosol and mitochondria from mice hepatic cells using a innovative column switching analytical approach. The method consisted of orthogonal chromatographic systems coupled to inductively coupling plasma-mass spectrometry equipped with a octopole reaction systems (ICP-ORS-MS) and UV detectors: size exclusion fractionation (SEC) of the cytosolic and mitochondrial extracts followed by online anion exchange chromatographic (AEC) separation of Cu/Zn containing species. After purification, Cu,Zn-SOD was identified after tryptic digestion by molecular mass spectrometry (MS). The MS/MS spectrum of a doubly charged peptide was used to obtain the sequence of the protein using the MASCOT searching engine. This optimized methodology reduces the time of analysis and avoids the use of sample preconcentration and clean-up procedures, such as cut-off centrifuged filters, solid phase extraction (SPE), precipitation procedures, off-line fractions insolates, etc. In this sense, the method is robust, reliable and fast with typical chromatographic run time less than 20 min. Precision in terms of relative standard deviation (n = 5) is of 3-5% and detection limits is 0.21 ngCug(-1). The application of the methodology to hepatic cells from mice exposed to inorganic mercury reveals decreased levels of Cu,Zn-SOD in cytosolic and mitochondrial extracts, as a consequence of the oxidative stress caused by this toxic metal. Additionally, the

  7. Effects of acamprosate on attentional set-shifting and cellular function in the prefrontal cortex of chronic alcohol-exposed mice

    NASA Astrophysics Data System (ADS)

    Hu, Wei

    Background: The medial prefrontal cortex (mPFC) inhibits impulsive and compulsive behaviors that characterize drug abuse and dependence. Acamprosate is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Whether acamprosate can modulate executive functions that are impaired by chronic ethanol exposure is unknown. Here we explored the effects of acamprosate on an attentional set-shifting task, and tested whether these behavioral effects are correlated with modulation of glutamatergic synaptic transmission and intrinsic excitability of mPFC neurons. Methods: We induced alcohol dependence in mice via chronic intermittent ethanol (CIE) exposure in vapor chambers and measured changes in alcohol consumption in a limited access 2-bottle choice paradigm. Impairments of executive function were assessed in an attentional set-shifting task. Acamprosate was applied subchronically for 2 days during withdrawal before the final behavioral test. Alcohol-induced changes in cellular function of layer 5/6 pyramidal neurons, and the potential modulation of these changes by acamprosate, were measured using patch clamp recordings in brain slices. Results: Chronic ethanol exposure impaired cognitive flexibility in the attentional set-shifting task. Acamprosate improved overall performance and reduced perseveration. Recordings of mPFC neurons showed that chronic ethanol exposure increased use-dependent presynaptic transmitter release and enhanced postsynaptic N-methyl-D-aspartate receptor (NMDAR) function. Moreover, CIE-treatment lowered input resistance, and decreased the threshold and the afterhyperpolarization (AHP) of action potentials, suggesting chronic ethanol exposure also impacted membrane excitability of mPFC neurons. However, acamprosate treatment did not reverse these ethanol-induced changes cellular function. Conclusion: Acamprosate improved attentional control of ethanol exposed animals

  8. 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. PMID

  9. Gene Deletion of nos2 Protects Against Manganese-Induced Neurological Dysfunction in Juvenile Mice

    PubMed Central

    Streifel, Karin M.; Moreno, Julie A.; Hanneman, William H.; Legare, Marie E.; Tjalkens, Ronald B.

    2012-01-01

    The mechanisms underlying cognitive and neurobehavioral abnormalities associated with childhood exposure to manganese (Mn) are not well understood but may be influenced by neuroinflammatory activation of microglia and astrocytes that results in nitrosative stress due to expression of inducible nitric oxide synthase (iNOS/NOS2). We therefore postulated that gene deletion of NOS2 would protect against the neurotoxic effects of Mn in vivo and in vitro. Juvenile NOS2 knockout (NOS2−/−) mice were orally exposed to 50 mg/kg of MnCl2 by intragastric gavage from days 21 to 34 postnatal. Results indicate that NOS2−/− mice exposed to Mn were protected against neurobehavioral alterations, despite histopathological activation of astrocytes and microglia in Mn-treated mice in both genotypes. NOS2−/− mice had decreased Mn-induced formation of 3-nitrotyrosine protein adducts within neurons in the basal ganglia that correlated with protection against Mn-induced neurobehavioral defects. Primary striatal astrocytes from wildtype mice caused apoptosis in cocultured striatal neurons following treatment with MnCl2 and tumor necrosis factor-α, whereas NOS2−/− astrocytes failed to cause any increase in markers of apoptosis in striatal neurons. Additionally, scavenging nitric oxide (NO) with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) prevented the ability of Mn- and cytokine-treated wildtype astrocytes to cause apoptosis in cocultured striatal neurons. These data demonstrate that NO plays a crucial role in Mn-induced neurological dysfunction in juvenile mice and that NOS2 expression in activated glia is an important mediator of neuroinflammatory injury during Mn exposure. PMID:22174044

  10. Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model.

    PubMed

    Hunter, Robert W; Ivy, Jessica R; Flatman, Peter W; Kenyon, Christopher J; Craigie, Eilidh; Mullins, Linda J; Bailey, Matthew A; Mullins, John J

    2015-07-01

    Na(+) transport in the renal distal convoluted tubule (DCT) by the thiazide-sensitive NaCl cotransporter (NCC) is a major determinant of total body Na(+) and BP. NCC-mediated transport is stimulated by aldosterone, the dominant regulator of chronic Na(+) homeostasis, but the mechanism is controversial. Transport may also be affected by epithelial remodeling, which occurs in the DCT in response to chronic perturbations in electrolyte homeostasis. Hsd11b2(-/-) mice, which lack the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and thus exhibit the syndrome of apparent mineralocorticoid excess, provided an ideal model in which to investigate the potential for DCT hypertrophy to contribute to Na(+) retention in a hypertensive condition. The DCTs of Hsd11b2(-/-) mice exhibited hypertrophy and hyperplasia and the kidneys expressed higher levels of total and phosphorylated NCC compared with those of wild-type mice. However, the striking structural and molecular phenotypes were not associated with an increase in the natriuretic effect of thiazide. In wild-type mice, Hsd11b2 mRNA was detected in some tubule segments expressing Slc12a3, but 11βHSD2 and NCC did not colocalize at the protein level. Thus, the phosphorylation status of NCC may not necessarily equate to its activity in vivo, and the structural remodeling of the DCT in the knockout mouse may not be a direct consequence of aberrant corticosteroid signaling in DCT cells. These observations suggest that the conventional concept of mineralocorticoid signaling in the DCT should be revised to recognize the complexity of NCC regulation by corticosteroids. PMID:25349206

  11. New Hippocampal Neurons Are Not Obligatory for Memory Formation; Cyclin D2 Knockout Mice with No Adult Brain Neurogenesis Show Learning

    ERIC Educational Resources Information Center

    Jaholkowski, Piotr; Kiryk, Anna; Jedynak, Paulina; Abdallah, Nada M. Ben; Knapska, Ewelina; Kowalczyk, Anna; Piechal, Agnieszka; Blecharz-Klin, Kamilla; Figiel, Izabela; Lioudyno, Victoria; Widy-Tyszkiewicz, Ewa; Wilczynski, Grzegorz M.; Lipp, Hans-Peter; Kaczmarek, Leszek; Filipkowski, Robert K.

    2009-01-01

    The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs…

  12. The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice.

    PubMed

    Cai, Yan; Jogasuria, Alvin; Yin, Huquan; Xu, Ming-Jiang; Hu, Xudong; Wang, Jiayou; Kim, Chunki; Wu, Jiashin; Lee, Kwangwon; Gao, Bin; You, Min

    2016-09-01

    We have previously shown that the ethanol-mediated elevation of lipocaline-2 (LCN2) is closely associated with the development of alcoholic fatty liver disease (AFLD) in mice. Herein, we aimed to understand the functional significance of LCN2 induction by ethanol and to explore its underlying mechanisms. We evaluated the effects of LCN2 in an in vitro cellular alcoholic steatosis model and in an animal study using wild-type and LCN2 knockout mice fed for 4 weeks with an ethanol-supplemented Lieber-DeCarli diet. In the cellular model of alcoholic steatosis, recombinant LCN2 or overexpression of LCN2 exacerbated ethanol-induced fat accumulation, whereas knocking down LCN2 prevented steatosis in hepatocytes exposed to ethanol. Consistently, removal of LCN2 partially but significantly alleviated alcoholic fatty liver injury in mice. Mechanistically, LCN2 mediates detrimental effects of ethanol in the liver via disrupted multiple signaling pathways, including aberrant nicotinamide phosphoribosyltransferase-sirtuin 1 axis, perturbed endocrine metabolic regulatory fibroblast growth factor 15/19 signaling, and impaired chaperone-mediated autophagy. Finally, compared with healthy human livers, liver samples from patients with AFLD had lower gene expression of several LCN2-regualted molecules. Our study demonstrated a pivotal and causal role of LCN2 in the development of AFLD and suggested that targeting the LCN2 could be of great value for the treatment of human AFLD. PMID:27427417

  13. Curcumin-induced heme oxygenase-1 expression prevents H2O2-induced cell death in wild type and heme oxygenase-2 knockout adipose-derived mesenchymal stem cells.

    PubMed

    Cremers, Niels A J; Lundvig, Ditte M S; van Dalen, Stephanie C M; Schelbergen, Rik F; van Lent, Peter L E M; Szarek, Walter A; Regan, Raymond F; Carels, Carine E; Wagener, Frank A D T G

    2014-01-01

    Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H2O2. Surprisingly, sensitivity to H2O2-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H2O2 exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H2O2-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H2O2-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy. PMID:25299695

  14. Curcumin-Induced Heme Oxygenase-1 Expression Prevents H2O2-Induced Cell Death in Wild Type and Heme Oxygenase-2 Knockout Adipose-Derived Mesenchymal Stem Cells

    PubMed Central

    Cremers, Niels A. J.; Lundvig, Ditte M. S.; van Dalen, Stephanie C. M.; Schelbergen, Rik F.; van Lent, Peter L. E. M.; Szarek, Walter A.; Regan, Raymond F.; Carels, Carine E.; Wagener, Frank A. D. T. G.

    2014-01-01

    Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H2O2. Surprisingly, sensitivity to H2O2-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H2O2 exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H2O2-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H2O2-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy. PMID:25299695

  15. In vivo modulation of epidermal growth factor receptor phosphorylation in mice expressing different gangliosides.

    PubMed

    Daniotti, Jose L; Crespo, Pilar M; Yamashita, Tadashi

    2006-12-01

    We studied in this work the in vivo phosphorylation of the epidermal growth factor receptor (EGFr) in skin from knockout mice lacking different ganglioside glycosyltransferases. Results show an enhancement of EGFr phosphorylation, after EGF stimulation, in skin from Sial-T2 knockout and Sial-T2/GalNAc-T double knockout mice as compared with wild-type and Sial-T1 knockout mice. Qualitative analysis of ganglioside composition in mice skin suggest that the increase of EGFr phosphorylation observed in skin from Sial-T2 knockout and Sial-T2/GalNAc-T double knockout mice in response to EGF might not be primary attributed to the expression of GD3 or a-series gangliosides in mice skin. These studies provide, for the first time, an approach for studying the molecular mechanisms involved in the in vivo regulation of EGFr function by gangliosides. PMID:16817235

  16. Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments.

    PubMed

    Liang, J; Xu, W; Hsu, Y-T; Yee, A X; Chen, L; Südhof, T C

    2015-07-01

    Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs. PMID:25824299

  17. Protective effect of Devosia sp. ANSB714 on growth performance, serum chemistry, immunity function and residues in kidneys of mice exposed to deoxynivalenol.

    PubMed

    Zhao, Lihong; Li, Xiaoying; Ji, Cheng; Rong, Xiaoping; Liu, Shujing; Zhang, Jianyun; Ma, Qiugang

    2016-06-01

    This study was conducted to investigate the toxic effects of deoxynivalenol (DON) and the ameliorating efficacy of Devosia sp. ANSB714 for the negative effects of DON on mice. In the experiment, 80 mice were randomly divided into 4 treatments: non-toxin control, toxin, non-toxin control + ANSB714 and toxin + ANSB714. During 28 days, the mice in treatment with 4.70 mg/kg DON only had significantly lower average daily gain as compared those with non-toxin control treatment (P < 0.05). Serum blood urea nitrogen, tumour necrosis factor-α and the residues of DON in kidneys in mice received the toxin diet were obviously higher than those with non-toxin control (P < 0.05). There were no significant differences (P > 0.05) between ANSB714 treatments and non-ANSB714 treatments on above parameters of mice. Adding ANSB714 to toxic diets could normalize deviant physiological effects of DON on mice. PMID:27016490

  18. TGF-B3 Dependent Modification of Radiosensitivity in Reporter Cells Exposed to Serum From Whole-Body Low Dose-Rate Irradiated Mice.

    PubMed

    Edin, Nina Jeppesen; Altaner, Čestmír; Altanerova, Veronica; Ebbesen, Peter

    2015-01-01

    Prior findings in vitro of a TGF-β3 dependent mechanism induced by low dose-rate irradiation and resulting in increased radioresistance and removal of low dose hyper-radiosensitivity (HRS) was tested in an in vivo model. DBA/2 mice were given whole-body irradiation for 1 h at low dose-rates (LDR) of 0.3 or 0.03 Gy/h. Serum was harvested and added to RPMI (4% mouse serum and 6% bovine serum).This medium was transferred to reporter cells (T-47D breast cancer cells or T98G glioblastoma cells). The response to subsequent challenge irradiation of the reporter cells was measured by the colony assay. While serum from unirradiated control mice had no effect on the radiosensitivity in the reporter cells, serum from mice given 0.3 Gy/h or 0.03 Gy/h for 1 h removed HRS and also increased survival in response to doses up to 5 Gy. The effect lasted for at least 15 months after irradiation. TGF-β3 neutralizer added to the medium containing mouse serum inhibited the effect. Serum from mice given irradiation of 0.3 Gy/h for 1 h and subsequently treated with iNOS inhibitor 1400W did not affect radiosensitivity in reporter cells; neither did serum from the unirradiated progeny of mice given 1h LDR whole-body irradiation. PMID:26673923

  19. Palmoplantar Keratoderma in Slurp2-Deficient Mice.

    PubMed

    Allan, Christopher M; Procaccia, Shiri; Tran, Deanna; Tu, Yiping; Barnes, Richard H; Larsson, Mikael; Allan, Bernard B; Young, Lorraine C; Hong, Cynthia; Tontonoz, Peter; Fong, Loren G; Young, Stephen G; Beigneux, Anne P

    2016-02-01

    SLURP1, a member of the lymphocyte antigen 6 protein family, is secreted by suprabasal keratinocytes. Mutations in SLURP1 cause a palmoplantar keratoderma (PPK) known as mal de Meleda. SLURP2, another secreted lymphocyte antigen 6 protein, is encoded by a gene located ?20 kb downstream from SLURP1. SLURP2 is produced by suprabasal keratinocytes. To investigate the importance of SLURP2, we first examined Slurp2 knockout mice in which exon 2-3 sequences had been replaced with lacZ and neo cassettes. Slurp2(-/-) mice exhibited hyperkeratosis on the volar surface of the paws (i.e., palmoplantar keratoderma), increased keratinocyte proliferation, and an accumulation of lipid droplets in the stratum corneum. They also exhibited reduced body weight and hind limb clasping. These phenotypes are similar to those of Slurp1(-/-) mice. To solidify a link between Slurp2 deficiency and palmoplantar keratoderma and to be confident that the disease phenotypes in Slurp2(-/-) mice were not secondary to the effects of the lacZ and neo cassettes on Slurp1 expression, we created a new line of Slurp2 knockout mice (Slurp2X(-/-)) in which Slurp2 was inactivated with a simple nonsense mutation. Slurp2X(-/-) mice exhibited the same disease phenotypes. Thus, Slurp2 deficiency and Slurp1 deficiencies cause the same disease phenotypes. PMID:26967477

  20. Palmoplantar keratoderma in Slurp2-deficient mice

    PubMed Central

    Allan, Christopher M.; Procaccia, Shiri; Tran, Deanna; Tu, Yiping; Barnes, Richard H.; Larsson, Mikael; Allan, Bernard B.; Young, Lorraine C.; Hong, Cynthia; Tontonoz, Peter; Fong, Loren G.; Young, Stephen G.; Beigneux, Anne P.

    2015-01-01

    SLURP1, a member of the Ly6 protein family, is secreted by suprabasal keratinocytes. Mutations in SLURP1 cause a palmoplantar keratoderma (PPK) known as mal de Meleda. Another secreted Ly6 protein, SLURP2, is encoded by a gene located ~20 kb downstream from SLURP1. SLURP2 is produced by suprabasal keratinocytes. To investigate the importance of SLURP2, we first examined Slurp2 knockout mice in which exon 2–3 sequences had been replaced with lacZ and neo cassettes. Slurp2−/− mice exhibited hyperkeratosis on the volar surface of the paws (i.e., PPK), increased keratinocyte proliferation, and an accumulation of lipid droplets in the stratum corneum. They also exhibited reduced body weight and hind limb clasping. These phenotypes are very similar to those of Slurp1−/− mice. To solidify a link between Slurp2 deficiency and PPK and to be confident that the disease phenotypes in Slurp2−/− mice were not secondary to the effects of the lacZ and neo cassettes on Slurp1 expression, we created a new line of Slurp2 knockout mice (Slurp2X−/−) in which Slurp2 was inactivated with a simple nonsense mutation. Slurp2X−/− mice exhibited the same disease phenotypes. Thus, Slurp2 deficiency and Slurp1 deficiencies cause the same disease phenotypes. PMID:26967477

  1. HYDRONEPHROSIS IN MICE EXPOSED TO TCDD-CONTAMINATED BREAST MILK: IDENTIFICATION OF THE PEAK PERIOD OF SENSITIVITY AND ASSESSMENT OF POTENTIAL RECOVERY

    EPA Science Inventory

    2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of hydronephrosis in mice both pre- and post-natally. ritical period of sensitivity to TCDD could not be identified for the hydronephrotic response induced prenatally since the urinary tract appeared equally sensitive...

  2. The influence of sex on life shortening and tumor induction in CBA/Cne mice exposed to x rays or fission neutrons

    SciTech Connect

    Di Majo, V.; Coppola, M.; Rebessi, S.; Saran, A.

    1996-07-01

    An experimental study of male and female CBA/Cne mice was set up at Casaccia primarily to investigate the influence of sex on long-term survival and tumor induction after exposure to high- and low-LET radiation. Mice were whole-body-irradiated at 3 months of age with fission-neutron doses of 0.1, 0.2, 0.4, 0.8, 1.2 and 1.8 Gy at the RSV-TAPIRO reactor (mean neutron energy 0.4 MeV, in terms of kerma, y{sub D} = 51.5 KeV/{mu}m), or with 250 KVp X-ray doses of 1, 3, 5 and 7 Gy. Control and irradiated animals were then followed for their entire life span. As a general finding, male CBA/Cne mice appear more susceptible to tumori-genesis than females. In particular, the incidences of induced acute myeloid leukemia and malignant lymphomas are significant only in male mice. Benign and malignant solid tumors of many types are observed in mice of both sexes, the most frequent being in the lung, liver and ovary. However, evidence for a radiation response is limited to the case of Harderian gland neoplasms. In addition, a comparison of the observed frequency of all irradiated compared to unirradiated animals bearing solid tumors shows that the total tumor occurrence is not altered markedly by radiation exposure. A decrease in survival time is observed for both sexes and radiation types and correlates well with increasing dose. Moreover, both sex and radiation quality appear to influence the life shortening. A similar dose dependence of survival time is found when tumor-free animals alone are considered, suggesting a non-specific component of life-shortening. 18 refs., 3 figs., 5 tabs.

  3. Micro-computed tomography assisted distal femur metaphyseal blunt punch compression for determining trabecular bone strength in mice.

    PubMed

    Sankar, Uma; Pritchard, Zachary J; Voor, Michael J

    2016-05-01

    Shorter generation time and the power of genetic manipulation make mice an ideal model system to study bone biology as well as bone diseases. However their small size presents a challenge to perform strength measurements, particularly of the weight-bearing cancellous bone in the murine long bones. We recently developed an improved method to measure the axial compressive strength of the cancellous bone in the distal femur metaphysis in mice. Transverse micro-computed tomography image slices that are 7µm thick were used to locate the position where the epiphysis-metaphysis transition occurs. This enabled the removal of the distal femur epiphysis at the exact transition point exposing the full extent of metaphyseal trabecular bone, allowing more accurate and consistent measurement of its strength. When applied to a murine model system consisting of five month old male wild-type (WT) and Ca(2+)/calmodulin dependent protein kinase kinase 2 (CaMKK2) knockout (KO) Camkk2(-/-) mice that possess recorded differences in trabecular bone volume, data collected using this method showed good correlation between bone volume fraction and strength of trabecular bone. In combination with micro-computed tomography and histology, this method will provide a comprehensive and consistent assessment of the microarchitecture and tissue strength of the cancellous bone in murine mouse models. PMID:26947030

  4. The viral theory of schizophrenia revisited: Abnormal placental gene expression and structural changes with lack of evidence of H1N1 viral presence in placentae of infected mice or brains of exposed offspring

    PubMed Central

    Fatemi, S. Hossein; Folsom, Timothy D.; Rooney, Robert J.; Mori, Susumu; Kornfield, Tess E.; Reutiman, Teri J.; Kneeland, Rachel E.; Liesch, Stephanie B.; Hua, Kegang; Hsu, John; Patel, Divyen H.

    2011-01-01

    Researchers have long noted an excess of patients with schizophrenia were born during the months of January and March. This winter birth effect has been hypothesized to result either from various causes such as vitamin D deficiency (McGrath, 1999; McGrath et al., 2010), or from maternal infection during pregnancy. Infection with a number of viruses during pregnancy including influenza, and rubella are known to increase the risk of schizophrenia in the offspring (Brown, 2006). Animal models using influenza virus or PolyI:C, a viral mimic, have been able to replicate many of the brain morphological, genetic, and behavioral deficits of schizophrenia (Meyer et al., 2006, 2008a, 2009; Bitanihirwe et al. 2010; Meyer and Feldon, 2010; Short et al., 2010). Using a murine model of prenatal viral infection, our laboratory has shown that viral infection on embryonic days 9, 16, and 18 leads to abnormal expression of brain genes and brain structural abnormalities in the exposed offspring (Fatemi et al., 2005, 2008a,b, 2009a,b). The purpose of the current study was to examine gene expression and morphological changes in the placenta, hippocampus, and prefrontal cortex as a result of viral infection on embryonic day 7 of pregnancy. Pregnant mice were either infected with influenza virus [A/WSN/33 strain (H1N1)] or sham-infected with vehicle solution. At E16, placentas were harvested and prepared for either microarray analysis or for light microscopy. We observed significant, upregulation of 77 genes and significant downregulation of 93 genes in placentas. In brains of exposed offspring following E7 infection, there were changes in gene expression in prefrontal cortex (6 upregulated and 24 downregulated at P0; 5 upregulated and 14 downregulated at P56) and hippocampus (4 upregulated and 6 downregulated at P0; 6 upregulated and 13 downregulated at P56). QRT-PCR verified the direction and magnitude of change for a number of genes associated with hypoxia, inflammation, schizophrenia

  5. [Induction of DNA damage in blood leucocytes and of cytogenetic injuries in bone marrow polychromatic erythrocytes in mice exposed to low-LET and high-LET radiation and in their progeny].

    PubMed

    Kuznetsova, E A; Zaichkina, S I; Sirota, N P; Abdullaev, S A; Rozanova, O M; Aptikaeva, G F; Sorokina, S S; Romanchenko, S P; Smirnova, E N

    2014-01-01

    The present work was aimed at studying the molecular and cellular levels of the response of the hematopoietic system in mice and their progeny to the action of low-LET and high-LET radiation at different times after exposure. The damage to the genome at the molecular level was assessed by the comet assay in peripheral blood leucocytes, whereas at the cellular level it was estimated by means of the micronuclear test in the marrow cells, after exposure of mice to X-radiation of 1, 3 and 5 Gy and to a high-LET low-intensity radiation at thedoses of 0.14 and 0.35 Gy, as well as to a combined effect of these types of radiation. When accessing the level of the DNA damage to individual cells by the comet assay, we also used, apart from a commonly accepted parameter %TDNA, additional characteristics: the proportions of leucocytes with an intact and highly fragmented DNA. Using these parameters, we detected the changes characterizing the dynamics of the leukocyte population in mouse blood at different times after the action of X-ray and high-LET radiation. It was found that: (1) the DNA damage increases with the dose of high-LET radiation; (2) the level of damage in the progeny of the animals exposed to high-LET radiation does not differ from that in unirradiated animals both at the molecular and cytogenetic levels; and (3) a decrease in the radiosensitivity of the progeny of the mice exposed to high-LET radiation at a dose of 0.35 Gy makes itself evident only at the molecular level, which may point to the possible transgeneration transmission of genomic lesions. PMID:25775822

  6. Hydronephrosis in mice exposed to TCDD-contaminated breast milk: Identification of the peak period of sensitivity and assessment of potential recovery

    SciTech Connect

    Couture-Haws, L.; Harris, M.W.; McDonald, M.M.; Lockhart, A.C.; Birnbaum, L.S.

    1991-01-01

    2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of hydronephrosis in mice both pre- and post-natally. To identify the critical period of susceptibility for development of TCDD-induced hydronephrosis in neonatal mice, as well as to characterize the potential for recovery from this renal lesion, dose-response and time-course studies were conducted using lactational exposure. Pregnant C57BL/6N mice were allowed natural delivery. In the dose-response phase of the investigation, mothers were administered 0, 3, 6, or 12 microgram TCDD/kg once by gavage on post natal day (pnd) 1, 4, 8, or 14, and dams and pups were sacrificed on pnd 26. In the time-course studies, dams were given a single oral dose of 0 or 9 microgram TCDD/kg on pnd 1, and mothers and litters were subsequently sacrificed on pnd 7, 13, 19, or 26. Neonatal kidneys were examined, and hydronephrotic severity was scored. The incidence and severity of hydronephrosis were significantly elevated above controls at all dose levels on pnd 26 following treatment on pnds 1 and 4, while treatment on pnd 8 or 14 was ineffective at inducing hydronephrosis.

  7. [Changes in the Expression of Dopaminergic Genes in Brain Structures of Male Mice Exposed to Chronic Social Defeat Stress: An RNA-seq Study].

    PubMed

    Kovalenko, I L; Smagin, D A; Galyamina, A G; Orlov, Yu L; Kudryavtseva, N N

    2016-01-01

    Whole-transcriptome analysis (RNA-seq) has been used to analyze changes in the expression of dopaminergic genes that encode proteins involved in the synthesis, inactivation, and neurotransmission of dopamine in the striatum, ventral tegmental area, raphe nuclei of the midbrain, hypothalamus, and hippocampus of male mice subjected to chronic social defeat. The expression of Th, Ddc, and Slc6A3 (Dat1) was upregulated, while that of Ppp1r1b and Sncg was downregulated in the ventral tegmental area; the expression of Th, Ddc, Drd2, and Sncg was downregulated in the raphe nuclei of midbrain; the expression of Th, Aldh2, and Ppp1r1b was upregulated, while that of Маоа was downregulated in the hypothalamus; Drd1 and Snca expression was downregulated and that of Sncb was upregulated in the striatum, and Sncb expression was upregulated in the hippocampus. There were no statistically significant changes in the expression of Comt, Maob, Drd3, Drd4, or Drd5 in the brain areas analyzed in stressed male mice (compared to control animals). Thus, the number of differentially expressed dopaminergic genes and the direction of expression changes in male mice experiencing chronic stress are specific to regions of the brain. PMID:27028825

  8. Voluntary wheel-running attenuates insulin and weight gain and affects anxiety-like behaviors in C57BL6/J mice exposed to a high-fat diet.

    PubMed

    Hicks, Jasmin A; Hatzidis, Aikaterini; Arruda, Nicole L; Gelineau, Rachel R; De Pina, Isabella Monteiro; Adams, Kenneth W; Seggio, Joseph A

    2016-09-01

    It is widely accepted that lifestyle plays a crucial role on the quality of life in individuals, particularly in western societies where poor diet is correlated to alterations in behavior and the increased possibility of developing type-2 diabetes. While exercising is known to produce improvements to overall health, there is conflicting evidence on how much of an effect exercise has staving off the development of type-2 diabetes or counteracting the effects of diet on anxiety. Thus, this study investigated the effects of voluntary wheel-running access on the progression of diabetes-like symptoms and open field and light-dark box behaviors in C57BL/6J mice fed a high-fat diet. C57BL/6J mice were placed into either running-wheel cages or cages without a running-wheel, given either regular chow or a high-fat diet, and their body mass, food consumption, glucose tolerance, insulin and c-peptide levels were measured. Mice were also exposed to the open field and light-dark box tests for anxiety-like behaviors. Access to a running-wheel partially attenuated the obesity and hyperinsulinemia associated with high-fat diet consumption in these mice, but did not affect glucose tolerance or c-peptide levels. Wheel-running strongly increased anxiety-like and decreased explorative-like behaviors in the open field and light-dark box, while high-fat diet consumption produced smaller increases in anxiety. These results suggest that voluntary wheel-running can assuage some, but not all, of the physiological problems associated with high-fat diet consumption, and can modify anxiety-like behaviors regardless of diet consumed. PMID:27154535

  9. Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD: implication for COPD-associated neuropathogenesis.

    PubMed

    Sundar, Isaac K; Yao, Hongwei; Huang, Yadi; Lyda, Elizabeth; Sime, Patricia J; Sellix, Michael T; Rahman, Irfan

    2014-01-01

    The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD. PMID:24520342

  10. Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen

    SciTech Connect

    Waalkes, Michael P. . E-mail: waalkes@niehs.nih.gov; Liu Jie; Ward, Jerrold M.; Diwan, Bhalchandra A.

    2006-09-15

    Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 {mu}g/pup/day) or tamoxifen (TAM; 10 {mu}g/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-{alpha}, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.

  11. Increased accumulation of neutrophils and decreased fibrosis in the lung of NADPH oxidase-deficient C57BL/6 mice exposed to carbon nanotubes

    SciTech Connect

    Shvedova, A.A. Kisin, E.R.; Murray, A.R.; Kommineni, C.; Castranova, V.; Fadeel, B.; Kagan, V.E.

    2008-09-01

    Single-walled carbon nanotubes (SWCNT) have been introduced into a large number of new technologies and consumer products. The combination of their exceptional features with very broad applications raised concerns regarding their potential health effects. The prime target for SWCNT toxicity is believed to be the lung where exposure may occur through inhalation, particularly in occupational settings. Our previous work has demonstrated that SWCNT cause robust inflammatory responses in rodents with very early termination of the acute phase and rapid onset of chronic fibrosis. Timely elimination of polymorphonuclear neutrophils (PMNs) through apoptosis and their subsequent clearance by macrophages is a necessary stage in the resolution of pulmonary inflammation whereby NADPH oxidase contributes to control of apoptotic cell death and clearance of PMNs. Thus, we hypothesized that NADPH oxidase may be an important regulator of the transition from the acute inflammation to the chronic fibrotic stage in response to SWCNT. To experimentally address the hypothesis, we employed NADPH oxidase-deficient mice which lack the gp91{sup phox} subunit of the enzymatic complex. We found that NADPH oxidase null mice responded to SWCNT exposure with a marked accumulation of PMNs and elevated levels of apoptotic cells in the lungs, production of pro-inflammatory cytokines, decreased production of the anti-inflammatory and pro-fibrotic cytokine, TGF-{beta}, and significantly lower levels of collagen deposition, as compared to C57BL/6 control mice. These results demonstrate a role for NADPH oxidase-derived reactive oxygen species in determining course of pulmonary response to SWCNT.

  12. [Comparative analysis of the susceptibility and productivity of respiratory tract target cells of mice and rats exposed to inflienza virus in vitro].

    PubMed

    Zhukov, V A; Shishkina, L N; Sergeev, A A; Malkova, E M; Riabchikova, E I; Petrishchenko, V A; Sergeev, A N; Ustiuzhanina, N V; Nesvizhskiĭ, Iu V; Vorob'ev, A A

    2008-01-01

    The levels of susceptibility to influenza virus A/Aichi/2/68 H3N2 and the virus yield were determined using primary cells of the trachea and lungs of CD-1 mice and Wistar rats, and for 3 sets of cells obtained from primary lung cells of the both species by centrifugation in the gradient of density and by sedimentation on a surface. The values of ID50 virus dose for 10(6) cells and virus yield per 1 infected cell determined for primary mice cells were 4.0+/-0.47 and 3.2+/-0.27 IgEID50 (lung cells), 3.8+/-0.17 and 3.3+/-0.20 IgEID50 (tracheal cells), and those determined for primary rat cells were 4.0+/-0.35 and 2.1+/-0.24 IgEID50 (lung cells), 3.7+/-0.27 and 2.2+/-0.46 IgEID50 (tracheal cells). The values of ID50 and yield measured for mixtures of cells obtained from primary lung cells by centrifugation in gradient of density and by sedimentation on a surface differed insignificantly (p = 0.05) from the values of the corresponding parameters measured for lung and tracheal cells for both rats and mice. The analysis of data on the variation of the concentrations of different cell types in the experimental cell mixtures shows that type 1 and 2 alveolocytes possess significantly lower (p = 0.05) susceptibility and productivity vs. ciliated cells of the both species. The investigation was conducted within the frame of the ISTC/DARPA#450p project. PMID:18368764

  13. Induction of chromosome instability and stomach cancer by altering the expression pattern of mitotic checkpoint genes in mice exposed to areca-nut

    PubMed Central

    2013-01-01

    Background There are strong indications for a causal association between areca-nut consumption and cancers. In Meghalaya, India, the variety of areca-nut is used as raw and unprocessed form whose chemical composition and pharmacological actions have been reported. Yet we know little on the initial pathway involved in areca-nut associated carcinogenesis since it is difficult to assess its effects on genetic alterations without interference of other compounding factors. Therefore, present study was undertaken in mice to verify the ability of raw areca-nut (RAN) to induce cancer and to monitor the expression of certain genes involved in carcinogenesis. This study was not intended to isolate any active ingredients from the RAN and to look its action. Methods Three groups of mice (n = 25 in each) were taken and used at different time-points for different experimental analysis. The other three groups of mice (n = 15 in each) were considered for tumor induction studies. In each set, two groups were administered RAN-extract ad libitum in drinking water with or without lime. The expression of certain genes was assessed by conventional RT-PCR and immunoblotting. The mice were given the whole RAN-extract with and without lime in order to mimic the human consumption style of RAN. Results Histological preparation of stomach tissue revealed that RAN induced stomach cancer. A gradual increase in the frequency of precocious anaphase and aneuploid cells was observed in the bone marrow cells with a greater increment following RAN + lime administeration. Levels of p53, Bax, Securin and p65 in esophageal and stomach cells were elevated during early days of RAN exposure while those of different mitotic checkpoint proteins were downregulated. Apoptotic cell death was detected in non-cancerous stomach cells but not in tumor cells which showed overexpression of Bax and absence of PARP. Conclusion Present study suggested (a) RAN induces stomach cancer, however, presence of lime

  14. Different behavioral effect dose–response profiles in mice exposed to two-carbon chlorinated hydrocarbons: Influence of structural and physical properties

    SciTech Connect

    Umezu, Toyoshi Shibata, Yasuyuki

    2014-09-01

    The present study aimed to clarify whether dose–response profiles of acute behavioral effects of 1,2-dichloroethane (DCE), 1,1,1-trichloroethane (TCE), trichloroethylene (TRIC), and tetrachloroethylene (PERC) differ. A test battery involving 6 behavioral endpoints was applied to evaluate the effects of DCE, TCE, TRIC, and PERC in male ICR strain mice under the same experimental conditions. The behavioral effect dose–response profiles of these compounds differed. Regression analysis was used to evaluate the relationship between the dose–response profiles and structural and physical properties of the compounds. Dose–response profile differences correlated significantly with differences in specific structural and physical properties. These results suggest that differences in specific structural and physical properties of DCE, TCE, TRIC, and PERC are responsible for differences in behavioral effects that lead to a variety of dose–response profiles. - Highlights: • We examine effects of 4 chlorinated hydrocarbons on 6 behavioral endpoints in mice. • The behavioral effect dose–response profiles for the 4 compounds are different. • We utilize regression analysis to clarify probable causes of the different profiles. • The compound's physicochemical properties probably produce the different profiles.

  15. Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress.

    PubMed

    Sun, Jing; Wang, Fangyan; Hong, Guangliang; Pang, Mengqi; Xu, Hailing; Li, Haixiao; Tian, Feng; Fang, Renchi; Yao, Ye; Liu, Jiaming

    2016-04-01

    Sodium butyrate (NaB) has exhibited neuroprotective activity. This study aimed to explore that NaB exerts beneficial effects on chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and its possible mechanisms. The behavioral tests including sucrose preference test (SPT), open field test (OFT), tail suspension test (TST) and forced swimming test (FST) were to evaluate the antidepressant effects of NaB. Then changes of Nissl's body in the hippocampus, brain serotonin (5-HT) concentration, brain-derived neurotrophic factor (BDNF) and tight junctions (TJs) proteins level were assessed to explore the antidepressant mechanisms. Our results showed that CUMS caused significant depression-like behaviors, neuropathological changes, and decreased brain 5-HT concentration, TJs protein levels and BDNF expression in the hippocampus. However, NaB treatment significantly ameliorated behavioral deficits of the CUMS-induced mice, increased 5-HT concentration, increased BDNF expression, and up-regulated Occludin and zonula occludens-1(ZO-1) protein levels in the hippocampus, which demonstrated that NaB could partially restore CUMS-induced blood-brain barrier (BBB) impairments. Besides, the pathologic changes were alleviated. In conclusion, these results demonstrated that NaB significantly improved depression-like behaviors in CUMS-induced mice and its antidepressant actions might be related with, at least in part, the increasing brain 5-HT concentration and BDNF expression and restoring BBB impairments. PMID:26957230

  16. Investigation into Variation of Endogenous Metabolites in Bone Marrow Cells and Plasma in C3H/He Mice Exposed to Benzene

    PubMed Central

    Sun, Rongli; Zhang, Juan; Yin, Lihong; Pu, Yuepu

    2014-01-01

    Benzene is identified as a carcinogen. Continued exposure of benzene may eventually lead to damage to the bone marrow, accompanied by pancytopenia, aplastic anemia or leukemia. This paper explores the variations of endogenous metabolites to provide possible clues for the molecular mechanism of benzene-induced hematotoxicity. Liquid chromatography coupled with time of flight-mass spectrometry (LC-TOF-MS) and principal component analysis (PCA) was applied to investigate the variation of endogenous metabolites in bone marrow cells and plasma of male C3H/He mice. The mice were injected subcutaneously with benzene (0, 300, 600 mg/day) once daily for seven days. The body weights, relative organ weights, blood parameters and bone marrow smears were also analyzed. The results indicated that benzene caused disturbances in the metabolism of oxidation of fatty acids and essential amino acids (lysine, phenylalanine and tyrosine) in bone marrow cells. Moreover, fatty acid oxidation was also disturbed in plasma and thus might be a common disturbed metabolic pathway induced by benzene in multiple organs. This study aims to investigate the underlying molecular mechanisms involved in benzene hematotoxicity, especially in bone marrow cells. PMID:24658442

  17. CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid.

    PubMed

    Porrini, V; Lanzillotta, A; Branca, C; Benarese, M; Parrella, E; Lorenzini, L; Calzà, L; Flaibani, R; Spano, P F; Imbimbo, B P; Pizzi, M

    2015-08-27

    Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1β), Tumor Necrosis Factor alpha (TNFα) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-α, IL-1β and iNOS induced by 10 μM β-amyloid1-42 (Aβ42). Moreover, CHF5074 significantly increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Aβ42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 μM or 500 μM) or R-flurbiprofen (3 μM or 100 μM), as both compounds limited the pro

  18. Chromium mapping in male mice reproductive glands exposed to CrCl 3 using proton and X-ray synchrotron radiation microbeams

    NASA Astrophysics Data System (ADS)

    Ortega, R.; Devès, G.; Bonnin-Mosbah, M.; Salomé, M.; Susini, J.; Anderson, L. M.; Kasprzak, K. S.

    2001-07-01

    Preconception exposure to certain chemicals may increase risk of tumors in offspring, especially with regard to occupational metals such as chromium. However, the mechanism of chromium trans-generation carcinogenicity remains unknown. Using scanning proton X-ray microanalysis we have been able to detect chromium in testicular tissue sections from mice treated by intraperitoneal injection of 1 mmol/kg CrCl 3. Chromium concentration was about 5 μg/g dry mass in average, but higher concentrations were found within the limiting membrane of the testes, the tunica albuginea. In addition, synchrotron radiation X-ray fluorescence measurements, with microscopic resolution, clearly demonstrated the presence of chromium in the tunica albuginea but also within isolated cells from the interstitial connective tissue.

  19. Acute Hematological Effects in Mice Exposed to the Expected Doses, Dose-rates, and Energies of Solar Particle Event-like Proton Radiation

    PubMed Central

    Sanzari, Jenine K.; Cengel, Keith A.; Wan, X. Steven; Rusek, Adam; Kennedy, Ann R.

    2014-01-01

    NASA has funded several projects that have provided evidence for the radiation risk in space. One radiation concern arises from solar particle event (SPE) radiation, which is composed of energetic electrons, protons, alpha particles and heavier particles. SPEs are unpredictable and the accompanying SPE radiation can place astronauts at risk of blood cell death, contributing to a weakened immune system and increased susceptibility to infection. The doses, dose rates, and energies of the proton radiation expected to occur during a SPE have been simulated at the NASA Space Radiation Laboratory, Brookhaven National Laboratory, delivering total body doses to mice. Hematological values were evaluated at acute time points, up to 24 hrs. post-radiation exposure. PMID:25202654

  20. Health Risk Assessment for Air Pollutants: Alterations in Lung and Cardiac Gene Expression in Mice Exposed to Milano Winter Fine Particulate Matter (PM2.5)

    PubMed Central

    Battaglia, Cristina; Cifola, Ingrid; Mangano, Eleonora; Mantecca, Paride; Camatini, Marina; Palestini, Paola

    2014-01-01

    Oxidative stress, pulmonary and systemic inflammation, endothelial cell dysfunction, atherosclerosis and cardiac autonomic dysfunction have been linked to urban particulate matter exposure. The chemical composition of airborne pollutants in Milano is similar to those of other European cities though with a higher PM2.5 fraction. Milano winter fine particles (PM2.5win) are characterized by the presence of nitrate, organic carbon fraction, with high amount of polycyclic aromatic hydrocarbons and elements such as Pb, Al, Zn, V, Fe, Cr and others, with a negligible endotoxin presence. In BALB/c mice, we examined, at biochemical and transcriptomic levels, the adverse effects of repeated Milano PM2.5win exposure in lung and heart. We found that ET-1, Hsp70, Cyp1A1, Cyp1B1 and Hsp-70, HO-1, MPO respectively increased within lung and heart of PM2.5win-treated mice. The PM2.5win exposure had a strong impact on global gene expression of heart tissue (181 up-regulated and 178 down-regulated genes) but a lesser impact on lung tissue (14 up-regulated genes and 43 down-regulated genes). Focusing on modulated genes, in lung we found two- to three-fold changes of those genes related to polycyclic aromatic hydrocarbons exposure and calcium signalling. Within heart the most striking aspect is the twofold to threefold increase in collagen and laminin related genes as well as in genes involved in calcium signaling. The current study extends our previous findings, showing that repeated instillations of PM2.5win trigger systemic adverse effects. PM2.5win thus likely poses an acute threat primarily to susceptible people, such as the elderly and those with unrecognized coronary artery or structural heart disease. The study of genomic responses will improve understanding of disease mechanisms and enable future clinical testing of interventions against the toxic effects of air pollutant. PMID:25296036

  1. Inhibition of Histone H3K9 Acetylation by Anacardic Acid Can Correct the Over-Expression of Gata4 in the Hearts of Fetal Mice Exposed to Alcohol during Pregnancy

    PubMed Central

    Peng, Chang; Zhu, Jing; Sun, Hui-Chao; Huang, Xu-Pei; Zhao, Wei-An; Zheng, Min; Liu, Ling-Juan; Tian, Jie

    2014-01-01

    Background Cardiovascular malformations can be caused by abnormalities in Gata4 expression during fetal development. In a previous study, we demonstrated that ethanol exposure could lead to histone hyperacetylation and Gata4 over-expression in fetal mouse hearts. However, the potential mechanisms of histone hyperacetylation and Gata4 over-expression induced by ethanol remain unclear. Methods and Results Pregnant mice were gavaged with ethanol or saline. Fetal mouse hearts were collected for analysis. The results of ethanol fed groups showed that global HAT activity was unusually high in the hearts of fetal mice while global HDAC activity remained unchanged. Binding of P300, CBP, PCAF, SRC1, but not GCN5, were increased on the Gata4 promoter relative to the saline treated group. Increased acetylation of H3K9 and increased mRNA expression of Gata4, α-MHC, cTnT were observed in these hearts. Treatment with the pan-histone acetylase inhibitor, anacardic acid, reduced the binding of P300, PCAF to the Gata4 promoter and reversed H3K9 hyperacetylation in the presence of ethanol. Interestingly, anacardic acid attenuated over-expression of Gata4, α-MHC and cTnT in fetal mouse hearts exposed to ethanol. Conclusions Our results suggest that P300 and PCAF may be critical regulatory factors that mediate Gata4 over-expression induced by ethanol exposure. Alternatively, P300, PCAF and Gata4 may coordinate over-expression of cardiac downstream genes in mouse hearts exposed to ethanol. Anacardic acid may thus protect against ethanol-induced Gata4, α-MHC, cTnT over-expression by inhibiting the binding of P300 and PCAF to the promoter region of these genes. PMID:25101666

  2. Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response

    PubMed Central

    2010-01-01

    Background Ciguatoxins (CTXs) are polyether marine neurotoxins and potent activators of voltage-gated sodium channels. This toxin is carried by multiple reef-fish species and human consumption of ciguatoxins can result in an explosive gastrointestinal/neurologic illness. This study characterizes the global transcriptional response in mouse brain to a symptomatic dose of the highly toxic Pacific ciguatoxin P-CTX-1 and additionally compares this data to transcriptional profiles from liver and whole blood examined previously. Adult male C57/BL6 mice were injected with 0.26 ng/g P-CTX-1 while controls received only vehicle. Animals were sacrificed at 1, 4 and 24 hrs and transcriptional profiling was performed on brain RNA with Agilent whole genome microarrays. RT-PCR was used to independently validate gene expression and the web tool DAVID was used to analyze gene ontology (GO) and molecular pathway enrichment of the gene expression data. Results A pronounced 4°C hypothermic response was recorded in these mice, reaching a minimum at 1 hr and lasting for 8 hrs post toxin exposure. Ratio expression data were filtered by intensity, fold change and p-value, with the resulting data used for time course analysis, K-means clustering, ontology classification and KEGG pathway enrichment. Top GO hits for this gene set included acute phase response and mono-oxygenase activity. Molecular pathway analysis showed enrichment for complement/coagulation cascades and metabolism of xenobiotics. Many immediate early genes such as Fos, Jun and Early Growth Response isoforms were down-regulated although others associated with stress such as glucocorticoid responsive genes were up-regulated. Real time PCR confirmation was performed on 22 differentially expressed genes with a correlation of 0.9 (Spearman's Rho, p < 0.0001) with microarray results. Conclusions Many of the genes differentially expressed in this study, in parallel with the hypothermia, figure prominently in protection against

  3. Induction of p53-mediated apoptosis in splenocytes and thymocytes of C57BL/6 mice exposed to perfluorooctane sulfonate (PFOS)

    SciTech Connect

    Dong, Guang-Hui; Wang, Jing; Zhang, Ying-Hua; Liu, Miao-Miao; Wang, Da; Zheng, Li; Jin, Yi-He

    2012-10-15

    Perfluorooctane sulfonate (PFOS) is a persistent environmental contaminant found in human and wildlife tissues. It has been reported that PFOS can cause atrophy of the immune organs and apoptosis of immunocytes in rodents. However, the mechanism behind such cause is still unclear. To understand the model of cell death and its mechanism on lymphoid cells in vivo, we conducted a dose/response experiment in which 4 groups of male adult C57BL/6 mice (12 mice per group) were dosed daily by oral gavage with PFOS at 0, 0.0167, 0.0833, or 0.8333 mg/kg/day, yielding targeted Total Administered Dose (TAD) of 0, 1, 5, or 50 mg PFOS/kg, respectively, over 60 days. The results showed that spleen and thymus weight were significantly reduced in the highest PFOS-dose-group (TAD 50 mg PFOS/kg) compared to the control group, whereas liver weight was significantly increased. We analyzed the cell death via apoptosis with an annexin-V/propidium iodide assay by flow cytometry, and observed that both the percentage of apoptosis and the expression of the pro-apoptotic proteins p53 in splenocytes and thymocytes increased in a dose-related manner after PFOS treatment. We also observed that PFOS induced p53-dependent apoptosis through the cooperation between the Bcl-xl down regulation without changing the Bcl-2 and Bax expression. The down regulation of Bcl-xl was strongly indicating mitochondrial involvement in apoptosis. It is confirmed by the release of cytochrome c and activation of caspase-3. All of these findings establish an important role of p53 and mitochondrial function in PFOS induced toxic environment in the host. -- Highlights: ► PFOS immunotoxicity is caused by induction of apoptosis via the p53 activation. ► PFOS exposure can induce down regulation of Bcl-xl. ► Mitochondria are involved in PFOS-induced apoptosis. ► PFOS exposure can cause the release of cytochrome c and activation of caspase-3.

  4. Antidepressant-like behavioral, anatomical, and biochemical effects of petroleum ether extract from maca (Lepidium meyenii) in mice exposed to chronic unpredictable mild stress.

    PubMed

    Ai, Zhong; Cheng, Ai-Fang; Yu, Yuan-Tao; Yu, Long-Jiang; Jin, Wenwen

    2014-05-01

    Maca has been consumed as a medical food in Peru for thousands of years, and exerts anxiolytic and antidepressant effects. Our present study aimed to evaluate the behavior and anatomical and biochemical effects of petroleum ether extract from maca (ME) in the chronic unpredictable mild stress (CUMS) model of depression in mice. Three different doses of maca extract (125, 250, and 500 mg/kg) were orally administrated in the six-week CUMS procedure. Fluoxetine (10 mg/kg) was used as a positive control drug. Maca extract (250 and 500 mg/kg) significantly decreased the duration of immobility time in the tail suspension test. After treatment with maca extract (250 and 500 mg/kg), the granule cell layer in the dentate gyrus appeared thicker. Maca extract (250 and 500 mg/kg) also induced a significant reduction in corticosterone levels in mouse serum. In mouse brain tissue, after six weeks of treatment, noradrenaline and dopamine levels were increased by maca extract, and the activity of reactive oxygen species was significantly inhibited. Serotonin levels were not significantly altered. These results demonstrated that maca extract (250 and 500 mg/kg) showed antidepressant-like effects and was related to the activation of both noradrenergic and dopaminergic systems, as well as attenuation of oxidative stress in mouse brain. PMID:24730393

  5. Saponins, especially platyconic acid A, from Platycodon grandiflorum reduce airway inflammation in ovalbumin-induced mice and PMA-exposed A549 cells.

    PubMed

    Choi, Jae Ho; Jin, Sun Woo; Kim, Hyung Gyun; Choi, Chul Yung; Lee, Hyun Sun; Ryu, Shi Yong; Chung, Young Chul; Hwang, Young Jung; Um, Yeon Ji; Jeong, Tae Cheon; Jeong, Hye Gwang

    2015-02-11

    We investigated the inhibitory effects of Platycodon grandiflorum root-derived saponins (Changkil saponins: CKS) on ovalbumin-induced airway inflammation in mice. CKS suppressed leukocytes number, IgE, Th1/Th2 cytokines, and MCP-1 chemokine secretion in bronchoalveolar lavage fluid. Also, ovalbumin-increased MUC5AC, MMP-2/9, and TIMP-1/-2 mRNA expression, NF-κB activation, leukocytes recruitment, and mucus secretion were inhibited by CKS treatment. Moreover, the active component of CKS, platyconic acid A (PA), suppressed PMA-induced MUC5AC mRNA expression (from 2.1 ± 0.2 to 1.1 ± 0.1) by inhibiting NF-κB activation (from 2.3 ± 0.2 to 1.2 ± 0.1) via Akt (from 3.7 ± 0.3 to 2.1 ± 0.2) (p < 0.01) in A549 cells. Therefore, we demonstrate that CKS or PA suppressed the development of respiratory inflammation, hyperresponsiveness, and remodeling by reducing allergic responses, and they may be potential herbal drugs for allergen-induced respiratory disease prevention. PMID:25590691

  6. Antidepressant-Like Behavioral, Anatomical, and Biochemical Effects of Petroleum Ether Extract from Maca (Lepidium meyenii) in Mice Exposed to Chronic Unpredictable Mild Stress

    PubMed Central

    Ai, Zhong; Cheng, Ai-Fang; Yu, Yuan-Tao; Yu, Long-Jiang

    2014-01-01

    Abstract Maca has been consumed as a medical food in Peru for thousands of years, and exerts anxiolytic and antidepressant effects. Our present study aimed to evaluate the behavior and anatomical and biochemical effects of petroleum ether extract from maca (ME) in the chronic unpredictable mild stress (CUMS) model of depression in mice. Three different doses of maca extract (125, 250, and 500 mg/kg) were orally administrated in the six-week CUMS procedure. Fluoxetine (10 mg/kg) was used as a positive control drug. Maca extract (250 and 500 mg/kg) significantly decreased the duration of immobility time in the tail suspension test. After treatment with maca extract (250 and 500 mg/kg), the granule cell layer in the dentate gyrus appeared thicker. Maca extract (250 and 500 mg/kg) also induced a significant reduction in corticosterone levels in mouse serum. In mouse brain tissue, after six weeks of treatment, noradrenaline and dopamine levels were increased by maca extract, and the activity of reactive oxygen species was significantly inhibited. Serotonin levels were not significantly altered. These results demonstrated that maca extract (250 and 500 mg/kg) showed antidepressant-like effects and was related to the activation of both noradrenergic and dopaminergic systems, as well as attenuation of oxidative stress in mouse brain. PMID:24730393

  7. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.

    PubMed

    Nicolas, Gaël; Bennoun, Myriam; Porteu, Arlette; Mativet, Sandrine; Beaumont, Carole; Grandchamp, Bernard; Sirito, Mario; Sawadogo, Michèle; Kahn, Axel; Vaulont, Sophie

    2002-04-01

    We recently reported the hemochromatosis-like phenotype observed in our Usf2 knockout mice. In these mice, as in murine models of hemochromatosis and patients with hereditary hemochromatosis, iron accumulates in parenchymal cells (in particular, liver and pancreas), whereas the reticuloendothelial system is spared from this iron loading. We suggested that this phenotypic trait could be attributed to the absence, in the Usf2 knockout mice, of a secreted liver-specific peptide, hepcidin. We conjectured that the reverse situation, namely overexpression of hepcidin, might result in phenotypic traits of iron deficiency. This question was addressed by generating transgenic mice expressing hepcidin under the control of the liver-specific transthyretin promoter. We found that the majority of the transgenic mice were born with a pale skin and died within a few hours after birth. These transgenic animals had decreased body iron levels and presented severe microcytic hypochromic anemia. So far, three mosaic transgenic animals have survived. They were unequivocally identified by physical features, including reduced body size, pallor, hairless and crumpled skin. These pleiotropic effects were found to be associated with erythrocyte abnormalities, with marked anisocytosis, poikylocytosis and hypochromia, which are features characteristic of iron-deficiency anemia. These results strongly support the proposed role of hepcidin as a putative iron-regulatory hormone. The animal models devoid of hepcidin (the Usf2 knockout mice) or overexpressing the peptide (the transgenic mice presented in this paper) represent valuable tools for investigating iron homeostasis in vivo and for deciphering the molecular mechanisms of hepcidin action. PMID:11930010

  8. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin

    PubMed Central

    Nicolas, Gaël; Bennoun, Myriam; Porteu, Arlette; Mativet, Sandrine; Beaumont, Carole; Grandchamp, Bernard; Sirito, Mario; Sawadogo, Michèle; Kahn, Axel; Vaulont, Sophie

    2002-01-01

    We recently reported the hemochromatosis-like phenotype observed in our Usf2 knockout mice. In these mice, as in murine models of hemochromatosis and patients with hereditary hemochromatosis, iron accumulates in parenchymal cells (in particular, liver and pancreas), whereas the reticuloendothelial system is spared from this iron loading. We suggested that this phenotypic trait could be attributed to the absence, in the Usf2 knockout mice, of a secreted liver-specific peptide, hepcidin. We conjectured that the reverse situation, namely overexpression of hepcidin, might result in phenotypic traits of iron deficiency. This question was addressed by generating transgenic mice expressing hepcidin under the control of the liver-specific transthyretin promoter. We found that the majority of the transgenic mice were born with a pale skin and died within a few hours after birth. These transgenic animals had decreased body iron levels and presented severe microcytic hypochromic anemia. So far, three mosaic transgenic animals have survived. They were unequivocally identified by physical features, including reduced body size, pallor, hairless and crumpled skin. These pleiotropic effects were found to be associated with erythrocyte abnormalities, with marked anisocytosis, poikylocytosis and hypochromia, which are features characteristic of iron-deficiency anemia. These results strongly support the proposed role of hepcidin as a putative iron-regulatory hormone. The animal models devoid of hepcidin (the Usf2 knockout mice) or overexpressing the peptide (the transgenic mice presented in this paper) represent valuable tools for investigating iron homeostasis in vivo and for deciphering the molecular mechanisms of hepcidin action. PMID:11930010

  9. Chronic exposure to a predator or its scent does not inhibit male–male competition in male mice lacking brain serotonin

    PubMed Central

    Huo, Ying; Fang, Qi; Shi, Yao-Long; Zhang, Yao-Hua; Zhang, Jian-Xu

    2014-01-01

    Although it is well-known that defective signaling of the 5-HT system in the brain and stressful stimuli can cause psychological disorders, their combined effects on male–male aggression and sexual attractiveness remain unknown. Our research aimed at examining such effects using tryptophan hydroxylase 2 (Tph2) knockout male mice vs. a rat- or rat scent-based chronic stress model. Tph2+/+ and Tph2−/− male mice were placed individually into the rat home cage (rat), a cage containing soiled rat bedding (rat scent) or a cage containing fresh bedding (control) for 5 h every other day for 56 consecutive days. In Tph2+/+ male mice, rat-exposure decreased male–male aggression and sexual attractiveness of urine odor relative to either rat scent-exposure or control; and rat scent-exposure decreased aggression rather than sexual attractiveness of urine odor compared with control. However, such dose-dependent and long-lasting behavioral inhibitory effects vanished in Tph2−/− male mice. RT-PCR assay further revealed that putative regulatory genes, such as AR, ERα and GluR4 in the prefrontal cortex, and TrkB-Tc and 5-HTR1A in the hippocampus, were down-regulated at the mRNA level in either rat- or rat scent-exposed Tph2+/+ male mice, but partially in the Tph2−/− ones. Hence, we suggest that the dose-dependent and long-lasting inhibitory effects of chronic predator exposure on male–male aggression, sexual attractiveness of urine odor, and mRNA expression of central regulatory genes might be mediated through the 5-HT system in the brain of male mice. PMID:24782727

  10. S-Nitrosylation in Organs of Mice Exposed to Low or High Doses of γ-Rays: The Modulating Effect of Iodine Contrast Agent at a Low Radiation Dose

    PubMed Central

    Nicolas, Fadia; Wu, Changgong; Bukhari, Salwa; de Toledo, Sonia M.; Li, Hong; Shibata, Masayuki; Azzam, Edouard I.

    2015-01-01

    The covalent addition of nitric oxide (NO•) onto cysteine thiols, or S-nitrosylation, modulates the activity of key signaling proteins. The dysregulation of normal S-nitrosylation contributes to degenerative conditions and to cancer. To gain insight into the biochemical changes induced by low-dose ionizing radiation, we determined global S-nitrosylation by the “biotin switch” assay coupled with mass spectrometry analyses in organs of C57BL/6J mice exposed to acute 0.1 Gy of 137Cs γ-rays. The dose of radiation was delivered to the whole body in the presence or absence of iopamidol, an iodinated contrast agent used during radiological examinations. To investigate whether similar or distinct nitrosylation patterns are induced following high-dose irradiation, mice were exposed in parallel to acute 4 Gy of 137Cs γ rays. Analysis of modulated S-nitrosothiols (SNO-proteins) in freshly-harvested organs of animals sacrificed 13 days after irradiation revealed radiation dose- and contrast agent-dependent changes. The major results were as follows: (i) iopamidol alone had significant effects on S-nitrosylation in brain, lung and liver; (ii) relative to the control, exposure to 0.1 Gy without iopamidol resulted in statistically-significant SNO changes in proteins that differ in molecular weight in liver, lung, brain and blood plasma; (iii) iopamidol enhanced the decrease in S-nitrosylation induced by 0.1 Gy in brain; (iv) whereas a decrease in S-nitrosylation occurred at 0.1 Gy for proteins of ~50 kDa in brain and for proteins of ~37 kDa in liver, an increase was detected at 4 Gy in both organs; (v) mass spectrometry analyses of nitrosylated proteins in brain revealed differential modulation of SNO proteins (e.g., sodium/potassium-transporting ATPase subunit beta-1; beta tubulins; ADP-ribosylation factor 5) by low- and high-dose irradiation; and (vi) ingenuity pathway analysis identified major signaling networks to be modulated, in particular the neuronal nitric oxide

  11. Mutational specificities of environmental carcinogens in the lacl gene of Escherichia coli H. V: DNA sequence analysis of mutations in bacteria recovered from the liver of Swiss mice exposed to 1,2-dimethylhydrazine, azoxymethane, and methylazoxymethanolacetate

    SciTech Connect

    Zeilmaker, M.J.; Horsfall, M.J.; van Helten, J.B.; Glickman, B.W.; Mohn, G.R. )

    1991-01-01

    The host-mediated assay (HMA) was used to determine the spectra of mutations induced in the lacl gene of Escherichia coli cells recovered from the livers of Swiss mice exposed to the carcinogens 1,2-dimethylhydrazine (SDMH), azoxymethane (AOM), and methylazoxymethanolacetate (MAMA). These spectra were further compared with changes induced by dimethylnitrosamine (DMNA) in the HMA methodology. A total of 177 independent lacl mutations arising in the HMA following exposure to SDMH, AOM, and MAMA were analyzed. Single-base substitutions accounted for 97% of all mutations analyzed. The vast majority of the single-base substitutions consisted of G:C----A:T transitions (94% of all mutations). The remaining mutations consisted of A:T----G:C transitions (3% of all mutations) while non-base substitutions accounted for only 3% of the total mutagenesis. The latter mutations consisted of one frameshift mutation and four lacO deletions. The distribution of G:C----A:T transitions induced by the three chemicals in the first 200 bp of the lacl gene was not random, but rather clustered at sites where a target guanine was flanked at the 5{prime} site by a purine residue.

  12. Intermittent hypoxia promotes recovery of respiratory motor function in spinal cord-injured mice depleted of serotonin in the central nervous system.

    PubMed

    Komnenov, Dragana; Solarewicz, Julia Z; Afzal, Fareeza; Nantwi, Kwaku D; Kuhn, Donald M; Mateika, Jason H

    2016-08-01

    We examined the effect of repeated daily exposure to intermittent hypoxia (IH) on the recovery of respiratory and limb motor function in mice genetically depleted of central nervous system serotonin. Electroencephalography, diaphragm activity, ventilation, core body temperature, and limb mobility were measured in spontaneously breathing wild-type (Tph2(+/+)) and tryptophan hydroxylase 2 knockout (Tph2(-/-)) mice. Following a C2 hemisection, the mice were exposed daily to IH (i.e., twelve 4-min episodes of 10% oxygen interspersed with 4-min normoxic periods followed by a 90-min end-recovery period) or normoxia (i.e., sham protocol, 21% oxygen) for 10 consecutive days. Diaphragm activity recovered to prehemisection levels in the Tph2(+/+) and Tph2(-/-) mice following exposure to IH but not normoxia [Tph2(+/+) 1.3 ± 0.2 (SE) vs. 0.3 ± 0.2; Tph2(-/-) 1.06 ± 0.1 vs. 0.3 ± 0.1, standardized to prehemisection values, P < 0.01]. Likewise, recovery of tidal volume and breathing frequency was evident, although breathing frequency values did not return to prehemisection levels within the time frame of the protocol. Partial recovery of limb motor function was also evident 2 wk after spinal cord hemisection. However, recovery was not dependent on IH or the presence of serotonin in the central nervous system. We conclude that IH promotes recovery of respiratory function but not basic motor tasks. Moreover, we conclude that spontaneous or treatment-induced recovery of respiratory and motor limb function is not dependent on serotonin in the central nervous system in a mouse model of spinal cord injury. PMID:27402561

  13. Window contamination on Expose-R

    NASA Astrophysics Data System (ADS)

    Demets, R.; Bertrand, M.; Bolkhovitinov, A.; Bryson, K.; Colas, C.; Cottin, H.; Dettmann, J.; Ehrenfreund, P.; Elsaesser, A.; Jaramillo, E.; Lebert, M.; van Papendrecht, G.; Pereira, C.; Rohr, T.; Saiagh, K.

    2015-01-01

    Expose is a multi-user instrument for astrobiological and astrochemical experiments in space. Installed at the outer surface of the International Space Station, it enables investigators to study the impact of the open space environment on biological and biochemical test samples. Two Expose missions have been completed so far, designated as Expose-E (Rabbow et al. 2012) and Expose-R (Rabbow et al. this issue). One of the space-unique environmental factors offered by Expose is full-spectrum, ultraviolet (UV)-rich electromagnetic radiation from the Sun. This paper describes and analyses how on Expose-R, access of the test samples to Solar radiation degraded during space exposure in an unpredicted way. Several windows in front of the Sun-exposed test samples acquired a brown shade, resulting in a reduced transparency in visible light, UV and vacuum UV (VUV). Post-flight investigations revealed the discolouration to be caused by a homogenous film of cross-linked organic polymers at the inside of the windows. The chemical signature varied per sample carrier. No such films were found on windows from sealed, pressurized compartments, or on windows that had been kept out of the Sun. This suggests that volatile compounds originating from the interior of the Expose facility were cross-linked and photo-fixed by Solar irradiation at the rear side of the windows. The origin of the volatiles was not fully identified; most probably there was a variety of sources involved including the biological test samples, adhesives, plastics and printed circuit boards. The outer surface of the windows (pointing into space) was chemically impacted as well, with a probable effect on the transparency in VUV. The reported analysis of the window contamination on Expose-R is expected to help the interpretation of the scientific results and offers possibilities to mitigate this problem on future missions - in particular Expose-R2, the direct successor of Expose-R.

  14. Involvement of heparan sulfate 6-O-sulfation in the regulation of energy metabolism and the alteration of thyroid hormone levels in male mice.

    PubMed

    Nagai, Naoko; Habuchi, Hiroko; Sugaya, Noriko; Nakamura, Masao; Imamura, Toru; Watanabe, Hideto; Kimata, Koji

    2013-08-01

    Here, we report that male heparan sulfate 6-O-sulfotransferase-2 (Hs6st2) knockout mice showed increased body weight in an age-dependent manner even when fed with a normal diet and showed a phenotype of impaired glucose metabolism and insulin resistance. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the expression of mitochondrial uncoupling proteins Ucp1 and Ucp3 was reduced in the interscapular brown adipose tissue (BAT) of male Hs6st2 knockout mice, suggesting reduced energy metabolism. The serum level of thyroid-stimulating hormone was significantly higher and that of thyroxine was lower in the knockout mice. When cultures of brown adipocytes from wild-type and Hs6st2 knockout mice isolated and differentiated in vitro were treated with FGF19 (fibroblast growth factor 19) or FGF21 in the presence or the absence of heparitinase I, phosphorylation of p42/p44 mitogen-activated protein (MAP) kinase was reduced. Heparan sulfate (HS) 6-O-sulfation was reduced not only in BAT but also in the thyroid tissue of the knockout mice. Thus, 6-O-sulfation in HS seems to play an important role in mediating energy metabolism by controlling thyroid hormone levels and signals from the FGF19 subfamily proteins, and the alteration of the HS composition may result in metabolic syndrome phenotypes such as altered glucose and insulin tolerance. PMID:23690091

  15. EXPOSE-R cosmic radiation time profile

    NASA Astrophysics Data System (ADS)

    Dachev, Tsvetan; Horneck, Gerda; Häder, Donat-Peter; Schuster, Martin

    2015-01-01

    The aim of the paper is to present the time profile of cosmic radiation exposure obtained by the radiation risks radiometer-dosimeter (R3DR) during the ESA exposition facility for EXPOSE-R mission (EXPOSE-R) in the EXPOSE-R facility outside the Russian Zvezda module of the International Space Station (ISS). Another aim is to make the obtained results available to other EXPOSE-R teams for use in their data analysis. R3DR is a low mass and small dimensions automated device, which measures solar radiation in four channels and in addition cosmic ionizing radiation. The main results of cosmic ionizing radiation measurements are: three different radiation sources were detected and quantified: galactic cosmic rays (GCR), energetic protons from the inner radiation belt (IRB) in the region of the South Atlantic anomaly and energetic electrons from the outer radiation belt (ORB). The highest daily averaged absorbed dose rate of 506 μGy day-1 came from IRB protons; GCR delivered much smaller daily absorbed dose rates of 81.4 μGy day-1 on average, and ORB source delivered on average a dose rate of 89 μGy day-1. The IRB and ORB daily averaged absorbed dose rates were higher than those observed during the ESA exposition facility for EXPOSE-E mission (EXPOSE-E), whereas the GCR rate was smaller than that measured during the EXPOSE-E mission. The reason for this difference is much less surrounding constructions shielding of the R3DR instrument in comparison with the R3DE instrument.

  16. Urocortin 2 modulates aspects of social behaviour in mice.

    PubMed

    Breu, Johannes; Touma, Chadi; Hölter, Sabine M; Knapman, Alana; Wurst, Wolfgang; Deussing, Jan M

    2012-08-01

    Urocortin 2 (UCN2), a member of the corticotropin-releasing hormone family, is involved in the regulation of stress-related behaviours in rodents. To determine its physiological function we generated mice lacking UCN2 by applying a classical knockout strategy. We examined hypothalamus-pituitary-adrenocortical axis activity, anxiety- and depression-related behaviours without finding significant differences between mutant and wild-type littermates. Investigating social abilities we observed, that male, but not female, UCN2 knockout animals showed an altered social behaviour. Here we report that male UCN2 null mice showed more passive social interactions and reduced aggressiveness in comparison to wild-type animals. In conclusion, UCN2 seems to modulate aggressive behaviour in male mice. Furthermore, our findings provide additional evidence for previously reported sex-specific effects of UCN2. PMID:22640813

  17. The effect of dose on 2,3,7,8-TCDD tissue distribution, metabolism and elimination in CYP1A2(-/_) knockout and C57BL/6N parental strains of mice

    EPA Science Inventory

    Numerous metabolism studies have demonstrated that the toxic contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is poorly metabolized. A hallmark feature of TCDD exposure is induction of hepatic CYP1A2 and subsequent sequestration leading to high liver-to-fat concentration ra...

  18. The Effect of Dose on 2,3,7,8-TCDD Tissue Distribution, Metabolism and Elimination in CYP1A2 (-/-) Knockout and C57BL/6N Parental Strains of Mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous metabolism studies have demonstrated that the highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is poorly metabolized. A hallmark feature of TCDD exposure is induction of hepatic CYP1A2 and subsequent sequestration leading to high liver to fat concentration ratios. This study was in...

  19. Minimal impact of age and housing temperature on the metabolic phenotype of Acc2-/- mice.

    PubMed

    Brandon, Amanda E; Stuart, Ella; Leslie, Simon J; Hoehn, Kyle L; James, David E; Kraegen, Edward W; Turner, Nigel; Cooney, Gregory J

    2016-03-01

    An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12-16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42-54 weeks of age, male WT and Acc2(-/-) mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2(-/-) mice, aged Acc2(-/-) mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2(-/-) mice respectively, P<0.05) and skeletal muscle glycogen content (+60%, P<0.05) without any detectable change in whole-body energy expenditure. Hyperinsulinaemic-euglycaemic clamp studies revealed no difference in insulin action between groups with similar glucose infusion rates and tissue glucose uptake. Housing Acc2(-/-) mice at 29 °C did not alter body composition, glucose tolerance or the effects of fat feeding compared with WT mice. These results confirm that manipulation of Acc2 may alter FAO in mice, but this has little impact on body composition or insulin action. PMID:26668208

  20. COMPARISON OF OVERALL METABOLISM OF 1, 2, 7, 8-PECDD IN CYP1A2(-L-) KNOCKOUT AND C57BL/6N PARENTAL STRAINS OF MICE

    EPA Science Inventory

    COMPARISON OF OVERALL METABOLISM OF 1,2,3,7,8-PeCDD
    IN CYP1A2 (-/-) KNOCKOUT AND C57BL/6N PARENTAL
    STRAINS OF MICE

    Heldur Hakk1 and Janet J. Diliberto2

    1 USDA-ARS, Biosciences Research Laboratory, P.O. Box 5674, Fargo, ND, USA
    2 US EPA, ORD, National Heal...

  1. Auditory processing and morphological anomalies in medial geniculate nucleus of Cntnap2 mutant mice.

    PubMed

    Truong, Dongnhu T; Rendall, Amanda R; Castelluccio, Brian C; Eigsti, Inge-Marie; Fitch, R Holly

    2015-12-01

    Genetic epidemiological studies support a role for CNTNAP2 in developmental language disorders such as autism spectrum disorder, specific language impairment, and dyslexia. Atypical language development and function represent a core symptom of autism spectrum disorder (ASD), with evidence suggesting that aberrant auditory processing-including impaired spectrotemporal processing and enhanced pitch perception-may both contribute to an anomalous language phenotype. Investigation of gene-brain-behavior relationships in social and repetitive ASD symptomatology have benefited from experimentation on the Cntnap2 knockout (KO) mouse. However, auditory-processing behavior and effects on neural structures within the central auditory pathway have not been assessed in this model. Thus, this study examined whether auditory-processing abnormalities were associated with mutation of the Cntnap2 gene in mice. Cntnap2 KO mice were assessed on auditory-processing tasks including silent gap detection, embedded tone detection, and pitch discrimination. Cntnap2 knockout mice showed deficits in silent gap detection but a surprising superiority in pitch-related discrimination as compared with controls. Stereological analysis revealed a reduction in the number and density of neurons, as well as a shift in neuronal size distribution toward smaller neurons, in the medial geniculate nucleus of mutant mice. These findings are consistent with a central role for CNTNAP2 in the ontogeny and function of neural systems subserving auditory processing and suggest that developmental disruption of these neural systems could contribute to the atypical language phenotype seen in autism spectrum disorder. PMID:26501174

  2. Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU) treatment

    PubMed Central

    Webster, Anna Francina; Williams, Andrew; Recio, Leslie; Yauk, Carole L.

    2014-01-01

    Standard methodology for identifying chemical carcinogens is both time-consuming and resource intensive. Researchers are actively investigating how new technologies can be used to identify chemical carcinogens in a more rapid and cost-effective manner. Here we performed a toxicogenomic case study of the liver carcinogen furan. Full study and mode of action details were previously published in the Journal of Toxicology and Applied Pharmacology. Female B6C3F1 mice were sub-chronically treated with two non-carcinogenic (1 and 2 mg/kg bw) and two carcinogenic (4 and 8 mg/kg bw) doses of furan for 21 days. Half of the mice in each dose group were also treated with 0.02% bromodeoxyuridine (BrdU) for five days prior to sacrifice [13]. Agilent gene expression microarrays were used to measure changes in liver gene and long non-coding RNA expression (published in Toxicological Sciences). Here we describe the experimental and quality control details for the microarray data. We also provide the R code used to analyze the raw data files, produce fold change and false discovery rate (FDR) adjusted p values for each gene, and construct hierarchical clustering between datasets. PMID:26484082

  3. Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU) treatment.

    PubMed

    Webster, Anna Francina; Williams, Andrew; Recio, Leslie; Yauk, Carole L

    2014-12-01

    Standard methodology for identifying chemical carcinogens is both time-consuming and resource intensive. Researchers are actively investigating how new technologies can be used to identify chemical carcinogens in a more rapid and cost-effective manner. Here we performed a toxicogenomic case study of the liver carcinogen furan. Full study and mode of action details were previously published in the Journal of Toxicology and Applied Pharmacology. Female B6C3F1 mice were sub-chronically treated with two non-carcinogenic (1 and 2 mg/kg bw) and two carcinogenic (4 and 8 mg/kg bw) doses of furan for 21 days. Half of the mice in each dose group were also treated with 0.02% bromodeoxyuridine (BrdU) for five days prior to sacrifice [13]. Agilent gene expression microarrays were used to measure changes in liver gene and long non-coding RNA expression (published in Toxicological Sciences). Here we describe the experimental and quality control details for the microarray data. We also provide the R code used to analyze the raw data files, produce fold change and false discovery rate (FDR) adjusted p values for each gene, and construct hierarchical clustering between datasets. PMID:26484082

  4. Hematotoxicity and genotoxicity evaluations in Swiss mice intraperitoneally exposed to Bacillus thuringiensis (var kurstaki) spore crystals genetically modified to express individually Cry1Aa, Cry1Ab, Cry1Ac, or Cry2Aa.

    PubMed

    Mezzomo, Bélin Poletto; Miranda-Vilela, Ana Luisa; Barbosa, Lilian Carla Pereira; Albernaz, Vanessa Lima; Grisolia, Cesar Koppe

    2016-08-01

    Bacillus thuringiensis (Bt) has been widely used in foliar sprays as part of integrated pest management strategies against insect pests of agricultural crops. Since the advent of genetically modified plants expressing Bt δ-endotoxins, the bioavailability of Cry proteins has increased, and therefore for biosafety reasons their adverse effects should be studied, mainly for nontarget organisms. We evaluated, in Swiss mice, the hematotoxicity and genotoxicity of the genetically modified strains of Bt spore crystals Cry1Aa, 1Ab, 1Ac, or 2Aa at 27 mg/kg, and Cry1Aa, 1Ab and 2Aa also at 136 and 270 mg/kg, administered with a single intraperitoneal injection 24 h before euthanasia. Controls received filtered water or cyclophosphamide. Blood samples collected by cardiac puncture were used to perform hemogram, and bone marrow was extracted for the micronucleus test. Bt spore crystals presented toxicity for lymphocytes when in higher doses, which varied according to the type of spore crystal studied, besides promoting cytotoxic and genotoxic effects for the erythroid lineage of bone marrow, mainly at highest doses. Although the profile of such adverse side effects can be related to their high level of exposure, which is not commonly found in the environment, results indicated that these Bt spore crystals were not harmless to mice. This suggests that a more specific approach should be taken to increase knowledge about their toxicological properties and to establish the toxicological risks to nontarget organisms. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 970-978, 2016. PMID:25899034

  5. Ameliorative Effects of Operculina turpethum and its Isolated Stigma-5,22dien-3-o-β-D-glucopyranoside on the Hematological Parameters of Male Mice Exposed to N-Nitrosodimethylamine, a Potent Carcinogen

    PubMed Central

    Sharma, Veena; Singh, Manu

    2014-01-01

    Objectives: Enormous propensity of plants to synthesize a variety of structurally diverse bioactive compounds, has made the plant kingdom a potential source of chemical constituents with various therapeutic values, including antitumor and cytotoxic activities. Blood is a good indicator to determine the physiological and pathological status of man and animal. The objective of the present study is to determine the effect of Operculina turpethum root extract and its isolated glycoside treatment on the hematological parameters in the mice with N-Nitrosodimethylamine (NDMA) induced cancer. Materials and Methods: The body weights of the animals were recorded before and after the experiment. Non-coagulated blood was tested for total erythrocyte count, total leukocyte count, hemoglobin, differential leukocyte count (DLC) and for other blood indices. Results: A significant (P < 0.01), (P < 0.001) recovery of the red blood cell and white blood cell counts, packed cell volume and hemoglobin content in the host after 21 day treatment was shown. Conclusion: These results show that the extract of Operculina turpethum is relatively safe following oral administration and have possible stimulatory effect on red blood cell production and there was dose dependent therapeutic effect. PMID:24748732

  6. Mutations in Mll2, an H3K4 Methyltransferase, Result in Insulin Resistance and Impaired Glucose Tolerance in Mice

    PubMed Central

    Schröter, David; Matthews, Helen C.; Bogani, Debora; Moir, Lee; Long, Anna; Church, Christopher; Hugill, Alison; Anstee, Quentin M.; Goldin, Rob; Thursz, Mark; Hollfelder, Florian; Cox, Roger D.

    2013-01-01

    We employed a random mutagenesis approach to identify novel monogenic determinants of type 2 diabetes. Here we show that haplo-insufficiency of the histone methyltransferase myeloid-lineage leukemia (Mll2/Wbp7) gene causes type 2 diabetes in the mouse. We have shown that mice heterozygous for two separate mutations in the SET domain of Mll2 or heterozygous Mll2 knockout mice were hyperglycaemic, hyperinsulinaemic and developed non-alcoholic fatty liver disease. Consistent with previous Mll2 knockout studies, mice homozygous for either ENU mutation (or compound heterozygotes) died during embryonic development at 9.5–14.5 days post coitum. Heterozygous deletion of Mll2 induced in the adult mouse results in a normal phenotype suggesting that changes in chromatin methylation during development result in the adult phenotype. Mll2 has been shown to regulate a small subset of genes, a number of which Neurod1, Enpp1, Slc27a2, and Plcxd1 are downregulated in adult mutant mice. Our results demonstrate that histone H3K4 methyltransferase Mll2 is a component of the genetic regulation necessary for glucose homeostasis, resulting in a specific disease pattern linking chromatin modification with causes and progression of type 2 diabetes, providing a basis for its further understanding at the molecular level. PMID:23826075

  7. Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice.

    PubMed

    Seino, S; Iwanaga, T; Nagashima, K; Miki, T

    2000-03-01

    The regulation of insulin secretion from pancreatic beta-cells depends critically on the activities of their plasma membrane ion channels. ATP-sensitive K+ channels (K(ATP) channels) are present in many cells and regulate a variety of cellular functions by coupling cell metabolism with membrane potential. The activity of the K(ATP) channels in pancreatic beta-cells is regulated by changes in the ATP and ADP concentrations (ATP/ADP ratio) caused by glucose metabolism. Thus, the K(ATP) channels are the ATP and ADP sensors in the regulation of glucose-induced insulin secretion. K(ATP) channels are also the target of sulfonylureas, which are widely used in the treatment of type 2 diabetes. Molecular cloning of the two subunits of the pancreatic beta-cell K(ATP) channel, Kir6.2 (an inward rectifier K+ channel member) and SUR1 (a receptor for sulfonylureas), has provided great insight into its structure and function. Kir6.2 subunits form the K+ ion-permeable pore and primarily confer inhibition of the channels by ATP, while SUR1 subunits confer activation of the channels by MgADP and K+ channel openers, such as diazoxide, as well as inhibition by sulfonylureas. The SUR1 subunits also enhance the sensitivity of the channels to ATP. To determine the physiological roles of K(ATP) channels directly, we have generated two kinds of genetically engineered mice: mice expressing a dominant-negative form of Kir6.2 specifically in the pancreatic beta-cells (Kir6.2G132S Tg mice) and mice lacking Kir6.2 (Kir6.2 knockout mice). Studies of these mice elucidated various roles of the K(ATP) channels in endocrine pancreatic function: 1) the K(ATP) channels are the major determinant of the resting membrane potential of pancreatic beta-cells, 2) both glucose- and sulfonylurea-induced membrane depolarization of beta-cells require closure of the K(ATP) channels, 3) both glucose- and sulfonylurea-induced rises in intracellular calcium concentration in beta-cells require closure of the K

  8. Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice

    PubMed Central

    Zhang, Hongsheng; Kang, Eunchai; Wang, Yaqing; Yang, Chaojuan; Yu, Hui; Wang, Qin; Chen, Zheyu; Zhang, Chen; Christian, Kimberly M.; Song, Hongjun; Ming, Guo-li; Xu, Zhiheng

    2016-01-01

    Several genome- and proteome-wide studies have associated transcription and translation changes of CRMP2 (collapsing response mediator protein 2) with psychiatric disorders, yet little is known about its function in the developing or adult mammalian brain in vivo. Here we show that brain-specific Crmp2 knockout (cKO) mice display molecular, cellular, structural and behavioural deficits, many of which are reminiscent of neural features and symptoms associated with schizophrenia. cKO mice exhibit enlarged ventricles and impaired social behaviour, locomotor activity, and learning and memory. Loss of Crmp2 in the hippocampus leads to reduced long-term potentiation, abnormal NMDA receptor composition, aberrant dendrite development and defective synapse formation in CA1 neurons. Furthermore, knockdown of crmp2 specifically in newborn neurons results in stage-dependent defects in their development during adult hippocampal neurogenesis. Our findings reveal a critical role for CRMP2 in neuronal plasticity, neural function and behavioural modulation in mice. PMID:27249678

  9. Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice.

    PubMed

    Zhang, Hongsheng; Kang, Eunchai; Wang, Yaqing; Yang, Chaojuan; Yu, Hui; Wang, Qin; Chen, Zheyu; Zhang, Chen; Christian, Kimberly M; Song, Hongjun; Ming, Guo-Li; Xu, Zhiheng

    2016-01-01

    Several genome- and proteome-wide studies have associated transcription and translation changes of CRMP2 (collapsing response mediator protein 2) with psychiatric disorders, yet little is known about its function in the developing or adult mammalian brain in vivo. Here we show that brain-specific Crmp2 knockout (cKO) mice display molecular, cellular, structural and behavioural deficits, many of which are reminiscent of neural features and symptoms associated with schizophrenia. cKO mice exhibit enlarged ventricles and impaired social behaviour, locomotor activity, and learning and memory. Loss of Crmp2 in the hippocampus leads to reduced long-term potentiation, abnormal NMDA receptor composition, aberrant dendrite development and defective synapse formation in CA1 neurons. Furthermore, knockdown of crmp2 specifically in newborn neurons results in stage-dependent defects in their development during adult hippocampal neurogenesis. Our findings reveal a critical role for CRMP2 in neuronal plasticity, neural function and behavioural modulation in mice. PMID:27249678

  10. Effect of low frequency low energy pulsing electromagnetic fields on mice injected with cyclophosphamide

    SciTech Connect

    Cadossi, R.; Zucchini, P.; Emilia, G.; Franceschi, C.; Cossarizza, A.; Santantonio, M.; Mandolini, G.; Torelli, G. )

    1991-03-01

    C3H mice have been used to investigate the effect of a combination of cyclophosphamide (CY) and electromagnetic fields (PEMF). Mice were injected i.p. with a single dose of 200 mg/kg body weight of CY and then exposed to PEMF 24 h per day. In an initial series of experiments immediately after CY injection mice were exposed to PEMF until sacrifice. WBC counts in the peripheral blood demonstrated a quicker decline in WBC at days 1 and 2 in mice exposed to PEMF. Groups of mice were sacrificed at days 1, 4, 6, 8, and 10 after CY injection. In mice exposed to PEMF the spleen weight was less than in controls at days 6, 8, and 10. Autoradiographic studies demonstrated that the labeling index of bone marrow smears did not significantly differ between controls and experimental mice exposed to PEMF, whereas the spleen labeling index proved to be higher among control mice versus mice exposed to PEMF at day 6, and higher among mice exposed to PEMF versus controls at day 8. In a second series of experiments mice were exposed to PEMF only over the 24 h following CY injection. We found that the spleens of mice exposed to PEMF weighed less than those of controls at days 6 and 8. The labeling index of bone marrow did evidence a slight decrease among mice exposed to PEMF at days 8 and 10 after CY injection versus control mice. The spleen labeling index proved to be lower in experimental mice exposed to PEMF than in controls at days 4, 6, and 8. Mice were then injected with CY, half were exposed to PEMF, and 24 h later bone marrow was recovered from both groups of animals. The same number of bone marrow cells was injected via the tail vein into recipient mice irradiated to 8.5 Gy.

  11. Nrf2-mediated haeme oxygenase-1 up-regulation induced by cobalt protoporphyrin has antinociceptive effects against inflammatory pain in the formalin test in mice.

    PubMed

    Rosa, Angelo O; Egea, Javier; Lorrio, Silvia; Rojo, Ana I; Cuadrado, Antonio; López, Manuela G

    2008-07-15

    This study investigated the effect of haeme oxygenase-1 (HO-1) in nociception induced by formalin injection in the mice hind paw. Intraperitoneal (i.p.) administration of cobalt protoporphyrin (CoPP, an HO-1 inducer, 5mg/kg) 24h before the test, inhibited the nociceptive response during the second phase, but not during the first phase of the formalin test. The effect of CoPP was prevented by treatment with tin protoporphyrin (SnPP, an inhibitor of HO-1 activity) administered either by i.p. (25mg/kg, 30 min before the test) or intraplantar (400 nmol/paw, 5 min before the test) routes. Human embryonic kidney (HEK) 293T cells treated with 10 microM CoPP expressed 20-fold higher HO-1 levels when compared to controls; this effect was suppressed by transfection with the dominant negative for the nuclear factor-erythroid 2-related factor 2 (Nrf2). Western blot analysis also revealed that CoPP treatment induced a similar 20-fold increase in HO-1 expression in the paw; this effect was attenuated in knockout mice for Nrf2. CoPP treatment of wild-type, but not in Nrf2 knockout mice, resulted in a striking increase of HO-1 stained cells surrounding the muscular tissues of the hind limbs. HO-1 positive cells were scarce in wild-type and in Nrf2 knockout untreated mice. CoPP-induced HO-1 expression in Nrf2 knockout mice was lost and correlated with the loss of antinociceptive effects. In conclusion, Nrf2-mediated HO-1 expression induced an antinociceptive effect at peripheral sites. These results suggest that HO-1 modulates the inflammatory pain pathways. Hence, the development of drugs that could raise peripheral HO-1 could be relevant in inflammatory pain treatment. PMID:17964723

  12. Biochemical markers in butadiene-exposed workers

    SciTech Connect

    Bechtold, W.E.; Hayes, R.B.; Thornton-Manning, J.R.; Henderson, R.F.

    1994-11-01

    1,3-Butadiene (BD) is used to manufacture a wide range of polymers and copolymers including styrene-butadiene rubber, polybutadiene, and acrylonitrile-butadiene-syrene resins. The carcinogenicity of BD has been determined in life-span inhalation studies in both Sprague-Dawley rats and B6C3F{sub 1} mice. Results suggest a marked species difference in the carcinogenic effects of BD. For example, female mice exposed to as low as 6.25 ppm BD exhibited increased alveolar/bronchiolar neoplasms. In contrast, BD was only a weak carcinogen in Sprague-Dawley rats. Rats were observed to have an increase only in mammary tumors after exposure to 1000 ppm. A biochemical study of highly exposed BD workers and unexposed controls is providing valuable information on BD metabolism in humans, and how this relates to the development of intermediate biologic effects. A group of heavily exposed workers were identified in a BD production facility in China. The purpose of this paper is to report the initial results from the sampling trip in the first quarter of 1994.

  13. Delayed cutaneous wound closure in HO-2 deficient mice despite normal HO-1 expression

    PubMed Central

    Lundvig, Ditte M S; Scharstuhl, Alwin; Cremers, Niels A J; Pennings, Sebastiaan W C; te Paske, Jeroen; van Rheden, René; van Run-van Breda, Coby; Regan, Raymond F; Russel, Frans G M; Carels, Carine E; Maltha, Jaap C; Wagener, Frank A D T G

    2014-01-01

    Impaired wound healing can lead to scarring, and aesthetical and functional problems. The cytoprotective haem oxygenase (HO) enzymes degrade haem into iron, biliverdin and carbon monoxide. HO-1 deficient mice suffer from chronic inflammatory stress and delayed cutaneous wound healing, while corneal wound healing in HO-2 deficient mice is impaired with exorbitant inflammation and absence of HO-1 expression. This study addresses the role of HO-2 in cutaneous excisional wound healing using HO-2 knockout (KO) mice. Here, we show that HO-2 deficiency also delays cutaneous wound closure compared to WT controls. In addition, we detected reduced collagen deposition and vessel density in the wounds of HO-2 KO mice compared to WT controls. Surprisingly, wound closure in HO-2 KO mice was accompanied by an inflammatory response comparable to WT mice. HO-1 induction in HO-2 deficient skin was also similar to WT controls and may explain this protection against exaggerated cutaneous inflammation but not the delayed wound closure. Proliferation and myofibroblast differentiation were similar in both two genotypes. Next, we screened for candidate genes to explain the observed delayed wound closure, and detected delayed gene and protein expression profiles of the chemokine (C-X-C) ligand-11 (CXCL-11) in wounds of HO-2 KO mice. Abnormal regulation of CXCL-11 has been linked to delayed wound healing and disturbed angiogenesis. However, whether aberrant CXCL-11 expression in HO-2 KO mice is caused by or is causing delayed wound healing needs to be further investigated. PMID:25224969

  14. [Vaccines and exposed occupations].

    PubMed

    Gendrel, Dominique

    2007-04-01

    The use of safe and efficacious vaccines in occupational settings to protect workers from diseases to which they may be exposed is obvious and has been included in the employment law. Healthcare workers are particular exposed. Immunization has two purposes : protect the worker from contracting a disease, but also prevent him from disseminating the disease to weakened patients. It is important not only to take into account existing recommendations for immunization, but also to envisage their extension to teachers and staff of nurseries and primary schools. Routine vaccination against whooping cough, varicella, measles and hepatitis A is particularly warranted in these categories. Recommendations should also extend to medical students who are too often poorly protected and insufficiently warned against potential occupational exposure to pathogens and dissemination to their patients. PMID:17433233

  15. AMP Activated Protein Kinase Is Indispensable for Myocardial Adaptation to Caloric Restriction in Mice

    PubMed Central

    Chen, Kai; Kobayashi, Satoru; Xu, Xianmin; Viollet, Benoit; Liang, Qiangrong

    2013-01-01

    Caloric restriction (CR) is a robust dietary intervention known to enhance cardiovascular health. AMP activated protein kinase (AMPK) has been suggested to mediate the cardioprotective effects of CR. However, this hypothesis remains to be tested by using definitive loss-of-function animal models. In the present study, we subjected AMPKα2 knockout (KO) mice and their wild type (WT) littermates to a CR regimen that reduces caloric intake by 20%–40% for 4 weeks. CR decreased body weight, heart weight and serum levels of insulin in both WT and KO mice to the same degree, indicating the effectiveness of the CR protocol. CR activated cardiac AMPK signaling in WT mice, but not in AMPKα2 KO mice. Correspondingly, AMPKα2 KO mice had markedly reduced cardiac function during CR as determined by echocardiography and hemodynamic measurements. The compromised cardiac function was associated with increased markers of oxidative stress, endoplasmic reticulum stress and myocyte apoptosis. Mechanistically, CR down-regulated the expression of ATP5g2, a subunit of mitochondrial ATP synthase, and reduced ATP content in AMPKα2 KO hearts, but not in WT hearts. In addition, CR accelerated cardiac autophagic flux in WT mice, but failed to do so in AMPKα2 KO mice. These results demonstrated that without AMPK, CR triggers adverse effects that can lead to cardiac dysfunction, suggesting that AMPK signaling pathway is indispensible for energy homeostasis and myocardial adaptation to CR, a dietary intervention that normally produces beneficial cardiac effects. PMID:23527250

  16. Time- and age-dependent effects of serotonin on gasping and autoresuscitation in neonatal mice.

    PubMed

    Chen, Jianping; Magnusson, Jennifer; Karsenty, Gerard; Cummings, Kevin J

    2013-06-15

    The role of brain stem serotonin (5-hydroxytryptamine, 5-HT) in autoresuscitation in neonatal life is unclear. We hypothesized that a specific loss of 5-HT would compromise gasping and autoresuscitation mainly in the second postnatal week and that acute restoration of 5-HT would reverse the defects. We exposed postnatal day (P)4-5, P8-9, and P11-12 tryptophan-hydroxylase-2 knockout (TPH2(-/-)) and wild-type littermates (WT) to 10 episodes of anoxia (97% N2, 3% CO2), measuring survival, gasp latency, gasp frequency (fB), and the time required to restore eupnea and heart rate. We also tested P8-9 TPH2(-/-) mice after restoring 5-HT with a single injection of 5-hydroxytryptophan (5-HTP) 1-2 h before testing or with multiple injections beginning 24 h before testing. At P4-5 and P8-9, but not at P11-12, gasp latency and the recovery of eupnea were delayed ~2- to 3-fold in TPH2(-/-) pups compared with WT (P < 0.001). At all ages, TPH2(-/-) pups displayed reduced gasp fB (~20-30%; P < 0.001) and delayed heart rate recovery (~60%; P = 0.002) compared with WT littermates. TPH2(-/-) survival was reduced compared with WT (P < 0.001), especially at P8-9 and P11-12 (P = 0.004). Whereas 1-2 h of 5-HTP treatment improved the gasp latency and fB of P8-9 TPH2(-/-) pups, improved cardiorespiratory recovery and survival required 24 h of treatment. Our data suggest that 5-HT operates over a long time span (24 h) to improve survival during episodic severe hypoxia. Early in development (P4-9), 5-HT is critical for both respiratory and cardiovascular components of autoresuscitation; later (P11-12), it is critical mainly for cardiovascular components. Nevertheless, the effect of 5-HT deficiency on survival is most striking from P8 to P12. PMID:23558391

  17. 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 ...

  18. Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice

    PubMed Central

    Li, Qun; Degano, Alicia L.; Penati, Judith; Zhuo, Justin; Roe, Charles R.; Ronnett, Gabriele V.

    2014-01-01

    Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT. PMID:25299635

  19. Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice.

    PubMed

    Park, Min Jung; Aja, Susan; Li, Qun; Degano, Alicia L; Penati, Judith; Zhuo, Justin; Roe, Charles R; Ronnett, Gabriele V

    2014-01-01

    Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT. PMID:25299635

  20. Differential Fmo3 Gene Expression in Various Liver Injury Models Involving Hepatic Oxidative Stress in Mice

    PubMed Central

    Rudraiah, Swetha; Moscovitz, Jamie E.; Donepudi, Ajay C.; Campion, Sarah N.; Slitt, Angela L.; Aleksunes, Lauren M.; Manautou, José E.

    2015-01-01

    Flavin-containing monooxygenase-3 (FMO3) catalyzes metabolic reactions similar to cytochrome P450 monooxygenase however, most metabolites of FMO3 are considered non-toxic. Recent findings in our laboratory demonstrated Fmo3gene induction following toxic acetaminophen (APAP) treatment in mice.The goal of this study was to evaluate Fmo3gene expression in diverseother mouse models of hepatic oxidative stress and injury. Fmo3 gene regulation by Nrf2 was also investigated using Nrf2 knockout (Nrf2 KO) mice. In our studies, male C57BL/6J mice were treated with toxic dosesof hepatotoxicants or underwent bile duct ligation (BDL, 10d). Hepatotoxicants included APAP (400 mg/kg, 24 to 72h), alpha-naphthylisothiocyanate (ANIT; 50 mg/kg, 2 to 48h), carbontetrachloride (CCl4;10 or 30 μL/kg, 24 and 48h) and allyl alcohol (AlOH; 30 or 60 mg/kg, 6 and 24h). Because oxidative stress activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2), additional studies investigated Fmo3 gene regulation by Nrf2 using Nrf2 knockout (Nrf2 KO) mice. At appropriate time-points, blood and liver samples were collected for assessment of plasma alanine aminotransferase (ALT) activity, plasma and hepatic bile acid levels, as well as liver Fmo3 mRNA and protein expression. Fmo3 mRNA expression increased significantly by 43-fold at 12h after ANIT treatment,and this increase translates to a 4-fold change in protein levels. BDL also increased Fmo3 mRNA expression by 1899-fold, but with no change in protein levels. Treatment of mice with CCl4decreased liver Fmo3gene expression, whileno change in expression was detected with AlOH treatment. Nrf2 KO mice are more susceptible to APAP (400 mg/kg, 72h) treatment compared to their wild-type (WT) counterparts, which is evidenced by greater plasma ALT activity. Fmo3 mRNA and protein expression increased in Nrf2 KO mice after APAP treatment. Collectively, not all hepatotoxicantsthat produce oxidative stress alter Fmo3gene expression. Along with APAP, toxic ANIT

  1. Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine.

    PubMed

    Jedynak, Paulina; Kos, Tomasz; Sandi, Carmen; Kaczmarek, Leszek; Filipkowski, Robert K

    2014-09-01

    The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression. PMID:24931850

  2. Sall1, Sall2, and Sall4 Are Required for Neural Tube Closure in Mice

    PubMed Central

    Böhm, Johann; Buck, Anja; Borozdin, Wiktor; Mannan, Ashraf U.; Matysiak-Scholze, Uta; Adham, Ibrahim; Schulz-Schaeffer, Walter; Floss, Thomas; Wurst, Wolfgang; Kohlhase, Jürgen; Barrionuevo, Francisco

    2008-01-01

    Four homologs to the Drosophila homeotic gene spalt (sal) exist in both humans and mice (SALL1 to SALL4/Sall1 to Sall4, respectively). Mutations in both SALL1 and SALL4 result in the autosomal-dominant developmental disorders Townes-Brocks and Okihiro syndrome, respectively. In contrast, no human diseases have been associated with SALL2 to date, and Sall2-deficient mice have shown no apparent abnormal phenotype. We generated mice deficient in Sall2 and, contrary to previous reports, 11% of our Sall2-deficient mice showed background-specific neural tube defects, suggesting that Sall2 has a role in neurogenesis. To investigate whether Sall4 may compensate for the absence of Sall2, we generated compound Sall2 knockout/Sall4 genetrap mutant mice. In these mutants, the incidence of neural tube defects was significantly increased. Furthermore, we found a similar phenotype in compound Sall1/4 mutant mice, and in vitro studies showed that SALL1, SALL2, and SALL4 all co-localized in the nucleus. We therefore suggest a fundamental and redundant function of the Sall proteins in murine neurulation, with the heterozygous loss of a particular SALL protein also possibly compensated in humans during development. PMID:18818376

  3. 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 ...

  4. In Utero and Lactational Exposure to PCBs in Mice: Adult Offspring Show Altered Learning and Memory Depending on Cyp1a2 and Ahr Genotypes

    PubMed Central

    Curran, Christine P.; Genter, Mary Beth; Patel, Krishna V.; Schaefer, Tori L.; Skelton, Matthew R.; Williams, Michael T.; Vorhees, Charles V.

    2011-01-01

    Background: Both coplanar and noncoplanar polychlorinated biphenyls (PCBs) exhibit neurotoxic effects in animal studies, but individual congeners do not always produce the same effects as PCB mixtures. Humans genetically have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2)-uninduced basal levels and > 12-fold variability in aryl hydrocarbon receptor (AHR)affinity; because CYP1A2 is known to sequester coplanar PCBs and because AHR ligands include coplanar PCBs, both genotypes can affect PCB response. Objectives: We aimed to develop a mouse paradigm with extremes in Cyp1a2 and Ahr genotypes to explore genetic susceptibility to PCB-induced developmental neurotoxicity using an environmentally relevant mixture of PCBs. Methods: We developed a mixture of eight PCBs to simulate human exposures based on their reported concentrations in human tissue, breast milk, and food supply. We previously characterized specific differences in PCB congener pharmacokinetics and toxicity, comparing high-affinity–AHR Cyp1a2 wild-type [Ahrb1_Cyp1a2(+/+)], poor-affinity–AHR Cyp1a2 wild-type [Ahrd_Cyp1a2(+/+)], and high-affinity–AHR Cyp1a2 knockout [Ahrb1_Cyp1a2(–/–)] mouse lines [Curran CP, Vorhees CV, Williams MT, Genter MB, Miller ML, Nebert DW. 2011. In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes. Toxicol Sci 119:189–208]. Dams received a mixture of three coplanar and five noncoplanar PCBs on gestational day 10.5 and postnatal day (PND) 5. In the present study we conducted behavioral phenotyping of exposed offspring at PND60, examining multiple measures of learning, memory, and other behaviors. Results: We observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2(–/–) mice, including impaired novel object recognition and increased failure rate in the Morris water maze. However, all PCB-treated genotypes showed significant differences on

  5. Hyperphagia and leptin resistance in Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) deficient mice

    PubMed Central

    Stradecki, Holly M.; Jaworski, Diane M.

    2011-01-01

    Obesity is a complex genetic and behavioral disorder arising from improper integration of peripheral signals at central autonomic centers. For the hypothalamus to respond to dynamic physiological alterations, it must retain a degree of plasticity throughout life. Evidence is mounting that an intricate balance between matrix metalloproteinase (MMP)-mediated extracellular matrix proteolysis and tissue inhibitor of metalloproteinase (TIMP)-mediated proteolysis inhibition contributes to tissue remodeling. However, few studies have examined the role of MMPs/TIMPs in hypothalamic remodeling and energy homeostasis. To determine TIMP-2’s contribution to hypothalamic regulation of feeding, body mass and food consumption was monitored in TIMP-2 knockout (KO) mice fed a standard chow or high fat diet (HFD). TIMP-2 KO mice of both sexes gained more weight than wild-type (WT) mice even when fed the chow diet. Prior to obesity onset, TIMP-2 KO mice were hyperphagic, without increased orexigenic or decreased anorexigenic neuropeptide expression, but leptin resistant (i.e. reduced leptin-induced anorexigenic response and STAT3 activation). HFD exacerbated weight gain and hyperleptinemia. In addition, proteolysis was increased in the arcuate nucleus of TIMP-2 KO mice. These data suggest a role for TIMP-2 in hypothalamic control of feeding and energy homeostasis. PMID:21175899

  6. Generation of Immunodeficient Mice Bearing Human Immune Systems by the Engraftment of Hematopoietic Stem Cells.

    PubMed

    Hasgur, Suheyla; Aryee, Ken Edwin; Shultz, Leonard D; Greiner, Dale L; Brehm, Michael A

    2016-01-01

    Immunodeficient mice are being used as recipients of human hematopoietic stem cells (HSC) for in vivo analyses of human immune system development and function. The development of several stocks of immunodeficient Prkdc (scid) (scid), or recombination activating 1 or 2 gene (Rag1 or Rag2) knockout mice bearing a targeted mutation in the gene encoding the IL2 receptor gamma chain (IL2rγ), has greatly facilitated the engraftment of human HSC and enhanced the development of functional human immune systems. These "humanized" mice are being used to study human hematopoiesis, human-specific immune therapies, human-specific pathogens, and human immune system homeostasis and function. The establishment of these model systems is technically challenging, and levels of human immune system development reported in the literature are variable between laboratories. The use of standard protocols for optimal engraftment of HSC and for monitoring the development of the human immune systems would enable more direct comparisons between humanized mice generated in different laboratories. Here we describe a standard protocol for the engraftment of human HSC into 21-day-old NOD-scid IL2rγ (NSG) mice using an intravenous injection approach. The multiparameter flow cytometry used to monitor human immune system development and the kinetics of development are described. PMID:27150084

  7. [Sphingomyelin synthase 2 deficiency decreases atherosclerosis and inhibits inflammation in mice].

    PubMed

    Qin, Rui; Chen, Ming-Liang; Zhu, Ke; Deng, Jin-Bo; Shi, Yuan-Yuan

    2010-08-25

    Plasma sphingomyelin (SM) has been shown to be an independent risk factor for coronary heart disease, and sphingomyelin synthase 2 (SMS2) contributes to de novo SM biosynthesis and plasma membrane SM levels. The aim of the present study is to evaluate the in vivo role of SMS2 deficiency in serum SM metabolism and atherosclerosis (AS) development. We used male SMS2 knockout (SMS2(-/-)) and C57BL/6J (wild-type, WT) mice as experimental and control groups, respectively. Each group was fed high-fat diet (1% cholesterol, 20% leaf fat), as well as bile salt for accelerating the atherosclerotic formation. After three months of feeding, the mice were killed to observe aortic arches and oil red-stained longitudinal sections of thoracoabdominal aortae. Fasting blood samples were taken from the tail vein before and after high-fat diet, and the serum lipid and SM levels were measured by using kits and enzymatic method respectively. Western blot was used to analyze the contents of nuclear factor-kappaB (NFkappaB) p65 subunit in peritoneal macrophages stimulated with lipopolysaccharide (LPS) after high-fat diet. The results showed that after high-fat diet, SMS2(-/-) mice presented decreased atherosclerotic lesions in aortic arch and thoracoabdominal aorta compared with WT mice. Regardless of whether high-fat diet were given or not, SMS2(-/-) mice showed a significant decrease in serum SM level (P<0.05), but no significant changes in serum lipid levels, compared with WT mice. The expressions of NFkappaB p65 were attenuated in macrophages from SMS2(-/-) mice in response to LPS stimulation compared with those of the WT mice. These results suggest that SMS2 deficiency decreases AS and inhibits inflammation in mice. Thus, SMS2 deficiency may be a potential therapeutic strategy. PMID:20717634

  8. EXPOSE-R on Mission on the ISS

    NASA Astrophysics Data System (ADS)

    Panitz, Corinna; Rabbow, Elke; Rettberg, Petra; Barczyk, Simon; Kloss, Maria; Reitz, Guenther

    Currently EXPOSE-R is on mission! This astrobiological exposure facility was accommodated at the universal workplace URM-D Zenith payload site, located outside the Russian Svezda Module of the International Space Station (ISS) by extravehicular activity (EVA) on March 10th 2009. It contains 3 trays accommodating 12 sample compartments with sample carriers in three levels either open to space vacuum or kept in a defined gas environment. In its 8 experiments of biological and chemical content, more than 1200 individual samples are exposed to solar ultraviolet (UV) radiations, vacuum, cosmic rays or extreme temperature variations. In their different experiments the involved scientists are studying the question of life's origin on Earth and the results of their experiments are contributing to different aspects of the evolution and distribution of life in the Universe. Additionally integrated into the EXPOSE-R facility are several dosimeters monitoring the ionising and the solar UV-radiation during the mission to deliver useful information to complement the sample analysis. In close cooperation with the DLR and the Technical University Munich (TUM), the Rheinisch -Westfülische Technischen Hochschule Aachen (RWTH Aachen) operates the experiment "Spores". a This is one of the 6 astrobiological experiments of the ROSE-Consortium" (Response of Or-ganisms to Space Environment) of the EXPOSE-R mission. In these experiments spores of bacteria, fungi and ferns are being over layered or mixed with meteorite material. The analysis of the effect of the space parameters on different biological endpoints of the spores of the mi-croorganism Bacillus subtilis will be performed after the retrieval of the experiment scheduled for the end of 2010. Parallel to the space mission an identical set of samples was accommodated into EXPOSE-R trays identical in construction to perform the Mission Ground Reference (MGR) Test. Currently this MGR Test is carried out in the Planetary and Space

  9. Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2.

    PubMed

    Chugh, Deepti; Ali, Idrish; Bakochi, Anahita; Bahonjic, Elma; Etholm, Lars; Ekdahl, Christine T

    2015-01-01

    Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age) and tonic-clonic (3.5-4 months) phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread. PMID:26177381

  10. Cochlear function in mice following inhalation of brevetoxin-3

    PubMed Central

    Benson, Janet M.; Stagner, Barden B.; Martin, Glen K.; Friedman, Melissa; Durr, Sarah E.; Gomez, Andrea; McDonald, Jacob; Fleming, Lora E.; Backer, Lorraine C.; Baden, Daniel G.; Bourdelais, Andrea; Naar, Jerome; Lonsbury-Martin, Brenda L.

    2009-01-01

    Brevetoxin-3 was shown previously to adversely affect central auditory function in goldfish. The present study evaluated the effects of exposure to this agent on cochlear function in mice using the 2f1-f2 distortion-product otoacoustic emission (DPOAE). Towards this end, inbred CBA/CaJ mice were exposed to a relatively high concentration of brevetoxin-3 (∼400 μg/m3) by nose-only inhalation for a 2-h period. Further, a subset of these mice received a second exposure a day later that lasted for an additional 4 h. Mice exposed only once for 2 h did not exhibit any notable cochlear effects. Similarly, mice exposed two times, for a cumulative dose of 6 h, exhibited essentially no change in DPOAE levels. PMID:15902474

  11. Welding tritium exposed stainless steel

    SciTech Connect

    Kanne, W.R. Jr.

    1994-11-01

    Stainless steels that are exposed to tritium become unweldable by conventional methods due to buildup of decay helium within the metal matrix. With longer service lives expected for tritium containment systems, methods for welding on tritium exposed material will become important for repair or modification of the systems. Solid-state resistance welding and low-penetration overlay welding have been shown to mitigate helium embrittlement cracking in tritium exposed 304 stainless steel. These processes can also be used on stainless steel containing helium from neutron irradiation, such as occurs in nuclear reactors.

  12. Nucleotide-Binding Oligomerization Domain-1 and -2 Play No Role in Controlling Brucella abortus Infection in Mice

    PubMed Central

    Oliveira, Fernanda S.; Carvalho, Natalia B.; Zamboni, Dario S.; Oliveira, Sergio C.

    2012-01-01

    Nucleotide-binding oligomerization domain proteins (NODs) are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. Further, several in vivo studies have demonstrated a role for Nod1 and Nod2 in host defense against bacterial pathogens. Here, we demonstrated that macrophages from NOD1-, NOD2-, and Rip2-deficient mice produced lower levels of TNF-α following infection with live Brucella abortus compared to wild-type mice. Similar reduction on cytokine synthesis was not observed for IL-12 and IL-6. However, NOD1, NOD2, and Rip2 knockout mice were no more susceptible to infection with virulent B. abortus than wild-type mice. Additionally, spleen cells from NOD1-, NOD2-, and Rip2-deficient mice showed unaltered production of IFN-γ compared to C57BL/6 mice. Taken together, this study demonstrates that NOD1, NOD2 and Rip2 are dispensable for the control of B. abortus during in vivo infection. PMID:22203860

  13. Subchronic exposure of mice to Love Canal soil contaminants

    SciTech Connect

    Silkworth, J.B.; McMartin, D.N.; Rej, R.; Narang, R.S.; Stein, V.B.; Briggs, R.G.; Kaminsky, L.S.

    1984-04-01

    The health hazard potential of soil collected from the surface of the Love Canal chemical dump site in Niagara Falls, New York, was assessed in 90-day exposure studies. Female CD-1 mice were exposed to two concentrations of the volatile components of 1 kg of soil with and without direct soil contact. Control mice were identically housed but without soil. The soil was replaced weekly and 87 compounds were detected in the air in the cages above fresh and 7-day-old soil as analyzed by gas chromatography/mass spectrometry. The concentration of many of these compounds decreased during the 7-day exposure cycle. Histopathologic, hematologic, and serum enzyme studies followed necropsy of all mice. There was no mortality of mice exposed for up to 90 days under any condition. Thymus and spleen weights relative to body weight were increased after 4 weeks of exposure by inhalation but not after 8 or 12 weeks of exposure. alpha-, beta-, and delta- Benzenehexachlorides , pentachlorobenzene, and hexachlorobenzene were detected in liver tissue from these animals. Mice exposed to 5- to 10-fold elevated concentration of volatiles had increased body and relative kidney weights. There was no chemically induced lesion in any animal exposed only to the volatile soil contaminants. Mice exposed by direct contact with the soil without elevated volatile exposure had increased body (10%) and relative liver weights (169%). Centrolobular hepatocyte hypertrophy, which involved 40 to 70% of the lobules, was observed in all mice in this group.

  14. Interferon-induced Ifit2/ISG54 protects mice from lethal VSV neuropathogenesis.

    PubMed

    Fensterl, Volker; Wetzel, Jaime L; Ramachandran, Srividya; Ogino, Tomoaki; Stohlman, Stephen A; Bergmann, Cornelia C; Diamond, Michael S; Virgin, Herbert W; Sen, Ganes C

    2012-01-01

    Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2(-/-)) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1(-/-) mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2(-/-) mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2(-/-) mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2(-/-) mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2(-/-) mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2(-/-) mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2(-/-) mice. Our study provides a clear demonstration of tissue-, virus- and

  15. Effect of amphetamine on extracellular concentrations of amino acids in striatum in neurotensin subtype 1 and 2 receptor null mice: a possible interaction between neurotensin receptors and amino acid systems for study of schizophrenia.

    PubMed

    Li, Zhimin; Liang, Yanqi; Boules, Mona; Gordillo, Andres; Richelson, Elliott

    2010-06-01

    Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors: NTS1 and NTS2. The present study was done to determine the roles of NTS1 and NTS2 on amino acid release in striatum with the use of NTS1 or NTS2 knockout ((-/-)) mice given d-amphetamine. Both NTS1(-/-) and NTS2(-/-) mice had lower extracellular concentrations of D-serine in striatum than did wild type (WT) mice. NTS2(-/-) but not NTS1(-/-) mice also had significantly lower basal concentrations of glutamate in striatum as compared to that for WT mice. Systemic administration of d-amphetamine (4 mg/kg, ip) increased glutamate release by 500% in WT mice, as compared to 300% in NTS2(-/-) mice, and 250% in NTS1(-/-) mice. Additionally, d-amphetamine injection caused a 4-fold increase in GABA release in both WT and NTS2(-/-) mice, but only a 2-fold increase in NTS1(-/-) mice. Therefore, NTS1 and NTS2 modulate basal release of D-serine and glutamate, and also d-amphetamine-induced GABA and glutamate release in striatum. These results provide further support for the involvement of NT receptors in the pathogenesis of schizophrenia and provide a better understanding of the imbalance of amino acid systems through investigation of a DA-based animal model. PMID:20193696

  16. Subacute exposure to 50-Hz electromagnetic fields affect prenatal and neonatal mice's motor coordination

    NASA Astrophysics Data System (ADS)

    Sakhnini, Lama; Ali, Hassan Al; Qassab, Narjis Al; Arab, Eman Al; Kamal, Amer

    2012-04-01

    In this study, we investigate the possible effect of ELF-EMFs on motor performance in mice (prenatal and neonatal exposed mice). The mice performance is evaluated after 5 days of subacute exposure. Immature mice have been chosen for this study because the immature rodent brain still has the capacity to undergo proliferation, differentiation, and reorganization. Results from the rotarod experiments demonstrated a pronounced deficit in the learning abilities of the prenatal exposed groups, but no pronounced effect was observed for the neonatal exposed group.

  17. Metabolite Signatures in Hydrophilic Extracts of Mouse Lungs Exposed to Cigarette Smoke Revealed by 1H NMR Metabolomics Investigation

    PubMed Central

    JZ, Hu; X, Wang; J, Feng; BJ, Robertson; KM, Waters; SC, Tilton; JG, Pounds; RA, Corley; M, Liu; M, Hu

    2015-01-01

    1H-NMR metabolomics was used to investigate the changes of metabolites in the lungs of mice with and without being exposed to a controlled amount of cigarette smoke. It was found that the concentrations of adenosine derivatives (i.e. ATP, ADP and AMP), inosine and uridine were significantly changed in the lungs of mice exposed to cigarette smoke when compared with controls regardless the mice were obese or of regular weight. The decreased ATP, ADP, AMP and elevated inosine suggested that the deaminases in charge of adenosine derivatives to inosine derivatives conversion would be significantly changed in the lungs of mice exposed to cigarette smoke. Indeed, transcriptional study confirmed that the concentrations of adenosine monophosphate deaminase 2 and adenosine deaminase 2 were significantly changed in the lungs of mice exposed to cigarette smoke. We also found that the ratio of glycerophosphocholine (GPC) to phosphocholine (PC) was significantly increased in the lungs of obese mice compared with those of the regular weight mice. The GPC/PC ratio was further elevated in the lungs of obese group exposed to cigarette smoke. PMID:26609465

  18. Chrysophanol attenuates lead exposure-induced injury to hippocampal neurons in neonatal mice

    PubMed Central

    Zhang, Ji; Yan, Chunlin; Wang, Shu; Hou, Yong; Xue, Guiping; Zhang, Li

    2014-01-01

    Previous studies have shown that chrysophanol protects against learning and memory impairments in lead-exposed adult mice. In the present study, we investigated whether chrysophanol can alleviate learning and memory dysfunction and hippocampal neuronal injury in lead-exposed neonatal mice. At the end of lactation, chrysophanol (0.1, 1.0, 10.0 mg/kg) was administered to the neonatal mice by intraperitoneal injection for 15 days. Chrysophanol significantly alleviated injury to hippocampal neurons and improved learning and memory abilities in the lead-poisoned neonatal mice. Chrysophanol also significantly decreased lead content in blood, brain, heart, spleen, liver and kidney in the lead-exposed neonatal mice. The levels of malondialdehyde in the brain, liver and kidney were significantly reduced, and superoxide dismutase and glutathione peroxidase activities were significantly increased after chrysophanol treatment. Collectively, these findings indicate that chrysophanol can significantly reduce damage to hippocampal neurons in lead-exposed neonatal mice. PMID:25206913

  19. Characterization of the role of sphingomyelin synthase 2 in glucose metabolism in whole-body and peripheral tissues in mice.

    PubMed

    Sugimoto, Masayuki; Shimizu, Yoichi; Zhao, Songji; Ukon, Naoyuki; Nishijima, Ken-ichi; Wakabayashi, Masato; Yoshioka, Takeshi; Higashino, Kenichi; Numata, Yoshito; Okuda, Tomohiko; Tamaki, Nagara; Hanamatsu, Hisatoshi; Igarashi, Yasuyuki; Kuge, Yuji

    2016-08-01

    Sphingomyelin synthase 2 (SMS2) is a proposed potential therapeutic target for obesity and insulin resistance. However, the contributions of SMS2 to glucose metabolism in tissues and its possible therapeutic mechanisms remain unclear. Thus, to determine whole-body glucose utilization and the contributions of each insulin-targeted tissue to glucose uptake, we performed a glucose kinetics study, using the radiolabeled glucose analog (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG), in wild-type (WT) and SMS2 knockout (KO) mice. Insulin signaling was enhanced in the liver, white adipose tissue and skeletal muscle of SMS2 KO mice compared with those of WT mice. In addition, compared with in WT mice, blood clearance of (18)F-FDG was accelerated in SMS2 KO mice when they were fed either a normal or a high fat diet. (18)F-FDG uptake was also increased in insulin-targeted tissues such as skeletal muscle in the SMS2 KO mice. Whereas skeletal muscle sphingolipid content was not clearly affected, plasma levels of very long-chain fatty acid (VLCFA)-containing ceramides were markedly increased in SMS2 KO mice, compared with in WT mice. We also generated liver-conditional SMS2 KO mice and performed glucose and insulin tolerance tests on mice with a high fat diet. However, no significant effect was observed. Thus, our study provided evidence that genetic inhibition of SMS2 elevated glucose clearance through activation of glucose uptake into insulin-targeted tissues such as skeletal muscle by a mechanism independent of hepatic SMS2. Our findings further indicate that this occurs, at least in part, via indirect mechanisms such as elevation of VLCFA-containing ceramides. PMID:27151272

  20. Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2'/') were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsen...

  1. BIOSYNTHESIS OF DIMETHYLNITROSAMINE IN DIMETHYLAMINE-TREATED MICE AFTER EXPOSURE TO NITROGEN DIOXIDE

    EPA Science Inventory

    These studies demonstrate the nitrosating potential of NO2 in vivo in 1CR mice. Groups of mice were gavaged with 2 mg dimethylamine (DMA) and exposed to NO2 at levels from 0.04 to 44.5 ppm for periods up to 4 hours. Mice were individually frozen and blended to a powder, aliquots ...

  2. Inactivation of the adrenergic receptor β2 disrupts glucose homeostasis in mice

    PubMed Central

    Fernandes, Gustavo W; Ueta, Cintia B; Fonseca, Tatiane L; Gouveia, Cecilia H A; Lancellotti, Carmen L; Brum, Patrícia C; Christoffolete, Marcelo A; Bianco, Antonio C; Ribeiro, Miriam O

    2016-01-01

    Three types of beta adrenergic receptors (ARβ1–3) mediate the sympathetic activation of brown adipose tissue (BAT), the key thermogenic site for mice which is also present in adult humans. In this study, we evaluated adaptive thermogenesis and metabolic profile of a mouse with Arβ2 knockout (ARβ2KO). At room temperature, ARβ2KO mice have normal core temperature and, upon acute cold exposure (4 °C for 4 h), ARβ2KO mice accelerate energy expenditure normally and attempt to maintain body temperature. ARβ2KO mice also exhibited normal interscapular BAT thermal profiles during a 30-min infusion of norepinephrine or dobutamine, possibly due to marked elevation of interscapular BAT (iBAT) and of Arβ1, and Arβ3 mRNA levels. In addition, ARβ2KO mice exhibit similar body weight, adiposity, fasting plasma glucose, cholesterol, and triglycerides when compared with WT controls, but exhibit marked fasting hyperinsulinemia and elevation in hepatic Pepck (Pck1) mRNA levels. The animals were fed a high-fat diet (40% fat) for 6 weeks, ARβ2KO mice doubled their caloric intake, accelerated energy expenditure, and induced Ucp1 expression in a manner similar to WT controls, exhibiting a similar body weight gain and increase in the size of white adipocytes to the WT controls. However, ARβ2KO mice maintain fasting hyperglycemia as compared with WT controls despite very elevated insulin levels, but similar degrees of liver steatosis and hyperlipidemia. In conclusion, inactivation of the ARβ2KO pathway preserves cold- and diet-induced adaptive thermogenesis but disrupts glucose homeostasis possibly by accelerating hepatic glucose production and insulin secretion. Feeding on a high-fat diet worsens the metabolic imbalance, with significant fasting hyperglycemia but similar liver structure and lipid profile to the WT controls. PMID:24868110

  3. Inactivation of the adrenergic receptor β2 disrupts glucose homeostasis in mice.

    PubMed

    Fernandes, Gustavo W; Ueta, Cintia B; Fonseca, Tatiane L; Gouveia, Cecilia H A; Lancellotti, Carmen L; Brum, Patrícia C; Christoffolete, Marcelo A; Bianco, Antonio C; Ribeiro, Miriam O

    2014-06-01

    Three types of beta adrenergic receptors (ARβ1-3) mediate the sympathetic activation of brown adipose tissue (BAT), the key thermogenic site for mice which is also present in adult humans. In this study, we evaluated adaptive thermogenesis and metabolic profile of a mouse with Arβ2 knockout (ARβ2KO). At room temperature, ARβ2KO mice have normal core temperature and, upon acute cold exposure (4 °C for 4 h), ARβ2KO mice accelerate energy expenditure normally and attempt to maintain body temperature. ARβ2KO mice also exhibited normal interscapular BAT thermal profiles during a 30-min infusion of norepinephrine or dobutamine, possibly due to marked elevation of interscapular BAT (iBAT) and of Arβ1, and Arβ3 mRNA levels. In addition, ARβ2KO mice exhibit similar body weight, adiposity, fasting plasma glucose, cholesterol, and triglycerides when compared with WT controls, but exhibit marked fasting hyperinsulinemia and elevation in hepatic Pepck (Pck1) mRNA levels. The animals were fed a high-fat diet (40% fat) for 6 weeks, ARβ2KO mice doubled their caloric intake, accelerated energy expenditure, and induced Ucp1 expression in a manner similar to WT controls, exhibiting a similar body weight gain and increase in the size of white adipocytes to the WT controls. However, ARβ2KO mice maintain fasting hyperglycemia as compared with WT controls despite very elevated insulin levels, but similar degrees of liver steatosis and hyperlipidemia. In conclusion, inactivation of the ARβ2KO pathway preserves cold- and diet-induced adaptive thermogenesis but disrupts glucose homeostasis possibly by accelerating hepatic glucose production and insulin secretion. Feeding on a high-fat diet worsens the metabolic imbalance, with significant fasting hyperglycemia but similar liver structure and lipid profile to the WT controls. PMID:24868110

  4. Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice

    PubMed Central

    2013-01-01

    Background Synaptosomal-associated protein, 25 kDa (SNAP-25) regulates the exocytosis of neurotransmitters. Growing evidence suggests that SNAP-25 is involved in neuropsychiatric disorders, such as schizophrenia, attention-deficit/hyperactivity disorder, and epilepsy. Recently, increases in anxiety-related behaviors and epilepsy have been observed in SNAP-25 knock-in (KI) mice, which have a single amino acid substitution of Ala for Ser187. However, the molecular and cellular mechanisms underlying the abnormalities in this mutant remain unknown. Results In this study, we found that a significant number of dentate gyrus (DG) granule cells was histologically and electrophysiologically similar to immature DG neurons in the dentate gyrus of the adult mutants, a phenomenon termed the “immature DG” (iDG). SNAP-25 KI mice and other mice possessing the iDG phenotype, i.e., alpha-calcium/calmodulin-dependent protein kinase II heterozygous mice, Schnurri-2 knockout mice, and mice treated with the antidepressant fluoxetine, showed similar molecular expression patterns, with over 100 genes similarly altered. A working memory deficit was also identified in mutant mice during a spontaneous forced alternation task using a modified T-maze, a behavioral task known to be dependent on hippocampal function. Chronic treatments with the antiepileptic drug valproate abolished the iDG phenotype and the working memory deficit in mutants. Conclusions These findings suggest that the substitution of Ala for Ser187 in SNAP-25 induces the iDG phenotype, which can also be caused by epilepsy, and led to a severe working memory deficit. In addition, the iDG phenotype in adulthood is likely an endophenotype for at least a part of some common psychiatric disorders. PMID:23497716

  5. Noninvasive assessment of antenatal hydronephrosis in mice reveals a critical role for Robo2 in maintaining anti-reflux mechanism.

    PubMed

    Wang, Hang; Li, Qinggang; Liu, Juan; Mendelsohn, Cathy; Salant, David J; Lu, Weining

    2011-01-01

    Antenatal hydronephrosis and vesicoureteral reflux (VUR) are common renal tract birth defects. We recently showed that disruption of the Robo2 gene is associated with VUR in humans and antenatal hydronephrosis in knockout mice. However, the natural history, causal relationship and developmental origins of these clinical conditions remain largely unclear. Although the hydronephrosis phenotype in Robo2 knockout mice has been attributed to the coexistence of ureteral reflux and obstruction in the same mice, this hypothesis has not been tested experimentally. Here we used noninvasive high-resolution micro-ultrasonography and pathological analysis to follow the progression of antenatal hydronephrosis in individual Robo2-deficient mice from embryo to adulthood. We found that hydronephrosis progressed continuously after birth with no spontaneous resolution. With the use of a microbubble ultrasound contrast agent and ultrasound-guided percutaneous aspiration, we demonstrated that antenatal hydronephrosis in Robo2-deficient mice is caused by high-grade VUR resulting from a dilated and incompetent ureterovesical junction rather than ureteral obstruction. We further documented Robo2 expression around the developing ureterovesical junction and identified early dilatation of ureteral orifice structures as a potential fetal origin of antenatal hydronephrosis and VUR. Our results thus demonstrate that Robo2 is crucial for the formation of a normal ureteral orifice and for the maintenance of an effective anti-reflux mechanism. This study also establishes a reproducible genetic mouse model of progressive antenatal hydronephrosis and primary high-grade VUR. PMID:21949750

  6. Food intake, tumor growth, and weight loss in EP2 receptor subtype knockout mice bearing PGE2-producing tumors

    PubMed Central

    Iresjö, Britt-Marie; Wang, Wenhua; Nilsberth, Camilla; Andersson, Marianne; Lönnroth, Christina; Smedh, Ulrika

    2015-01-01

    Previous studies in our laboratory have demonstrated that prostaglandin (PG) E2 is involved in anorexia/cachexia development in MCG 101 tumor-bearing mice. In the present study, we investigate the role of PGE receptor subtype EP2 in the development of anorexia after MCG 101 implantation in wild-type (EP2+/+) or EP2-receptor knockout (EP2−/−) mice. Our results showed that host absence of EP2 receptors attenuated tumor growth and development of anorexia in tumor-bearing EP2 knockout mice compared to tumor-bearing wild-type animals. Microarray profiling of the hypothalamus revealed a relative twofold change in expression of around 35 genes including mRNA transcripts coding for Phospholipase A2 and Prostaglandin D2 synthase (Ptgds) in EP2 receptor knockout mice compared to wild-type mice. Prostaglandin D2 synthase levels were increased significantly in EP2 receptor knockouts, suggesting that improved food intake may depend on altered balance of prostaglandin production in hypothalamus since PGE2 and PGD2 display opposing effects in feeding control. PMID:26197930

  7. SOD2 deficiency in hematopoietic cells in mice results in reduced red blood cell deformability and increased heme degradation

    PubMed Central

    Mohanty, Joy G.; Nagababu, Enika; Friedman, Jeffrey S.; Rifkind, Joseph M.

    2013-01-01

    Among the three types of super oxide dismutases (SODs) known, SOD2 deficiency is lethal in neonatal mice owing to cardiomyopathy caused by severe oxidative damage. SOD2 is found in red blood cell (RBC) precursors, but not in mature RBCs. To investigate the potential damage to mature RBCs resulting from SOD2 deficiency in precursor cells, we studied RBCs from mice in which fetal liver stem cells deficient in SOD2 were capable of efficiently rescuing lethally irradiated host animals. These transplanted animals lack SOD2 only in hematopoietically generated cells and live longer than SOD2 knockouts. In these mice, approximately 2.8% of their total RBCs in circulation are iron-laden reticulocytes, with numerous siderocytic granules and increased protein oxidation similar to that seen in sideroblastic anemia. We have studied the RBC deformability and oxidative stress in these animals and the control group by measuring them with a microfluidic ektacytometer and assaying fluorescent heme degradation products with a fluorimeter, respectively. In addition, the rate of hemoglobin oxidation in RBCs from these mice and the control group were measured spectrophotometrically. The results show that RBCs from these SOD2-deficient mice have reduced deformability, increased heme degradation products, and an increased rate of hemoglobin oxidation compared with control animals, indicative of increased RBC oxidative stress. PMID:23142655

  8. IgG Suppresses Antibody Responses in Mice Lacking C1q, C3, Complement Receptors 1 and 2, or IgG Fc-Receptors

    PubMed Central

    Bergström, Joakim J. E.; Heyman, Birgitta

    2015-01-01

    Antigen-specific IgG antibodies, passively administered to mice or humans together with large particulate antigens like erythrocytes, can completely suppress the antibody response against the antigen. This is used clinically in Rhesus prophylaxis, where administration of IgG anti-RhD prevents RhD-negative women from becoming immunized against RhD-positive fetal erythrocytes aquired transplacentally. The mechanisms by which IgG suppresses antibody responses are poorly understood. We have here addressed whether complement or Fc-receptors for IgG (FcγRs) are required for IgG-mediated suppression. IgG, specific for sheep red blood cells (SRBC), was administered to mice together with SRBC and the antibody responses analyzed. IgG was able to suppress early IgM- as well as longterm IgG-responses in wildtype mice equally well as in mice lacking FcγRIIB (FcγRIIB knockout mice) or FcγRI, III, and IV (FcRγ knockout mice). Moreover, IgG was able to suppress early IgM responses equally well in mice lacking C1q (C1qA knockout mice), C3 (C3 knockout mice), or complement receptors 1 and 2 (Cr2 knockout mice) as in wildtype mice. Owing to the previously described severely impaired IgG responses in the complement deficient mice, it was difficult to assess whether passively administered IgG further decreased their IgG response. In conclusion, Fc-receptor binding or complement-activation by IgG does not seem to be required for its ability to suppress antibody responses to xenogeneic erythrocytes. PMID:26619292

  9. Impact of chronic low to moderate alcohol consumption on blood lipid and heart energy profile in acetaldehyde dehydrogenase 2-deficient mice

    PubMed Central

    Fan, Fan; Cao, Quan; Wang, Cong; Ma, Xin; Shen, Cheng; Liu, Xiang-wei; Bu, Li-ping; Zou, Yun-zeng; Hu, Kai; Sun, Ai-jun; Ge, Jun-bo

    2014-01-01

    Aim: To investigate the roles of acetaldehyde dehydrogenase 2 (ALDH2), the key enzyme of ethanol metabolism, in chronic low to moderate alcohol consumption-induced heart protective effects in mice. Methods: Twenty-one male wild-type (WT) or ALDH2-knockout (KO) mice were used in this study. In each genotype, 14 animals received alcohol (2.5%, 5% and 10% in week 1–3, respectively, and 18% in week 4–7), and 7 received water for 7 weeks. After the treatments, survival rate and general characteristics of the animals were evaluated. Serum ethanol and acetaldehyde levels and blood lipids were measured. Metabolomics was used to characterize the heart and serum metabolism profiles. Results: Chronic alcohol intake decreased the survival rate of KO mice by 50%, and significantly decreased their body weight, but did not affect those of WT mice. Chronic alcohol intake significantly increased the serum ethanol levels in both WT and KO mice, but KO mice had significantly higher serum acetaldehyde levels than WT mice. Chronic alcohol intake significantly increased the serum HDL cholesterol levels in WT mice, and did not change the serum HDL cholesterol levels in KO mice. After chronic alcohol intake, WT and KO mice showed differential heart and serum metabolism profiles, including the 3 main energy substrate types (lipids, glucose and amino acids) and three carboxylic acid cycles. Conclusion: Low to moderate alcohol consumption increases HDL cholesterol levels and improves heart energy metabolism profile in WT mice but not in ALDH2-KO mice. Thus, preserved ALDH2 function is essential for the protective effect of low to moderate alcohol on the cardiovascular system. PMID:24998256

  10. Euthanasia of neonatal mice with carbon dioxide

    USGS Publications Warehouse

    Pritchett, K.; Corrow, D.; Stockwell, J.; Smith, A.

    2005-01-01

    Exposure to carbon dioxide (CO2) is the most prevalent method used to euthanize rodents in biomedical research. The purpose of this study was to determine the time of CO2 exposure required to euthanize neonatal mice (0 to 10 days old). Multiple groups of mice were exposed to 100% CO 2 for time periods between 5 and 60 min. Mice were placed in room air for 10 or 20 min after CO2 exposure, to allow for the chance of recovery. If mice recovered at one time point, a longer exposure was examined. Inbred and outbred mice were compared. Results of the study indicated that time to death varied with the age of the animals and could be as long as 50 min on the day of birth and differed between inbred and outbred mice. Institutions euthanizing neonatal mice with CO2 may wish to adjust their CO 2 exposure time periods according the age of the mice and their genetic background. Copyright 2005 by the American Association for Laboratory Animal Science.

  11. Brucellosis in Occupationally Exposed Groups

    PubMed Central

    Sajjan, Annapurna G.; Mohite, Shivajirao T.; Gajul, Shivali

    2016-01-01

    Introduction In India, high incidence of human brucellosis may be expected, as the conditions conducive for human brucellosis exist. Limited studies have been undertaken on human brucellosis especially in occupationally-exposed groups. Aim To estimate prevalence of anti-brucellar antibodies, evaluate the clinical manifestations, risk factors and Knowledge, Attitude and Practices (KAP) levels about brucellosis among occupationally exposed groups. Materials and Methods Blood samples were collected from 2337 occupationally exposed individuals. The serum samples were screened for the presence of anti-brucellar antibodies by Rose Bengal Plate Test (RBPT), Serum Agglutination Test (SAT) and 2-Mercaptoethanol test (2-ME). Clinical manifestations, risk factors and KAP levels were evaluated by personal interview using a structured questionnaire. Results Seroprevalence of brucellosis by RBPT, SAT and 2-ME test was 9.46%, 4.45% and 3.64 % respectively. Clinical symptoms resembling brucellosis were seen in 91 subjects. The major risk factors were animal exposure in veterinarians and abattoirs, both animal exposure and raw milk ingestion in farmers and shepherds, exposure to raw milk and its ingestion in dairy workers and exposure to Brucella culture in laboratory workers. Except laboratory workers, few veterinarians and dairy workers none had heard about brucellosis. KAP levels regarding brucellosis were too poor in all the groups except laboratory workers. Conclusion Brucellosis most of the times was missed or misdiagnosed. Regular screenings for brucellosis and awareness programmes to increase KAP levels are necessary to control brucellosis in occupationally exposed groups. PMID:27190804

  12. Effect of carbon monoxide and nitrogen dioxide on ICR mice