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Sample records for exposure alters l-a-amino-3-hydroxy-5-methyl-4-isoxazole

  1. Neural alterations from lead exposure in zebrafish.

    PubMed

    Roy, Nicole M; DeWolf, Sarah; Schutt, Alexius; Wright, Ashia; Steele, Latina

    2014-01-01

    Lead was used extensively as a gas additive and pesticide, in paints, batteries, lead shot, pipes, canning and toy manufacturing. Although uses of lead have been restricted, lead persists in our environment especially in older homes, and generally in soil and water. Although extensive studies have determined that fetal and childhood exposures to lead have been associated with childhood and adolescent memory impairments and learning disabilities, there are limited studies investigating early neural and morphological effects that may lead to these behavioral and learning abnormalities. Here we utilize the zebrafish vertebrate model system to study early effects of lead exposure on the brain. We treat embryos with 0.2mM lead for 24, 48 and 72 h and analyze neural structures through live imagery and transgenic approaches. We find structural abnormalities in the hindbrain region as well as changes in branchiomotor neuron development and altered neural vasculature. Additionally, we find areas of increased apoptosis. We conclude that lead is developmentally neurotoxic to a specific region of the brain, the hindbrain and is toxic to branchiomotor neurons residing in rhombomeres 2 through 7 of the hindbrain and hindbrain central artery vasculature. PMID:25242292

  2. Daily Exposure to Dust Alters Innate Immunity

    PubMed Central

    Sahlander, Karin; Larsson, Kjell; Palmberg, Lena

    2012-01-01

    Pig farmers are exposed to organic material in pig barns on a daily basis and have signs of an ongoing chronic airway inflammation and increased prevalence of chronic inflammatory airway diseases, predominantly chronic bronchitis. Interestingly, the inflammatory response to acute exposure to organic dust is attenuated in farmers. The aim of the study was to closer characterize innate immunity features in blood and airways in farmers and in naïve, non-exposed, controls. The expression of pattern recognition receptors (TLR2, TLR4 and CD14) whose ligands are abundant in pig barn dust and adhesion proteins (CD11b, CD62L and CD162L) on blood and sputum neutrophils in pig farmers and soluble TLR2 and CD14 (sTLR2 and sCD14) in blood and sputum were assessed in pig farmers and previously unexposed controls. The release of pro-inflammatory cytokines from blood cells stimulated with LPS ex vivo was measured in the absence and presence of anti-ST2. We also examined, in a separate study population, serum levels of soluble ST2 (sST2), before and after exposure in a pig barn and a bronchial LPS challenge. Farmers had signs of ongoing chronic inflammation with increased number of blood monocytes, and decreased expression of CD62L and CD162 on blood neutrophils. Farmers also had lower levels of sTLR2 and sCD14 in sputum and reduced expression of CD14 on sputum neutrophils than controls. Exposure to organic dust and LPS induced increase of serum sST2 in controls but not in farmers. In conclusion, farmers have signs of local and systemic inflammation associated with altered innate immunity characteristics. PMID:22355383

  3. Exposure to Environmental Ozone Alters Semen Quality

    PubMed Central

    Sokol, Rebecca Z.; Kraft, Peter; Fowler, Ian M.; Mamet, Rizvan; Kim, Elizabeth; Berhane, Kiros T.

    2006-01-01

    Idiopathic male infertility may be due to exposure to environmental toxicants that alter spermatogenesis or sperm function. We studied the relationship between air pollutant levels and semen quality over a 2-year period in Los Angeles, California, by analyzing repeated semen samples collected by sperm donors. Semen analysis data derived from 5,134 semen samples from a sperm donor bank were correlated with air pollutant levels (ozone, nitrogen dioxide, carbon monoxide, and particulate matter < 10 μm in aerodynamic diameter) measured 0–9, 10–14, and 70–90 days before semen collection dates in Los Angeles between January 1996 and December 1998. A linear mixed-effects model was used to model average sperm concentration and total motile sperm count for the donation from each subject. Changes were analyzed in relationship to biologically relevant time points during spermatogenesis, 0–9, 10–14, and 70–90 days before the day of semen collection. We estimated temperature and seasonality effects after adjusting for a base model, which included donor’s date of birth and age at donation. Forty-eight donors from Los Angeles were included as subjects. Donors were included if they collected repeated semen samples over a 12-month period between January 1996 and December 1998. There was a significant negative correlation between ozone levels at 0–9, 10–14, and 70–90 days before donation and average sperm concentration, which was maintained after correction for donor’s birth date, age at donation, temperature, and seasonality (p < 0.01). No other pollutant measures were significantly associated with sperm quality outcomes. Exposure to ambient ozone levels adversely affects semen quality. PMID:16507458

  4. POSTNATAL ALTERATIONS IN DEVELOPMENT RESULTING FROM PRENATAL EXPOSURE TO PESTICIDES

    EPA Science Inventory

    Alterations in the developmental processes of embryos resulting from exposure to chemicals are not limited to morphological abnormalities that can be observed in the near term fetus. In the research on the developmental toxicology of pesticides the authors have noted morphologica...

  5. Alterations in cognitive and psychological functioning after organic solvent exposure

    SciTech Connect

    Morrow, L.A.; Ryan, C.M.; Hodgson, M.J.; Robin, N. )

    1990-05-01

    Exposure to organic solvents has been linked repeatedly to alterations in both personality and cognitive functioning. To assess the nature and extent of these changes more thoroughly, 32 workers with a history of exposure to mixtures of organic solvents and 32 age- and education-matched blue-collar workers with no history of exposure were assessed with a comprehensive battery of neuropsychological tests. Although both groups were comparable on measures of general intelligence, significant differences were found in virtually all other cognitive domains tested (Learning and Memory, Visuospatial, Attention and Mental Flexibility, Psychomotor Speed). In addition, Minnesota Multiphasic Personality Inventories of exposed workers indicated clinically significant levels of depression, anxiety, somatic concerns and disturbances in thinking. The reported psychological distress was unrelated to degree of cognitive deficit. Finally, several exposure-related variables were associated with poorer performance on tests of memory and visuospatial ability.

  6. Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

    PubMed Central

    Lee, Kuei-Fang; Weng, Julia Tzu-Ya; Hsu, Paul Wei-Che; Chi, Yu-Hsiang; Chen, Ching-Kai; Liu, Ingrid Y.; Chen, Yi-Cheng; Wu, Lawrence Shih-Hsin

    2014-01-01

    Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders. PMID:25276823

  7. Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

    PubMed Central

    Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

    2014-01-01

    Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

  8. Produced water exposure alters bacterial response to biocides.

    PubMed

    Vikram, Amit; Lipus, Daniel; Bibby, Kyle

    2014-11-01

    Microbial activity during the holding and reuse of wastewater from hydraulic fracturing operations, termed produced water, may lead to issues with corrosion, sulfide release, and fouling. Biocides are applied to control biological activity, often with limited efficacy, which is typically attributed to chemical interactions with the produced water. However, it is unknown whether there is a biologically driven mechanism to biocide tolerance in produced water. Here, we demonstrate that produced water exposure results in an enhanced tolerance against the typically used biocide glutaraldehyde and increased susceptibility to the oxidative biocide hypochlorite in a native and a model bacteria and that this altered resistance is due to the salinity of the produced water. In addition, we elucidate the genetic response of the model organism Pseudomonas fluorescens to produced water exposure to provide a mechanistic interpretation of the altered biocide resistance. The RNA-seq data demonstrated the induction of genes involved in osmotic stress, energy production and conversion, membrane integrity, and protein transport following produced water exposure, which facilitates bacterial survival and alters biocide tolerance. Efforts to fundamentally understand biocide resistance mechanisms, which enable the optimization of biocide application, hold significant implications for greening of the fracturing process through encouraging produced water recycling. Specifically, these results suggest the necessity of optimizing biocide application at the level of individual shale plays, rather than historical experience, based upon produced water characteristics and salinity. PMID:25279933

  9. Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats

    PubMed Central

    Jolous-Jamshidi, Banafsheh; Cromwell, Howard C.; McFarland, Ashley M.; Meserve, Lee A.

    2014-01-01

    Perinatal exposure to polychlorinated biphenyls (PCBs) leads to significant alterations of neural and hormonal systems. These alterations have been shown to impair motor and sensory development. Less is known about the influence of PCB exposure on developing emotional and motivational systems involved in social interactions and social learning. The present study examined the impact of perinatal PCB exposure (mixture of congeners 47 and 77) on social recognition in juvenile animals, conspecific-directed investigation in adults and on neural and hormonal systems involved in social functions. We used a standard habituation–dishabituation paradigm to evaluate juvenile recognition and a social port paradigm to monitor adult social investigation. Areal measures of the periventricular nucleus (PVN) of the hypothalamus were obtained to provide correlations with related hormone and brain systems. PCB exposed rats were significantly impaired in social recognition as indicated by persistent conspecific-directed exploration by juvenile animals regardless of social experience. As adults, PCB exposure led to a dampening of the isolation-induced enhancement of social investigation. There was not a concomitant alteration of social investigation in pair-housed PCB exposed animals at this stage of development. Interestingly, PVN area was significantly decreased in juvenile animals exposed to PCB during the perinatal period. Shifts in hypothalamic regulation of hormones involved in social behavior and stress could be involved in the behavioral changes observed. Overall, the results suggest that PCB exposure impairs context or experience-dependent modulation of social approach and investigation. These types of social-context deficits are similar to behavioral deficits observed in social disorders such as autism and other pervasive developmental disorders. PMID:20813172

  10. Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats.

    PubMed

    Jolous-Jamshidi, Banafsheh; Cromwell, Howard C; McFarland, Ashley M; Meserve, Lee A

    2010-11-30

    Perinatal exposure to polychlorinated biphenyls (PCBs) leads to significant alterations of neural and hormonal systems. These alterations have been shown to impair motor and sensory development. Less is known about the influence of PCB exposure on developing emotional and motivational systems involved in social interactions and social learning. The present study examined the impact of perinatal PCB exposure (mixture of congeners 47 and 77) on social recognition in juvenile animals, conspecific-directed investigation in adults and on neural and hormonal systems involved in social functions. We used a standard habituation-dishabituation paradigm to evaluate juvenile recognition and a social port paradigm to monitor adult social investigation. Areal measures of the periventricular nucleus (PVN) of the hypothalamus were obtained to provide correlations with related hormone and brain systems. PCB exposed rats were significantly impaired in social recognition as indicated by persistent conspecific-directed exploration by juvenile animals regardless of social experience. As adults, PCB exposure led to a dampening of the isolation-induced enhancement of social investigation. There was not a concomitant alteration of social investigation in pair-housed PCB exposed animals at this stage of development. Interestingly, PVN area was significantly decreased in juvenile animals exposed to PCB during the perinatal period. Shifts in hypothalamic regulation of hormones involved in social behavior and stress could be involved in the behavioral changes observed. Overall, the results suggest that PCB exposure impairs context or experience-dependent modulation of social approach and investigation. These types of social-context deficits are similar to behavioral deficits observed in social disorders such as autism and other pervasive developmental disorders. PMID:20813172

  11. Chronic bisphenol A exposure alters behaviors of zebrafish (Danio rerio).

    PubMed

    Wang, Ju; Wang, Xia; Xiong, Can; Liu, Jian; Hu, Bing; Zheng, Lei

    2015-11-01

    The adult zebrafish (Danio rerio) were exposed to treated-effluent concentration of bisphenol A (BPA) or 17β-estradiol (E2) for 6 months to evaluate their effects on behavioral characteristics: motor behavior, aggression, group preference, novel tank test and light/dark preference. E2 exposure evidently dampened fish locomotor activity, while BPA exposure had no marked effect. Interestingly, BPA-exposed fish reduced their aggressive behavior compared with control or E2. Both BPA and E2 exposure induced a significant decrease in group preference, as well as a weaker adaptability to new environment, exhibiting lower latency to reach the top, more entries to the top, longer time spent in the top, fewer frequent freezing, and fewer erratic movements. Furthermore, the circadian rhythmicity of light/dark preference was altered by either BPA or E2 exposure. Our results suggest that chronic exposure of treated-effluent concentration BPA or E2 induced various behavioral anomalies in adult fish and enhanced ecological risk to wildlife. PMID:26204572

  12. Radiation Exposure Alters Expression of Metabolic Enzyme Genes In Mice

    NASA Technical Reports Server (NTRS)

    Wotring, Virginia E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2010-01-01

    Most pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Because of the importance of the liver in drug metabolism it is important to understand the effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. This study is an effort to examine the effects of adaptive mechanisms that may be triggered by early exposure to low radiation doses. Using procedures approved by the JSC Animal Care & Use Committee, C57 male mice were exposed to Cs-137 in groups: controls, low dose (50 mGy), high dose (6Gy) and a fourth group that received both radiation doses separated by 24 hours. Animals were anesthetized and sacrificed 4 hours after their last radiation exposure. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted and purified (Absolutely RNA, Agilent). Quality of RNA samples was evaluated (Agilent Bioanalyzer 2100). Complementary DNA was prepared from high-quality RNA samples, and used to run RT-qPCR screening arrays for DNA Repair and Drug Metabolism (SuperArray, SABiosciences/Qiagen; BioRad Cfx96 qPCR System). Of 91 drug metabolism genes examined, expression of 7 was altered by at least one treatment condition. Genes that had elevated expression include those that metabolize promethazine and steroids (4-8-fold), many that reduce oxidation products, and one that reduces heavy metal exposure (greater than 200-fold). Of the 91 DNA repair and general metabolism genes examined, expression of 14 was altered by at least one treatment condition. These gene expression changes are likely homeostatic and could lead to development of new radioprotective countermeasures.

  13. Vanadium Exposure-Induced Neurobehavioral Alterations among Chinese Workers

    PubMed Central

    Li, Hong; Zhou, Dinglun; Zhang, Qin; Feng, Chengyong; Zheng, Wei; He, Keping; Lan, Yajia

    2014-01-01

    Vanadium-containing products are manufactured and widely used in the modern industry. Yet the neurobehavioral toxicity due to occupational exposure to vanadium remained elusive. This cross-sectional study was designed to examine the neurotoxic effects of occupational vanadium exposure. A total of 463 vanadium-exposed workers (exposed group) and 251 non-exposed workers (control group) were recruited from a Steel and Iron Group in Sichuan, China. A WHO-recommended neurobehavioral core test battery (NCTB) and event-related auditory evoked potentials test (P300) were used to assess the neurobehavioral functions of all study subjects. A general linear model was used to compare outcome scores between the two groups while controlling for possible confounders. The exposed group showed a statistically significant neurobehavioral alteration more than the control group in the NCTB tests. The exposed workers also exhibited an increased anger-hostility, depression-dejection and fatigue-inertia on the profile of mood states (p<0.05). Performances in the Simple Reaction Time, Digit Span, Benton Visual Retention and Pursuit Aiming were also poorer among exposed workers as compared to unexposed control workers(p<0.05). Some of these poor performances in tests were also significantly related to workers’ exposure duration. P300 latencies were longer in the exposed group than in the control (p<0.05). Longer mean reaction times and more counting errors were also found in the exposed workers (p<0.05). Given the findings of our study and the limitations of neurobehavioral workplace testing, we found evidence of altered neurobehavioral outcomes by occupational exposure to vanadium. PMID:23500660

  14. DNA methylation alterations in response to pesticide exposure in vitro

    PubMed Central

    Zhang, Xiao; Wallace, Andrew D.; Du, Pan; Kibbe, Warren A.; Jafari, Nadereh; Xie, Hehuang; Lin, Simon; Baccarelli, Andrea; Soares, Marcelo Bento; Hou, Lifang

    2013-01-01

    Although pesticides are subject to extensive carcinogenicity testing before regulatory approval, pesticide exposure has repeatedly been associated with various cancers. This suggests that pesticides may cause cancer via non-mutagenicity mechanisms. The present study provides evidence to support the hypothesis that pesticide-induced cancer may be mediated in part by epigenetic mechanisms. We examined whether exposure to 7 commonly used pesticides (i.e., fonofos, parathion, terbufos, chlorpyrifos, diazinon, malathion, and phorate) induces DNA methylation alterations in vitro. We conducted genome-wide DNA methylation analyses on DNA samples obtained from the human hematopoietic K562 cell line exposed to ethanol (control) and several OPs using the Illumina Infinium HumanMethylation27 BeadChip. Bayesian-adjusted t-tests were used to identify differentially methylated gene promoter CpG sites. In this report, we present our results on three pesticides (fonofos, parathion, and terbufos) that clustered together based on principle component analysis and hierarchical clustering. These three pesticides induced similar methylation changes in the promoter regions of 712 genes, while also exhibiting their own OP-specific methylation alterations. Functional analysis of methylation changes specific to each OP, or common to all three OPs, revealed that differential methylation was associated with numerous genes that are involved in carcinogenesis-related processes. Our results provide experimental evidence that pesticides may modify gene promoter DNA methylation levels, suggesting that epigenetic mechanisms may contribute to pesticide-induced carcinogenesis. Further studies in other cell types and human samples are required, as well as determining the impact of these methylation changes on gene expression. PMID:22847954

  15. Predator exposure alters stress physiology in guppies across timescales.

    PubMed

    Fischer, Eva K; Harris, Rayna M; Hofmann, Hans A; Hoke, Kim L

    2014-02-01

    In vertebrates, glucocorticoids mediate a wide-range of responses to stressors. For this reason, they are implicated in adaptation to changes in predation pressure. Trinidadian guppies (Poecilia reticulata) from high-predation environments have repeatedly and independently colonized and adapted to low-predation environments, resulting in parallel changes in life history, morphology, and behavior. We validated methods for non-invasive waterborne hormone sample collection in this species, and used this technique to examine genetic and environmental effects of predation on basal glucocorticoid (cortisol) levels. To examine genetic differences, we compared waterborne cortisol levels in high- and low-predation fish from two distinct population pairs. We found that fish from high-predation localities had lower cortisol levels than their low-predation counterparts. To isolate environmental influences, we compared waterborne cortisol levels in genetically similar fish reared with and without exposure to predator chemical cues. We found that fish reared with predator chemical cues had lower waterborne cortisol levels than those reared without. Comparisons of waterborne and whole-body cortisol levels demonstrated that populations differed in overall cortisol levels in the body, whereas rearing conditions altered the release of cortisol from the body into the water. Thus, evolutionary history with predators and lifetime exposure to predator cues were both associated with lower cortisol release, but depended on distinct physiological mechanisms. PMID:24370688

  16. Alterations in the laryngeal mucosa after exposure to asbestos.

    PubMed Central

    Kambic, V; Radsel, Z; Gale, N

    1989-01-01

    The laryngeal mucosa of 195 workers in an asbestos cement factory (Salonit Anhovo, Yugoslavia) and in a control group was examined. The factory manufactures asbestos cement products containing about 13% of asbestos (8% amosite, 12% crocidolite, and 80% chrysotile) of different provenance. Alterations in the laryngeal mucosa were more frequent in the factory workers than in the control group. The changes, mostly consistent with chronic laryngitis, were closely related to the degree of workplace pollution and less so to the duration of employment Ten workers exhibiting the most severe clinical changes underwent biopsy, the results of which showed histomorphological changes characteristic of hyperplastic chronic laryngitis. Four tissue specimens were examined also by scanning electron microscopy and in three of them asbestos fibres were found on the epithelial surface. No case of laryngeal carcinoma was identified. On the basis of our results it is thought that asbestos related changes of the larynx should receive more attention and that the use of the term "laryngeal asbestosis" is justified. The clinical picture is non-specific but in view of their frequency such changes should be considered a consequence of exposure to asbestos. Images PMID:2489023

  17. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FAILS TO ALTER BRAINSTEM AUDITORY EVOKED RESPONSE (BAERS) IN RATS.

    EPA Science Inventory

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Cholinergic transmission is involved in auditory structures in the periphery and the brainstem and is altered following chlorpyrifos exposure. This study e...

  18. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FAILS TO ALTER FLASH OR PATTERN REVERSAL EVOKED POTENTIALS IN RATS.

    EPA Science Inventory

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Visual disturbances are often reported following exposure to xenobiotics, and cholinesterase-inhibiting compounds have been reported to alter visual functi...

  19. FINE PARTICLE EXPOSURE IS ASSOCIATED WITH ALTERED VENTRICULAR REPOLARIZATION

    EPA Science Inventory

    Exposure to fine airborne particulate matter (PM2.5) has previously been associated with cardiac events, especially in older people with cardiovascular disease and in diabetics. This study examined the cardiac effects of short-term exposures to ambient PM2.5 in a prospective pane...

  20. NEONATAL CHIORDECONE EXPOSURE ALTERS BEHAVIORAL SEX DIFFERENTIATION IN FEMALE HAMSTERS

    EPA Science Inventory

    The present study was designed in order to determine if exposure to the weakly estrogenic pesticide Chlordecone during a critical period of behavioral sex differentiation of the brain could masculinize and defeminize the behavior of female hamsters.

  1. In utero and postnatal exposure to arsenic alters pulmonary structure and function

    SciTech Connect

    Lantz, R. Clark Chau, Binh; Sarihan, Priyanka; Witten, Mark L.; Pivniouk, Vadim I.; Chen, Guan Jie

    2009-02-15

    In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airway reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 {mu}m in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.

  2. Developmental timing of perchlorate exposure alters threespine stickleback dermal bone

    PubMed Central

    Furin, Christoff G.; von Hippel, Frank A.; Postlethwait, John; Buck, C. Loren; Cresko, William A.; O’Hara, Todd M.

    2015-01-01

    Adequate levels of thyroid hormone are critical during development and metamorphosis, and for maintaining metabolic homeostasis. Perchlorate, a common contaminant of water sources, inhibits thyroid function in vertebrates. We utilized threespine stickleback (Gasterosteus aculeatus) to determine if timing of perchlorate exposure during development impacts adult dermal skeletal phenotypes. Fish were exposed to water contaminated with perchlorate (30 mg/L or 100 mg/L) beginning at 0, 3, 7, 14, 21, 42, 154 or 305 days post fertilization until sexual maturity at one year of age. A reciprocal treatment moved stickleback from contaminated to clean water on the same schedule providing for different stages of initial exposure and different treatment durations. Perchlorate exposure caused concentration-dependent significant differences in growth for some bony traits. Continuous exposure initiated within the first 21 days post fertilization had the greatest effects on skeletal traits. Exposure to perchlorate at this early stage can result in small traits or abnormal skeletal morphology of adult fish which could affect predator avoidance and survival. PMID:25753171

  3. Alteration of mammary gland development and gene expression by in utero exposure to arsenic

    PubMed Central

    Parodi, Daniela A.; Greenfield, Morgan; Evans, Claire; Chichura, Anna; Alpaugh, Alexandra; Williams, James; Martin, Mary Beth

    2015-01-01

    Early life exposure to estrogens and estrogen like contaminants in the environment are thought to contribute to the early onset of puberty and consequently increase the risk of developing breast cancer in the exposed female. The results of this study show that in utero exposure to the metalloestrogen arsenite altered mammary gland development prior to its effect on puberty onset. In the prepubertal gland, in utero exposure resulted in an increase in the number of mammosphere-forming cells and an increase in branching, epithelial cells, and density. In the postpubertal gland, in utero exposure resulted in the overexpression of estrogen receptor-alpha (ERα) that was due to the increased and altered response of the ERα transcripts derived from exons O and OT to estradiol. These results suggest that, in addition to advancing puberty onset, in utero exposure to arsenite alters the pre- and postpubertal development of the mammary gland and possibly, the risk of developing breast cancer. PMID:25543096

  4. Radiation Exposure Alters Expression of Metabolic Enzyme Genes in Mice

    NASA Technical Reports Server (NTRS)

    Wotring, V. E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2011-01-01

    Most administered pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand the effects of spaceflight on the enzymes of the liver and exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. Additionally, it has been previous noted that pre-exposure to small radiation doses seems to confer protection against later and larger radiation doses. This protective power of pre-exposure has been called a priming effect or radioadaptation. This study is an effort to examine the drug metabolizing effects of radioadaptation mechanisms that may be triggered by early exposure to low radiation doses.

  5. Acute neuroactive drug exposures alter locomotor activity in larval zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA's prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after exposure to prototypic drugs that act on the central nervous system. MPTP (1-methyl-4phenyl- 1 ,2,3,6-...

  6. Prenatal cadmium exposure alters postnatal immune cell development and function

    PubMed Central

    Hanson, Miranda L.; Holásková, Ida; Elliott, Meenal; Brundage, Kathleen M.; Schafer, Rosana; Barnett, John B.

    2012-01-01

    Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl2 (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-γ production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4+FoxP3+CD25+ (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8+CD223+ T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental

  7. EXPOSURE OF CULTURED MYOCYTES TO ZINC RESULTS IN ALTERED BEAT RATE AND INTERCELLULAR COMMUNICATION.

    EPA Science Inventory

    Exposure of cultured myocytes to zinc results in altered beat rate and intercellular communication

    Graff, Donald W, Devlin, Robert B, Brackhan, Joseph A, Muller-Borer, Barbara J, Bowman, Jill S, Cascio, Wayne E.

    Exposure to ambient air pollution particulate matter (...

  8. ACUTE EXPOSURE TO MOLINATE ALTERS NEUROENDOCRINE CONTROL OF OVULATION IN THE RAT

    EPA Science Inventory

    Molinate, a thiocarbamate herbicide, has been shown previously to impair reproductive capability in the male rat. In a two-generation study, molinate exposure to female rats resulted in altered pregnancy outcome. However, published data is lacking on the effects of acute exposure...

  9. Prenatal cadmium exposure alters postnatal immune cell development and function

    SciTech Connect

    Hanson, Miranda L.; Holásková, Ida; Elliott, Meenal; Brundage, Kathleen M.; Schafer, Rosana; Barnett, John B.

    2012-06-01

    Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl{sub 2} (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-γ production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4{sup +}FoxP3{sup +}CD25{sup +} (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8{sup +}CD223{sup +} T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can

  10. Exposure to bisphenol A in young adult mice does not alter ovulation but does alter the fertilization ability of oocytes.

    PubMed

    Moore-Ambriz, Teresita Rocio; Acuña-Hernández, Deyanira Guadalupe; Ramos-Robles, Brenda; Sánchez-Gutiérrez, Manuel; Santacruz-Márquez, Ramsés; Sierra-Santoyo, Adolfo; Piña-Guzmán, Belem; Shibayama, Mineko; Hernández-Ochoa, Isabel

    2015-12-15

    Follicle growth culminates in ovulation, which allows for the expulsion of fertilizable oocytes and the formation of corpora lutea. Bisphenol A (BPA) is present in many consumer products, and it has been suggested that BPA impairs ovulation; however, the underlying mechanisms are unknown. Therefore, this study first evaluated whether BPA alters ovulation by affecting folliculogenesis, the number of corpora lutea or eggs shed to the oviduct, ovarian gonadotropin responsiveness, hormone levels, and estrous cyclicity. Because it has been suggested (but not directly confirmed) that BPA exerts toxic effects on the fertilization ability of oocytes, a second aim was to evaluate whether BPA impacts the oocyte fertilization rate using an in vitro fertilization assay and mating. The possible effects on early zygote development were also examined. Young adult female C57BL/6J mice (39 days old) were orally dosed with corn oil (vehicle) or 50 μg/kgbw/day BPA for a period encompassing the first three reproductive cycles (12-15 days). BPA exposure did not alter any parameters related to ovulation. Moreover, BPA exposure reduced the percentage of fertilized oocytes after either in vitro fertilization or mating, but it did not alter the zygotic stages. The data indicate that exposure to the reference dose of BPA does not impact ovulation but that it does influence the oocyte quality in terms of its fertilization ability. PMID:26493930

  11. Dietary exposure to chlorpyrifos alters core temperature in the rat.

    PubMed

    Gordon, Christopher J; Padnos, Beth K

    2002-08-15

    Administration of the organophosphate pesticide chlorpyrifos (CHP) to the male rat at a dose of 25-80 mg/kg (p.o.) results in hypothermia followed by a delayed fever lasting for several days. These are high doses of CHP that cause marked cholinergic stimulation. It is important to understand if chronic exposure to CHP would evoke changes in thermoregulation that are comparable to the acute administration. Male rats of the Long-Evans strain were subjected to dietary treatment of 0, 1, or 5 mg/(kg day) CHP for 6 months. A limited amount of food was given per day to maintain body weight at 350 g. The constant body weight allowed for the regulation of a consistent dosage of CHP per kg body weight throughout the feeding period. Core temperature (T(a)) and motor activity (MA) were monitored by radio telemetric transmitters implanted in the abdominal cavity. After 5 months of treatment, T(c) and MA were monitored in undisturbed animals for 96 h. CHP at 5 mg/(kg day) led to a slight elevation in T(c) without affecting MA. The rats were then administered a challenge dose of CHP (30 mg/kg, p.o.) while T(c) and MA were monitored. Rats fed the 1 and 5 mg/kg CHP diets showed a significantly greater hypothermic response and reduction in MA following CHP challenge compared to controls. The restricted feeding schedule resulted in marked changes in the pattern of the circadian rhythm. Therefore, in another study, rats were treated ad libitum for 17 days with a CHP diet that resulted in a dosage of 7 mg CHP/(mg day). There was a significant increase in T(c) during the daytime but not during the night throughout most of the treatment period. Overall, chronic CHP was associated with a slight but significant elevation in T(c) and greater hypothermic response to a CHP challenge. This latter finding was unexpected and suggests that chronic exposure to CHP sensitizes the rat's thermoregulatory response to acute CHP exposure. PMID:12135625

  12. Exposure to mercury alters early activation events in fish leukocytes.

    PubMed Central

    MacDougal, K C; Johnson, M D; Burnett, K G

    1996-01-01

    Although fish in natural populations may carry high body burdens of both organic and inorganic mercury, the effects of this divalent metal on such lower vertebrates is poorly understood. In this report, inorganic mercury in the form of mercuric chloride (HgCl2) is shown to produce both high-dose inhibition and low-dose activation of leukocytes in a marine teleost fish, Sciaenops ocellatus. Concentrations of inorganic mercury > or = 10 microM suppressed DNA synthesis and induced rapid influx of radiolabeled calcium, as well as tyrosine phosphorylation of numerous cellular proteins. Lower concentrations (0.1-1 microM) of HgCl2 that activated cell growth also induced a slow sustained rise in intracellular calcium in cells loaded with the calcium indicator dye fura-2, but did not produce detectable tyrosine phosphorylation of leukocyte proteins. These studies support the possibility that subtoxic doses of HgCl2 may inappropriately activate teleost leukocytes, potentially altering the processes that regulate the magnitude and specificity of the fish immune response to environmental pathogens. Images Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. PMID:8930553

  13. Developmental exposure to paracetamol causes biochemical alterations in medulla oblongata.

    PubMed

    Blecharz-Klin, Kamilla; Joniec-Maciejak, Ilona; Jawna, Katarzyna; Pyrzanowska, Justyna; Piechal, Agnieszka; Wawer, Adriana; Widy-Tyszkiewicz, Ewa

    2015-09-01

    The effect and safety of prenatal and early life administration of paracetamol - routinely used over-the-counter antipyretic and analgesic medication on monoamines content and balance of amino acids in the medulla oblongata is still unknown. In this study we have determined the level of neurotransmitters in this structure in two-month old Wistar male rats exposed to paracetamol in the dose of 5 (P5, n=10) or 15mg/kg b.w. (P15, n=10) during prenatal period, lactation and till the end of the second month of life. Control group received drinking water (Con, n=10). Monoamines, their metabolites and amino acids concentration in medulla oblongata of rats were determined using high performance liquid chromatography (HPLC) in 60 postnatal day (PND60). This experiment shows that prenatal and early life paracetamol exposure modulates neurotransmission associated with serotonergic, noradrenergic and dopaminergic system in medulla oblongata. Reduction of alanine and taurine levels has also been established. PMID:26233562

  14. Alteration of Rat Fetal Cerebral Cortex Development after Prenatal Exposure to Polychlorinated Biphenyls

    PubMed Central

    Naveau, Elise; Pinson, Anneline; Gérard, Arlette; Nguyen, Laurent; Charlier, Corinne; Thomé, Jean-Pierre; Zoeller, R. Thomas; Bourguignon, Jean-Pierre; Parent, Anne-Simone

    2014-01-01

    Polychlorinated biphenyls (PCBs) are environmental contaminants that persist in environment and human tissues. Perinatal exposure to these endocrine disruptors causes cognitive deficits and learning disabilities in children. These effects may involve their ability to interfere with thyroid hormone (TH) action. We tested the hypothesis that developmental exposure to PCBs can concomitantly alter TH levels and TH-regulated events during cerebral cortex development: progenitor proliferation, cell cycle exit and neuron migration. Pregnant rats exposed to the commercial PCB mixture Aroclor 1254 ended gestation with reduced total and free serum thyroxine levels. Exposure to Aroclor 1254 increased cell cycle exit of the neuronal progenitors and delayed radial neuronal migration in the fetal cortex. Progenitor cell proliferation, cell death and differentiation rate were not altered by prenatal exposure to PCBs. Given that PCBs remain ubiquitous, though diminishing, contaminants in human systems, it is important that we further understand their deleterious effects in the brain. PMID:24642964

  15. PRENATAL EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE ALTERS GENE EXPRESSION IN THE DEVELOPING MURINE HIPPOCAMPUS

    PubMed Central

    Mukhopadhyay, Partha; Horn, Kristin H.; Greene, Robert M.; Pisano, M. Michele

    2010-01-01

    Background Little is known about the effects of passive smoke exposures on the developing brain. Objective The purpose of the current study was to identify changes in gene expression in the murine hippocampus as a consequence of in utero exposure to sidestream cigarette smoke (an experimental equivalent of environmental tobacco smoke (ETS)) at exposure levels that do not result in fetal growth inhibition. Methods A whole body smoke inhalation exposure system was utilized to deliver ETS to pregnant C57BL/6J mice for six hours/day from gestational days 6–17 (gd 6–17) [for microarray] or gd 6–18.5 [for fetal phenotyping]. Results There were no significant effects of ETS exposure on fetal phenotype. However, 61 “expressed” genes in the gd 18.5 fetal hippocampus were differentially regulated (up- or down-regulated by 1.5 fold or greater) by maternal exposure to ETS. Of these 61 genes, 25 genes were upregulated while 36 genes were downregulated. A systems biology approach, including computational methodologies, identified cellular response pathways, and biological themes, underlying altered fetal programming of the embryonic hippocampus by in utero cigarette smoke exposure. Conclusions Results from the present study suggest that even in the absence of effects on fetal growth, prenatal smoke exposure can alter gene expression during the “early” period of hippocampal growth and may result in abnormal hippocampal morphology, connectivity, and function. PMID:19969065

  16. Regionally specific alterations in the low-affinity GABAA receptor following perinatal exposure to diazepam.

    PubMed

    Gruen, R J; Elsworth, J D; Roth, R H

    1990-04-23

    Alterations in a low affinity form of the GABAA receptor were examined with [3H]bicuculline methylchloride in the adult rat following perinatal exposure to diazepam. Perinatal exposure resulted in a significant reduction in [3H]bicuculline binding in the cingulate cortex. A significant decrease in the ability of GABA to displace bound [3H]bicuculline was observed only in the hypothalamus. The results suggest that the effects of perinatal exposure to diazepam are regionally specific and that benzodiazepine receptors and low affinity GABAA receptors are functionally linked during the perinatal period. PMID:2162709

  17. FINE AMBIENT AIR PARTICULAR MATTER EXPOSURE INDUCES MOLECULAR ALTERATIONS INDICATIVE OF CARDIOVASCULAR DISEASE PROGRESSION IN ATHEROSCLEROTIC SUSCEPTIBLE MICE

    EPA Science Inventory

    Epidemiological, clinical, and toxicological studies have demonstrated that exposure to ambient air particulate matter (PM) can alter cardiovascular function and may influence cardiovascular disease (CVD). It has been shown that exposure to concentrated ambient air particles (CA...

  18. Human Ozone (O3) Exposure Alters Serum Profile of Lipid Metabolites

    EPA Science Inventory

    HUMAN OZONE (O3) EXPOSURE ALTERS SERUM PROFILE OF LIPID METABOLITES Miller, D B.1; Kodavanti, U P.2 Karoly, E D.3; Cascio W.E2, Ghio, A J. 21. UNC-Chapel Hill, Chapel Hill, N.C., United States. 2. NHEERL, U.S. EPA, RTP, N.C., United States. 3. METABOLON INC., Durham, N.C., United...

  19. PERINATAL EXPOSURE TO THE PESTICIDE HEPTACHLOR PRODUCES ALTERATIONS IN IMMUNE FUNCTION PARAMETERS IN SPRAGUE DAWLEY RATS

    EPA Science Inventory

    PERINATAL EXPOSURE TO THE PESTICIDE HEPTACHLOR PRODUCES ALTERATIONS IN IMMUNE FUNCTION PARAMETERS IN SPRAGUE DAWLEY RATS. R A Matulka1, AA Rooney3, W Williams2, CB Copeland2, and R J Smialowicz2. 1Curriculum in Toxicology, UNC, Chapel Hill, NC, USA; 2US EPA, ITB, ETD, NHEERL, RT...

  20. ALTERATIONS IN BRAIN PROTEIN KINASE C ISOFORMS FOLLOWING DEVELOPMENTAL EXPOSURE TO POLYCHLORINATED BIPHENYL MIXTURE.

    EPA Science Inventory

    PCBs have been shown to alter several neurochemical end-points and are implicated in the etiology of some neurological diseases. Recent in vivo studies from our laboratory indicated that developmental exposure to a commercial PCB mixture, Aroclor 1254, caused perturbations in cal...

  1. Adaptive Responses to Prochloraz Exposure That Alter Dose-Response and Time-Course Behaviors

    EPA Science Inventory

    Dose response and time-course (DRTC) are, along with exposure, the major determinants of health risk. Adaptive changes within exposed organisms in response to environmental stress are common, and alter DRTC behaviors to minimize the effects caused by stressors. In this project, ...

  2. GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE (EDS) ALTERS DEVELOPMENT OF THE MOUSE TESTIS

    EPA Science Inventory

    GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE (EDS) ALTERS DEVELOPMENT OF THE MOUSE TESTIS. D.K. Tarka*1,2, J.D. Suarez*2, N.L. Roberts*2, J.M. Rogers*1,2, M.P. Hardy3, and G.R. Klinefelter1,2. 1University of North Carolina, Curriculum in Toxicology, Chapel Hill, NC; 2USEPA,...

  3. Postnatal sulfur dioxide exposure reversibly alters parasympathetic regulation of heart rate.

    PubMed

    Woerman, Amanda L; Mendelowitz, David

    2013-08-01

    Perinatal sulfur dioxide exposure disrupts parasympathetic regulation of cardiovascular activity. Here, we examine the relative risks of prenatal versus postnatal exposure to the air pollutant and the reversibility of the cardiovascular effects. Two groups of animals were used for this study. For prenatal exposure, pregnant Sprague-Dawley dams were exposed to 5 parts per million sulfur dioxide for 1 hour daily throughout gestation and with their pups after birth to medical-grade air through 6 days postnatal. For postnatal exposure, dams were exposed to air, and after delivery along with their pups to 5 parts per million sulfur dioxide through postnatal day 6. ECGs were recorded from pups on postnatal day 5 to examine changes in heart rate. Whole-cell patch-clamp electrophysiology was used to examine changes in neurotransmission to cardiac vagal neurons in the nucleus ambiguus on sulfur dioxide exposure. Postnatal sulfur dioxide exposure diminished glutamatergic neurotransmission to cardiac vagal neurons by 40.9% and increased heart rate, whereas prenatal exposure altered neither of these properties. When postnatal exposure concluded on postnatal day 5, excitatory neurotransmission remained decreased through day 6 and returned to basal levels by day 7. ECGs showed that heart rate remained elevated through day 6 and recovered by day 7. On activation of the parasympathetic diving reflex, the response was significantly blunted by postnatal sulfur dioxide exposure through day 7 but recovered by day 8. Postnatal, but not prenatal, exposure to sulfur dioxide can disrupt parasympathetic regulation of cardiovascular activity. Neonates can recover from these effects within 2 to 3 days of discontinued exposure. PMID:23774227

  4. Postnatal Sulfur Dioxide Exposure Reversibly Alters Parasympathetic Regulation of Heart Rate

    PubMed Central

    Woerman, Amanda L.; Mendelowitz, David

    2014-01-01

    Perinatal sulfur dioxide exposure disrupts parasympathetic regulation of cardiovascular activity. Here, we examine the relative risks of prenatal versus postnatal exposure to the air pollutant, and the reversibility of the cardiovascular effects. Two groups of animals were used for this study. For prenatal exposure, pregnant Sprague-Dawley dams were exposed to 5 parts per million sulfur dioxide for 1 hour daily throughout gestation, and with their pups upon birth to medical-grade air through 6 days postnatal. For postnatal exposure, dams were exposed to air, and upon delivery along with their pups to 5 parts per million sulfur dioxide through postnatal day 6. Electrocardiograms were recorded from pups on postnatal day 5 to examine changes in heart rate. Whole-cell patch-clamp electrophysiology was used to examine changes in neurotransmission to cardiac vagal neurons upon sulfur dioxide exposure. Postnatal sulfur dioxide exposure diminished glutamatergic neurotransmission to cardiac vagal neurons by 40.9% and increased heart rate, whereas prenatal exposure altered neither of these properties. When postnatal exposure concluded on postnatal day 5, excitatory neurotransmission remained decreased through day 6, and returned to basal levels by day 7. Electrocardiograms showed that heart rate remained elevated through day 6 and recovered by day 7. Upon activation of the parasympathetic diving reflex, the response was significantly blunted by postnatal sulfur dioxide exposure through day 7 but recovered by day 8. Postnatal, but not prenatal, exposure to sulfur dioxide can disrupt parasympathetic regulation of cardiovascular activity. Neonates can recover from these effects within 2–3 days of discontinued exposure. PMID:23774227

  5. Ozone Exposure Alters Serotonin and Serotonin Receptor Expression in the Developing Lung

    PubMed Central

    Van Winkle, Laura S.

    2013-01-01

    Ozone, a pervasive environmental pollutant, adversely affects functional lung growth in children. Animal studies demonstrate that altered lung development is associated with modified signaling within the airway epithelial mesenchymal trophic unit, including mediators that can change nerve growth. We hypothesized that ozone exposure alters the normal pattern of serotonin, its transporter (5-HTT), and two key receptors (5-HT2A and 5-HT4), a pathway involved in postnatal airway neural, epithelial, and immune processes. We exposed monkeys to acute or episodic ozone during the first 2 or 6 months of life. There were three exposure groups/age: (1) filtered air, (2) acute ozone challenge, and (3) episodic ozone + acute ozone challenge. Lungs were prepared for compartment-specific qRT-PCR, immunohistochemistry, and stereology. Airway epithelial serotonin immunopositive staining increased in all exposure groups with the most prominent in 2-month midlevel and 6-month distal airways. Gene expression of 5-HTT, 5-HT2AR, and 5-HT4R increased in an age-dependent manner. Overall expression was greater in distal compared with midlevel airways. Ozone exposure disrupted both 5-HT2AR and 5-HT4R protein expression in airways and enhanced immunopositive staining for 5-HT2AR (2 months) and 5-HT4R (6 months) on smooth muscle. Ozone exposure increases serotonin in airway epithelium regardless of airway level, age, and exposure history and changes the spatial pattern of serotonin receptor protein (5-HT2A and 5-HT4) and 5-HTT gene expression depending on compartment, age, and exposure history. Understanding how serotonin modulates components of reversible airway obstruction exacerbated by ozone exposure sets the foundation for developing clinically relevant therapies for airway disease. PMID:23570994

  6. Preweaning cocaine exposure alters brain glucose metabolic rates following repeated amphetamine administration in the adult rat.

    PubMed

    Melnick, Susan M; Torres-Reveron, Annelyn; Dow-Edwards, Diana L

    2004-10-15

    Developmental cocaine exposure produces long-term alterations in function of many neuronal circuits. This study examined glucose metabolic rates following repeated amphetamine administration in adult male and female rats pretreated with cocaine during postnatal days (PND) 11-20. PND11-20 cocaine increased the response to amphetamine in many components of the motor system and the dorsal caudate-putamen, in particular, and decreased the metabolic response in the hypothalamus. While amphetamine alone produced widespread increases in metabolism, there were no cocaine-related effects in the mesolimbic, limbic or sensory structures. These data suggest that a brief cocaine exposure during development can alter ontogeny and result in abnormal neuronal responses to repeated psychostimulant administration in adulthood. PMID:15464226

  7. Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure.

    PubMed

    Klaren, W D; Gadupudi, G S; Wels, B; Simmons, D L; Olivier, A K; Robertson, L W

    2015-12-01

    Polychlorinated Biphenyls (PCBs) are industrial chemicals that have become a persistent threat to human health due to ongoing exposure. A subset of PCBs, known as dioxin-like PCBs, pose a special threat given their potent hepatic effects. Micronutrients, especially Cu, Zn and Se, homeostatic dysfunction is commonly seen after exposure to dioxin-like PCBs. This study investigates whether micronutrient alteration is the byproduct of the ongoing hepatotoxicity, marked by lipid accumulation, or a concurrent, yet independent event of hepatic damage. A time course study was carried out using male Sprague-Dawley rats with treatments of PCB126, the prototypical dioxin-like PCB, resulting in 6 different time points. Animals were fed a purified diet, based on AIN-93G, for three weeks to ensure micronutrient equilibration. A single IP injection of either tocopherol-stripped soy oil vehicle (5 mL/kg) or 5 μmol/kg PCB126 dose in vehicle was given at various time points resulting in exposures of 9h, 18 h, 36 h, 3 days, 6 days, and 12 days. Mild hepatic vacuolar change was seen as early as 36 h with drastic changes at the later time points, 6 and 12 days. Micronutrient alterations, specifically Cu, Zn, and Se, were not seen until after day 3 and only observed in the liver. No alterations were seen in the duodenum, suggesting that absorption and excretion may not be involved. Micronutrient alterations occur with ROS formation, lipid accumulation, and hepatomegaly. To probe the mechanistic underpinnings, alteration of gene expression of several copper chaperones was investigated; only metallothionein appeared elevated. These data suggest that the disruption in micronutrient status is a result of the hepatic injury elicited by PCB126 and is mediated in part by metallothionein. PMID:26410179

  8. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FALLS TO ALTER SOMATOSENSORY EVOKED POTENTIALS, COMPOUND NERVE ACTION POTENTIALS, OR NERVE CONDUCTION VELOCITY IN RATS.

    EPA Science Inventory

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Cholinergic transmission is involved in sensory modulation in the cortex and cerebellum, and therefore may be altered following chlorpyrifos (CPF) exposure...

  9. Developmental alterations in olivary climbing fiber distribution following postnatal ethanol exposure in the rat.

    PubMed

    Pierce, D R; Hayar, A; Williams, D K; Light, K E

    2010-09-01

    Ethanol exposure during postnatal days (PN) 4-6 in rats alters cerebellar development resulting in significant loss of Purkinje cells. There is little knowledge, however, on what happens to the neurons that survive. In this study, rat pups were treated with a daily dose of ethanol (either 3.6 or 4.5 g/kg body weight) delivered by intragastric intubation on PN4, PN4-6, or PN7-9. Then the interactions between climbing fibers and Purkinje cells were examined on PN14 using confocal microscopy. Mid-vermal cerebellar sections were stained with antibodies to calbindin-D28k (to visualize Purkinje cells) and vesicular glutamate transporter 2 (VGluT2, to visualize climbing fibers). Confocal z-stack images were obtained from Lobule 1 and analyzed with Imaris software to quantify the staining of the two antibodies. The VGluT2 immunostaining was significantly reduced in the PN4 and PN4-6 ethanol groups for the 4.5 g/kg dose level, compared to controls, indicating that the cerebellar circuitry was significantly altered following developmental ethanol exposure. Not only were there fewer Purkinje cells following ethanol exposure, but the surviving neurons had significantly fewer VGluT2-labeled synapses. These alterations in the synaptic integrity were both dose dependent and temporally dependent. PMID:20542091

  10. Embryonic Atrazine Exposure Elicits Alterations in Genes Associated with Neuroendocrine Function in Adult Male Zebrafish.

    PubMed

    Wirbisky, Sara E; Sepúlveda, Maria S; Weber, Gregory J; Jannasch, Amber S; Horzmann, Katharine A; Freeman, Jennifer L

    2016-09-01

    The developmental origins of health and disease (DOHaD) hypothesis states that exposure to environmental stressors early in life can elicit genome and epigenome changes resulting in an increased susceptibility of a disease state during adulthood. Atrazine, a common agricultural herbicide used throughout the Midwestern United States, frequently contaminates potable water supplies and is a suspected endocrine disrupting chemical. In our previous studies, zebrafish was exposed to 0, 0.3, 3, or 30 parts per billion (μg/l) atrazine through embryogenesis, rinsed, and allowed to mature to adulthood. A decrease in spawning was observed with morphological alterations in offspring. In addition, adult females displayed an increase in ovarian progesterone and follicular atresia, alterations in levels of a serotonin metabolite and serotonin turnover in brain tissue, and transcriptome changes in brain and ovarian tissue supporting neuroendocrine alterations. As reproductive dysfunction is also influenced by males, this study assessed testes histology, hormone levels, and transcriptomic profiles of testes and brain tissue in the adult males. The embryonic atrazine exposure resulted in no alterations in body or testes weight, gonadosomatic index, testes histology, or levels of 11-ketotestosterone or testosterone. To further investigate potential alterations, transcriptomic profiles of adult male testes and brain tissue was completed. This analysis demonstrated alterations in genes associated with abnormal cell and neuronal growth and morphology; molecular transport, quantity, and production of steroid hormones; and neurotransmission with an emphasis on the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-thyroid axes. Overall, this data indicate future studies should focus on additional neuroendocrine endpoints to determine potential functional impairments. PMID:27413107

  11. Cholinergic Synaptic Transmissions Were Altered after Single Sevoflurane Exposure in Drosophila Pupa

    PubMed Central

    Chen, Rongfa; Zhang, Tao; Kuang, Liting; Chen, Zhen; Ran, Dongzhi; Niu, Yang; Gu, Huaiyu

    2015-01-01

    Purpose. Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Methods. Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. Results. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced (P < 0.05). Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure (P < 0.05). Conclusions. All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure. PMID:25705662

  12. Maternal mobile phone exposure alters intrinsic electrophysiological properties of CA1 pyramidal neurons in rat offspring.

    PubMed

    Razavinasab, Moazamehosadat; Moazzami, Kasra; Shabani, Mohammad

    2016-06-01

    Some studies have shown that exposure to electromagnetic field (EMF) may result in structural damage to neurons. In this study, we have elucidated the alteration in the hippocampal function of offspring Wistar rats (n = 8 rats in each group) that were chronically exposed to mobile phones during their gestational period by applying behavioral, histological, and electrophysiological tests. Rats in the EMF group were exposed to 900 MHz pulsed-EMF irradiation for 6 h/day. Whole cell recordings in hippocampal pyramidal cells in the mobile phone groups did show a decrease in neuronal excitability. Mobile phone exposure was mostly associated with a decrease in the number of action potentials fired in spontaneous activity and in response to current injection in both male and female groups. There was an increase in the amplitude of the afterhyperpolarization (AHP) in mobile phone rats compared with the control. The results of the passive avoidance and Morris water maze assessment of learning and memory performance showed that phone exposure significantly altered learning acquisition and memory retention in male and female rats compared with the control rats. Light microscopy study of brain sections of the control and mobile phone-exposed rats showed normal morphology.Our results suggest that exposure to mobile phones adversely affects the cognitive performance of both female and male offspring rats using behavioral and electrophysiological techniques. PMID:24604340

  13. Altered Hippocampal Lipid Profile Following Acute Postnatal Exposure to Di(2-Ethylhexyl) Phthalate in Rats

    PubMed Central

    Smith, Catherine A.; Farmer, Kyle; Lee, Hyunmin; Holahan, Matthew R.; Smith, Jeffrey C.

    2015-01-01

    Slight changes in the abundance of certain lipid species in the brain may drastically alter normal neurodevelopment via membrane stability, cell signalling, and cell survival. Previous findings have demonstrated that postnatal exposure to di (2-ethylhexyl) phthalate (DEHP) disrupts normal axonal and neural development in the hippocampus. The goal of the current study was to determine whether postnatal exposure to DEHP alters the lipid profile in the hippocampus during postnatal development. Systemic treatment with 10 mg/kg DEHP during postnatal development led to elevated levels of phosphatidylcholine and sphingomyelin in the hippocampus of female rats. There was no effect of DEHP exposure on the overall abundance of phosphatidylcholine or sphingomyelin in male rats or of lysophosphatidylcholine in male or female rats. Individual analyses of each identified lipid species revealed 10 phosphatidylcholine and six sphingomyelin lipids in DEHP-treated females and a single lysophosphatidylcholine in DEHP-treated males with a two-fold or higher increase in relative abundance. Our results are congruent with previous work that found that postnatal exposure to DEHP had a near-selective detrimental effect on hippocampal development in males but not females. Together, results suggest a neuroprotective effect of these elevated lipid species in females. PMID:26516880

  14. Environmentally Realistic Exposure to the Herbicide Atrazine Alters Some Sexually Selected Traits in Male Guppies

    PubMed Central

    Shenoy, Kausalya

    2012-01-01

    Male mating signals, including ornaments and courtship displays, and other sexually selected traits, like male-male aggression, are largely controlled by sex hormones. Environmental pollutants, notably endocrine disrupting compounds, can interfere with the proper functioning of hormones, thereby impacting the expression of hormonally regulated traits. Atrazine, one of the most widely used herbicides, can alter sex hormone levels in exposed animals. I tested the effects of environmentally relevant atrazine exposures on mating signals and behaviors in male guppies, a sexually dimorphic freshwater fish. Prolonged atrazine exposure reduced the expression of two honest signals: the area of orange spots (ornaments) and the number of courtship displays performed. Atrazine exposure also reduced aggression towards competing males in the context of mate competition. In the wild, exposure levels vary among individuals because of differential distribution of the pollutants across habitats; hence, differently impacted males often compete for the same mates. Disrupted mating signals can reduce reproductive success as females avoid mating with perceptibly suboptimal males. Less aggressive males are at a competitive disadvantage and lose access to females. This study highlights the effects of atrazine on ecologically relevant mating signals and behaviors in exposed wildlife. Altered reproductive traits have important implications for population dynamics, evolutionary patterns, and conservation of wildlife species. PMID:22312428

  15. Chronic alcohol exposure alters gene expression in HepG2 cells

    PubMed Central

    Pochareddy, Sirisha; Edenberg, Howard J.

    2011-01-01

    Background Liver is the primary site of alcohol metabolism and is highly vulnerable to injuries due to chronic alcohol abuse. Several molecular mechanisms, including oxidative stress and altered cellular metabolism, have been implicated in the development and progression of alcoholic liver disease. We sought to gain further insight into the molecular pathogenesis by studying the effects of ethanol exposure on global gene expression in HepG2 cells. Methods HepG2 cells were cultured in the presence or absence of 75 mM ethanol for nine days, with fresh media daily. Global gene expression changes were studied using Affymetrix GeneChip® Human Exon 1.0 ST Arrays. Gene expression differences were validated for thirteen genes by quantitative real-time RT-PCR. To identify biological pathways affected by ethanol treatment, differentially expressed genes were analyzed by Ingenuity Pathway Analysis software. Results Long term ethanol exposure altered the expression of 1093 genes (FDR ≤ 3%); many of these changes were modest. Long term ethanol exposure affected several pathways, including acute phase response, amino acid metabolism, carbohydrate metabolism and lipid metabolism. Conclusions Global measurements of gene expression show that a large number of genes are affected by chronic ethanol, although most show modest effect. These data provide insight into the molecular pathology resulting from extended alcohol exposure. PMID:22150570

  16. Altered Hippocampal Lipid Profile Following Acute Postnatal Exposure to Di(2-Ethylhexyl) Phthalate in Rats.

    PubMed

    Smith, Catherine A; Farmer, Kyle; Lee, Hyunmin; Holahan, Matthew R; Smith, Jeffrey C

    2015-10-01

    Slight changes in the abundance of certain lipid species in the brain may drastically alter normal neurodevelopment via membrane stability, cell signalling, and cell survival. Previous findings have demonstrated that postnatal exposure to di (2-ethylhexyl) phthalate (DEHP) disrupts normal axonal and neural development in the hippocampus. The goal of the current study was to determine whether postnatal exposure to DEHP alters the lipid profile in the hippocampus during postnatal development. Systemic treatment with 10 mg/kg DEHP during postnatal development led to elevated levels of phosphatidylcholine and sphingomyelin in the hippocampus of female rats. There was no effect of DEHP exposure on the overall abundance of phosphatidylcholine or sphingomyelin in male rats or of lysophosphatidylcholine in male or female rats. Individual analyses of each identified lipid species revealed 10 phosphatidylcholine and six sphingomyelin lipids in DEHP-treated females and a single lysophosphatidylcholine in DEHP-treated males with a two-fold or higher increase in relative abundance. Our results are congruent with previous work that found that postnatal exposure to DEHP had a near-selective detrimental effect on hippocampal development in males but not females. Together, results suggest a neuroprotective effect of these elevated lipid species in females. PMID:26516880

  17. Neonatal exposure to monosodium glutamate induces morphological alterations in suprachiasmatic nucleus of adult rat.

    PubMed

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Chávez-Saldaña, Margarita; Rojas, Patricia; Gutiérrez-Pérez, Oscar; Rojas, Carolina; Arteaga-Silva, Marcela

    2016-02-01

    Neonatal exposure to monosodium glutamate (MSG) induces circadian disorders in several physiological and behavioural processes regulated by the suprachiasmatic nucleus (SCN). The objective of this study was to evaluate the effects of neonatal exposure to MSG on locomotor activity, and on morphology, cellular density and expression of proteins, as evaluated by optical density (OD), of vasopressin (VP)-, vasoactive intestinal polypeptide (VIP)- and glial fibrillary acidic protein (GFAP)-immunoreactive cells in the SCN. Male Wistar rats were used: the MSG group was subcutaneously treated from 3 to 10 days of age with 3.5 mg/g/day. Locomotor activity was evaluated at 90 days of age using 'open-field' test, and the brains were processed for immunohistochemical studies. MSG exposure induced a significant decrease in locomotor activity. VP- and VIP-immunoreactive neuronal densities showed a significant decrease, while the somatic OD showed an increase. Major axes and somatic area were significantly increased in VIP neurons. The cellular and optical densities of GFAP-immunoreactive sections of SCN were significantly increased. These results demonstrated that newborn exposure to MSG induced morphological alterations in SCN cells, an alteration that could be the basis for behavioural disorders observed in the animals. PMID:26799547

  18. Altered surfactant protein A gene expression and protein metabolism associated with repeat exposure to inhaled endotoxin.

    PubMed

    George, Caroline L S; White, Misty L; O'Neill, Marsha E; Thorne, Peter S; Schwartz, David A; Snyder, Jeanne M

    2003-12-01

    Chronically inhaled endotoxin, which is ubiquitous in many occupational and domestic environments, can adversely affect the respiratory system resulting in an inflammatory response and decreased lung function. Surfactant-associated protein A (SP-A) is part of the lung innate immune system and may attenuate the inflammatory response in various types of lung injury. Using a murine model to mimic occupational exposures to endotoxin, we hypothesized that SP-A gene expression and protein would be elevated in response to repeat exposure to inhaled grain dust and to purified lipopolysaccharide (LPS). Our results demonstrate that repeat exposure to inhaled endotoxin, either in the form of grain dust or purified LPS, results in increased whole lung SP-A gene expression and type II alveolar epithelial cell hyperplasia, whereas SP-A protein levels in lung lavage fluid are decreased. Furthermore, these alterations in SP-A gene activity and protein metabolism are dependent on an intact endotoxin signaling system. PMID:12922979

  19. Repeated exposures of the male Sprague Dawley rat reproductive tract to environmental toxicants: Do earlier exposures to di-(2-ethylhexyl)phthalate (DEHP) alter the effects of later exposures?

    PubMed

    Traore, Kassim; Martinez-Arguelles, Daniel B; Papadopoulos, Vassilios; Chen, Haolin; Zirkin, Barry R

    2016-06-01

    Although exposures to environmental toxicants occur throughout life, little attention has been paid to the possible effects of exposures early in life on later exposure effects. We asked whether DEHP administered in utero (GD14-parturition) affects how male rats respond to later exposures. Neither in utero nor juvenile (PND21-35) exposures to 100mg/kg/day DEHP affected testis weight or histology as assessed on PND35. However, after in utero DEHP, subsequent juvenile exposure resulted in significantly reduced testis weight and altered testicular histology. Both in utero and juvenile exposures resulted in significant reductions in serum testosterone, but there was no effect of earlier on later exposure. Whether or not there had been in utero DEHP exposure, juvenile DEHP exposure had no effect on body, kidney or liver weights. These observations indicate that in utero exposure can, but will not necessarily, alter later exposure effects, with outcomes dependent upon endpoints measured and dose. PMID:27040317

  20. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development

    PubMed Central

    Caldwell, Katharine E.; Labrecque, Matthew T.; Solomon, Benjamin R.; Ali, Abdulmehdi; Allan, Andrea M.

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50 ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  1. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development.

    PubMed

    Caldwell, Katharine E; Labrecque, Matthew T; Solomon, Benjamin R; Ali, Abdulmehdi; Allan, Andrea M

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  2. Low-Level Environmental Phthalate Exposure Associates with Urine Metabolome Alteration in a Chinese Male Cohort.

    PubMed

    Zhang, Jie; Liu, Liangpo; Wang, Xiaofei; Huang, Qingyu; Tian, Meiping; Shen, Heqing

    2016-06-01

    The general population is exposed to phthalates through various sources and routes. Integration of omics data and epidemiological data is a key step toward directly linking phthalate biomonitoring data with biological response. Urine metabolomics is a powerful tool to identify exposure biomarkers and delineate the modes of action of environmental stressors. The objectives of this study are to investigate the association between low-level environmental phthalate exposure and urine metabolome alteration in male population, and to unveil the metabolic pathways involved in the mechanisms of phthalate toxicity. In this retrospective cross-sectional study, we studied the urine metabolomic profiles of 364 male subjects exposed to low-level environmental phthalates. Di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) are the most widely used phthalates. ∑DEHP and MBP (the major metabolite of DBP) were associated with significant alteration of global urine metabolome in the male population. We observed significant increase in the levels of acetylneuraminic acid, carnitine C8:1, carnitine C18:0, cystine, phenylglycine, phenylpyruvic acid and glutamylphenylalanine; and meanwhile, decrease in the levels of carnitine C16:2, diacetylspermine, alanine, taurine, tryptophan, ornithine, methylglutaconic acid, hydroxyl-PEG2 and keto-PGE2 in high exposure group. The observations indicated that low-level environmental phthalate exposure associated with increased oxidative stress and fatty acid oxidation and decreased prostaglandin metabolism. Urea cycle, tryptophan and phenylalanine metabolism disruption was also observed. The urine metabolome disruption effects associated with ∑DEHP and MBP were similar, but not identical. The multibiomarker models presented AUC values of 0.845 and 0.834 for ∑DEHP and MBP, respectively. The predictive accuracy rates of established models were 81% for ΣDEHP and 73% for MBP. Our results suggest that low-level environmental phthalate

  3. Lead Exposure Disrupts Global DNA Methylation in Human Embryonic Stem Cells and Alters Their Neuronal Differentiation

    PubMed Central

    Senut, Marie-Claude; Sen, Arko; Cingolani, Pablo; Shaik, Asra; Land, Susan J.; Ruden, Douglas M.

    2014-01-01

    Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9μM) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural progenitor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9μM Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina HumanMethylation450 BeadChip demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development. PMID:24519525

  4. Lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation.

    PubMed

    Senut, Marie-Claude; Sen, Arko; Cingolani, Pablo; Shaik, Asra; Land, Susan J; Ruden, Douglas M

    2014-05-01

    Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9μM) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural progenitor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9μM Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina HumanMethylation450 BeadChip demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development. PMID:24519525

  5. Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults.

    PubMed

    Cheung, Ivy N; Zee, Phyllis C; Shalman, Dov; Malkani, Roneil G; Kang, Joseph; Reid, Kathryn J

    2016-01-01

    Increasing evidence points to associations between light-dark exposure patterns, feeding behavior, and metabolism. This study aimed to determine the acute effects of 3 hours of morning versus evening blue-enriched light exposure compared to dim light on hunger, metabolic function, and physiological arousal. Nineteen healthy adults completed this 4-day inpatient protocol under dim light conditions (<20lux). Participants were randomized to 3 hours of blue-enriched light exposure on Day 3 starting either 0.5 hours after wake (n = 9; morning group) or 10.5 hours after wake (n = 10; evening group). All participants remained in dim light on Day 2 to serve as their baseline. Subjective hunger and sleepiness scales were collected hourly. Blood was sampled at 30-minute intervals for 4 hours in association with the light exposure period for glucose, insulin, cortisol, leptin, and ghrelin. Homeostatic model assessment of insulin resistance (HOMA-IR) and area under the curve (AUC) for insulin, glucose, HOMA-IR and cortisol were calculated. Comparisons relative to baseline were done using t-tests and repeated measures ANOVAs. In both the morning and evening groups, insulin total area, HOMA-IR, and HOMA-IR AUC were increased and subjective sleepiness was reduced with blue-enriched light compared to dim light. The evening group, but not the morning group, had significantly higher glucose peak value during blue-enriched light exposure compared to dim light. There were no other significant differences between the morning or the evening groups in response to blue-enriched light exposure. Blue-enriched light exposure acutely alters glucose metabolism and sleepiness, however the mechanisms behind this relationship and its impacts on hunger and appetite regulation remain unclear. These results provide further support for a role of environmental light exposure in the regulation of metabolism. PMID:27191727

  6. Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults

    PubMed Central

    Cheung, Ivy N.; Zee, Phyllis C.; Shalman, Dov; Malkani, Roneil G.; Kang, Joseph; Reid, Kathryn J.

    2016-01-01

    Increasing evidence points to associations between light-dark exposure patterns, feeding behavior, and metabolism. This study aimed to determine the acute effects of 3 hours of morning versus evening blue-enriched light exposure compared to dim light on hunger, metabolic function, and physiological arousal. Nineteen healthy adults completed this 4-day inpatient protocol under dim light conditions (<20lux). Participants were randomized to 3 hours of blue-enriched light exposure on Day 3 starting either 0.5 hours after wake (n = 9; morning group) or 10.5 hours after wake (n = 10; evening group). All participants remained in dim light on Day 2 to serve as their baseline. Subjective hunger and sleepiness scales were collected hourly. Blood was sampled at 30-minute intervals for 4 hours in association with the light exposure period for glucose, insulin, cortisol, leptin, and ghrelin. Homeostatic model assessment of insulin resistance (HOMA-IR) and area under the curve (AUC) for insulin, glucose, HOMA-IR and cortisol were calculated. Comparisons relative to baseline were done using t-tests and repeated measures ANOVAs. In both the morning and evening groups, insulin total area, HOMA-IR, and HOMA-IR AUC were increased and subjective sleepiness was reduced with blue-enriched light compared to dim light. The evening group, but not the morning group, had significantly higher glucose peak value during blue-enriched light exposure compared to dim light. There were no other significant differences between the morning or the evening groups in response to blue-enriched light exposure. Blue-enriched light exposure acutely alters glucose metabolism and sleepiness, however the mechanisms behind this relationship and its impacts on hunger and appetite regulation remain unclear. These results provide further support for a role of environmental light exposure in the regulation of metabolism. PMID:27191727

  7. Altered Proteome of Burkholderia pseudomallei Colony Variants Induced by Exposure to Human Lung Epithelial Cells

    PubMed Central

    Al-Maleki, Anis Rageh; Mariappan, Vanitha; Vellasamy, Kumutha Malar; Tay, Sun Tee; Vadivelu, Jamuna

    2015-01-01

    Burkholderia pseudomallei primary diagnostic cultures demonstrate colony morphology variation associated with expression of virulence and adaptation proteins. This study aims to examine the ability of B. pseudomallei colony variants (wild type [WT] and small colony variant [SCV]) to survive and replicate intracellularly in A549 cells and to identify the alterations in the protein expression of these variants, post-exposure to the A549 cells. Intracellular survival and cytotoxicity assays were performed followed by proteomics analysis using two-dimensional gel electrophoresis. B. pseudomallei SCV survive longer than the WT. During post-exposure, among 259 and 260 protein spots of SCV and WT, respectively, 19 were differentially expressed. Among SCV post-exposure up-regulated proteins, glyceraldehyde 3-phosphate dehydrogenase, fructose-bisphosphate aldolase (CbbA) and betaine aldehyde dehydrogenase were associated with adhesion and virulence. Among the down-regulated proteins, enolase (Eno) is implicated in adhesion and virulence. Additionally, post-exposure expression profiles of both variants were compared with pre-exposure. In WT pre- vs post-exposure, 36 proteins were differentially expressed. Of the up-regulated proteins, translocator protein, Eno, nucleoside diphosphate kinase (Ndk), ferritin Dps-family DNA binding protein and peptidyl-prolyl cis-trans isomerase B were implicated in invasion and virulence. In SCV pre- vs post-exposure, 27 proteins were differentially expressed. Among the up-regulated proteins, flagellin, Eno, CbbA, Ndk and phenylacetate-coenzyme A ligase have similarly been implicated in adhesion, invasion. Protein profiles differences post-exposure provide insights into association between morphotypic and phenotypic characteristics of colony variants, strengthening the role of B. pseudomallei morphotypes in pathogenesis of melioidosis. PMID:25996927

  8. Functional Alterations in the Dorsal Raphe Nucleus Following Acute and Chronic Ethanol Exposure

    PubMed Central

    Lowery-Gionta, Emily G; Marcinkiewcz, Catherine A; Kash, Thomas L

    2015-01-01

    Alcoholism is a pervasive disorder perpetuated in part to relieve negative mood states like anxiety experienced during alcohol withdrawal. Emerging evidence demonstrates a role for the serotonin-rich dorsal raphe (DR) in anxiety following ethanol withdrawal. The current study examined the effects of chronic ethanol vapor exposure on the DR using slice electrophysiology in male DBA2/J mice. We found that chronic ethanol exposure resulted in deficits in social approach indicative of increased anxiety-like behavior at both 24 h and 7 days post-ethanol exposure. At 24 h post-ethanol exposure, we observed increased excitability and decreased spontaneous inhibitory transmission (inhibitory postsynaptic currents, IPSCs) in the DR. At 7 days post-ethanol exposure, we observed increased spontaneous and miniature excitatory transmission (excitatory postsynaptic currents, EPSCs). Because acute ethanol alters GABA transmission in other brain regions, we assessed the effects of ex vivo ethanol (50 mM) on miniature IPSCs (mIPSCs) in the DR 24-h post-ethanol exposure. Bath application of ethanol enhanced the amplitude of mIPSCs in cells from ethanol-naive and chronic intermittent ethanol-exposed (CIE) mice, but significantly enhanced the frequency of mIPSCs only in cells from CIE mice, suggesting that DR neurons are more sensitive to the inhibitory effects of acute ethanol following CIE. On the basis of these findings, we hypothesize that net excitation of DR neurons following chronic ethanol exposure contributes to enhanced anxiety during ethanol withdrawal, and that increased sensitivity of DR neurons to subsequent ethanol exposure may mediate acute ethanol's ability to relieve anxiety during ethanol withdrawal. PMID:25120075

  9. Olivary climbing fiber alterations in PN40 rat cerebellum following postnatal ethanol exposure.

    PubMed

    Pierce, Dwight R; Hayar, Abdallah; Williams, D Keith; Light, Kim Edward

    2011-03-10

    Developmental ethanol exposure in rats during postnatal days (PN) 4-6 is known to cause significant loss of the cerebellar Purkinje cells. It is not known what happens to the surviving neurons as they continue to develop. This study was designed to quantify the interactions between the olivary climbing fibers and the Purkinje cells when the cerebellar circuits have matured. Rat pups were treated with a daily dose of ethanol (4.5g/kg body weight) delivered by intragastric intubation on PN4, PN4-6, or PN7-9. The interactions between the climbing fibers and the Purkinje cells were examined on PN40 using confocal microscopy. Mid-vermal cerebellar sections were stained with antibodies to calbindin-D28k (to visualize Purkinje cells) and vesicular glutamate transporter 2 (VGluT2, to visualize climbing fibers). Confocal z-stack images were obtained from Lobule 1 and analyzed with Imaris software to quantify the staining of the two antibodies. The VGluT2 immunostaining was significantly reduced and this was associated with alterations in the synaptic integrity, and synaptic number per Purkinje cell with only a single exposure on PN4 enough to cause the alterations. Previously, we demonstrated similar deficits in climbing fiber innervation when analyzed on PN14 (Pierce, Hayar, Williams, and Light, 2010). The present study confirms that these alterations are sustained and further identifies the decreased synaptic density as well as alterations to the general morphology of the molecular layer of the cerebellar cortex that are the result of the binge ethanol exposure. PMID:21241681

  10. Genistein exposure inhibits growth and alters steroidogenesis in adult mouse antral follicles.

    PubMed

    Patel, Shreya; Peretz, Jackye; Pan, Yuan-Xiang; Helferich, William G; Flaws, Jodi A

    2016-02-15

    Genistein is a naturally occurring isoflavone phytoestrogen commonly found in plant products such as soybeans, lentils, and chickpeas. Genistein, like other phytoestrogens, has the potential to mimic, enhance, or impair the estradiol biosynthesis pathway, thereby potentially altering ovarian follicle growth. Previous studies have inconsistently indicated that genistein exposure may alter granulosa cell proliferation and hormone production, but no studies have examined the effects of genistein on intact antral follicles. Thus, this study was designed to test the hypothesis that genistein exposure inhibits follicle growth and steroidogenesis in intact antral follicles. To test this hypothesis, antral follicles isolated from CD-1 mice were cultured with vehicle (dimethyl sulfoxide; DMSO) or genistein (6.0 and 36μM) for 18-96h. Every 24h, follicle diameters were measured to assess growth. At the end of each culture period, the media were pooled to measure hormone levels, and the cultured follicles were collected to measure expression of cell cycle regulators and steroidogenic enzymes. The results indicate that genistein (36μM) inhibits growth of mouse antral follicles. Additionally, genistein (6.0 and 36μM) increases progesterone, testosterone, and dehydroepiandrosterone (DHEA) levels, but decreases estrone and estradiol levels. The results also indicate that genistein alters the expression of steroidogenic enzymes at 24, 72 and 96h, and the expression of cell cycle regulators at 18h. These data indicate that genistein exposure inhibits antral follicle growth by inhibiting the cell cycle, alters sex steroid hormone levels, and dysregulates steroidogenic enzymes in cultured mouse antral follicles. PMID:26792615

  11. Early life exposure to allergen and ozone results in altered development in adolescent rhesus macaque lungs

    SciTech Connect

    Herring, M.J.; Putney, L.F.; St George, J.A.; Avdalovic, M.V.; Schelegle, E.S.; Miller, L.A.; Hyde, D.M.

    2015-02-15

    In rhesus macaques, previous studies have shown that episodic exposure to allergen alone or combined with ozone inhalation during the first 6 months of life results in a condition with many of the hallmarks of asthma. This exposure regimen results in altered development of the distal airways and parenchyma (Avdalovic et al., 2012). We hypothesized that the observed alterations in the lung parenchyma would be permanent following a long-term recovery in filtered air (FA) housing. Forty-eight infant rhesus macaques (30 days old) sensitized to house dust mite (HDM) were treated with two week cycles of FA, house dust mite allergen (HDMA), ozone (O{sub 3}) or HDMA/ozone (HDMA + O{sub 3}) for five months. At the end of the five months, six animals from each group were necropsied. The other six animals in each group were allowed to recover in FA for 30 more months at which time they were necropsied. Design-based stereology was used to estimate volumes of lung components, number of alveoli, size of alveoli, distribution of alveolar volumes, interalveolar capillary density. After 30 months of recovery, monkeys exposed to HDMA, in either group, had significantly more alveoli than filtered air. These alveoli also had higher capillary densities as compared with FA controls. These results indicate that early life exposure to HDMA alone or HDMA + O{sub 3} alters the development process in the lung alveoli. - Highlights: • Abnormal lung development after postnatal exposure to ozone and allergen • This remodeling is shown as smaller, more numerous alveoli and narrower airways. • Allergen appears to have more of an effect than ozone during recovery. • These animals also have continued airway hyperresponsiveness (Moore et al. 2014)

  12. Alcohol exposure during late ovine gestation alters fetal liver iron homeostasis without apparent dysmorphology.

    PubMed

    Sozo, Foula; Dick, Anna M; Bensley, Jonathan G; Kenna, Kelly; Brien, James F; Harding, Richard; De Matteo, Robert

    2013-06-15

    High levels of alcohol (ethanol) exposure during fetal life can affect liver development and can increase susceptibility to infection after birth. Our aim was to determine the effects of a moderate level of ethanol exposure in late gestation on the morphology, iron status, and inflammatory status of the ovine fetal liver. Pregnant ewes were chronically catheterized at 91 days of gestation (DG; term ~145 DG) for daily intravenous infusion of ethanol (0.75 g/kg maternal body wt; n = 8) or saline (n = 7) over 1 h from 95 to 133 DG. At necropsy (134 DG), fetal livers were collected for analysis. Liver weight, general liver morphology, hepatic cell proliferation and apoptosis, perivascular collagen deposition, and interleukin (IL)-1β, IL-6, or IL-8 mRNA levels were not different between groups. However, ethanol exposure led to significant decreases in hepatic content of ferric iron and gene expression of the iron-regulating hormone hepcidin and tumor necrosis factor (TNF)-α (all P < 0.05). In the placenta, there was no difference in transferrin receptor, divalent metal transporter 1, and ferritin mRNA levels; however, ferroportin mRNA levels were increased in ethanol-exposed animals (P < 0.05), and ferroportin protein tended to be increased (P = 0.054). Plasma iron concentration was not different between control and ethanol-exposed groups; control fetuses had significantly higher iron concentrations than their mothers, whereas maternal and fetal iron concentrations were similar in ethanol-exposed animals. We conclude that daily ethanol exposure during the third-trimester-equivalent in sheep does not alter fetal liver morphology; however, decreased fetal liver ferric iron content and altered hepcidin and ferroportin gene expression indicate that iron homeostasis is altered. PMID:23594612

  13. Acute exposure to 2,4-dinitrophenol alters zebrafish swimming performance and whole body triglyceride levels.

    PubMed

    Marit, Jordan S; Weber, Lynn P

    2011-06-01

    While swimming endurance (critical swimming speed or U(crit)) and lipid stores have both been reported to acutely decrease after exposure to a variety of toxicants, the relationship between these endpoints has not been clearly established. In order to examine these relationships, adult zebrafish (Danio rerio) were aqueously exposed to solvent control (ethanol) or two nominal concentrations of 2,4-dinitrophenol (DNP), a mitochondrial electron transport chain uncoupler, for a 24-h period. Following exposure, fish were placed in a swim tunnel in clean water for swimming testing or euthanized immediately without testing, followed by analysis of whole body triglyceride levels. U(crit) decreased in both the 6 mg/L and 12 mg/L DNP groups, with 12 mg/L approaching the LC₅₀. A decrease in tail beat frequency was observed without a significant change in tail beat amplitude. In contrast, triglyceride levels were elevated in a concentration-dependent manner in the DNP exposure groups, but only in fish subjected to swimming tests. This increase in triglyceride stores may be due to a direct interference of DNP on lipid catabolism as well as increased triglyceride production when zebrafish were subjected to the co-stressors of swimming and toxicant exposure. Future studies should be directed at determining how acute DNP exposure combines with swimming to cause alterations in triglyceride accumulation. PMID:21406246

  14. Growth Retardation and Altered Isotope Composition As Delayed Effects of PCB Exposure in Daphnia magna.

    PubMed

    Ek, Caroline; Gerdes, Zandra; Garbaras, Andrius; Adolfsson-Erici, Margaretha; Gorokhova, Elena

    2016-08-01

    Trophic magnification factor (TMF) analysis employs stable isotope signatures to derive biomagnification potential for environmental contaminants. This approach relies on species δ(15)N values aligning with their trophic position (TP). This, however, may not always be true, because toxic exposure can alter growth and isotope allocation patterns. Here, effects of PCB exposure (mixture of PCB18, PCB40, PCB128, and PCB209) on δ(15)N and δ(13)C as well as processes driving these effects were explored using the cladoceran Daphnia magna. A two-part experiment assessed effects of toxic exposure during and after exposure; juvenile daphnids were exposed during 3 days (accumulation phase) and then allowed to depurate for 4 days (depuration phase). No effects on survival, growth, carbon and nitrogen content, and stable isotope composition were observed after the accumulation phase, whereas significant changes were detected in adults after the depuration phase. In particular, a significantly lower nitrogen content and a growth inhibition were observed, with a concomitant increase in δ(15)N (+0.1 ‰) and decrease in δ(13)C (-0.1 ‰). Although of low magnitude, these changes followed the predicted direction indicating that sublethal effects of contaminant exposure can lead to overestimation of TP and hence underestimated TMF. PMID:27367056

  15. A Complex Interaction Between Reduced Reelin Expression and Prenatal Organophosphate Exposure Alters Neuronal Cell Morphology

    PubMed Central

    Mullen, Brian R.; Ross, Brennan; Chou, Joan Wang; Khankan, Rana; Khialeeva, Elvira; Bui, Kimberly

    2016-01-01

    Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders including schizophrenia, autism spectrum disorders, and major depressive disorders. Prior studies from our laboratory and others have demonstrated that the combinatorial effect of two factors—reduced expression of reelin protein and prenatal exposure to the organophosphate pesticide chlorpyrifos oxon—gives rise to acute biochemical effects and to morphological and behavioral phenotypes in adolescent and young adult mice. In the current study, we examine the consequences of these factors on reelin protein expression and neuronal cell morphology in adult mice. While the cell populations that express reelin in the adult brain appear unchanged in location and distribution, the levels of full length and cleaved reelin protein show persistent reductions following prenatal exposure to chlorpyrifos oxon. Cell positioning and organization in the hippocampus and cerebellum are largely normal in animals with either reduced reelin expression or prenatal exposure to chlorpyrifos oxon, but cellular complexity and dendritic spine organization is altered, with a skewed distribution of immature dendritic spines in adult animals. Paradoxically, combinatorial exposure to both factors appears to generate a rescue of the dendritic spine phenotypes, similar to the mitigation of behavioral and morphological changes observed in our prior study. Together, our observations support an interaction between reelin expression and chlorpyrifos oxon exposure that is not simply additive, suggesting a complex interplay between genetic and environmental factors in regulating brain morphology. PMID:27364165

  16. CHRONIC ZEBRAFISH PFOS EXPOSURE ALTERS SEX RATIO AND MATERNAL RELATED EFFECTS IN F1 OFFSPRING

    PubMed Central

    Wang, Mingyong; Chen, Jiangfei; Lin, Kuanfei; Chen, Yuanhong; Hu, Wei; Tanguay, Robert L.; Huang, Changjiang; Dong, Qiaoxiang

    2012-01-01

    Perfluorooctanesulfonic acid (PFOS) is an organic contaminant ubiquitous in the environment, wildlife, and humans. Few studies have assessed its chronic toxicity on aquatic organisms. The present study defined the effects of long-term exposure to PFOS on zebrafish development and reproduction. Specifically, zebrafish at 8 h postfertilization (hpf) were exposed to PFOS at 0, 5, 50, and 250 μg/L for five months. Growth suppression was observed in the 250 μg/L PFOS-treated group. The sex ratio was altered, with a significant female dominance in the high-dose PFOS group. Male gonad development was also impaired in a dose-dependent manner by PFOS exposure. Although female fecundity was not impacted, the F1 embryos derived from high-dose exposed females paired with males without PFOS exposure developed severe deformity at early development stages and resulted in 100% larval mortality at 7 d postfertilization (dpf). Perfluorooctanesulfonic acid quantification in embryos indicated that decreased larval survival in F1 offspring was directly correlated to the PFOS body burden, and larval lethality was attributable to maternal transfer of PFOS to the eggs. Lower-dose parental PFOS exposure did not result in decreased F1 survival; however, the offspring displayed hyperactivity of basal swimming speed in a light-to-dark behavior assessment test. These findings demonstrate that chronic exposure to PFOS adversely impacts embryonic growth, reproduction, and subsequent offspring development. Environ. PMID:21671259

  17. Polychlorinated biphenyl 126 exposure in L6 myotubes alters glucose metabolism: a pilot study.

    PubMed

    Mauger, Jean-François; Nadeau, Lucien; Caron, Audrey; Chapados, Natalie Ann; Aguer, Céline

    2016-04-01

    Polychlorinated biphenyls (PCBs) are increasingly recognized as metabolic disruptors. Due to its mass, skeletal muscle is the major site of glucose disposal. While muscle mitochondrial dysfunction and oxidative stress have been shown to play a central role in metabolic disease development, no studies to date have investigated the effect of PCB exposure on muscle energy metabolism and oxidative stress. In this pilot study, we tested the effect of exposure to PCB126 in L6 myotubes (from 1 to 2500 nM for 24 h) on mitochondrial function, glucose metabolism, and oxidative stress. Exposure to PCB126 had no apparent effect on resting, maximal, and proton leak-dependent oxygen consumption rate in intact L6 myotubes. However, basal glucose uptake and glycolysis were inhibited by 20-30 % in L6 myotubes exposed to PCB126. Exposure to PCB126 did not appear to alter skeletal muscle anti-oxidant defense or oxidative stress. In conclusion, our study shows for the first time that exposure to a dioxin-like PCB adversely affects skeletal muscle glucose metabolism. Given the importance of skeletal muscle in the maintenance of glucose homeostasis, PCB126 could play an important role in the development of metabolic disorders. PMID:26936477

  18. A Complex Interaction Between Reduced Reelin Expression and Prenatal Organophosphate Exposure Alters Neuronal Cell Morphology.

    PubMed

    Mullen, Brian R; Ross, Brennan; Chou, Joan Wang; Khankan, Rana; Khialeeva, Elvira; Bui, Kimberly; Carpenter, Ellen M

    2016-06-01

    Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders including schizophrenia, autism spectrum disorders, and major depressive disorders. Prior studies from our laboratory and others have demonstrated that the combinatorial effect of two factors-reduced expression of reelin protein and prenatal exposure to the organophosphate pesticide chlorpyrifos oxon-gives rise to acute biochemical effects and to morphological and behavioral phenotypes in adolescent and young adult mice. In the current study, we examine the consequences of these factors on reelin protein expression and neuronal cell morphology in adult mice. While the cell populations that express reelin in the adult brain appear unchanged in location and distribution, the levels of full length and cleaved reelin protein show persistent reductions following prenatal exposure to chlorpyrifos oxon. Cell positioning and organization in the hippocampus and cerebellum are largely normal in animals with either reduced reelin expression or prenatal exposure to chlorpyrifos oxon, but cellular complexity and dendritic spine organization is altered, with a skewed distribution of immature dendritic spines in adult animals. Paradoxically, combinatorial exposure to both factors appears to generate a rescue of the dendritic spine phenotypes, similar to the mitigation of behavioral and morphological changes observed in our prior study. Together, our observations support an interaction between reelin expression and chlorpyrifos oxon exposure that is not simply additive, suggesting a complex interplay between genetic and environmental factors in regulating brain morphology. PMID:27364165

  19. Perinatal exposure to diethylstilbestrol alters the functional differentiation of the adult rat uterus.

    PubMed

    Bosquiazzo, Verónica L; Vigezzi, Lucía; Muñoz-de-Toro, Mónica; Luque, Enrique H

    2013-11-01

    The exposure to endocrine disrupters and female reproductive tract disorders has not been totally clarified. The present study assessed the long-term effect of perinatal (gestation+lactation) exposure to diethylstilbestrol (DES) on the rat uterus and the effect of estrogen replacement therapy. DES (5μg/kg bw/day) was administered in the drinking water from gestational day 9 until weaning and we studied the uterus of young adult (PND90) and adult (PND360) females. To investigate whether perinatal exposure to DES modified the uterine response to a long-lasting estrogen treatment, 12-month-old rats exposed to DES were ovariectomized and treated with 17β-estradiol for 3 months (PND460). In young adult rats (PND90), the DES treatment decreased both the proliferation of glandular epithelial cells and the percentage of glandular perimeter occupied by α-smooth muscle actin-positive cells. The other tissue compartments remained unchanged. Cell apoptosis was not altered in DES-exposed females. In control adult rats (PND360), there were some morphologically abnormal uterine glands. In adult rats exposed to DES, the incidence of glands with cellular anomalies increased. In response to estrogens (PND460), the incidence of cystic glands increased in the DES group. We observed glands with daughter glands and conglomerates of glands only on PND460 and in response to estrogen replacement therapy, independently of DES exposure. The p63 isoforms were expressed without changes on PND460. Estrogen receptors α and β showed no changes, while the progesterone receptor decreased in the subepithelial stroma of DES-exposed animals with estrogen treatment. The long-lasting effects of perinatal exposure to DES included the induction of abnormalities in uterine tissues of aged female rats and an altered response of the adult uterus to estradiol. PMID:23454116

  20. Exposure to the Endocrine Disruptor Bisphenol A Alters Susceptibility for Mammary Cancer

    PubMed Central

    Lamartiniere, Coral A.; Jenkins, Sarah; Betancourt, Angela M.; Wang, Jun; Russo, Jose

    2011-01-01

    Bisphenol A (BPA) is a synthetically made chemical used in the production of polycarbonate plastics and epoxy resins. Recent studies have shown over ninety percent of humans investigated have detectable BPA concentrations. Yet, the biggest concern for BPA is exposure during early development because BPA has been shown to bind to the estrogen receptors (ER) and cause developmental and reproductive toxicity. We have investigated the potential of perinatal BPA to alter susceptibility for chemically-induced mammary cancer in rats. We demonstrate that prepubertal exposure to low concentrations of orally administered BPA given to lactating dams resulted in a significantly decreased tumor latency and increased tumor multiplicity in the dimethylbenz[a]anthracene (DMBA) model of rodent mammary carcinogenesis. Our data suggested that the mechanism of action behind this carcinogenic response was mediated through increased cell proliferation, decreased apoptosis, and centered on an up-regulation of steroid receptor coactivators (SRCs) 1–3, erbB3, and increased Akt signaling in the mammary gland. Also, we demonstrate that prenatal exposure to BPA shifts the time of susceptibility from 50 days to 100 days for chemically-induced mammary carcinogenesis. Proteomic data suggest that prenatal BPA exposure alters the expression of several proteins involved in regulating protein metabolism, signal transduction, developmental processes, and cell cycle and proliferation. Increases in ER-alpha, SRCs 1–3, Bcl-2, epidermal growth factor–receptor (EGFR), phospho-IGF-1R, phospho-c-Raf, phospho-ERKs 1/2, phospho-ErbB2 and phospho-Akt are accompanied by increase in cell proliferation. We conclude that exposure to low concentrations of BPA during the prenatal and early postnatal periods of life can predispose for chemically-induced mammary cancer. PMID:21687816

  1. Prenatal endotoxin exposure alters behavioural pain responses to lipopolysaccharide in adult offspring.

    PubMed

    Hodyl, Nicolette A; Walker, F Rohan; Krivanek, Klara M; Clifton, Vicki L; Hodgson, Deborah M

    2010-05-11

    Evidence suggests that exposure to bacterial endotoxin in early life can alter the production of pro-inflammatory cytokines in later life. This phenomenon may have significant consequences for pain and pain related behaviours as pro-inflammatory cytokines heighten pain sensitivity. This association has yet to be examined. As such, the aim of the present study was to characterize pain behaviours in adult rat offspring following prenatal endotoxin (PE) exposure. Pregnant F344 rats received endotoxin (200microg/kg, s.c.) or saline on gestational days 16, 18 and 20. Pain thresholds were assessed in the adult PE offspring (n=23) and control offspring (n=24) prior to and 4h following administration of lipopolysaccharide (LPS; 100microg/kg, s.c.). Three assays of pain were employed - the hot plate, tail immersion and von Frey tests. Results demonstrated sex-specific effects of prenatal endotoxin on the offspring, with PE males displaying unaltered pain thresholds on the von Frey test post-LPS administration (p<0.01), while male control offspring (n=24) displayed the expected hyperalgesia. Male PE offspring also displayed increased pain thresholds on the tail immersion test (p<0.01), while no change in pain sensitivity was observed in control males following LPS exposure. No difference in response was observed between the female PE and control offspring on the von Frey test, however PE female offspring displayed increased thresholds on the tail immersion test compared to baseline - an effect not observed in the control female offspring. Pain sensitivity on the hot plate test was unaffected by prenatal exposure to endotoxin. These data suggest that prenatal exposure to products associated with bacterial infection have the capacity to alter pain responses, which are evident in the adult offspring. PMID:20184906

  2. Alterations in the striatal dopamine system during intravenous methamphetamine exposure: effects of contingent and noncontingent administration.

    PubMed

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P

    2013-08-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long-term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a "humanized" plasma METH half life or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7 and 1.5 µM. Animals were sacrificed during their last METH administration for autoradiography assessment using [³H]ligands and D2 agonist-induced [³⁵S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15-20%) and [³⁵S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal's total intake was similar within and across three 24-h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans. PMID:23417852

  3. Alterations in the Striatal Dopamine System During Intravenous Methamphetamine Exposure: Effects of Contingent and Noncontingent Administration

    PubMed Central

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P.

    2014-01-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a ‘humanized’ plasma METH half life, or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7–1.5 μM. Animals were sacrificed during their last METH administration for autoradiography assessment using [3H]ligands and D2 agonist-induced [35S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15–20%) and [35S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal’s total intake was similar within and across three 24 h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans. PMID:23417852

  4. In Vitro Exposure of Harbor Seal Immune Cells to Aroclor 1260 Alters Phocine Distemper Virus Replication.

    PubMed

    Bogomolni, Andrea; Frasca, Salvatore; Levin, Milton; Matassa, Keith; Nielsen, Ole; Waring, Gordon; De Guise, Sylvain

    2016-01-01

    In the last 30 years, several large-scale marine mammal mortality events have occurred, often in close association with highly polluted regions, leading to suspicions that contaminant-induced immunosuppression contributed to these epizootics. Some of these recent events also identified morbillivirus as a cause of or contributor to death. The role of contaminant exposures regarding morbillivirus mortality is still unclear. The results of this study aimed to address the potential for a mixture of polychlorinated biphenyls (PCBs), specifically Aroclor 1260, to alter harbor seal T-lymphocyte proliferation and to assess if exposure resulted in increased likelihood of phocine distemper virus (PDV USA 2006) to infect susceptible seals in an in vitro system. Exposure of peripheral blood mononuclear cells to Aroclor 1260 did not significantly alter lymphocyte proliferation (1, 5, 10, and 20 ppm). However, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), lymphocytes exposed to 20 ppm Aroclor 1260 exhibited a significant decrease in PDV replication at day 7 and a significant increase at day 11 compared with unexposed control cells. Similar and significant differences were apparent on exposure to Aroclor 1260 in monocytes and supernatant. The results here indicate that in harbor seals, Aroclor 1260 exposure results in a decrease in virus early during infection and an increase during late infection. The consequences of this contaminant-induced infection pattern in a highly susceptible host could result in a greater potential for systemic infection with greater viral load, which could explain the correlative findings seen in wild populations exposed to a range of persistent contaminants that suffer from morbillivirus epizootics. PMID:26142119

  5. Chronic exposure to pentachlorophenol alters thyroid hormones and thyroid hormone pathway mRNAs in zebrafish.

    PubMed

    Yu, Li-Qin; Zhao, Gao-Feng; Feng, Min; Wen, Wu; Li, Kun; Zhang, Pan-Wei; Peng, Xi; Huo, Wei-Jie; Zhou, Huai-Dong

    2014-01-01

    Pentachlorophenol (PCP) is frequently detected in the aquatic environment and has been implicated as an endocrine disruptor in fish. In the present study, 4-month-old zebrafish (Danio rerio) were exposed to 1 of 4 concentrations of PCP (0.1, 1, 9, and 27 µg/L) for 70 d. The effects of PCP exposure on plasma thyroid hormone levels, and the expression levels of selected genes, were measured in the brain and liver. The PCP exposure at 27 µg/L resulted in elevated plasma thyroxine concentrations in male and female zebrafish and depressed 3, 5, 3'-triiodothyronine concentrations in males only. In both sexes, PCP exposure resulted in decreased messenger RNA (mRNA) expression levels of thyroid-stimulating hormone β-subunit (tshβ) and thyroid hormone receptor β (trβ) in the brain, as well as increased liver levels of uridine diphosphoglucuronosyl transferase (ugt1ab) and decreased deiodinase 1 (dio1). The authors also identified several sex-specific effects of PCP exposure, including changes in mRNA levels for deiodinase 2 (dio2), cytosolic sulfotransferase (sult1 st5), and transthyretin (ttr) genes in the liver. Environmental PCP exposure also caused an increased malformation rate in offspring that received maternal exposure to PCP. The present study demonstrates that chronic exposure to environmental levels of PCP alters plasma thyroid hormone levels, as well as the expression of genes associated with thyroid hormone signaling and metabolism in the hypothalamic-pituitary-thyroid (HPT) axis and liver, resulting in abnormal zebrafish development. PMID:24123209

  6. Elevated bulk-silica exposures and evidence for multiple aqueous alteration episodes in Nili Fossae, Mars

    NASA Astrophysics Data System (ADS)

    Amador, Elena S.; Bandfield, Joshua L.

    2016-09-01

    The Nili Fossae region of Mars contains some of the most mineralogically diverse bedrock on the planet. Previous studies have established three main stratigraphic units in the region: a phyllosilicate-bearing basement rock, a variably altered olivine-rich basalt, and a capping rock. Here, we present evidence for the localized alteration of the northeast Nili Fossae capping unit, previously considered to be unaltered. Both near-infrared and thermal-infrared spectral datasets were analyzed, including the application of a method for determining the relative abundance of bulk-silica (SiO2) over surfaces using thermal emission imaging system (THEMIS) images. Elevated bulk-silica exposures are present on surfaces previously defined as unaltered capping rock. Given the lack of spectral evidence for phyllosilicate, hydrated silica, or quartz phases coincident with the newly detected exposures-the elevated bulk-silica may have formed under a number of aqueous scenarios, including as a product of the carbonation of the underlying olivine-rich basalt under moderate water: rock scenarios and temperatures. Regardless of formation mechanism, the detection of elevated bulk-silica exposures in the Nili Fossae capping unit extends the history of aqueous activity in the region to include all three of the main stratigraphic units.

  7. Alterations induced by chronic lead exposure on the cells of circadian pacemaker of developing rats

    PubMed Central

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Rojas, Patricia; Chávez-Saldaña, Margarita; Pérez, Oscar Gutiérrez; Montes, Sergio; Ríos, Camilo

    2011-01-01

    Lead (Pb) exposure alters the temporal organization of several physiological and behavioural processes in which the suprachiasmatic nucleus (SCN) of the hypothalamus plays a fundamental role. In this study, we evaluated the effects of chronic early Pb exposure (CePbe) on the morphology, cellular density and relative optical density (OD) in the cells of the SCN of male rats. Female Wistar rats were exposed during gestation and lactation to a Pb solution containing 320 ppm of Pb acetate through drinking water. After weaning, the pups were maintained with the same drinking water until sacrificed at 90 days of age. Pb levels in the blood, hypothalamus, hippocampus and prefrontal cortex were significantly increased in the experimental group. Chronic early Pb exposure induced a significant increase in the minor and major axes and somatic area of vasoactive intestinal polypeptide (VIP)- and vasopressin (VP)-immunoreactive neurons. The density of VIP-, VP- and glial fibrillary acidic protein (GFAP)-immunoreactive cells showed a significant decrease in the experimental group. OD analysis showed a significant increase in VIP neurons of the experimental group. The results showed that CePbe induced alterations in the cells of the SCN, as evidenced by modifications in soma morphology, cellular density and OD in circadian pacemaker cells. These findings provide a morphological and cellular basis for deficits in circadian rhythms documented in Pb-exposed animals. PMID:21324006

  8. Alterations in Cell Signaling Pathways in Breast Cancer Cells after Environmental Exposure

    SciTech Connect

    Kulp, K; McCutcheon-Maloney, S M; Bennett, L M

    2003-02-01

    Recent human epidemiological studies suggest that up to 75% of human cancers can be attributed to environmental exposures. Understanding the biologic impact of being exposed to a lifetime of complex environmental mixtures that may not be fully characterized is currently a major challenge. Functional endpoints may be used to assess the gross health consequences of complex mixture exposures from groundwater contamination, superfund sites, biologic releases, or nutritional sources. Such endpoints include the stimulation of cell growth or the induction of a response in an animal model. An environmental exposure that upsets normal cell growth regulation may have important ramifications for cancer development. Stimulating cell growth may alter an individual's cancer risk by changing the expression of genes and proteins that have a role in growth regulatory pathways within cells. Modulating the regulation of these genes and their products may contribute to the initiation, promotion or progression of disease in response to environmental exposure. We are investigating diet-related compounds that induce cell proliferation in breast cancer cell lines. These compounds, PhIP, Flor-Essence{reg_sign} and Essiac{reg_sign}, may be part of an everyday diet. PhIP is a naturally occurring mutagen that is formed in well-cooked muscle meats. PhIP consistently causes dose-dependent breast tumor formation in rats and consumption of well-done meat has been linked to increased risk of breast cancer in women. Flor-Essence{reg_sign} and Essiac{reg_sign} herbal tonics are complementary and alternative medicines used by women who have been diagnosed with breast cancer as an alternative therapy for disease treatment and prevention. The long-term goal of this work is to identify those cellular pathways that are altered by a chemical or biologic environmental exposure and understand how those changes correlate with and or predict changes in human health risk. This project addressed this goal by

  9. Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs

    PubMed Central

    Schuster, Andrew; Skinner, Michael K.; Yan, Wei

    2016-01-01

    Exposure to the agricultural fungicide vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and vinclozolin lineage rats. Over 200 differentially expressed sncRNAs were identified and the tRNA-derived sncRNAs, namely 5′ halves of mature tRNAs (5′ halves), displayed the most dramatic changes. Gene targets of the altered miRNAs and tRNA 5′ halves revealed associations between the altered sncRNAs and differentially DNA methylated regions. Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes. Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon. PMID:27390623

  10. In vitro exposure of Ulva lactuca Linnaeus (Chlorophyta) to gasoline - Biochemical and morphological alterations.

    PubMed

    Pilatti, Fernanda Kokowicz; Ramlov, Fernanda; Schmidt, Eder Carlos; Kreusch, Marianne; Pereira, Débora Tomazi; Costa, Christopher; de Oliveira, Eva Regina; Bauer, Cláudia M; Rocha, Miguel; Bouzon, Zenilda Laurita; Maraschin, Marcelo

    2016-08-01

    Refined fuels have considerable share of pollution of marine ecosystems. Gasoline is one of the most consumed fuel worldwide, but its effects on marine benthic primary producers are poorly investigated. In this study, Ulva lactuca was chosen as a biological model due to its cosmopolitan nature and tolerance to high levels and wide range of xenobiotics and our goal was to evaluate the effects of gasoline on ultrastructure and metabolism of that seaweed. The experimental design consisted of in vitro exposure of U. lactuca to four concentrations of gasoline (0.001%, 0.01%, 0.1%, and 1.0%, v/v) over 30 min, 1 h, 12 h, and 24 h, followed by cytochemical, SEM, and biochemical analysis. Increase in the number of cytoplasmic granules, loss of cell turgor, cytoplasmic shrinkage, and alterations in the mucilage were some of the ultrastructural alterations observed in thalli exposed to gasoline. Decrease in carotenoid and polyphenol contents, as well as increase of soluble sugars and starch contents were associated with the time of exposure to the xenobiotic. In combination, the results revealed important morphological and biochemical alterations in the phenotype of U. lactuca upon acute exposure to gasoline. This seaweed contain certain metabolites assigned as candidates to biomarkers of the environmental stress investigated and it is thought to be a promise species for usage in coastal ecosystems perturbation monitoring system. In addition, the findings suggest that U. lactuca is able to metabolize gasoline hydrocarbons and use them as energy source, acting as bioremediator of marine waters contaminated by petroleum derivatives. PMID:27192480

  11. Adolescent Alcohol Exposure Alters GABAA Receptor Subunit Expression in Adult Hippocampus

    PubMed Central

    Centanni, Samuel W.; Teppen, Tara; Risher, Mary-Louise; Fleming, Rebekah L.; Moss, Julia L.; Acheson, Shawn K.; Mulholland, Patrick J.; Pandey, Subhash C.; Chandler, L. Judson; Swartzwelder, H. Scott

    2014-01-01

    Background The long-term consequences of adolescent alcohol abuse that persist into adulthood are poorly understood and have not been widely investigated. We have shown that intermittent exposure to alcohol during adolescence decreased the amplitude of GABAA receptor-mediated tonic currents in hippocampal dentate granule cells in adulthood. The aim of the present study was to investigate the enduring effects of chronic intermittent alcohol exposure during adolescence or adulthood on the expression of hippocampal GABAA receptors (GABAARs). Methods We used a previously characterized tissue fractionation method to isolate detergent resistant membranes and soluble fractions, followed by western blots to measure GABAAR protein expression. We also measured mRNA levels of GABAAR subunits using quantitative real-time PCR. Results Although the protein levels of α1-, α4- and δ-GABAAR subunits remained stable between postnatal day (PD) 30 (early adolescence) and PD71 (adulthood), the α5-GABAAR subunit was reduced across that period. In rats that were subjected to adolescent intermittent ethanol (AIE) exposure between PD30–46, there was a significant reduction in the protein levels of the δ-GABAAR, in the absence of any changes in mRNA levels, at 48 hours and 26 days after the last ethanol exposure. Protein levels of the α4-GABAAR subunit were significantly reduced, but mRNA levels were increased, 26 days (but not 48 hours) after the last AIE exposure. Protein levels of α5-GABAAR were not changed by AIE, but mRNA levels were reduced at 48hrs but normalized 26 days after AIE. In contrast to the effects of AIE, chronic intermittent exposure to ethanol during adulthood (CIE) had no effect on expression of any of the GABAAR subunits examined. Conclusions AIE produced both short- and long-term alterations of GABAAR subunits mRNA and protein expression in the hippocampus, whereas CIE produced no long lasting effects on those measures. The observed reduction of protein

  12. Intermittent prenatal MDMA exposure alters physiological but not mood related parameters in adult rat offspring.

    PubMed

    Adori, Csaba; Zelena, Dóra; Tímár, Júlia; Gyarmati, Zsuzsa; Domokos, Agnes; Sobor, Melinda; Fürst, Zsuzsanna; Makara, Gábor; Bagdy, György

    2010-01-20

    The recreational party drug "ecstasy" (3,4-methylenedioxymethamphetamine MDMA) is particularly popular among young adults who are in the childbearing age and thus there is a substantial risk of prenatal MDMA exposure. We applied an intermittent treatment protocol with an early first injection on pregnant Wistar rats (15 mg/kg MDMA s.c. on the E4, E11 and E18 days of gestation) to examine the potential physiological, endocrine and behavioral effects on adult male and female offspring. Prenatal MDMA-treatment provoked reduced body weight of offspring from the birth as far as the adulthood. Adult MDMA-offspring had a reduced blood-glucose concentration and hematocrit, altered relative spleen and thymus weight, had lower performance on wire suspension test and on the first trial of rotarod test. In contrast, no alteration in the locomotor activity was found. Anxiety and depression related behavioral parameters in elevated plus maze, sucrose preference or forced swimming tests were normal. MDMA-offspring had elevated concentration of the ACTH-precursor proopiomelanocortin and male MDMA-offspring exhibited elevated blood corticosterone concentration. No significant alteration was detected in the serotonergic marker tryptophan-hydroxylase and the catcholaminergic marker tyrosine-hydroxylase immunoreactive fiber densities in MDMA-offspring. The mothers exhibited reduced densities of serotonergic but not catecholaminergic fibers after the MDMA treatment. Our findings suggest that an intermittent prenatal MDMA exposure with an early first injection and a relatively low cumulative dose provokes mild but significant alterations in physical-physiological parameters and reduces motor skill learning in adulthood. In contrast, these adult offspring do not produce anxiety or depression like behavior. PMID:19782105

  13. Alterations in cytochrome P-450 levels in adult rats following neonatal exposure to xenobiotics

    SciTech Connect

    Zangar, R.C. Pacific Northwest Laboratories, Richland, WA ); Springer, D.L. ); Buhler, D.R. )

    1993-01-01

    Neonatal exposure to certain xenobiotics has been shown to alter hepatic metabolism in adult rats in a manner that indicates long-term changes in enzyme regulation. Previously, the authors have observed changes in adult testosterone metabolism and in cytochrome P-450 (P-450) mRNA levels in animals neonatally exposed to phenobarbital (PB) or diethylstilbestrol (DES). In order to test for other enzyme alterations, they used Western blot procedures for specific P-450s to analyze hepatic microsomes from adult rats (24 wk old) that had been exposed neonatally to DES, PB, 7,12-dimethylbenz[a]anthracene (DMBA), or pregnenolone 16[alpha]-carbonitrile (PCN). The most striking effects were observed in the DES-treated males: P-4502C6 and an immunologically similar protein were increased 60 and 90%, respectively, relative to control values, but P-4503A2 was decreased by 44%. No changes were observed in the DES-treated males in levels of P-4502E1, P-4502B, or the male-specific P-4502C13. Adult males neonatally treated with PB had 150% increase in levels of anti-P4502B-reactive protein without significant changes in the other enzymes. The DES- and DMBA-treated females had increased levels of the female-specific P-4502C12 of 38 and 48%, respectively, but no other observed alterations. The results confirm that neonatal exposure to DES or PB can cause alterations in adult hepatic cytochrome P-450 levels but show that these chemicals act on different enzymes. Neonatal DMBA resulted in changes in adult females similar to those produced by the synthetic estrogen DES, but did so at about two-thirds lower dose. 37 refs., 5 figs.

  14. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    SciTech Connect

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-06-27

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C {r_arrow} A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C {r_arrow} T, two C {r_arrow} A, one C {r_arrow} G, and one A {r_arrow} T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab.

  15. Formaldehyde exposure alters miRNA expression profiles in the olfactory bulb.

    PubMed

    Li, Guifa; Yang, Jing; Ling, Shucai

    2015-01-01

    It has been reported that inhaling formaldehyde (FA) causes damage to the central nervous system. However, it is unclear whether FA can disturb the function of the olfactory bulb. Using a microarray, we found that FA inhalation altered the miRNA expression profile. Functional enrichment analysis of the predicted targets of the changed miRNA showed that the enrichment canonical pathways and networks associated with cancer and transcriptional regulation. FA exposure disrupts miRNA expression profiles within the olfactory bulb. PMID:26161908

  16. Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome

    PubMed Central

    2014-01-01

    Background Environmental factors during perinatal development may influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring exposed perinatally to multiple doses of BPA through the maternal diet. Results Using a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 μg BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N = 4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response. Conclusions In this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways

  17. Common behaviors alterations after extremely low-frequency electromagnetic field exposure in rat animal model.

    PubMed

    Mahdavi, Seyed Mohammad; Sahraei, Hedayat; Rezaei-Tavirani, Mostafa; Najafi Abedi, Akram

    2016-01-01

    Naturally, the presence of electromagnetic waves in our living environment affects all components of organisms, particularly humans and animals, as the large part of their body consists of water. In the present study, we tried to investigate the relation between exposure to the extremely low-frequency electromagnetic field (ELF-EMF) and common behaviors such as body weight, food and water intake, anorexia (poor appetite), plasma glucose concentration, movement, rearing and sniffing in rats. For this purpose, rats were exposed to 40  Hz ELF-EMF once a day for 21 days, then at days 1, 3, 7, 14 and 21 after exposure, any changes in the above-mentioned items were assessed in the exposed rats and compared to the non-exposed group as control. Body weight of irradiated rats significantly increased only a week after exposure and decreased after that. No significant change was observed in food and water intake of irradiated rats compared to the control, and the anorexia parameter in the group exposed to ELF-EMF was significantly decreased at one and two weeks after irradiation. A week after exposure, the level of glucose was significantly increased but at other days these changes were not significant. Movements, rearing and sniffing of rats at day 1 after exposure were significantly decreased and other days these changes did not follow any particular pattern. However, the result of this study demonstrated that exposure to ELF-EMF can alter the normal condition of animals and may represent a harmful impact on behavior. PMID:26182237

  18. Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos

    SciTech Connect

    Meyer, Armando; Seidler, Frederic J.; Aldridge, Justin E.; Slotkin, Theodore A. . E-mail: t.slotkin@duke.edu

    2005-03-01

    Exposure to apparently unrelated neurotoxicants can nevertheless converge on common neurodevelopmental events. We examined the long-term effects of developmental exposure of rats to terbutaline, a {beta}-adrenoceptor agonist used to arrest preterm labor, and the organophosphorus insecticide chlorpyrifos (CPF) separately and together. Treatments mimicked the appropriate neurodevelopmental stages for human exposures: terbutaline on postnatal days (PN) 2-5 and CPF on PN11-14, with assessments conducted on PN45. Although neither treatment affected growth or viability, each elicited alterations in CNS cell signaling mediated by adenylyl cyclase (AC), a transduction pathway shared by numerous neuronal and hormonal signals. Terbutaline altered signaling in the brainstem and cerebellum, with gender differences particularly notable in the cerebellum (enhanced AC in males, suppressed in females). By itself, CPF exposure elicited deficits in AC signaling in the midbrain, brainstem, and striatum. However, sequential exposure to terbutaline followed by CPF produced larger alterations and involved a wider spectrum of brain regions than were obtained with either agent alone. In the cerebral cortex, adverse effects of the combined treatment intensified between PN45 and PN60, suggesting that exposures alter the long-term program for development of synaptic communication, leading to alterations in AC signaling that emerge even after adolescence. These findings indicate that terbutaline, like CPF, is a developmental neurotoxicant, and reinforce the idea that its use in preterm labor may create a subpopulation that is sensitized to long-term CNS effects of organophosphorus insecticides.

  19. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L. L.

    2003-10-01

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival of a given organism. The development and maintenance of vestibular connections are controlled by environmental gravitational stimulation as well as genetically controlled molecular interactions. This paper describes the effects of hypergravity on axonal growth and dendritic morphology, respectively. Two aspects of this vestibular adaptation are examined: (1) How does long-term exposure to hypergravity affect the development of vestibular axons? (2) How does short-term exposure to extremely rapid changes in gravity, such as those that occur during shuttle launch and landing, affect dendrites of the vestibulocerebellar system? To study the effects of longterm exposures to altered gravity, embryonic rats that developed in hypergravity were compared to microgravity-exposed and control rats. Examination of the vestibular projections from epithelia devoted to linear and angular acceleration revealed that the terminal fields segregate differently in rat embryos that gestated in each of the gravitational environments.To study the effects of short-term exposures to altered gravity, mice were exposed briefly to strong vestibular stimuli and the vestibulocerebellum was examined for any resulting morphological changes. My data show that these stimuli cause intense vestibular excitation of cerebellar Purkinje cells, which induce up-regulation of clathrin-mediated endocytosis and other morphological changes that are comparable to those seen in long-term depression. This system provides a basis for studying how the vestibular environment can modify cerebellar function, allowing animals to adapt to new environments.

  20. Exposure of rainbow trout milt to mercury and cadmium alters sperm motility parameters and reproductive success.

    PubMed

    Dietrich, Grzegorz J; Dietrich, Mariola; Kowalski, R K; Dobosz, Stefan; Karol, Halina; Demianowicz, Wiesław; Glogowski, Jan

    2010-05-10

    In the current work, seminal plasma was used for the first time as an incubation medium for monitoring short-time exposure effects of sublethal concentrations of mercury and cadmium ions on rainbow trout sperm. Sperm motility parameters (CASA) and hatching rates were used as gamete quality markers. Additionally live/dead sperm viability test and comet assay of DNA fragmentation were performed. We demonstrated that computer-assisted sperm motility analysis (CASA) may serve as a predictor of reproductive success, when milt contaminated with heavy metals is used. Results presented in this study demonstrate that mercury ions altered sperm motility characteristics at 1-10 mg Hg2+/l and 10 mg Cd2+/l and hatching rates at 10 mg Hg2+/l and 10 mg Cd2+/l after 4h of exposure. Although mercury ions affected sperm motility parameters immediately after dilution with milt as well as at 4h of exposure, no differences in sperm motility parameters were found between intact and mercury-treated milt after 24h of exposure. Our results suggest that rainbow trout seminal plasma has a protective role against the toxic effects of mercury ions of rainbow trout sperm motility. PMID:20044150

  1. Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour.

    PubMed

    Hines, Melissa; Pasterski, Vickie; Spencer, Debra; Neufeld, Sharon; Patalay, Praveetha; Hindmarsh, Peter C; Hughes, Ieuan A; Acerini, Carlo L

    2016-02-19

    Individual variability in human gender-related behaviour is influenced by many factors, including androgen exposure prenatally, as well as self-socialization and socialization by others postnatally. Many studies have looked at these types of influences in isolation, but little is known about how they work together. Here, we report that girls exposed to high concentrations of androgens prenatally, because they have the genetic condition congenital adrenal hyperplasia, show changes in processes related to self-socialization of gender-related behaviour. Specifically, they are less responsive than other girls to information that particular objects are for girls and they show reduced imitation of female models choosing particular objects. These findings suggest that prenatal androgen exposure may influence subsequent gender-related behaviours, including object (toy) choices, in part by changing processes involved in the self-socialization of gendered behaviour, rather than only by inducing permanent changes in the brain during early development. In addition, the findings suggest that some of the behavioural effects of prenatal androgen exposure might be subject to alteration by postnatal socialization processes. The findings also suggest a previously unknown influence of early androgen exposure on later processes involved in self-socialization of gender-related behaviour, and thus expand understanding of the developmental systems regulating human gender development. PMID:26833843

  2. Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells.

    PubMed

    Agarwal, Amit R; Yin, Fei; Cadenas, Enrique

    2014-08-01

    Cigarette smoke (CS)-induced alveolar destruction and energy metabolism changes are known contributors to the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examines the effect of CS exposure on metabolism in alveolar type II cells. Male A/J mice (8 wk old) were exposed to CS generated from a smoking machine for 4 or 8 weeks, and a recovery group was exposed to CS for 8 weeks and allowed to recover for 2 weeks. Alveolar type II cells were isolated from air- or CS- exposed mice. Acute CS exposure led to a reversible airspace enlargement in A/J mice as measured by the increase in mean linear intercept, indicative of alveolar destruction. The effect of CS exposure on cellular respiration was studied using the XF Extracellular Flux Analyzer. A decrease in respiration while metabolizing glucose was observed in the CS-exposed group, indicating altered glycolysis that was compensated by an increase in palmitate utilization; palmitate utilization was accompanied by an increase in the expression of CD36 and carnitine-palmitoyl transferase 1 in type II alveolar cells for the transport of palmitate into the cells and into mitochondria, respectively. The increase in palmitate use for energy production likely affects the surfactant biosynthesis pathway, as evidenced by the decrease in phosphatidylcholine levels and the increase in phospholipase A2 activity after CS exposure. These findings help our understanding of the mechanism underlying the surfactant deficiency observed in smokers and provide a target to delay the onset of COPD. PMID:24625219

  3. Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

    PubMed

    Manning, Elizabeth E; van den Buuse, Maarten

    2016-05-15

    Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. PMID:26965573

  4. Effects of radiation exposure on glass alteration in a steam environment

    SciTech Connect

    Wronkiewicz, D.J.; Bates, J.K.; Tani, B.S.; Wang, L.M.

    1992-12-31

    Several Savannah River Plant (SRL) glass compositions were reacted in steam at temperatures of 150 to 200{degrees}C. Half of the tests utilized actinide-doped monoliths and were exposed to an external ionizing gamma source, while the remainder were doped only with U and reacted without gamma exposure. All glass samples readily reacted to form secondary mineral phases within the first week of testing. An in situ layer of smectite initially developed on nonirradiated SRL 202 glass test samples. After 21 days, a thin layer of illite was precipitated from solution onto the smectite layer. A number of alteration products including zeolite, Casilicate, and alkali or alkaline earth uranyl silicate phases were also distributed over most sample surfaces. In the irradiated SRL 202 glass tests, up to three layers enveloped rounded, and sometimes fractured, glass cores. After 35 to 56 days these remnant cores were replaced by a mottled or banded Fe- and Si-rich material. The formation of some secondary mineral phases also has been accelerated in the irradiated tests, and in some instances, the irradiated environment may have led to the precipitation of a different suite of minerals. The alteration layer(s) developed at rates of 2.3 and 32 {mu}m/day for the nonirradiated and irradiated SRL 202 glasses, respectively, indicating that layer development is accelerated by a factor of {approximately} 10 to 15X due to radiation exposure under the test conditions.

  5. Alcohol Exposure Alters Mouse Lung Inflammation in Response to Inhaled Dust

    PubMed Central

    McCaskill, Michael L.; Romberger, Debra J.; DeVasure, Jane; Boten, Jessica; Sisson, Joseph H.; Bailey, Kristina L.; Poole, Jill A.; Wyatt, Todd A.

    2012-01-01

    Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs) are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE) collected from a CAFO results in the activation of protein kinase C (PKC), elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6), and the development of significant lung pathology. Because alcohol blocks airway epithelial cell release of IL-6 in vitro, we hypothesized that alcohol exposure would alter mouse lung inflammatory responses to HDE. To test this hypothesis, C57BL/6 mice were fed 20% alcohol or water ad libitum for 6 weeks and treated with 12.5% HDE by intranasal inhalation method daily during the final three weeks. Bronchoalveolar lavage fluid (BALF), tracheas and lungs were collected. HDE stimulated a 2–4 fold increase in lung and tracheal PKCε (epsilon) activity in mice, but no such increase in PKCε activity was observed in dust-exposed mice fed alcohol. Similarly, alcohol-fed mice demonstrated significantly less IL-6 in lung lavage in response to dust than that observed in control mice instilled with HDE. TNFα levels were also inhibited in the alcohol and HDE-exposed mouse lung tissue as compared to the HDE only exposed group. HDE-induced lung inflammatory aggregates clearly present in the tissue from HDE only exposed animals were not visually detectable in the HDE/alcohol co-exposure group. Statistically significant weight reductions and 20% mortality were also observed in the mice co-exposed to HDE and alcohol. These data suggest that alcohol exposure depresses the ability of the lung to activate PKCε

  6. Alcohol exposure alters mouse lung inflammation in response to inhaled dust.

    PubMed

    McCaskill, Michael L; Romberger, Debra J; DeVasure, Jane; Boten, Jessica; Sisson, Joseph H; Bailey, Kristina L; Poole, Jill A; Wyatt, Todd A

    2012-07-01

    Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs) are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE) collected from a CAFO results in the activation of protein kinase C (PKC), elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6), and the development of significant lung pathology. Because alcohol blocks airway epithelial cell release of IL-6 in vitro, we hypothesized that alcohol exposure would alter mouse lung inflammatory responses to HDE. To test this hypothesis, C57BL/6 mice were fed 20% alcohol or water ad libitum for 6 weeks and treated with 12.5% HDE by intranasal inhalation method daily during the final three weeks. Bronchoalveolar lavage fluid (BALF), tracheas and lungs were collected. HDE stimulated a 2-4 fold increase in lung and tracheal PKCε (epsilon) activity in mice, but no such increase in PKCε activity was observed in dust-exposed mice fed alcohol. Similarly, alcohol-fed mice demonstrated significantly less IL-6 in lung lavage in response to dust than that observed in control mice instilled with HDE. TNFα levels were also inhibited in the alcohol and HDE-exposed mouse lung tissue as compared to the HDE only exposed group. HDE-induced lung inflammatory aggregates clearly present in the tissue from HDE only exposed animals were not visually detectable in the HDE/alcohol co-exposure group. Statistically significant weight reductions and 20% mortality were also observed in the mice co-exposed to HDE and alcohol. These data suggest that alcohol exposure depresses the ability of the lung to activate PKCε

  7. Developmental exposure to endocrine disrupting chemicals alters the epigenome: Identification of reprogrammed targets

    PubMed Central

    Prusinski, Lauren; Al-Hendy, Ayman; Yang, Qiwei

    2016-01-01

    Endocrine disruptions induced by environmental toxicants have placed an immense burden on society to properly diagnose, treat and attempt to alleviate symptoms and disease. Environmental exposures during critical periods of development can permanently reprogram normal physiological responses, thereby increasing susceptibility to disease later in life - a process known as developmental reprogramming. During development, organogenesis and tissue differentiation occur through a continuous series of tightly-regulated and precisely-timed molecular, biochemical and cellular events. Humans may encounter endocrine disrupting chemicals (EDCs) daily and during all stages of life, from conception and fetal development through adulthood and senescence. Though puberty and perimenopausal periods may be affected by endocrine disruption due to hormonal effects, prenatal and early postnatal windows are most critical for proper development due to rapid changes in system growth. Developmental reprogramming is shown to be caused by alterations in the epigenome. Development is the time when epigenetic programs are ‘installed’ on the genome by ‘writers’, such as histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs), which add methyl groups to lysine and arginine residues on histone tails and to CpG sites in DNA, respectively. A number of environmental compounds, referred to as estrogenic endocrine disruptors (EEDs), are able to bind to estrogen receptors (ERs) and interfere with the normal cellular development in target tissues including the prostate and uterus. These EEDs, including diethylstilbestrol (DES), bisphenol A (BPA), and genistein (a phytoestrogen derived from soybeans), have been implicated in the malformation of reproductive organs and later development of disease. Due to the lack of fully understanding the underlying mechanisms of how environmental toxicants and their level of exposure affect the human genome, it can be challenging to create clear

  8. Developmental Exposure to Estrogen Alters Differentiation and Epigenetic Programming in a Human Fetal Prostate Xenograft Model

    PubMed Central

    Saffarini, Camelia M.; McDonnell-Clark, Elizabeth V.; Amin, Ali; Huse, Susan M.; Boekelheide, Kim

    2015-01-01

    Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM) isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure. PMID:25799167

  9. Prenatal cocaine exposure alters progenitor cell markers in the subventricular zone of the adult rat brain

    PubMed Central

    Patel, Dhyanesh Arvind; Booze, Rosemarie M.; Mactutus, Charles F.

    2013-01-01

    Long-term consequences of early developmental exposure to drugs of abuse may have deleterious effects on the proliferative plasticity of the brain. The purpose of this study was to examine the long-term effects of prenatal exposure to cocaine, using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, on the proliferative cell types of the subventricular zones (SVZ) in the adult (180 days-old) rat brain. Employing immunocytochemistry, the expression of GFAP+ (type B cells) and nestin+(GFAP−) (Type C and A cells) staining was quantified in the subcallosal area of the SVZ. GFAP+ expression was significantly different between the prenatal cocaine treated group and the vehicle (saline) control group. The prenatal cocaine treated group possessed significantly lower GFAP+ expression relative to the vehicle control group, suggesting that prenatal cocaine exposure significantly reduced the expression of type B neural stem cells of the SVZ. In addition, there was a significant sex difference in nestin+ expression with females showing approximately 8–13% higher nestin+ expression compared to the males. More importantly, a significant prenatal treatment condition (prenatal cocaine, control) by sex interaction in nestin+ expression was confirmed, indicating different effects of cocaine based on sex of the animal. Specifically, prenatal cocaine exposure eliminated the basal difference between the sexes. Collectively, the present findings suggest that prenatal exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, can selectively alter the major proliferative cell types in the subcallosal area of the SVZ in an adult rat brain, and does so differently for males and females. PMID:22119286

  10. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts

    PubMed Central

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-01-01

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird’s-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant’s developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  11. Hypertension Does Not Alter the Increase in Cardiac Baroreflex Sensitivity Caused by Moderate Cold Exposure.

    PubMed

    Hintsala, Heidi E; Kiviniemi, Antti M; Tulppo, Mikko P; Helakari, Heta; Rintamäki, Hannu; Mäntysaari, Matti; Herzig, Karl-Heinz; Keinänen-Kiukaanniemi, Sirkka; Jaakkola, Jouni J K; Ikäheimo, Tiina M

    2016-01-01

    Exposure to cold increases blood pressure and may contribute to higher wintertime cardiovascular morbidity and mortality in hypertensive people, but the mechanisms are not well-established. While hypertension does not alter responses of vagally-mediated heart rate variability to cold, it is not known how hypertension modifies baroreflex sensitivity (BRS) and blood pressure variability during cold exposure. Our study assessed this among untreated hypertensive men during short-term exposure comparable to habitual winter time circumstances in subarctic areas. We conducted a population-based recruitment of 24 untreated hypertensive and 17 men without hypertension (age 55-65 years) who underwent a whole-body cold exposure (-10°C, wind 3 m/s, winter clothes, 15 min, standing). Electrocardiogram and continuous blood pressure were measured to compute spectral powers of systolic blood pressure and heart rate variability at low (0.04-0.15 Hz) and high frequency (0.15-0.4 Hz) and spontaneous BRS at low frequency (LF). Comparable increases in BRS were detected in hypertensive men, from 2.6 (2.0, 4.2) to 3.8 (2.5, 5.1) ms/mmHg [median (interquartile range)], and in control group, from 4.3 (2.7, 5.0) to 4.4 (3.1, 7.1) ms/mmHg. Instead, larger increase (p < 0.05) in LF blood pressure variability was observed in control group; response as median (interquartile range): 8 (2, 14) mmHg(2), compared with hypertensive group [0 (-13, 20) mmHg(2)]. Untreated hypertension does not disturb cardiovascular protective mechanisms during moderate cold exposure commonly occurring in everyday life. Blunted response of the estimate of peripheral sympathetic modulation may indicate higher tonic sympathetic activity and decreased sympathetic responsiveness to cold in hypertension. PMID:27313543

  12. Hypertension Does Not Alter the Increase in Cardiac Baroreflex Sensitivity Caused by Moderate Cold Exposure

    PubMed Central

    Hintsala, Heidi E.; Kiviniemi, Antti M.; Tulppo, Mikko P.; Helakari, Heta; Rintamäki, Hannu; Mäntysaari, Matti; Herzig, Karl-Heinz; Keinänen-Kiukaanniemi, Sirkka; Jaakkola, Jouni J. K.; Ikäheimo, Tiina M.

    2016-01-01

    Exposure to cold increases blood pressure and may contribute to higher wintertime cardiovascular morbidity and mortality in hypertensive people, but the mechanisms are not well-established. While hypertension does not alter responses of vagally-mediated heart rate variability to cold, it is not known how hypertension modifies baroreflex sensitivity (BRS) and blood pressure variability during cold exposure. Our study assessed this among untreated hypertensive men during short-term exposure comparable to habitual winter time circumstances in subarctic areas. We conducted a population-based recruitment of 24 untreated hypertensive and 17 men without hypertension (age 55–65 years) who underwent a whole-body cold exposure (−10°C, wind 3 m/s, winter clothes, 15 min, standing). Electrocardiogram and continuous blood pressure were measured to compute spectral powers of systolic blood pressure and heart rate variability at low (0.04–0.15 Hz) and high frequency (0.15–0.4 Hz) and spontaneous BRS at low frequency (LF). Comparable increases in BRS were detected in hypertensive men, from 2.6 (2.0, 4.2) to 3.8 (2.5, 5.1) ms/mmHg [median (interquartile range)], and in control group, from 4.3 (2.7, 5.0) to 4.4 (3.1, 7.1) ms/mmHg. Instead, larger increase (p < 0.05) in LF blood pressure variability was observed in control group; response as median (interquartile range): 8 (2, 14) mmHg2, compared with hypertensive group [0 (−13, 20) mmHg2]. Untreated hypertension does not disturb cardiovascular protective mechanisms during moderate cold exposure commonly occurring in everyday life. Blunted response of the estimate of peripheral sympathetic modulation may indicate higher tonic sympathetic activity and decreased sympathetic responsiveness to cold in hypertension. PMID:27313543

  13. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts.

    PubMed

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-01-01

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird's-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant's developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  14. Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice.

    PubMed

    Martella, G; Madeo, G; Maltese, M; Vanni, V; Puglisi, F; Ferraro, E; Schirinzi, T; Valente, E M; Bonanni, L; Shen, J; Mandolesi, G; Mercuri, N B; Bonsi, P; Pisani, A

    2016-07-01

    Heterozygous mutations in the PINK1 gene are considered a susceptibility factor to develop early-onset Parkinson's disease (PD), as supported by dopamine hypometabolism in asymptomatic mutation carriers and subtle alterations of dopamine-dependent striatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-)) mice. The aim of the present study was to investigate whether exposure to low-dose rotenone of heterozygous PINK1(+/-) mice, compared to their wild-type PINK1(+/+) littermates, could impact on dopamine-dependent striatal synaptic plasticity, in the absence of apparent structural alterations. Mice were exposed to a range of concentrations of rotenone (0.01-1mg/kg). Chronic treatment with concentrations of rotenone up to 0.8mg/kg did not cause manifest neuronal loss or changes in ATP levels both in the striatum or substantia nigra of PINK1(+/-) and PINK1(+/+) mice. Moreover, rotenone (up to 0.8mg/kg) treatment did not induce mislocalization of the mitochondrial membrane protein Tom20 and release of cytochrome c in PINK1(+/-) striata. Accordingly, basic electrophysiological properties of nigral dopaminergic and striatal medium spiny neurons (MSNs) were normal. Despite the lack of gross alterations in neuronal viability in chronically-treated PINK1(+/-), a complete loss of both long-term depression (LTD) and long-term potentiation (LTP) was recorded in MSNs from PINK1(+/-) mice treated with a low rotenone (0.1mg/kg) concentration. Even lower concentrations (0.01mg/kg) blocked LTP induction in heterozygous PINK1(+/-) MSNs compared to PINK1(+/+) mice. Of interest, chronic pretreatment with the antioxidants alpha-tocopherol and Trolox, a water-soluble analog of vitamin E and powerful antioxidant, rescued synaptic plasticity impairment, confirming that, at the doses we utilized, rotenone did not induce irreversible alterations. In this model, chronic exposure to low-doses of rotenone was not sufficient to alter mitochondrial integrity and ATP production, but

  15. Bisphenol A Exposure Leads to Specific MicroRNA Alterations in Placental Cells

    PubMed Central

    Avissar-Whiting, Michele; Veiga, Keila; Uhl, Kristen; Maccani, Matthew; Gagne, Luc; Moen, Erika; Marsit, Carmen J.

    2010-01-01

    Exposure to bisphenol-A (BPA) has been observed to alter developmental pathways and cell processes, at least in part, through epigenetic mechanisms. This study sought to investigate the effect of BPA on microRNAs (miRNAs) in human placental cells. miRNA microarray was performed following BPA treatment in three immortalized cytotrophoblast cell lines and the results validated using quantitative real-time PCR. For functional analysis, overexpression constructs were stably transfected into cells that were then assayed for changes in proliferation and response to toxicants. Microarray analysis revealed several miRNAs to be significantly altered in response to BPA treatment in two cell lines. Real-time PCR results confirmed that miR-146a was particularly strongly induced and its overexpression in cells led to slower proliferation as well as higher sensitivity to the DNA damaging agent, bleomycin. Overall, these results suggest that BPA can alter miRNA expression in placental cells, a potentially novel mode of BPA toxicity. PMID:20417706

  16. Prenatal Cigarette Smoke Exposure Causes Hyperactivity and Agressive Behavior: Role of Altered Catcholamines and BDNF

    PubMed Central

    Yochum, Carrie; Doherty-Lyon, Shannon; Hoffman, Carol; Hossain, Muhammad M.; Zellikoff, Judith T.; Richardson, Jason R.

    2014-01-01

    Smoking during pregnancy is associated with a variety of untoward effects on the offspring. However, recent epidemiological studies have brought into question whether the association between neurobehavioral deficits and maternal smoking is causal. We utilized an animal model of maternal smoking to determine the effects of prenatal cigarette smoke (CS) exposure on neurobehavioral development. Pregnant mice were exposed to either filtered air or mainstream CS from gestation day (GD) 4 to parturition for 4 hr/d and 5 d/wk, with each exposure producing maternal plasma concentration of cotinine equivalent to smoking <1 pack of cigarettes per day (25 ng/ml plasma cotinine level). Pups were weaned at postnatal day (PND) 21 and behavior assessed on at 4 weeks of age and again at 4–6 months of age. Male, but not female, offspring of CS-exposed dams demonstrated a significant increase in locomotor activity during adolescence and adulthood that was ameliorated by methylphenidate treatment. Additionally, male offspring exhibited increased aggression, as evidenced by decreased latency to attack and number of attacks in a resident intruder task. These behavioral abnormalities were accompanied by a significant decrease in striatal and cortical dopamine and serotonin and a significant reduction in brain-derived neurotrophic factor (BDNF) mRNA and protein. Taken in concert, these data demonstrate that prenatal exposure to CS produces behavioral alterations in mice that are similar to those observed in epidemiological studies linking maternal smoking to neurodevelopmental disorders and suggest a role for monoaminergic and BDNF alterations in these effects. PMID:24486851

  17. Prenatal cigarette smoke exposure causes hyperactivity and aggressive behavior: role of altered catecholamines and BDNF.

    PubMed

    Yochum, Carrie; Doherty-Lyon, Shannon; Hoffman, Carol; Hossain, Muhammad M; Zelikoff, Judith T; Richardson, Jason R

    2014-04-01

    Smoking during pregnancy is associated with a variety of untoward effects on the offspring. However, recent epidemiological studies have brought into question whether the association between neurobehavioral deficits and maternal smoking is causal. We utilized an animal model of maternal smoking to determine the effects of prenatal cigarette smoke (CS) exposure on neurobehavioral development. Pregnant mice were exposed to either filtered air or mainstream CS from gestation day (GD) 4 to parturition for 4h/d and 5d/wk, with each exposure producing maternal plasma concentration of cotinine equivalent to smoking <1 pack of cigarettes per day (25ng/ml plasma cotinine level). Pups were weaned at postnatal day (PND) 21 and behavior was assessed at 4weeks of age and again at 4-6months of age. Male, but not female, offspring of CS-exposed dams demonstrated a significant increase in locomotor activity during adolescence and adulthood that was ameliorated by methylphenidate treatment. Additionally, male offspring exhibited increased aggression, as evidenced by decreased latency to attack and number of attacks in a resident-intruder task. These behavioral abnormalities were accompanied by a significant decrease in striatal and cortical dopamine and serotonin and a significant reduction in brain-derived neurotrophic factor (BDNF) mRNA and protein. Taken in concert, these data demonstrate that prenatal exposure to CS produces behavioral alterations in mice that are similar to those observed in epidemiological studies linking maternal smoking to neurodevelopmental disorders. Further, these data also suggest a role for monaminergic and BDNF alterations in these effects. PMID:24486851

  18. Prenatal Ethanol Exposure Alters Core Body Temperature and Corticosterone Rhythms in Adult Male Rats

    PubMed Central

    Handa, Robert J.; Zuloaga, Damian G.; McGivern, Robert F.

    2008-01-01

    Ethanol’s effects on the developing brain include alterations in morphological and biochemistry of the hypothalamus. In order to examine the potential functional consequences of ethanol’s interference with hypothalamic differentiation, we studied the long-term effects of prenatal ethanol exposure on basal circadian rhythms of core body temperature (CBT) and heart rate (HR). We also examined the late afternoon surge in corticosterone (CORT). CBT and HR rhythms were studied in separate groups of animals at 4 months, 8 months and 20 months of age. The normal late-afternoon rise in plasma corticosterone was examined in freely-moving male rats at 6 months of age via an indwelling right-atrial cannula. Results showed that the CBT circadian rhythm exhibited an earlier rise following the nadir of the rhythm in fetal alcohol exposed (FAE) males at all ages compared to controls. At 8 months of age, the amplitude of the CBT circadian rhythm in FAE males was significantly reduced to the level observed in controls at 20 months. No significant effects of prenatal ethanol exposure were observed on basal HR rhythm at any age. The diurnal rise in corticosterone secretion was blunted and prolonged in 6-month-old FAE males compared to controls. Both control groups exhibited a robust surge in corticosterone secretion around the onset of the dark phase of the light cycle, which peaked at 1930 hours. Instead, FAE males exhibited a linear rise beginning in mid afternoon, which peaked at 2130 hours. These results indicate that exposure to ethanol during the period of hypothalamic development can alter the long-term regulation of circadian rhythms in specific physiological systems. PMID:18047910

  19. Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats.

    PubMed

    McDougall, Sanders A; Mohd-Yusof, Alena; Kaplan, Graham J; Abdulla, Zuhair I; Lee, Ryan J; Crawford, Cynthia A

    2013-04-15

    Administering manganese chloride (Mn) to rats on postnatal day (PD) 1-21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as a persistent increase in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1-21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., "autoreceptor" doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired. PMID:23458069

  20. Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats

    PubMed Central

    McDougall, Sanders A.; Mohd-Yusof, Alena; Kaplan, Graham J.; Abdulla, Zuhair I.; Lee, Ryan J.; Crawford, Cynthia A.

    2013-01-01

    Administering manganese chloride (Mn) to rats on postnatal day (PD) 1–21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as persistent increases in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1–21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., “autoreceptor” doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired. PMID:23458069

  1. Association between mitochondrial C-tract alteration and tobacco exposure in oral precancer cases

    PubMed Central

    Pandey, Rahul; Mehrotra, Divya; Mahdi, Abbas Ali; Sarin, Rajiv; Kowtal, Pradnya; Maurya, Shailendra S.; Parmar, Devendra

    2013-01-01

    Introduction: Tobacco exposure is a known risk factor for oral cancer. India is home to oral cancer epidemic chiefly due to the prevalent use of both smoke and smokeless tobacco. To reduce the related morbidity early detection is required. The key to this is detailing molecular events during early precancer stage. Mitochondrion is an important cellular organelle involved in cell metabolism and apoptosis. Mitochondrial dysfunction is thought to be the key event in oncogenesis. Last decade has seen a spurt of reports implicating mitochondrial mutations in oral carcinogenesis. However, there are few reports that study mitochondrial deoxyribonucleic acid (mtDNA) changes in oral precancer. This study aims to understand and link effect of tobacco exposure on mtDNA in oral precancer cases. Subjects and Methods: A total of 100 oral precancer cases of which 50 oral leukoplakia and 50 oral submucous fibrosis were recruited in the study and a detailed questionnaire were filled about the tobacco habits. Their tissue and blood samples were collected. Total genomic DNA was isolated from both sources. Mitochondrial C-tract was amplified and bidirectional sequencing was carried out. Mutations were scored over matched blood DNA. Results: There was a significant association between the presence of mitochondrial C-tract alteration and duration of tobacco exposure. The probability increased with increasing duration of tobacco consumption. The risk of having this alteration was more in chewers than in smokers. Conclusions: Tobacco in both form, chewable and smoke, is oncogenic and causes early changes in mitochondrial genome and chances increases with increasing duration of tobacco consumption. PMID:24665180

  2. Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure.

    PubMed

    Gano, Anny; Doremus-Fitzwater, Tamara L; Deak, Terrence

    2016-09-01

    Acute ethanol intoxication is associated with Rapid Alterations in Neuroimmune Gene Expression (RANGE), including increased Interleukin (IL)-6 and Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), and suppressed IL-1β and Tumor necrosis factor (TNF) α, yet little is known about adaptations in cytokines across the first few ethanol exposures. Thus, the present studies examined central cytokines during intoxication (3h post-ethanol) following 2, 4 or 6 intragastric ethanol challenges (4g/kg) delivered either daily or every-other-day (EOD). Subsequent analyses of blood ethanol concentrations (BECs) and corticosterone were performed to determine whether the schedule of ethanol delivery would alter the pharmacokinetics of, or general sensitivity to, subacute ethanol exposure. As expected, ethanol led to robust increases in IL-6 and IκBα gene expression in hippocampus, amygdala and bed nucleus of the stria terminalis (BNST), whereas IL-1β and TNFα were suppressed, thereby replicating our prior work. Ethanol-dependent increases in IL-6 and IκBα remained significant in all structures - even after 6 days of ethanol. When these doses were administered EOD, modest IL-6 increases in BNST were observed, with TNFα and IL-1β suppressed exclusively in the hippocampus. Analysis of BECs revealed a small but significant reduction in ethanol after 4 EOD exposures - an effect which was not observed when ethanol was delivered after 6 daily intubations. These findings suggest that ethanol-induced RANGE effects are not simply a function of ethanol load per se, and underscore the critical role that ethanol dosing interval plays in determining the neuroimmune consequences of alcohol. PMID:27208497

  3. Acute exposure to methamphetamine alters TLR9-mediated cytokine expression in human macrophage.

    PubMed

    Burns, Ariel; Ciborowski, Pawel

    2016-02-01

    Recent studies show that methamphetamine (Meth) use leads to higher susceptibility to and progression of infections, which suggests impairment of the immune system. The first line of defense against infections is the innate immune system and the macrophage is a key player in preventing and fighting infections. So we profiled cytokines over time in Meth treated THP-1 cells, as a human macrophage model, at a relevant concentration using high throughput screening to find a signaling target. We showed that after a single exposure, the effect of Meth on macrophage cytokine production was rapid and time dependent and shifted the balance of expression of cytokines to pro-inflammatory. Our results were analogous to previous reports in that Meth up-regulates TNF-α and IL-8 after two hours of exposure. However, global screening led to the novel identification of CXCL16, CXCL1 and many other up-regulated cytokines. We also showed CCL7 as the most down-regulated chemokine due to Meth exposure, which led us to hypothesize that Meth dysregulates the MyD88-dependent Toll-like receptor 9 (TLR9) signaling pathway. In conclusion, altered cytokine expression in macrophages suggests it could lead to a suppressed innate immunity in people who use Meth. PMID:26387832

  4. Neuroplastic alterations in the limbic system following cocaine or alcohol exposure.

    PubMed

    Stuber, Garret D; Hopf, F Woodward; Tye, Kay M; Chen, Billy T; Bonci, Antonello

    2010-01-01

    Neuroplastic changes in the CNS are thought to be a fundamental component of learning and memory. While pioneering studies in the hippocampus and cerebellum have detailed many of the basic mechanisms that can lead to alterations in synaptic transmission based on previous activity, only more recently has synaptic plasticity been monitored after behavioral manipulation or drug exposure. In this chapter, we review evidence that drugs of abuse are powerful modulators of synaptic plasticity. Both the dopaminergic neurons of the ventral tegmental area as well medium spiny neurons in nucleus accumbens show enhanced excitatory synaptic strength following passive or active exposure to drugs such as cocaine and alcohol. In the VTA, both the enhancement of excitatory synaptic strength and the acquisition of drug-related behaviors depend on signaling through the N-methyl-D: -aspartate receptors (NMDARs) which are mechanistically thought to lead to increased synaptic insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Synaptic insertion of AMPARs by drugs of abuse can be long lasting, depending on the route of administration, number of drug exposures, or whether the drugs are received passively or self-administered. PMID:21161748

  5. Metabolic and histopathological alterations in the marine bivalve Mytilus galloprovincialis induced by chronic exposure to acrylamide.

    PubMed

    Larguinho, Miguel; Cordeiro, Ana; Diniz, Mário S; Costa, Pedro M; Baptista, Pedro V

    2014-11-01

    Although the neurotoxic and genotoxic potential of acrylamide has been established in freshwater fish, the full breadth of the toxicological consequences induced by this xenobiotic has not yet been disclosed, particularly in aquatic invertebrates. To assess the effects of acrylamide on a bivalve model, the Mediterranean mussel (Mytilus galloprovincialis), two different setups were accomplished: 1) acute exposure to several concentrations of waterborne acrylamide to determine lethality thresholds of the substance and 2) chronic exposure to more reduced acrylamide concentrations to survey phases I and II metabolic endpoints and to perform a whole-body screening for histopathological alterations. Acute toxicity was low (LC50≈400mg/L). However, mussels were responsive to prolonged exposure to chronic concentrations of waterborne acrylamide (1-10mg/L), yielding a significant increase in lipid peroxidation plus EROD and GST activities. Still, total anti-oxidant capacity was not exceeded. In addition, no neurotoxic effects could be determined through acetylcholine esterase (AChE) activity. The findings suggest aryl-hydrocarbon receptor (Ahr)-dependent responses in mussels exposed to acrylamide, although reduced comparatively to vertebrates. No significant histological damage was found in digestive gland or gills but female gonads endured severe necrosis and oocyte atresia. Altogether, the results indicate that acrylamide may induce gonadotoxicity in mussels, although the subject should benefit from further research. Altogether, the findings suggest that the risk of acrylamide to aquatic animals, especially molluscs, may be underestimated. PMID:25262075

  6. Neonatal exposure to amphetamine alters social affiliation and central dopamine activity in adult male prairie voles.

    PubMed

    Fukushiro, D F; Olivera, A; Liu, Y; Wang, Z

    2015-10-29

    The prairie vole (Microtus ochrogaster) is a socially monogamous rodent species that forms pair bonds after mating. Recent data have shown that amphetamine (AMPH) is rewarding to prairie voles as it induces conditioned place preferences. Further, repeated treatment with AMPH impairs social bonding in adult prairie voles through a central dopamine (DA)-dependent mechanism. The present study examined the effects of neonatal exposure to AMPH on behavior and central DA activity in adult male prairie voles. Our data show that neonatal exposure to AMPH makes voles less social in an affiliation test during adulthood, but does not affect animals' locomotor activity and anxiety-like behavior. Neonatal exposure to AMPH also increases the levels of tyrosine hydroxylase (TH) and DA transporter (DAT) mRNA expression in the ventral tegmental area (VTA) in the brain, indicating an increase in central DA activity. As DA has been implicated in AMPH effects on behavioral and cognitive functions, altered DA activity in the vole brain may contribute to the observed changes in social behavior. PMID:26321240

  7. Polychlorinated biphenyl exposure alters the expression profile of microRNAs associated with vascular diseases.

    PubMed

    Wahlang, Banrida; Petriello, Michael C; Perkins, Jordan T; Shen, Shu; Hennig, Bernhard

    2016-09-01

    Exposure to persistent organic pollutants, including polychlorinated biphenyls (PCBs) is correlated with multiple vascular complications including endothelial cell dysfunction and atherosclerosis. PCB-induced activation of the vasculature subsequently leads to oxidative stress and induction of pro-inflammatory cytokines and adhesion proteins. Gene expression of these cytokines/proteins is known to be regulated by small, endogenous oligonucleotides known as microRNAs that interact with messenger RNA. MicroRNAs are an acknowledged component of the epigenome, but the role of environmentally-driven epigenetic changes such as toxicant-induced changes in microRNA profiles is currently understudied. The objective of this study was to determine the effects of PCB exposure on microRNA expression profile in primary human endothelial cells using the commercial PCB mixture Aroclor 1260. Samples were analyzed using Affymetrix GeneChip® miRNA 4.0 arrays for high throughput detection and selected microRNA gene expression was validated (RT-PCR). Microarray analysis identified 557 out of 6658 microRNAs that were changed with PCB exposure (p<0.05). In-silico analysis using MetaCore database identified 21 of these microRNAs to be associated with vascular diseases. Further validation showed that Aroclor 1260 increased miR-21, miR-31, miR-126, miR-221 and miR-222 expression levels. Upregulated miR-21 has been reported in cardiac injury while miR-126 and miR-31 modulate inflammation. Our results demonstrated evidence of altered microRNA expression with PCB exposure, thus providing novel insights into mechanisms of PCB toxicity. PMID:27288564

  8. Early Phthalates Exposure in Pregnant Women Is Associated with Alteration of Thyroid Hormones

    PubMed Central

    Tsai, Chih-Hsin; Liang, Wei-Yen; Li, Sih-Syuan; Huang, Han-Bin

    2016-01-01

    Introduction Previous studies revealed that phthalate exposure could alter thyroid hormones during the last trimester of pregnancy. However, thyroid hormones are crucial for fetal development during the first trimester. We aimed to clarify the effect of phthalate exposure on thyroid hormones during early pregnancy. Method We recruited 97 pregnant women who were offered an amniocentesis during the early trimester from an obstetrics clinic in southern Taiwan from 2013 to 2014. After signing an informed consent form, we collected amniotic fluid and urine samples from pregnant women to analyze 11 metabolites, including mono-ethyl phthalate (MEP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MnBP), of 9 phthalates using liquid chromatography/ tandem mass spectrometry. We collected blood samples from each subject to analyze serum thyroid hormones including thyroxine (T4), free T4, and thyroid-binding globulin (TBG). Results Three phthalate metabolites were discovered to be >80% in the urine samples of the pregnant women: MEP (88%), MnBP (81%) and MECPP (86%). Median MnBP and MECPP levels in pregnant Taiwanese women were 21.5 and 17.6 μg/g-creatinine, respectively, that decreased after the 2011 Taiwan DEHP scandal. Results of principal component analysis suggested two major sources (DEHP and other phthalates) of phthalates exposure in pregnant women. After adjusting for age, gestational age, TBG, urinary creatinine, and other phthalate metabolites, we found a significantly negative association between urinary MnBP levels and serum T4 (β = –5.41; p-value = 0.012; n = 97) in pregnant women using Bonferroni correction. Conclusion We observed a potential change in the thyroid hormones of pregnant women during early pregnancy after DnBP exposure. Additional study is necessitated to clarify these associations. PMID:27455052

  9. Asthmatics Exhibit Altered Oxylipin Profiles Compared to Healthy Individuals after Subway Air Exposure

    PubMed Central

    Nording, Malin; Klepczynska-Nyström, Anna; Sköld, Magnus; Haeggström, Jesper Z.; Grunewald, Johan; Svartengren, Magnus; Hammock, Bruce D.; Larsson, Britt-Marie; Eklund, Anders; Wheelock, Åsa M.; Wheelock, Craig E.

    2011-01-01

    Background Asthma is a chronic inflammatory lung disease that causes significant morbidity and mortality worldwide. Air pollutants such as particulate matter (PM) and oxidants are important factors in causing exacerbations in asthmatics, and the source and composition of pollutants greatly affects pathological implications. Objectives This randomized crossover study investigated responses of the respiratory system to Stockholm subway air in asthmatics and healthy individuals. Eicosanoids and other oxylipins were quantified in the distal lung to provide a measure of shifts in lipid mediators in association with exposure to subway air relative to ambient air. Methods Sixty-four oxylipins representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of bronchoalveolar lavage (BAL)-fluid. Validations through immunocytochemistry staining of BAL-cells were performed for 15-LOX-1, COX-1, COX-2 and peroxisome proliferator-activated receptor gamma (PPARγ). Multivariate statistics were employed to interrogate acquired oxylipin and immunocytochemistry data in combination with patient clinical information. Results Asthmatics and healthy individuals exhibited divergent oxylipin profiles following exposure to ambient and subway air. Significant changes were observed in 8 metabolites of linoleic- and α-linolenic acid synthesized via the 15-LOX pathway, and of the COX product prostaglandin E2 (PGE2). Oxylipin levels were increased in healthy individuals following exposure to subway air, whereas asthmatics evidenced decreases or no change. Conclusions Several of the altered oxylipins have known or suspected bronchoprotective or anti-inflammatory effects, suggesting a possible reduced anti-inflammatory response in asthmatics following exposure to subway air. These observations may have ramifications for sensitive subpopulations in urban areas. PMID:21897859

  10. Perinatal Exposure to Oestradiol and Bisphenol A Alters the Prostate Epigenome and Increases Susceptibility to Carcinogenesis

    PubMed Central

    Prins, Gail S.; Tang, Wan-Yee; Belmonte, Jessica; Ho, Shuk-Mei

    2010-01-01

    An important and controversial health concern is whether low-dose exposures to hormonally active environmental oestrogens such as bisphenol A can promote human diseases including prostate cancer. Our studies in rats have shown that pharmacological doses of oestradiol administered during the critical window of prostate development result in marked prostate pathology in adulthood that progress to neoplastic lesions with ageing. Our recent studies have also demonstrated that transient developmental exposure of rats to low, environmentally relevant doses of bisphenol A or oestradiol increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. These findings indicate that a wide range of oestrogenic exposures during development can predispose to prostatic neoplasia that suggests a potential developmental basis for this adult disease. To identify a molecular basis for oestrogen imprinting, we screened for DNA methylation changes over time in the exposed prostate glands. We found permanent alterations in DNA methylation patterns of multiple cell signalling genes suggesting an epigenetic mechanism of action. For phosphodiesterase type 4 variant 4 (PDE4D4), an enzyme responsible for intracellular cyclic adenosine monophosphate breakdown, a specific methylation cluster was identified in the 5′-flanking CpG island that was gradually hypermethylated with ageing in normal prostates resulting in loss of gene expression. However, in prostates exposed to neonatal oestradiol or bisphenol A, this region became hypomethylated with ageing resulting in persistent and elevated PDE4D4 expression. In total, these findings indicate that low-dose exposures to ubiquitous environmental oestrogens impact the prostate epigenome during development and in so doing, promote prostate disease with ageing. PMID:18226066

  11. PRENATAL ALCOHOL EXPOSURE ALTERS STEADY-STATE AND ACTIVATED GENE EXPRESSION IN THE ADULT RAT BRAIN

    PubMed Central

    Stepien, Katarzyna A.; Lussier, Alexandre A.; Neumann, Sarah M.; Pavlidis, Paul; Kobor, Michael S.; Weinberg, Joanne

    2016-01-01

    Background Prenatal alcohol exposure (PAE) is associated with alterations in numerous physiological systems, including the stress and immune systems . We have previously shown that PAE increases the course and severity of arthritis in an adjuvant-induced arthritis (AA) model. While the molecular mechanisms underlying these effects are not fully known, changes in neural gene expression are emerging as important factors in the etiology of PAE effects. As the prefrontal cortex (PFC) and hippocampus (HPC) play key roles in neuroimmune function, PAE-induced alterations to their transcriptome may underlie abnormal steady-state functions and responses to immune challenge. The current study examined brains from adult PAE and control females from our recent AA study to determine whether PAE causes long-term alterations in gene expression and whether these mediate the altered severity and course of arthritis in PAE females Methods Adult females from PAE, pair-fed [PF], and ad libitum-fed control [C]) groups were injected with either saline or complete Freund’s adjuvant. Animals were terminated at the peak of inflammation or during resolution (days 16 and 39 post-injection, respectively); cohorts of saline-injected PAE, PF and C females were terminated in parallel. Gene expression was analyzed in the PFC and HPC using whole genome mRNA expression microarrays. Results Significant changes in gene expression in both the PFC and HPC were found in PAE compared to controls in response to ethanol exposure alone (saline-injected females), including genes involved in neurodevelopment, apoptosis, and energy metabolism. Moreover, in response to inflammation (adjuvant-injected females), PAE animals showed unique expression patterns, while failing to exhibit the activation of genes and regulators involved in the immune response observed in control and pair-fed animals. Conclusions These results support the hypothesis that PAE affects neuroimmune function at the level of gene expression

  12. Neuropsychological evaluation for detecting alterations in the central nervous system after chemical exposure.

    PubMed

    Bolla, K I

    1996-08-01

    Individuals with multiple chemical sensitivity (MCS) report decreased attention/concentration, memory loss, disorientation, confusion, fatigue, depression, irritability, decreased libido, sleep disturbances, headaches, and weakness. These neurobehavioral symptoms represent possible alterations in the central nervous system (CNS). The evaluation of neurobehavioral functioning using neuropsychological techniques provides an indirect method for determining the integrity of the CNS. However, caution must be used in interpreting neuropsychological test results, since this technique is extremely sensitive but is not specific. Clinically significant aberrant test performance may be noted after chemical exposure as well as with other diseases of the CNS. In addition, neuropsychiatric conditions such as anxiety and depression are often manifested as cognitive difficulties that are similar in pattern to the cognitive dysfunction caused by toxic chemicals. Herein, limitations and cautions in the interpretations of neuropsychological test results are discussed. PMID:8921555

  13. Does ozone exposure alter growth and carbon allocation of mycorrhizal plants

    SciTech Connect

    Yoshida, L.C.; Gamon, J.A. ); Andersen, C.P. )

    1994-06-01

    Ozone is known to adversely affect plant growth. However, it is less clear how ozone affects belowground processes. This study tests the hypothesis that ozone alters growth and carbon allocation of vesicular arbuscular mycorrhizal (VAM) plants. Two ecotypes of Elymus glaucus (blue wild rye) were exposed to mycorrhizal inoculation and episodic ozone exposures simulating atmospheric conditions in the Los Angeles Basin. Preliminary results show that effects of ozone on growth were subtle. In both ecotypes, growth of aboveground biomass was not affected by ozone while root growth was decreased. In most treatments, mycorrhizal inoculation decreased growth of leaves and stems, but had no significant effect on root growth. Three-way ANOVA tests indicated interactive effects between ecotype, mycorrhiza and ozone. Further experimental work is needed to reveal the biological processes governing these responses.

  14. Nicotine exposure during adolescence alters the rules for prefrontal cortical synaptic plasticity during adulthood

    PubMed Central

    Goriounova, Natalia A.; Mansvelder, Huibert D.

    2012-01-01

    The majority of adolescents report to have smoked a cigarette at least once. Adolescence is a critical period of brain development during which maturation of areas involved in cognitive functioning, such as the medial prefrontal cortex (mPFC), is still ongoing. Tobacco smoking during this age may compromise the normal course of prefrontal development and lead to cognitive impairments in later life. In addition, adolescent smokers suffer from attention deficits, which progress with the years of smoking. Recent studies in rodents reveal the molecular changes induced by adolescent nicotine exposure that alter the functioning of synapses in the PFC and underlie the lasting effects on cognitive function. In particular, the expression and function of metabotropic glutamate receptors (mGluRs) are changed and this has an impact on short- and long-term plasticity of glutamatergic synapses in the PFC and ultimately on the attention performance. Here, we review and discuss these recent findings. PMID:22876231

  15. 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

  16. Functional and inflammatory alterations in the lung following exposure of rats to nitrogen mustard

    SciTech Connect

    Sunil, Vasanthi R.; Patel, Kinal J.; Shen, Jianliang; Reimer, David; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2011-01-01

    Nitrogen mustard is a vesicant that causes damage to the respiratory tract. In these studies, we characterized the acute effects of nitrogen mustard on lung structure, inflammatory mediator expression, and pulmonary function, with the goal of identifying mediators potentially involved in toxicity. Treatment of rats (male Wistar, 200-225 g) with nitrogen mustard (mechlorethamine hydrochloride, i.t., 0.25 mg/kg) resulted in marked histological changes in the respiratory tract, including necrotizing bronchiolitis, thickening of alveolar septa, and inflammation which was evident within 24 h. This was associated with increases in bronchoalveolar lavage protein and cells, confirming injury to alveolar epithelial regions of the lung. Nitrogen mustard administration also resulted in increased expression of inducible nitric oxide synthase and cyclooxygenase-2, pro-inflammatory proteins implicated in lung injury, in alveolar macrophages and alveolar and bronchial epithelial cells. Expression of connective tissue growth factor and matrix metalloproteinase-9, mediators regulating extracellular matrix turnover was also increased, suggesting that pathways leading to chronic lung disease are initiated early in the pathogenic process. Following nitrogen mustard exposure, alterations in lung mechanics and function were also observed. These included decreases in baseline static compliance, end-tidal volume and airway resistance, and a pronounced loss of methacholine responsiveness in resistance, tissue damping and elastance. Taken together, these data demonstrate that nitrogen mustard induces rapid structural and inflammatory changes in the lung which are associated with altered lung functioning. Understanding the nature of the injury induced by nitrogen mustard and related analogs may aid in the development of efficacious therapies for treatment of pulmonary injury resulting from exposure to vesicants.

  17. Sulfite exposure-induced hepatocyte death is not associated with alterations in p53 protein expression.

    PubMed

    Bai, Jianying; Lei, Peiyu; Zhang, Jidong; Zhao, Chunyan; Liang, Ruifeng

    2013-10-01

    Although sulfite (SO3(2-)) is commonly used as an antimicrobial agent and preservative in foods, medicines and wine, it has also been listed as an important risk factor for the initiation and progression of liver diseases due to oxidative damage. In general, apoptosis that is induced by oxidative stress is triggered by increases in p53 and alterations in Mdm2 and Bcl-2. However, the level of involvement of the p53 signaling pathway, which has been shown to be upregulated in some animal studies, in hepatocyte death remains unclear. To examine the response of the p53 signaling pathway to stimulation with different concentrations of sulfite, a time course study of p53, Mdm2, and Bcl-2 expression was conducted in an immortalized hepatic cell line, HL-7702. When the HL-7702 cells were cultured in the presence of Na2SO3, the cell viability was significantly decreased after 24h compared to that of the control group (0mmol/L) (p<0.05). Meanwhile, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the supernatants of HL-7702 cells were significantly increased following Na2SO3 administration. Interestingly, the expression of p53 and p-p53 (Ser15) remained unchanged. In addition, no obvious alterations in Mdm2 and Bcl-2 expression were observed in HL-7702 cells that had been stimulated with various concentrations of sulfite. To further investigate the detailed mechanism underlying sulfite toxicity, caspase-3, PCNA and RIP1 expression in HL-7702 cells was studied. The expression levels of caspase-3 and PCNA were unchanged, but RIP1 expression was increased significantly after 24h of exposure. In light of this evidence, we propose that sulfite is cytotoxic to hepatocytes, but this cytotoxicity is not achieved by direct interruption of the p53 signaling pathway. In addition, we propose that an alternative necrotic process underlies hepatocellular death following sulfite exposure. PMID:23973939

  18. Altered lung function at mid-adulthood in mice following neonatal exposure to hyperoxia.

    PubMed

    Sozo, Foula; Horvat, Jay C; Essilfie, Ama-Tawiah; O'Reilly, Megan; Hansbro, Philip M; Harding, Richard

    2015-11-01

    Infants born very preterm are usually exposed to high oxygen concentrations but this may impair lung function in survivors in later life. However, the precise changes involved are poorly understood. We determined how neonatal hyperoxia alters lung function at mid-adulthood in mice. Neonatal C57BL/6J mice inhaled 65% oxygen (HE group) from birth for 7 days. They then breathed room air until 11 months of age (P11mo); these mice experienced growth restriction. Controls breathed only room air. To exclude the effects of growth restriction, a group of dams was rotated between hyperoxia and normoxia during the exposure period (HE+DR group). Lung function was measured at P11mo. HE mice had increased inspiratory capacity, work of breathing and tissue damping. HE+DR mice had further increases in inspiratory capacity and work of breathing, and reduced FEV100/FVC. Total lung capacity was increased in HE+DR males. HE males had elevated responses to methacholine. Neonatal hyperoxia alters lung function at mid-adulthood, especially in males. PMID:26197245

  19. Maternal caffeine exposure alters neuromotor development and hippocampus acetylcholinesterase activity in rat offspring.

    PubMed

    Souza, Ana Claudia; Souza, Andressa; Medeiros, Liciane Fernandes; De Oliveira, Carla; Scarabelot, Vanessa Leal; Da Silva, Rosane Souza; Bogo, Mauricio Reis; Capiotti, Katiucia Marques; Kist, Luiza Wilges; Bonan, Carla D; Caumo, Wolnei; Torres, Iraci L S

    2015-01-21

    The objective of this study was to evaluate the effects of maternal caffeine intake on the neuromotor development of rat offspring and on acetylcholine degradation and acetylcholinesterase (AChE) expression in the hippocampus of 14-day-old infant rats. Rat dams were treated with caffeine (0.3g/L) throughout gestation and lactation until the pups were 14 days old. The pups were divided into three groups: (1) control, (2) caffeine, and (3) washout caffeine. The washout group received a caffeine solution until the seventh postnatal day (P7). Righting reflex (RR) and negative geotaxis (NG) were assessed to evaluate postural parameters as an index of neuromotor reflexes. An open-field (OF) test was conducted to assess locomotor and exploratory activities as well as anxiety-like behaviors. Caffeine treatment increased both RR and NG latency times. In the OF test, the caffeine group had fewer outer crossings and reduced locomotion compared to control, while the washout group showed increased inner crossings in relation to the other groups and fewer rearings only in comparison to the control group. We found decreased AChE activity in the caffeine group compared to the other groups, with no alteration in AChE transcriptional regulation. Chronic maternal exposure to caffeine promotes important alterations in neuromotor development. These results highlight the ability of maternal caffeine intake to interfere with cholinergic neurotransmission during brain development. PMID:25451122

  20. In utero exposure to chloroquine alters sexual development in the male fetal rat

    SciTech Connect

    Clewell, Rebecca A. Pluta, Linda; Thomas, Russell S.; Andersen, Melvin E.

    2009-06-15

    Chloroquine (CQ), a drug that has been used extensively for the prevention and treatment of malaria, is currently considered safe for use during pregnancy. However, CQ has been shown to disrupt steroid homeostasis in adult rats and similar compounds, such as quinacrine, inhibit steroid production in the Leydig cell in vitro. To explore the effect of in utero CQ exposure on fetal male sexual development, pregnant Sprague-Dawley rats were given a daily dose of either water or chloroquine diphosphate from GD 16-18 by oral gavage. Chloroquine was administered as 200 mg/kg CQ base on GD 16, followed by two maintenance doses of 100 mg/kg CQ base on GD 16 and 18. Three days of CQ treatment resulted in reduced maternal and fetal weight on GD 19 and increased necrosis and steatosis in the maternal liver. Fetal livers also displayed mild lipid accumulation. Maternal serum progesterone was increased after CQ administration. Fetal testes testosterone, however, was significantly decreased. Examination of the fetal testes revealed significant alterations in vascularization and seminiferous tubule development after short-term CQ treatment. Anogenital distance was not altered. Microarray and RT-PCR showed down-regulation of several genes associated with cholesterol transport and steroid synthesis in the fetal testes. This study indicates that CQ inhibits testosterone synthesis and normal testis development in the rat fetus at human relevant doses.

  1. RNA-Seq identifies key reproductive gene expression alterations in response to cadmium exposure.

    PubMed

    Hu, Hanyang; Lu, Xing; Cen, Xiang; Chen, Xiaohua; Li, Feng; Zhong, Shan

    2014-01-01

    Cadmium is a common toxicant that is detrimental to many tissues. Although a number of transcriptional signatures have been revealed in different tissues after cadmium treatment, the genes involved in the cadmium caused male reproductive toxicity, and the underlying molecular mechanism remains unclear. Here we observed that the mice treated with different amount of cadmium in their rodent chow for six months exhibited reduced serum testosterone. We then performed RNA-seq to comprehensively investigate the mice testicular transcriptome to further elucidate the mechanism. Our results showed that hundreds of genes expression altered significantly in response to cadmium treatment. In particular, we found several transcriptional signatures closely related to the biological processes of regulation of hormone, gamete generation, and sexual reproduction, respectively. The expression of several testosterone synthetic key enzyme genes, such as Star, Cyp11a1, and Cyp17a1, were inhibited by the cadmium exposure. For better understanding of the cadmium-mediated transcriptional regulatory mechanism of the genes, we computationally analyzed the transcription factors binding sites and the mircoRNAs targets of the differentially expressed genes. Our findings suggest that the reproductive toxicity by cadmium exposure is implicated in multiple layers of deregulation of several biological processes and transcriptional regulation in mice. PMID:24982889

  2. RNA-Seq Identifies Key Reproductive Gene Expression Alterations in Response to Cadmium Exposure

    PubMed Central

    Hu, Hanyang; Lu, Xing; Cen, Xiang; Chen, Xiaohua; Li, Feng; Zhong, Shan

    2014-01-01

    Cadmium is a common toxicant that is detrimental to many tissues. Although a number of transcriptional signatures have been revealed in different tissues after cadmium treatment, the genes involved in the cadmium caused male reproductive toxicity, and the underlying molecular mechanism remains unclear. Here we observed that the mice treated with different amount of cadmium in their rodent chow for six months exhibited reduced serum testosterone. We then performed RNA-seq to comprehensively investigate the mice testicular transcriptome to further elucidate the mechanism. Our results showed that hundreds of genes expression altered significantly in response to cadmium treatment. In particular, we found several transcriptional signatures closely related to the biological processes of regulation of hormone, gamete generation, and sexual reproduction, respectively. The expression of several testosterone synthetic key enzyme genes, such as Star, Cyp11a1, and Cyp17a1, were inhibited by the cadmium exposure. For better understanding of the cadmium-mediated transcriptional regulatory mechanism of the genes, we computationally analyzed the transcription factors binding sites and the mircoRNAs targets of the differentially expressed genes. Our findings suggest that the reproductive toxicity by cadmium exposure is implicated in multiple layers of deregulation of several biological processes and transcriptional regulation in mice. PMID:24982889

  3. Alteration of transcriptional networks in the entorhinal cortex after maternal immune activation and adolescent cannabinoid exposure.

    PubMed

    Hollins, Sharon L; Zavitsanou, Katerina; Walker, Frederick Rohan; Cairns, Murray J

    2016-08-01

    Maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) have both been identified as major environmental risk factors for schizophrenia. We examined the effects of these two risk factors alone, and in combination, on gene expression during late adolescence. Pregnant rats were exposed to the viral infection mimic polyriboinosinic-polyribocytidylic acid (poly I:C) on gestational day (GD) 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14days starting on postnatal day (PND) 35. Gene expression was examined in the left entorhinal cortex (EC) using mRNA microarrays. We found prenatal treatment with poly I:C alone, or HU210 alone, produced relatively minor changes in gene expression. However, following combined treatments, offspring displayed significant changes in transcription. This dramatic and persistent alteration of transcriptional networks enriched with genes involved in neurotransmission, cellular signalling and schizophrenia, was associated with a corresponding perturbation in the expression of small non-coding microRNA (miRNA). These results suggest that a combination of environmental exposures during development leads to significant genomic remodeling that disrupts maturation of the EC and its associated circuitry with important implications as the potential antecedents of memory and learning deficits in schizophrenia and other neuropsychiatric disorders. PMID:26923065

  4. Repeated Stimulus Exposure Alters the Way Sound Is Encoded in the Human Brain

    PubMed Central

    Tremblay, Kelly L.; Inoue, Kayo; McClannahan, Katrina; Ross, Bernhard

    2010-01-01

    Auditory training programs are being developed to remediate various types of communication disorders. Biological changes have been shown to coincide with improved perception following auditory training so there is interest in determining if these changes represent biologic markers of auditory learning. Here we examine the role of stimulus exposure and listening tasks, in the absence of training, on the modulation of evoked brain activity. Twenty adults were divided into two groups and exposed to two similar sounding speech syllables during four electrophysiological recording sessions (24 hours, one week, and up to one year later). In between each session, members of one group were asked to identify each stimulus. Both groups showed enhanced neural activity from session-to-session, in the same P2 latency range previously identified as being responsive to auditory training. The enhancement effect was most pronounced over temporal-occipital scalp regions and largest for the group who participated in the identification task. The effects were rapid and long-lasting with enhanced synchronous activity persisting months after the last auditory experience. Physiological changes did not coincide with perceptual changes so results are interpreted to mean stimulus exposure, with and without being paired with an identification task, alters the way sound is processed in the brain. The cumulative effect likely involves auditory memory; however, in the absence of training, the observed physiological changes are insufficient to result in changes in learned behavior. PMID:20421969

  5. Ethanol exposure during gastrulation alters neuronal morphology and behavior in zebrafish.

    PubMed

    Shan, Shubham D; Boutin, Savanna; Ferdous, Jannatul; Ali, Declan W

    2015-01-01

    Ethanol (EtOH) exposure during development has been shown to lead to deficits in fine and gross motor control. In this study we used zebrafish embryos to determine the effects of EtOH treatment during gastrulation. We treated embryos in the gastrulation stage (5.25 hours post fertilization (hpf) to 10.75 hpf) with 10 mM, 50 mM or 100 mM EtOH and examined the effects on general animal morphology, the c-start reflex behavior, Mauthner cell (M-cell) morphology and motor neuron morphology. EtOH treated fish exhibited a minor but significant increase in gross morphological deformities compared with untreated fish. Behavioral studies showed that EtOH treatment resulted in an increase in the peak speed of the tail during the escape response. Furthermore, there was a marked increase in abnormally directed c-starts, with treated fish showing greater incidences of c-starts in inappropriate directions. Immunolabeling of the M-cells, which are born during gastrulation, revealed that they were significantly smaller in fish treated with 100 mM EtOH compared with controls. Immunolabeling of primary motor neurons using anti-znp1, showed no significant effect on axonal branching, whereas secondary motor axons had a greater number of branches in ethanol treated fish compared with controls. Together these findings indicate that ethanol exposure during gastrulation can lead to alterations in behavior, neuronal morphology and possibly function. PMID:25599605

  6. Prior exposure to extreme pain alters neural response to pain in others.

    PubMed

    Eidelman-Rothman, Moranne; Goldstein, Abraham; Weisman, Omri; Schneiderman, Inna; Zagoory-Sharon, Orna; Decety, Jean; Feldman, Ruth

    2016-08-01

    In the extant literature examining the brain mechanisms implicated in pain perception, researchers have theorized that the overlapping responses to pain in the self and in others mark the human capacity for empathy. Here we investigated how prior exposure to extreme pain affects pain perception, by assessing the dynamics of pain processing in veterans who were previously exposed to severe injury. Forty-three participants (28 pain-exposed and 15 controls) underwent whole-head magnetoencephalography (MEG) while viewing photographs of limbs in painful and nonpainful (neutral) conditions. Among controls, an early (0-220 ms) "pain effect" in the posterior cingulate and sensorimotor cortices, and a later (760-900 ms) "pain effect" in the posterior cingulate cortex, superior temporal gyrus/insula, and fusiform gyrus were found, indicated by enhanced alpha suppression to the pain versus nonpain conditions. Importantly, pain-exposed participants exhibited an atypical pain response in the posterior cingulate cortex, indicated by a normative response to pain, but no pain-to-no-pain differentiation. This may suggest that individuals exposed to extreme pain may perceive neutral stimuli as potentially threatening. Our findings demonstrate alterations in pain perception following extreme pain exposure, chart the sequence from automatic to evaluative pain processing, and emphasize the importance of considering past experiences in studying the neural response to others' states. PMID:27032959

  7. Levonorgestrel exposure to fathead minnows (Pimephales promelas) alters survival, growth, steroidogenic gene expression and hormone production.

    PubMed

    Overturf, Matthew D; Overturf, Carmen L; Carty, Dennis R; Hala, David; Huggett, Duane B

    2014-03-01

    Human pharmaceuticals are commonly detected in the environment. Concern over these compounds in the environment center around the potential for pharmaceuticals to interfere with the endocrine system of aquatic organisms. The main focus of endocrine disruption research has centered on how estrogenic and androgenic compounds interact with the endocrine system to elicit reproductive effects. Other classes of compounds, such as progestins, have been overlooked. Recently, studies have investigated the potential for synthetic progestins to impair reproduction and growth in aquatic organisms. The present study utilizes the OECD 210 Early-life Stage (ELS) study to investigate the impacts levonorgestrel (LNG), a synthetic progestin, on fathead minnow (FHM) survival and growth. After 28 days post-hatch, survival of larval FHM was impacted at 462 ng/L, while growth was significantly reduced at 86.9 ng/L. Further analysis was conducted by measuring specific endocrine related mRNA transcript profiles in FHM larvae following the 28 day ELS exposure to LNG. Transcripts of 3β-HSD, 20β-HSD, CYP17, AR, ERα, and FSH were significantly down-regulated following 28d exposure to 16.3 ng/L LNG, while exposure to 86.9 ng/L significantly down-regulated 3β-HSD, 20β-HSD, CYP19A, and FSH. At 2,392 ng/L of LNG, a significant down-regulation occurred with CYP19A and ERβ transcripts, while mPRα and mPRβ profiles were significantly induced. No significant changes occurred in 11β-HSD, CYP11A, StAR, LHβ, and VTG mRNA expression following LNG exposure. An ex vivo steroidogenesis assay was conducted with sexually mature female FHM following a 7 day exposure 100 ng/L LNG with significant reductions observed in pregnenolone, 17α,20β-dihydroxy-4-pregnen-3-one (17,20-DHP), testosterone, and 11-ketotestosterone. Together these data suggest LNG can negatively impact FHM larval survival and growth, with significant alterations in endocrine related responses. PMID:24503577

  8. Alterations in DNA methylation corresponding with lung inflammation and as a biomarker for disease development after MWCNT exposure.

    PubMed

    Brown, Traci A; Lee, Joong Won; Holian, Andrij; Porter, Virginia; Fredriksen, Harley; Kim, Minju; Cho, Yoon Hee

    2016-05-01

    Use of multi-walled carbon nanotubes (MWCNT) is growing which increases occupational exposures to these materials. Their toxic potential makes it important to have an in-depth understanding of the inflammation and disease that develops due to exposure. Epigenetics is one area of interest that has been quickly developing to assess disease processes due to its ability to change gene expression and thus the lung environment after exposure. In this study, promoter methylation of inflammatory genes (IFN-γ and TNF-α) was measured after MWCNT exposure using the pyrosequencing assay and found to correlate with initial cytokine production. In addition, methylation of a gene involved in tissue fibrosis (Thy-1) was also altered in a way that matched collagen deposition. In addition to using epigenetics to better understand disease processes, it has also been used as a biomarker of exposure and disease. In this study, global methylation was determined in the lung to ascertain whether MWCNT alter global methylation at the site of exposure and if those alterations coincide with disease development. Then, global methylation levels were determined in the blood to ascertain whether global methylation could be used as a biomarker of exposure in a more easily accessible tissue. Using the LuUminometric Methylation Assay (LUMA) and 5-Methylcytosine (5-mC) Quantification assay, we found that MWCNT lead to DNA hypomethylation in the lung and blood, which coincided with disease development. This study provides initial data showing that alterations in gene-specific methylation correspond with an inflammatory response to MWCNT exposure. In addition, global DNA methylation in the lung and blood coincides with MWCNT-induced disease development, suggesting its potential as a biomarker of both exposure and disease development. PMID:26375518

  9. Exposure to Acetylcholinesterase Inhibitors Alters the Physiology and Motor Function of Honeybees

    PubMed Central

    Williamson, Sally M.; Moffat, Christopher; Gomersall, Martha A. E.; Saranzewa, Nastja; Connolly, Christopher N.; Wright, Geraldine A.

    2013-01-01

    Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24 h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15 min. At a 10 nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1 μM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival. PMID:23386834

  10. Alteration of the aPA ELISA by UV exposure of polystyrene microtiter plates.

    PubMed

    Goldberg, J S; Wagenknecht, D R; McIntyre, J A

    1996-01-01

    Interlaboratory inconsistencies in antiphospholipid antibody (aPA) solid phase assays have prompted controversy in clinical laboratory testing for aPA. We found that the aPA ELISA can be influenced by the type of microtiter plate utilized and by the conditions in which the plates are stored. By exposing 96-well, flat-bottom polystyrene microtiter plates to short wave UV light (254 nm), the aPA ELISA signal decreased in a UV dose-dependent manner. No effect was seen with long wave UV light (366 nm). These results were independent of the antibody isotype under study or the phospholipid (PL) antigen used: anionic phosphatidylserine (PS) and cardiolipin (CL), or zwitterionic phosphatidylethanolamine (PE). Purified human beta 2-glycoprotein I (beta 2 GPI), a known cofactor for anionic PL, and rabbit anti-beta 2 GPI antisera were used to demonstrate that beta 2 GPI bound equally to UV treated and untreated microtiter plates. In contrast, recognition of beta 2 GPI on an anionic PL surface was decreased on UV treated plates, suggesting that UV exposure alters the lipid binding properties of the microliter plate. To determine whether UV exposure inhibited PL binding directly or caused a change in the way the PL was bound, the amount of PL bound to UV treated and untreated plates was measured by using fluorescent labeled PS and a fluorimeter. PS binding was decreased by 53% in UV treated wells as compared to untreated wells. These data show that short wave UV exposure reduces PL binding to polystyrene microtiter plates, thereby reducing the amount of beta 2 GPI bound to PL coated ELISA plates. Thus by using UV exposed microtiter plates, decreased or false-negative a PA ELISA results may be obtained for aPA positive plasmas. PMID:8887002

  11. Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain.

    PubMed

    Ngai, Ying Fai; Sulistyoningrum, Dian C; O'Neill, Ryan; Innis, Sheila M; Weinberg, Joanne; Devlin, Angela M

    2015-09-01

    Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE. PMID:26180184

  12. Exposure of Persian sturgeon (Acipenser persicus) to cadmium results in biochemical, histological and transcriptional alterations.

    PubMed

    Miandare, Hamed Kolangi; Niknejad, Mahtab; Shabani, Ali; Safari, Roghieh

    2016-01-01

    Sturgeon is one of the endangered families of fish in the Caspian Sea region, where there is up to 80% of their global caching. Unfortunately, in recent years, increase of pollutants has been resulted in their total population reduction. Due to their benthic nature, sturgeons are at great risk of exposing to contaminants such as cadmium. Despite their endangered status in the Caspian Sea, there are only a few studies on characterizing the relative sensitivity of sturgeons to cadmium. Adverse effects associated with pollution on angiogenesis are mediated by hypoxia inducing factor-1 (HIF-1) and vascular endothelial growth factor (VEGF). In this investigation, gene expression of two distinct HIFs-1, HIF-1α and HIF-2α, and VEGF was investigated at the mRNA transcript levels after exposure of Persian sturgeon (Acipenser persicus) to cadmium. VEGF, HIF-1α and HIF-2α expressions in treated Persian sturgeon were greater than controls. Significant increases (P<0.05) were also observed in cortisol and glucose levels compared to the control group especially in the fish exposed to higher cadmium concentration (800 μg/L). Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactic acid dehydrogenase (LDH) levels were increased in the cadmium-exposed fish, although the observed increases were not significant between the control and 200 μg/L cadmium treatment at some sampling time points. Gill tissues also showed histopathological changes in the cadmium treatments. Overall, results indicated that cadmium resulted in some alterations in biochemical parameters, mRNA transcript level expression of two important angiogenesis related genes as well as histological alterations in Persian sturgeon. PMID:26687766

  13. The timing of embryonic exposure to elevated temperature alters stress endocrinology in domestic chickens (Gallus domesticus).

    PubMed

    Wilsterman, Kathryn; Mast, Andrew D; Luu, Thuyvan H; Haussmann, Mark F

    2015-02-01

    Patterns of glucocorticoid (GC) release in response to stimuli vary both among individuals and within individuals across their lifetime. While much work has focused on how the prenatal steroid environment can affect GC release, relatively little is known about how environmental parameters, such as incubation temperature affect GCs. We tested the hypothesis that variation and timing of elevated incubation temperature within the thermoneutral zone can alter the pattern of GC release. We incubated domestic chicken eggs (Gallus domesticus) at the optimal incubation temperature (37.5 °C) or at a slightly higher temperature (+1.1 °C) either early, late, or throughout incubation. At three weeks post-hatch, all birds were (i) exposed to a capture-restraint stress to measure stress-induced GC release (naïve). Three days following the naïve stressor, birds were (ii) exposed to a heat challenge, which was followed the next day by a second capture-restraint stress (post-heat challenge). Regardless of treatment, birds had similar patterns of GC release following the naïve stress series. However, during the post-heat challenge stress series, birds incubated at optimal temperatures increased their peak GC release. In contrast, birds exposed to slightly elevated temperatures for any period of development failed to increase peak GC release, and their specific response varied with timing of exposure to the elevated incubation temperature. Our results demonstrate that subtle variation in the embryonic environment, such as elevated incubation temperature within the thermoneutral zone, can impact the pattern of GC release of offspring. Further work is needed to understand the mechanisms underlying these changes and the relationship between fitness and environmentally-altered phenotypes. PMID:25623149

  14. Exposure to Synthetic Gray Water Inhibits Amoeba Encystation and Alters Expression of Legionella pneumophila Virulence Genes

    PubMed Central

    Lu, Jingrang; Ashbolt, Nicholas J.

    2014-01-01

    Water conservation efforts have focused on gray water (GW) usage, especially for applications that do not require potable water quality. However, there is a need to better understand environmental pathogens and their free-living amoeba (FLA) hosts within GW, given their growth potential in stored gray water. Using synthetic gray water (sGW) we examined three strains of the water-based pathogen Legionella pneumophila and its FLA hosts Acanthamoeba polyphaga, A. castellanii, and Vermamoeba vermiformis. Exposure to sGW for 72 h resulted in significant inhibition (P < 0.0001) of amoebal encystation versus control-treated cells, with the following percentages of cysts in sGW versus controls: A. polyphaga (0.6 versus 6%), A. castellanii (2 versus 62%), and V. vermiformis (1 versus 92%), suggesting sGW induced maintenance of the actively feeding trophozoite form. During sGW exposure, L. pneumophila culturability decreased as early as 5 h (1.3 to 2.9 log10 CFU, P < 0.001) compared to controls (Δ0 to 0.1 log10 CFU) with flow cytometric analysis revealing immediate changes in membrane permeability. Furthermore, reverse transcription-quantitative PCR was performed on total RNA isolated from L. pneumophila cells at 0 to 48 h after sGW incubation, and genes associated with virulence (gacA, lirR, csrA, pla, and sidF), the type IV secretion system (lvrB and lvrE), and metabolism (ccmF and lolA) were all shown to be differentially expressed. These results suggest that conditions within GW may promote interactions between water-based pathogens and FLA hosts, through amoebal encystment inhibition and alteration of bacterial gene expression, thus warranting further exploration into FLA and L. pneumophila behavior in GW systems. PMID:25381242

  15. Exposure of Soil Microbial Communities to Chromium and Arsenic Alters Their Diversity and Structure

    PubMed Central

    Rizvi, Fariha Z.; Rehman, Yasir; Faisal, Muhammad; Hasnain, Shahida; McInerney, Michael J.; Krumholz, Lee R.

    2012-01-01

    Extensive use of chromium (Cr) and arsenic (As) based preservatives from the leather tanning industry in Pakistan has had a deleterious effect on the soils surrounding production facilities. Bacteria have been shown to be an active component in the geochemical cycling of both Cr and As, but it is unknown how these compounds affect microbial community composition or the prevalence and form of metal resistance. Therefore, we sought to understand the effects that long-term exposure to As and Cr had on the diversity and structure of soil microbial communities. Soils from three spatially isolated tanning facilities in the Punjab province of Pakistan were analyzed. The structure, diversity and abundance of microbial 16S rRNA genes were highly influenced by the concentration and presence of hexavalent chromium (Cr (VI)) and arsenic. When compared to control soils, contaminated soils were dominated by Proteobacteria while Actinobacteria and Acidobacteria (which are generally abundant in pristine soils) were minor components of the bacterial community. Shifts in community composition were significant and revealed that Cr (VI)-containing soils were more similar to each other than to As contaminated soils lacking Cr (VI). Diversity of the arsenic resistance genes, arsB and ACR3 were also determined. Results showed that ACR3 becomes less diverse as arsenic concentrations increase with a single OTU dominating at the highest concentration. Chronic exposure to either Cr or As not only alters the composition of the soil bacterial community in general, but affects the arsenic resistant individuals in different ways. PMID:22768219

  16. Exposure of soil microbial communities to chromium and arsenic alters their diversity and structure.

    PubMed

    Sheik, Cody S; Mitchell, Tyler W; Rizvi, Fariha Z; Rehman, Yasir; Faisal, Muhammad; Hasnain, Shahida; McInerney, Michael J; Krumholz, Lee R

    2012-01-01

    Extensive use of chromium (Cr) and arsenic (As) based preservatives from the leather tanning industry in Pakistan has had a deleterious effect on the soils surrounding production facilities. Bacteria have been shown to be an active component in the geochemical cycling of both Cr and As, but it is unknown how these compounds affect microbial community composition or the prevalence and form of metal resistance. Therefore, we sought to understand the effects that long-term exposure to As and Cr had on the diversity and structure of soil microbial communities. Soils from three spatially isolated tanning facilities in the Punjab province of Pakistan were analyzed. The structure, diversity and abundance of microbial 16S rRNA genes were highly influenced by the concentration and presence of hexavalent chromium (Cr (VI)) and arsenic. When compared to control soils, contaminated soils were dominated by Proteobacteria while Actinobacteria and Acidobacteria (which are generally abundant in pristine soils) were minor components of the bacterial community. Shifts in community composition were significant and revealed that Cr (VI)-containing soils were more similar to each other than to As contaminated soils lacking Cr (VI). Diversity of the arsenic resistance genes, arsB and ACR3 were also determined. Results showed that ACR3 becomes less diverse as arsenic concentrations increase with a single OTU dominating at the highest concentration. Chronic exposure to either Cr or As not only alters the composition of the soil bacterial community in general, but affects the arsenic resistant individuals in different ways. PMID:22768219

  17. Tobacco Smoke Exposure and Altered Nasal Responses to Live Attenuated Influenza Virus

    PubMed Central

    Noah, Terry L.; Zhou, Haibo; Monaco, Jane; Horvath, Katie; Herbst, Margaret; Jaspers, Ilona

    2011-01-01

    Background Epidemiologic evidence links tobacco smoke and increased risk for influenza in humans, but the specific host defense pathways involved are unclear. Objective We developed a model to examine influenza-induced innate immune responses in humans and test the hypothesis that exposure to cigarette smoke alters nasal inflammatory and antiviral responses to live attenuated influenza virus (LAIV). Methods This was an observational cohort study comparing nasal mucosal responses to LAIV among young adult active smokers (n = 17), nonsmokers exposed to secondhand smoke (SHS; n = 20), and unexposed controls (n = 23). Virus RNA and inflammatory factors were measured in nasal lavage fluids (NLF) serially after LAIV inoculation. For key end points, peak and total (area under curve) responses were compared among groups. Results Compared with controls, NLF interleukin-6 (IL-6) responses to LAIV (peak and total) were suppressed in smokers. Virus RNA in NLF cells was significantly increased in smokers, as were interferon-inducible protein 10:virus ratios. Responses in SHS-exposed subjects were generally intermediate between controls and smokers. We observed significant associations between urine cotinine and NLF IL-6 responses (negative correlation) or virus RNA in NLF cells (positive correlation) for all subjects combined. Conclusions Nasal inoculation with LAIV results in measurable inflammatory and antiviral responses in human volunteers, thus providing a model for investigating environmental effects on influenza infections in humans. Exposure to cigarette smoke was associated with suppression of specific nasal inflammatory and antiviral responses, as well as increased virus quantity, after nasal inoculation with LAIV. These data suggest mechanisms for increased susceptibility to influenza infection among persons exposed to tobacco smoke. PMID:20920950

  18. TIME-DEPENDENT EFFECTS ON GENE EXPRESSION IN RAT SEMINAL VESICLE DEVELOPMENTALLY ALTERED BY IN UTERO EXPOSURE TO TCDD

    EPA Science Inventory

    TIME-DEPENDENT EFFECTS ON GENE EXPRESSION IN RAT SEMINAL VESICLE DEVELOPMENTALLY ALTERED BY IN UTERO EXPOSURE TO TCDD. V M Richardson', J T Hamm2, and L S Birnbaum1. 'USEPA, ORD/NHEERL/ETD, Research Triangle Park, NC, USA, 'Curriculum in Toxicology, University of North Carolina, ...

  19. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L.

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival. We are studying two aspects of this vestibular adaptation: (1) How does long-term exposure to microgravity and hypergravity affect the development of vestibular afferents? (2) How does short- term exposure to extremely rapid changes in gravity, such as those that occur during launch and landing, affect the vestibular system. During space flight the gravistatic receptors in the otolith organs are effectively unloaded. In hypergravity conditions they are overloaded. However, the angular acceleration receptors of the semicircular canals receive relatively normal stimulation in both micro- and hypergravity.Rat embryos exposed to microgravity from gestation day 10 (prior to vestibular function) until gestation day 20 (vestibular system is somewhat functional) showed that afferents from the posterior vertical canal projecting to the medial vestibular nucleus developed similarly in microgravity, hypergravity, and in controls . However, afferents from the saccule showed delayed development in microgravity as compared to development in hypergravity and in controls. Cerebellar plasticity is crucial for modification of sensory-motor control and learning. Thus we explored the possibility that strong vestibular stimuli would modify cerebellar motor control (i.e., eye movement, postural control, gut motility) by altering the morphology of cerebellar Purkinje cells. To study the effects of short-term exposures to strong vestibular stimuli we focused on structural changes in the vestibulo-cerebellum that are caused by strong vestibular stimuli. Adult mice were exposed to various combinations of constant and/or rapidly changing angular and linear accelerations for 8.5 min (the time length of shuttle launch). Our data shows that these stimuli cause intense excitation of cerebellar Purkinje cells, inducing up-regulation of clathrin-mediated endocytosis

  20. Microbial exposure alters HIV-1-induced mucosal CD4+ T cell death pathways Ex vivo

    PubMed Central

    2014-01-01

    bystander CD4+ T cells, but microbial exposure shifted the PCD mechanism toward apoptosis of productively infected T cells. These results suggest that mucosal CD4+ T cell death pathways may be altered in HIV-infected individuals after gut barrier function is compromised, with potential consequences for mucosal inflammation, viral dissemination and systemic immune activation. PMID:24495380

  1. Prenatal exposure to gamma/neutron irradiation: Sensorimotor alterations and paradoxical effects on learning

    SciTech Connect

    Di Cicco, D.; Antal, S.; Ammassari-Teule, M. )

    1991-01-01

    The effects of prenatal exposure on gamma/neutron radiations (0.5 Gy at about the 18th day of fetal life) were studied in a hybrid strain of mice (DBA/Cne males x C57BL/Cne females). During ontogeny, measurements of sensorimotor reflexes revealed in prenatally irradiated mice (1) a delay in sensorial development, (2) deficits in tests involving body motor control, and (3) a reduction of both motility and locomotor activity scores. In adulthood, the behaviour of prenatally irradiated and control mice was examined in the open field test and in reactivity to novelty. Moreover, their learning performance was compared in several situations. The results show that, in the open field test, only rearings were more frequent in irradiated mice. In the presence of a novel object, significant sex x treatment interactions were observed since ambulation and leaning against the novel object increased in irradiated females but decreased in irradiated males. Finally, when submitted to different learning tasks, irradiated mice were impaired in the radial maze, but paradoxically exhibited higher avoidance scores than control mice, possibly because of their low pain thresholds. Taken together, these observations indicate that late prenatal gamma/neutron irradiation induces long lasting alterations at the sensorimotor level which, in turn, can influence learning abilities of adult mice.

  2. Prenatal nicotine exposure alters respiratory long term facilitation in neonatal rats

    PubMed Central

    Fuller, DD; Dougherty, BJ; Sandhu, MS; Doperalski, NJ; Reynolds, CR; Hayward, LF

    2009-01-01

    Intermittent hypoxia can evoke persistent increases in ventilation (ν̇ E) in neonates (i.e. long-term facilitation, LTF) (Julien et al. Am J Physiol Regul Integr Comp Physiol 294: R1356–R1366, 2008). Since prenatal nicotine (PN) exposure alters neonatal respiratory control (Fregosi & Pilarski. Respir. Physiol. Neurobiol. 164: 80–86, 2008), we hypothesized that PN would influence LTF of ventilation (ν̇ E) in neonatal rats. An osmotic minipump delivered nicotine (6 mg/kg/day) or saline to pregnant dams. ν̇ E was assessed in unanesthetized pups via whole body plethysmography at post-natal (P) days 9–11 or 15–17 during baseline (BL, 21% O2), hypoxia (10 × 5 min, 5% O2) and 30 min post-hypoxia. PN pups had reduced BL ν̇ E (p<0.05) but greater increases in ν̇ E during hypoxia (p<0.05). Post-hypoxia ν̇ E (i.e. LTF) showed an age × treatment interaction (p<0.01) with similar values at P9-11 but enhanced LTF in saline (30±8 %BL) vs. PN pups (6±5 %BL; p=0.01) at P15-17. We conclude that the post-natal developmental time course of hypoxia-induced LTF is influenced by PN. PMID:19818419

  3. Ethanol Exposure Alters Protein Expression in a Mouse Model of Fetal Alcohol Spectrum Disorders

    PubMed Central

    Mason, Stephen; Anthony, Bruce; Lai, Xianyin; Ringham, Heather N.; Wang, Mu; Witzmann, Frank A.; You, Jin-Sam; Zhou, Feng C.

    2012-01-01

    Alcohol exposure during development can result in variable growth retardation and facial dysmorphology known as fetal alcohol spectrum disorders. Although the mechanisms underlying the disorder are not fully understood, recent progress has been made that alcohol induces aberrant changes in gene expression and in the epigenome of embryos. To inform the gene and epigenetic changes in alcohol-induced teratology, we used whole-embryo culture to identify the alcohol-signature protein profile of neurulating C6 mice. Alcohol-treated and control cultures were homogenized, isoelectrically focused, and loaded for 2D gel electrophoresis. Stained gels were cross matched with analytical software. We identified 40 differentially expressed protein spots (P < 0.01), and 9 spots were selected for LC/MS-MS identification. Misregulated proteins include serotransferrin, triosephosphate isomerase and ubiquitin-conjugating enzyme E2 N. Misregulation of serotransferrin and triosephosphate isomerase was confirmed with immunologic analysis. Alteration of proteins with roles in cellular function, cell cycle, and the ubiquitin-proteasome pathway was induced by alcohol. Several misregulated proteins interact with effectors of the NF-κB and Myc transcription factor cascades. Using a whole-embryo culture, we have identified misregulated proteins known to be involved in nervous system development and function. PMID:22745907

  4. Acute exposure to pure cylindrospermopsin results in oxidative stress and pathological alterations in tilapia (Oreochromis niloticus).

    PubMed

    Puerto, María; Jos, Angeles; Pichardo, Silvia; Moyano, Rosario; Blanco, Alfonso; Cameán, Ana M

    2014-04-01

    Cylindrospermopsin (CYN) is increasingly recognized as a potential threat to drinking water safety, due to its ubiquity. This cyanotoxin has been found to cause toxic effects in mammals, and although fish could be in contact with this toxin, acute toxicity studies on fish are nonexistent. This is the first study showing that single doses of CYN pure standard (200 or 400 μg CYN/kg fish bw) by oral route (gavage) generate histopathological effects in fish (Tilapia-Oreochromis niloticus) exposed to the toxin under laboratory condition. Among the morphological changes, disorganized parenchymal architecture in the liver, dilated Bowman's space in the kidney, fibrolysis in the heart, necrotic enteritis in the intestines, and hemorrhages in the gills, were observed. Moreover, some oxidative stress biomarkers in the liver and kidney of tilapias were altered. Thus, CYN exposure induced increased protein oxidation products in both organs, NADPH oxidase activity was significantly increased with the kidney being the most affected organ, and decreased GSH contents were also detected in both organs, at the higher dose assayed. PMID:22331699

  5. Characterization of proteome alterations in Phanerochaete chrysosporium in response to lead exposure

    PubMed Central

    2011-01-01

    Background Total soluble proteome alterations of white rot fungus Phanerochaete chrysosporium in response to different doses (25, 50 and 100 μM) of Pb (II) were characterized by 2DE in combination with MALDI-TOF-MS. Results Dose-dependent molecular response to Pb (II) involved a total of 14 up-regulated and 21 down-regulated proteins. The induction of an isoform of glyceraldehyde 3-phosphate dehydrogenase, alcohol dehydrogenase class V, mRNA splicing factor, ATP-dependent RNA helicase, thioredoxin reductase and actin required a Pb (II) dose of at least 50 μM. Analysis of the proteome dynamics of mid-exponential phase cells of P. chrysosporium subjected to 50 μM lead at exposure time intervals of 1, 2, 4 and 8 h, identified a total of 23 proteins in increased and 67 proteins in decreased amount. Overall, the newly induced/strongly up-regulated proteins involved in (i) amelioration of lipid peroxidation products, (ii) defense against oxidative damage and redox metabolism, (iii) transcription, recombination and DNA repair (iv) a yet unknown function represented by a putative protein. Conclusion The present study implicated the particular role of the elements of DNA repair, post-tanscriptional regulation and heterotrimeric G protein signaling in response to Pb (II) stress as shown for the first time for a basidiomycete. PMID:21388532

  6. Long-term in vivo polychlorinated biphenyl 126 exposure induces oxidative stress and alters proteomic profile on islets of Langerhans

    PubMed Central

    Loiola, Rodrigo Azevedo; dos Anjos, Fabyana Maria; Shimada, Ana Lúcia; Cruz, Wesley Soares; Drewes, Carine Cristiane; Rodrigues, Stephen Fernandes; Cardozo, Karina Helena Morais; Carvalho, Valdemir Melechco; Pinto, Ernani; Farsky, Sandra Helena

    2016-01-01

    It has been recently proposed that exposure to polychlorinated biphenyls (PCBs) is a risk factor to type 2 diabetes mellitus (DM2). We investigated this hypothesis using long-term in vivo PCB126 exposure to rats addressing metabolic, cellular and proteomic parameters. Male Wistar rats were exposed to PCB126 (0.1, 1 or 10 μg/kg of body weight/day; for 15 days) or vehicle by intranasal instillation. Systemic alterations were quantified by body weight, insulin and glucose tolerance, and blood biochemical profile. Pancreatic toxicity was measured by inflammatory parameters, cell viability and cycle, free radical generation, and proteomic profile on islets of Langerhans. In vivo PCB126 exposure enhanced the body weight gain, impaired insulin sensitivity, reduced adipose tissue deposit, and elevated serum triglycerides, cholesterol, and insulin levels. Inflammatory parameters in the pancreas and cell morphology, viability and cycle were not altered in islets of Langerhans. Nevertheless, in vivo PCB126 exposure increased free radical generation and modified the expression of proteins related to oxidative stress on islets of Langerhans, which are indicative of early β-cell failure. Data herein obtained show that long-term in vivo PCB126 exposure through intranasal route induced alterations on islets of Langerhans related to early end points of DM2. PMID:27292372

  7. Long-term in vivo polychlorinated biphenyl 126 exposure induces oxidative stress and alters proteomic profile on islets of Langerhans.

    PubMed

    Loiola, Rodrigo Azevedo; Dos Anjos, Fabyana Maria; Shimada, Ana Lúcia; Cruz, Wesley Soares; Drewes, Carine Cristiane; Rodrigues, Stephen Fernandes; Cardozo, Karina Helena Morais; Carvalho, Valdemir Melechco; Pinto, Ernani; Farsky, Sandra Helena

    2016-01-01

    It has been recently proposed that exposure to polychlorinated biphenyls (PCBs) is a risk factor to type 2 diabetes mellitus (DM2). We investigated this hypothesis using long-term in vivo PCB126 exposure to rats addressing metabolic, cellular and proteomic parameters. Male Wistar rats were exposed to PCB126 (0.1, 1 or 10 μg/kg of body weight/day; for 15 days) or vehicle by intranasal instillation. Systemic alterations were quantified by body weight, insulin and glucose tolerance, and blood biochemical profile. Pancreatic toxicity was measured by inflammatory parameters, cell viability and cycle, free radical generation, and proteomic profile on islets of Langerhans. In vivo PCB126 exposure enhanced the body weight gain, impaired insulin sensitivity, reduced adipose tissue deposit, and elevated serum triglycerides, cholesterol, and insulin levels. Inflammatory parameters in the pancreas and cell morphology, viability and cycle were not altered in islets of Langerhans. Nevertheless, in vivo PCB126 exposure increased free radical generation and modified the expression of proteins related to oxidative stress on islets of Langerhans, which are indicative of early β-cell failure. Data herein obtained show that long-term in vivo PCB126 exposure through intranasal route induced alterations on islets of Langerhans related to early end points of DM2. PMID:27292372

  8. Long-term in vivo polychlorinated biphenyl 126 exposure induces oxidative stress and alters proteomic profile on islets of Langerhans

    NASA Astrophysics Data System (ADS)

    Loiola, Rodrigo Azevedo; Dos Anjos, Fabyana Maria; Shimada, Ana Lúcia; Cruz, Wesley Soares; Drewes, Carine Cristiane; Rodrigues, Stephen Fernandes; Cardozo, Karina Helena Morais; Carvalho, Valdemir Melechco; Pinto, Ernani; Farsky, Sandra Helena

    2016-06-01

    It has been recently proposed that exposure to polychlorinated biphenyls (PCBs) is a risk factor to type 2 diabetes mellitus (DM2). We investigated this hypothesis using long-term in vivo PCB126 exposure to rats addressing metabolic, cellular and proteomic parameters. Male Wistar rats were exposed to PCB126 (0.1, 1 or 10 μg/kg of body weight/day; for 15 days) or vehicle by intranasal instillation. Systemic alterations were quantified by body weight, insulin and glucose tolerance, and blood biochemical profile. Pancreatic toxicity was measured by inflammatory parameters, cell viability and cycle, free radical generation, and proteomic profile on islets of Langerhans. In vivo PCB126 exposure enhanced the body weight gain, impaired insulin sensitivity, reduced adipose tissue deposit, and elevated serum triglycerides, cholesterol, and insulin levels. Inflammatory parameters in the pancreas and cell morphology, viability and cycle were not altered in islets of Langerhans. Nevertheless, in vivo PCB126 exposure increased free radical generation and modified the expression of proteins related to oxidative stress on islets of Langerhans, which are indicative of early β-cell failure. Data herein obtained show that long-term in vivo PCB126 exposure through intranasal route induced alterations on islets of Langerhans related to early end points of DM2.

  9. Inhalation exposure of rats to asphalt fumes generated at paving temperatures alters pulmonary xenobiotic metabolism pathways without lung injury.

    PubMed Central

    Ma, Jane Y C; Rengasamy, Apavoo; Frazer, Dave; Barger, Mark W; Hubbs, Ann F; Battelli, Lori; Tomblyn, Seith; Stone, Samuel; Castranova, Vince

    2003-01-01

    Asphalt fumes are complex mixtures of various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). PAHs require bioactivation by the cytochrome P-450 monooxygenase system to exert toxic/carcinogenic effects. The present study was carried out to characterize the acute pulmonary inflammatory responses and the alterations of pulmonary xenobiotic pathways in rats exposed to asphalt fumes by inhalation. Rats were exposed at various doses and time periods to air or to asphalt fumes generated at paving temperatures. To assess the acute damage and inflammatory responses, differential cell counts, acellular lactate dehydrogenase (LDH) activity, and protein content of bronchoalveolar lavage fluid were determined. Alveolar macrophage (AM) function was assessed by monitoring generation of chemiluminescence and production of tumor necrosis factor-alpha and interleukin-1. Alteration of pulmonary xenobiotic pathways was determined by monitoring the protein levels and activities of P-450 isozymes (CYP1A1 and CYP2B1), glutathioneS-transferase (GST), and NADPH:quinone oxidoreductase (QR). The results show that acute asphalt fume exposure did not cause neutrophil infiltration, alter LDH activity or protein content, or affect AM function, suggesting that short-term asphalt fume exposure did not induce acute lung damage or inflammation. However, acute asphalt fume exposure significantly increased the activity and protein level of CYP1A1 whereas it markedly reduced the activity and protein level of CYP2B1 in the lung. The induction of CYP1A1 was localized in nonciliated bronchiolar epithelial (Clara) cells, alveolar septa, and endothelial cells by immunofluorescence microscopy. Cytosolic QR activity was significantly elevated after asphalt fume exposure, whereas GST activity was not affected by the exposure. This induction of CYP1A1 and QR with the concomitant down-regulation of CYP2B1 after asphalt fume exposure could alter PAH metabolism and may lead to potential

  10. Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation.

    PubMed

    Szutorisz, Henrietta; DiNieri, Jennifer A; Sweet, Eric; Egervari, Gabor; Michaelides, Michael; Carter, Jenna M; Ren, Yanhua; Miller, Michael L; Blitzer, Robert D; Hurd, Yasmin L

    2014-05-01

    Recent attention has been focused on the long-term impact of cannabis exposure, for which experimental animal studies have validated causal relationships between neurobiological and behavioral alterations during the individual's lifetime. Here, we show that adolescent exposure to Δ(9)-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, results in behavioral and neurobiological abnormalities in the subsequent generation of rats as a consequence of parental germline exposure to the drug. Adult F1 offspring that were themselves unexposed to THC displayed increased work effort to self-administer heroin, with enhanced stereotyped behaviors during the period of acute heroin withdrawal. On the molecular level, parental THC exposure was associated with changes in the mRNA expression of cannabinoid, dopamine, and glutamatergic receptor genes in the striatum, a key component of the neuronal circuitry mediating compulsive behaviors and reward sensitivity. Specifically, decreased mRNA and protein levels, as well as NMDA receptor binding were observed in the dorsal striatum of adult offspring as a consequence of germline THC exposure. Electrophysiologically, plasticity was altered at excitatory synapses of the striatal circuitry that is known to mediate compulsive and goal-directed behaviors. These findings demonstrate that parental history of germline THC exposure affects the molecular characteristics of the striatum, can impact offspring phenotype, and could possibly confer enhanced risk for psychiatric disorders in the subsequent generation. PMID:24385132

  11. Prenatal diazepam exposure alters respiratory control system and GABAA and adenosine receptor gene expression in newborn rats.

    PubMed

    Picard, Nathalie; Guénin, Stéphanie; Perrin, Yolande; Hilaire, Gérard; Larnicol, Nicole

    2008-07-01

    In experimental animals, prenatal diazepam exposure has clearly been associated with behavioral disturbances. Its impact on newborn breathing has not been documented despite potential deleterious consequences for later brain development. We addressed this issue in neonatal rats (0-2 d) born from dams, which consumed 2 mg/kg/d diazepam via drinking fluid throughout gestation. In vivo, prenatal diazepam exposure significantly altered the normoxic-breathing pattern, lowering breathing frequency (105 vs. 125 breaths/min) and increasing tidal volume (16.2 vs. 12.7 mL/kg), and the ventilatory response to hypoxia, inducing an immediate and marked decrease in tidal volume (-30%) absent in controls. In vitro, prenatal diazepam exposure significantly increased the respiratory-like frequency produced by pontomedullary and medullary preparations (+38% and +19%, respectively) and altered the respiratory-like response to application of nonoxygenated superfusate. Both in vivo and in vitro, the recovery from oxygen deprivation challenges was delayed by prenatal diazepam exposure. Finally, real-time PCR showed that prenatal diazepam exposure affected mRNA levels of alpha1 and alpha2 GABAA receptor subunits and of A1 and A2A adenosine receptors in the brainstem. These mRNA changes, which are region-specific, suggest that prenatal diazepam exposure interferes with developmental events whose impact on the respiratory system maturation deserves further studies. PMID:18360306

  12. Binge Toluene Exposure Alters Glutamate, Glutamine and GABA in the Adolescent Rat Brain as Measured by Proton Magnetic Resonance Spectroscopy*

    PubMed Central

    Perrine, Shane A.; O'Leary-Moore, Shonagh K.; Galloway, Matthew P.; Hannigan, John H.; Bowen, Scott E.

    2010-01-01

    Despite the high incidence of toluene abuse in adolescents, little is known regarding the effect of binge exposure on neurochemical profiles during this developmental stage. In the current study, the effects of binge toluene exposure during adolescence on neurotransmitter levels were determined using high-resolution proton magnetic resonance spectroscopy ex vivo at 11.7 T. Adolescent male Sprague-Dawley rats were exposed to toluene (0, 8,000 , or 12,000 ppm) for 15 min twice daily from postnatal day 28 (P28) through P34 and then euthanized either one or seven days later (on P35 or P42) to assess glutamate, glutamine, and GABA levels in intact tissue punches from the medial prefrontal cortex (mPFC), anterior striatum and hippocampus. In the mPFC, toluene reduced glutamate one day after exposure, with no effect on GABA, while after seven days, glutamate was no longer affected but there was an increase in GABA levels. In the hippocampus, neither GABA nor glutamate was altered one day after exposure, whereas seven days after exposure, increases were observed in GABA and glutamate. Striatal glutamate and GABA levels measured after either one or seven days were not altered after toluene exposure. These findings show that one week of binge toluene inhalation selectively alters these neurotransmitters in the mPFC and hippocampus in adolescent rats, and that some of these effects endure at least one week after the exposure. The results suggest that age-dependent, differential neurochemical responses to toluene may contribute to the unique behavioral patterns associated with drug abuse among older children and young teens. PMID:21126832

  13. Association between occupational exposure to benzene and chromosomal alterations in lymphocytes of Brazilian petrochemical workers removed from exposure.

    PubMed

    Gonçalves, Rozana Oliveira; de Almeida Melo, Neli; Rêgo, Marco Antônio Vasconcelos

    2016-06-01

    We aimed to investigate the association between chronic exposure to benzene and genotoxicity in the lymphocytes of workers removed from exposure. The study included 20 workers with hematological disorders who had previously worked in the petrochemical industry of Salvador, Bahia, Brazil; 16 workers without occupational exposure to benzene served as the control group. Chromosomal analysis was performed on lymphocytes from peripheral blood, to assess chromosomal breaks and gaps and to identify aneuploidy. The Kruskal-Wallis test was used to compare the mean values between two groups, and Student's t test for comparison of two independent means. The frequency of gaps was statistically higher in and the exposed group than in the controls (2.13 ± 2.86 vs. 0.97 ± 1.27, p = 0.001). The frequency of chromosomal breaks was significantly higher among cases (0.21 ± 0.58) than among controls (0.12 ± 0.4) (p = 0.0002). An association was observed between chromosomal gaps and breaks and occupational exposure to benzene. Our study showed that even when removed from exposure for several years, workers still demonstrated genotoxic damage. Studies are still needed to clarify the long-term genotoxic potential of benzene after removal from exposure. PMID:27155858

  14. Alteration of Bacterial Antibiotic Sensitivity After Short-Term Exposure to Diagnostic Ultrasound

    PubMed Central

    Mortazavi, Seyed Mohammad Javad; Darvish, Leili; Abounajmi, Mohammad; Zarei, Samira; Zare, Tahereh; Taheri, Mohammad; Nematollahi, Samaneh

    2015-01-01

    inhibition zones in exposed and non-exposed samples of Klebsiella pneumonia and Streptococcus. Conclusions This study clearly shows that short-term exposure of microorganisms to diagnostic ultrasonic waves can significantly alter their sensitivity to antibiotics. We believe that this physical method of making the antibiotic-resistant population susceptible can open new horizons in antibiotic therapy of a broad range of diseases, including tuberculosis. PMID:26732124

  15. Acute Exposure to Microcystin-Producing Cyanobacterium Microcystis aeruginosa Alters Adult Zebrafish (Danio rerio) Swimming Performance Parameters

    PubMed Central

    Kist, Luiza Wilges; Piato, Angelo Luis; da Rosa, João Gabriel Santos; Koakoski, Gessi; Barcellos, Leonardo José Gil; Yunes, João Sarkis; Bonan, Carla Denise; Bogo, Maurício Reis

    2011-01-01

    Microcystins (MCs) are toxins produced by cyanobacteria (blue-green algae), primarily Microcystis aeruginosa, forming water blooms worldwide. When an organism is exposed to environmental perturbations, alterations in normal behavioral patterns occur. Behavioral repertoire represents the consequence of a diversity of physiological and biochemical alterations. In this study, we assessed behavioral patterns and whole-body cortisol levels of adult zebrafish (Danio rerio) exposed to cell culture of the microcystin-producing cyanobacterium M. aeruginosa (MC-LR, strain RST9501). MC-LR exposure (100 μg/L) decreased by 63% the distance traveled and increased threefold the immobility time when compared to the control group. Interestingly, no significant alterations in the number of line crossings were found at the same MC-LR concentration and time of exposure. When animals were exposed to 50 and 100 μg/L, MC-LR promoted a significant increase (around 93%) in the time spent in the bottom portion of the tank, suggesting an anxiogenic effect. The results also showed that none of the MC-LR concentrations tested promoted significant alterations in absolute turn angle, path efficiency, social behavior, or whole-body cortisol level. These findings indicate that behavior is susceptible to MC-LR exposure and provide evidence for a better understanding of the ecological consequences of toxic algal blooms. PMID:22253623

  16. An embryonic atrazine exposure results in reproductive dysfunction in adult zebrafish and morphological alterations in their offspring.

    PubMed

    Wirbisky, Sara E; Weber, Gregory J; Sepúlveda, Maria S; Lin, Tsang-Long; Jannasch, Amber S; Freeman, Jennifer L

    2016-01-01

    The herbicide atrazine, a suspected endocrine disrupting chemical (EDC), frequently contaminates potable water supplies. Studies suggest alterations in the neuroendocrine system along the hypothalamus-pituitary-gonadal axis; however, most studies address either developmental, pubertal, or adulthood exposures, with few investigations regarding a developmental origins hypothesis. In this study, zebrafish were exposed to 0, 0.3, 3, or 30 parts per billion (ppb) atrazine through embryogenesis and then allowed to mature with no additional chemical exposure. Reproductive function, histopathology, hormone levels, offspring morphology, and the ovarian transcriptome were assessed. Embryonic atrazine exposure resulted in a significant increase in progesterone levels in the 3 and 30 ppb groups. A significant decrease in spawning and a significant increase in follicular atresia in the 30 ppb group were observed. In offspring, a decrease in the head length to body ratio in the 30 ppb group, along with a significant increase in head width to body ratio in the 0.3 and 3 ppb groups occurred. Transcriptomic alterations involved genes associated with endocrine system development and function, tissue development, and behavior. This study provides evidence to support atrazine as an EDC causing reproductive dysfunction and molecular alterations in adults exposed only during embryogenesis and morphological alterations in their offspring. PMID:26891955

  17. An embryonic atrazine exposure results in reproductive dysfunction in adult zebrafish and morphological alterations in their offspring

    PubMed Central

    Wirbisky, Sara E.; Weber, Gregory J.; Sepúlveda, Maria S.; Lin, Tsang-Long; Jannasch, Amber S.; Freeman, Jennifer L.

    2016-01-01

    The herbicide atrazine, a suspected endocrine disrupting chemical (EDC), frequently contaminates potable water supplies. Studies suggest alterations in the neuroendocrine system along the hypothalamus-pituitary-gonadal axis; however, most studies address either developmental, pubertal, or adulthood exposures, with few investigations regarding a developmental origins hypothesis. In this study, zebrafish were exposed to 0, 0.3, 3, or 30 parts per billion (ppb) atrazine through embryogenesis and then allowed to mature with no additional chemical exposure. Reproductive function, histopathology, hormone levels, offspring morphology, and the ovarian transcriptome were assessed. Embryonic atrazine exposure resulted in a significant increase in progesterone levels in the 3 and 30 ppb groups. A significant decrease in spawning and a significant increase in follicular atresia in the 30 ppb group were observed. In offspring, a decrease in the head length to body ratio in the 30 ppb group, along with a significant increase in head width to body ratio in the 0.3 and 3 ppb groups occurred. Transcriptomic alterations involved genes associated with endocrine system development and function, tissue development, and behavior. This study provides evidence to support atrazine as an EDC causing reproductive dysfunction and molecular alterations in adults exposed only during embryogenesis and morphological alterations in their offspring. PMID:26891955

  18. Honey Bee Gut Microbiome Is Altered by In-Hive Pesticide Exposures.

    PubMed

    Kakumanu, Madhavi L; Reeves, Alison M; Anderson, Troy D; Rodrigues, Richard R; Williams, Mark A

    2016-01-01

    Honey bees (Apis mellifera) are the primary pollinators of major horticultural crops. Over the last few decades, a substantial decline in honey bees and their colonies have been reported. While a plethora of factors could contribute to the putative decline, pathogens, and pesticides are common concerns that draw attention. In addition to potential direct effects on honey bees, indirect pesticide effects could include alteration of essential gut microbial communities and symbionts that are important to honey bee health (e.g., immune system). The primary objective of this study was to determine the microbiome associated with honey bees exposed to commonly used in-hive pesticides: coumaphos, tau-fluvalinate, and chlorothalonil. Treatments were replicated at three independent locations near Blacksburg Virginia, and included a no-pesticide amended control at each location. The microbiome was characterized through pyrosequencing of V2-V3 regions of the bacterial 16S rRNA gene and fungal ITS region. Pesticide exposure significantly affected the structure of bacterial but not fungal communities. The bee bacteriome, similar to other studies, was dominated by sequences derived from Bacilli, Actinobacteria, α-, β-, γ-proteobacteria. The fungal community sequences were dominated by Ascomycetes and Basidiomycetes. The Multi-response permutation procedures (MRPP) and subsequent Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis indicated that chlorothalonil caused significant change to the structure and functional potential of the honey bee gut bacterial community relative to control. Putative genes for oxidative phosphorylation, for example, increased while sugar metabolism and peptidase potential declined in the microbiome of chlorothalonil exposed bees. The results of this field-based study suggest the potential for pesticide induced changes to the honey bee gut microbiome that warrant further investigation. PMID:27579024

  19. Honey Bee Gut Microbiome Is Altered by In-Hive Pesticide Exposures

    PubMed Central

    Kakumanu, Madhavi L.; Reeves, Alison M.; Anderson, Troy D.; Rodrigues, Richard R.; Williams, Mark A.

    2016-01-01

    Honey bees (Apis mellifera) are the primary pollinators of major horticultural crops. Over the last few decades, a substantial decline in honey bees and their colonies have been reported. While a plethora of factors could contribute to the putative decline, pathogens, and pesticides are common concerns that draw attention. In addition to potential direct effects on honey bees, indirect pesticide effects could include alteration of essential gut microbial communities and symbionts that are important to honey bee health (e.g., immune system). The primary objective of this study was to determine the microbiome associated with honey bees exposed to commonly used in-hive pesticides: coumaphos, tau-fluvalinate, and chlorothalonil. Treatments were replicated at three independent locations near Blacksburg Virginia, and included a no-pesticide amended control at each location. The microbiome was characterized through pyrosequencing of V2–V3 regions of the bacterial 16S rRNA gene and fungal ITS region. Pesticide exposure significantly affected the structure of bacterial but not fungal communities. The bee bacteriome, similar to other studies, was dominated by sequences derived from Bacilli, Actinobacteria, α-, β-, γ-proteobacteria. The fungal community sequences were dominated by Ascomycetes and Basidiomycetes. The Multi-response permutation procedures (MRPP) and subsequent Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis indicated that chlorothalonil caused significant change to the structure and functional potential of the honey bee gut bacterial community relative to control. Putative genes for oxidative phosphorylation, for example, increased while sugar metabolism and peptidase potential declined in the microbiome of chlorothalonil exposed bees. The results of this field-based study suggest the potential for pesticide induced changes to the honey bee gut microbiome that warrant further investigation. PMID:27579024

  20. Developmental exposure to chlorpyrifos alters reactivity to environmental and social cues in adolescent mice.

    PubMed

    Ricceri, Laura; Markina, Nadja; Valanzano, Angela; Fortuna, Stefano; Cometa, Maria Francesca; Meneguz, Annarita; Calamandrei, Gemma

    2003-09-15

    Neonatal mice were treated daily on postnatal days (pnds) 1 through 4 or 11 through 14 with the organophosphate pesticide chlorpyrifos (CPF), at doses (1 or 3 mg/kg) that do not evoke systemic toxicity. Brain acetylcholinesterase (AChE) activity was evaluated within 24 h from termination of treatments. Pups treated on pnds 1-4 underwent ultrasonic vocalization tests (pnds 5, 8, and 11) and a homing test (orientation to home nest material, pnd 10). Pups in both treatment schedules were then assessed for locomotor activity (pnd 25), novelty-seeking response (pnd 35), social interactions with an unfamiliar conspecific (pnd 45), and passive avoidance learning (pnd 60). AChE activity was reduced by 25% after CPF 1-4 but not after CPF 11-14 treatment. CPF selectively affected only the G(4) (tetramer) molecular isoform of AChE. Behavioral analysis showed that early CPF treatment failed to affect neonatal behaviors. Locomotor activity on pnd 25 was increased in 11-14 CPF-treated mice at both doses, and CPF-treated animals in both treatment schedules were more active when exposed to environmental novelty in the novelty-seeking test. All CPF-treated mice displayed more agonistic responses, and such effect was more marked in male mice exposed to the low CPF dose on pnds 11-14. Passive avoidance learning was not affected by CPF. These data indicate that developmental exposure to CPF induces long-term behavioral alterations in the mouse species and support the involvement of neural systems in addition to the cholinergic system in the delayed behavioral toxicity of CPF. PMID:13678652

  1. ONTOGENETIC ALTERATIONS IN MOLECULAR AND STRUCTURAL CORRELATES OF DENDRITIC GROWTH FOLLOWING DEVELOPMENTAL EXPOSURE TO POLYCHLORINATED BIPHENYLS.

    EPA Science Inventory

    This is the first report showing both molecular and structural changes in brain following developmental exposure to a neurotoxicant. It is known that perinatal exposure to a neurotoxicant, polychlorinated biphenyls (PCBs), is associated with decreased IQ scores, impaired learnin...

  2. Associations between personal exposures to VOCs and alterations in cardiovascular physiology: Detroit Exposure and Aerosol Research Study (DEARS) - presentation

    EPA Science Inventory

    Introduction: An adult cohort consisting of 63 participants engaged in the US EPA’s recent Detroit Exposure and Aerosol Research Study (DEARS) and a University of Michigan cardiovascular sub-study conducted during summer and winter periods over 3 years between 2004 and 2007...

  3. Associations between Personal Exposures to VOCs and Alterations in Cardiovascular Physiology: Detroit Exposure and Aerosol Research Study (DEARS)

    EPA Science Inventory

    Background: An adult cohort consisting of 63 participants engaged in the US EPA’s recent Detroit Exposure and Aerosol Research Study (DEARS) and a University of Michigan cardiovascular sub-study conducted during summer and winter periods over 3 years between 2004 and 2007 (5 seas...

  4. Exposure to ozone reduces influenza disease severity and alters distribution of influenza viral antigens in murine lungs.

    PubMed

    Wolcott, J A; Zee, Y C; Osebold, J W

    1982-09-01

    Exposure to ambient levels of ozone (0.5 ppm) was shown to alter the pathogenesis of respiratory infection after aerosol infection of mice with influenza A virus. A semiquantitative method for determination of the sites of virus replication by direct immunofluorescence indicated that exposure to ozone reduced the involvement of respiratory epithelium in the infectious process and resulted in a less widespread infection of the alveolar parenchyma. Furthermore, the ozone-mediated alteration in viral antigen distribution was consistent with significantly reduced influenza disease mortality and prolonged survival time, but only when the oxidant was present during the course of infection. Reduced disease severity in ozone-exposed animals appeared to be independent of peak pulmonary virus titers, pulmonary interferon titers, and pulmonary and serum-neutralizing antibody titers. These studies suggested that the distribution of influenza virus in the murine lung was a key factor in disease severity. PMID:6182839

  5. In vivo hydroquinone exposure alters circulating neutrophil activities and impairs LPS-induced lung inflammation in mice.

    PubMed

    Ribeiro, André Luiz Teroso; Shimada, Ana Lúcia Borges; Hebeda, Cristina Bichels; de Oliveira, Tiago Franco; de Melo Loureiro, Ana Paula; Filho, Walter Dos Reis Pereira; Santos, Alcinéa Meigikos Dos Anjos; de Lima, Wothan Tavares; Farsky, Sandra Helena Poliselli

    2011-10-01

    Hydroquinone (HQ) is an environmental contaminant which causes immune toxicity. In this study, the effects of exposure to low doses of HQ on neutrophil mobilization into the LPS-inflamed lung were investigated. Male Swiss mice were exposed to aerosolized vehicle (control) or 12.5, 25 or 50ppm HQ (1h/day for 5 days). One hour later, oxidative burst, cell cycle, DNA fragmentation and adhesion molecules expressions in circulating neutrophils were determined by flow cytometry, and plasma malondialdehyde (MDA) levels were measured by HPLC. Also, 1h later the last exposures, inflammation was induced by LPS inhalation (0.1mg/ml/10min) and 3h later, the numbers of leukocytes in peripheral blood and in the bronchoalveolar lavage fluid (BALF) were determined using a Neubauer chamber and stained smears; adhesion molecules expressed on lung microvessel endothelial cells were quantified by immunohistochemistry; myeloperoxidase (MPO) activity was measured in the lung tissue by colorimetric assay; and cytokines in the BALF were determined by ELISA. In vivo HQ exposure augmented plasma MDA levels and oxidative activity of neutrophils, but did not cause alterations in cell cycle and DNA fragmentation. Under these conditions, the number of circulating leukocytes was not altered, but HQ exposure reduced LPS-induced neutrophil migration into the alveolar space, as these cells remained in the lung tissue. The impaired neutrophil migration into BALF may not be dependent on reduced cytokines secretions in the BALF and lung endothelial adhesion molecules expressions. However, HQ exposure increased the expression of β(2) and β(3) integrins and platelet-endothelial cell adhesion molecule-1 (PECAM-1) in neutrophils, which were not further enhanced by fMLP in vitro stimulation, indicating that HQ exposure activates circulating neutrophils, impairing further stimulatory responses. Therefore, it has been shown, for the first time, that neutrophils are target of lower levels of in vivo HQ

  6. Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons

    PubMed Central

    de Salas-Quiroga, Adán; Díaz-Alonso, Javier; García-Rincón, Daniel; Remmers, Floortje; Vega, David; Gómez-Cañas, María; Lutz, Beat; Guzmán, Manuel; Galve-Roperh, Ismael

    2015-01-01

    The CB1 cannabinoid receptor, the main target of Δ9-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling. PMID:26460022

  7. Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.

    PubMed

    de Salas-Quiroga, Adán; Díaz-Alonso, Javier; García-Rincón, Daniel; Remmers, Floortje; Vega, David; Gómez-Cañas, María; Lutz, Beat; Guzmán, Manuel; Galve-Roperh, Ismael

    2015-11-01

    The CB1 cannabinoid receptor, the main target of Δ(9)-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling. PMID:26460022

  8. Tissue and cellular alterations in Asian clam (Potamocorbula amurensis) from San Francisco Bay: toxicological indicators of exposure and effect?

    PubMed

    Clark, S L; Teh, S J; Hinton, D E

    2000-01-01

    The US Geological Survey has reported the presence of a metal contamination gradient in clam tissues, decreased condition indices, and irregular reproductive patterns have been reported in the Asian clam, Potamocorbula amurensis, from San Francisco Bay. If metals are driving the observed patterns in the field, then biomarkers of exposure, and possibly deleterious effect, should show a corresponding gradient. In this study, biomarkers from sub-cellular to tissue levels of biological organization were assessed in P. amurensis collected from the Bay or exposed to cadmium in the laboratory. Cellular and tissue alterations were assessed using histopathology and enzyme histochemistry (EH). Alterations in the ovary, testis, kidney, and gill tissues were most common at the most contaminated station when data were averaged over a 12-month sampling period. EH analysis indicated decreased active transport, energy status, and glucose oxidation in kidney and digestive gland at the most contaminated site which may indicate a decreased potential for growth. Ovarian lesions observed in feral Asian clams were experimentally induced in healthy clams by cadmium exposure in laboratory exposures. Our results suggest a contaminant etiology for tissue alterations. PMID:11460709

  9. Postnatal manganese exposure alters dopamine transporter function in adult rats: Potential impact on nonassociative and associative processes.

    PubMed

    McDougall, S A; Reichel, C M; Farley, C M; Flesher, M M; Der-Ghazarian, T; Cortez, A M; Wacan, J J; Martinez, C E; Varela, F A; Butt, A E; Crawford, C A

    2008-06-23

    In the present study, we examined whether exposing rats to a high-dose regimen of manganese chloride (Mn) during the postnatal period would depress presynaptic dopamine functioning and alter nonassociative and associative behaviors. To this end, rats were given oral supplements of Mn (750 microg/day) on postnatal days (PD) 1-21. On PD 90, dopamine transporter (DAT) immunoreactivity and [3H]dopamine uptake were assayed in the striatum and nucleus accumbens, while in vivo microdialysis was used to measure dopamine efflux in the same brain regions. The effects of postnatal Mn exposure on nigrostriatal functioning were evaluated by assessing rotorod performance and amphetamine-induced stereotypy in adulthood. In terms of associative processes, both cocaine-induced conditioned place preference (CPP) and sucrose-reinforced operant responding were examined. Results showed that postnatal Mn exposure caused persistent declines in DAT protein expression and [3H]dopamine uptake in the striatum and nucleus accumbens, as well as long-term reductions in striatal dopamine efflux. Rotorod performance did not differ according to exposure condition, however Mn-exposed rats did exhibit substantially more amphetamine-induced stereotypy than vehicle controls. Mn exposure did not alter performance on any aspect of the CPP task (preference, extinction, or reinstatement testing), nor did Mn affect progressive ratio responding (a measure of motivation). Interestingly, acquisition of a fixed ratio task was impaired in Mn-exposed rats, suggesting a deficit in procedural learning. In sum, these results indicate that postnatal Mn exposure causes persistent declines in various indices of presynaptic dopaminergic functioning. Mn-induced alterations in striatal functioning may have long-term impact on associative and nonassociative behavior. PMID:18485605

  10. Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

    PubMed Central

    Blossom, Sarah J.; Melnyk, Stepan; Cooney, Craig A.; Gilbert, Kathleen M.; James, S. Jill

    2012-01-01

    Previous studies have shown that continuous exposure throughout gestation until the juvenile period to environmentally-relevant doses of trichloroethylene (TCE) in the drinking water of MRL+/+ mice promoted adverse behavior associated with glutathione depletion in the cerebellum indicating increased sensitivity to oxidative stress. The purpose of this study was to extend our findings and further characterize the impact of TCE exposure on redox homeostasis and biomarkers of oxidative stress in the hippocampus, a brain region prone to oxidative stress. Instead of a continuous exposure, the mice were exposed to water only or two environmentally relevant doses of TCE in the drinking water postnatally from birth until 6 weeks of age. Biomarkers of plasma metabolites in the transsulfuration pathway and the transmethylation pathway of the methionine cycle were also examined. Gene expression of neurotrophins was examined to investigate a possible relationship between oxidative stress, redox imbalance and neurotrophic factor expression with TCE exposure. Our results show that hippocampi isolated from male mice exposed to TCE showed altered glutathione redox homeostasis indicating a more oxidized state. Also observed was a significant, dose dependent increase in glutathione precursors. Plasma from the TCE treated mice showed alterations in metabolites in the transsulfuration and transmethylation pathways indicating redox imbalance and altered methylation capacity. 3-Nitrotyrosine, a biomarker of protein oxidative stress, was also significantly higher in plasma and hippocampus of TCE-exposed mice compared to controls. In contrast, expression of key neurotrophic factors in the hippocampus (BDNF, NGF, and NT-3) was significantly reduced compared to controls. Our results demonstrate that low-level postnatal and early life TCE exposure modulates neurotrophin gene expression in the mouse hippocampus and may provide a mechanism for TCE-mediated neurotoxicity. PMID:22421312

  11. Cannabinoid exposure during zebra finch sensorimotor vocal learning persistently alters expression of endocannabinoid signaling elements and acute agonist responsiveness

    PubMed Central

    2011-01-01

    Background Previously we have found that cannabinoid treatment of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. Such persistently altered behavior must be attributable to changes in physiological substrates responsible for song. We are currently working to identify the nature of such physiological changes, and to understand how they contribute to altered vocal learning. One possibility is that developmental agonist exposure results in altered expression of elements of endocannabinoid signaling systems. To test this hypothesis we have studied effects of the potent cannabinoid receptor agonist WIN55212-2 (WIN) on endocannabinoid levels and densities of CB1 immunostaining in zebra finch brain. Results We found that late postnatal WIN treatment caused a long-term global disregulation of both levels of the endocannabinoid, 2-arachidonyl glycerol (2-AG) and densities of CB1 immunostaining across brain regions, while repeated cannabinoid treatment in adults produced few long-term changes in the endogenous cannabinoid system. Conclusions Our findings indicate that the zebra finch endocannabinoid system is particularly sensitive to exogenous agonist exposure during the critical period of song learning and provide insight into susceptible brain areas. PMID:21211022

  12. Perinatal Lead Exposure Alters Gut Microbiota Composition and Results in Sex-specific Bodyweight Increases in Adult Mice.

    PubMed

    Wu, Jianfeng; Wen, Xiaoquan William; Faulk, Christopher; Boehnke, Kevin; Zhang, Huapeng; Dolinoy, Dana C; Xi, Chuanwu

    2016-06-01

    Heavy metal pollution is a principle source of environmental contamination. Epidemiological and animal data suggest that early life lead (Pb) exposure results in critical effects on epigenetic gene regulation and child and adult weight trajectories. Using a mouse model of human-relevant exposure, we investigated the effects of perinatal Pb exposure on gut microbiota in adult mice, and the link between gut microbiota and bodyweight changes. Following Pb exposure during gestation and lactation via maternal drinking water, bodyweight in A(vy) strain wild-type non-agouti (a/a) offspring was tracked through adulthood. Gut microbiota of adult mice were characterized by deep DNA sequencing of bacterial 16S ribosomal RNA genes. Data analyses were stratified by sex and adjusted for litter effects. A Bayesian variable selection algorithm was used to analyze associations between bacterial operational taxonomic units and offspring adult bodyweight. Perinatal Pb exposure was associated with increased adult bodyweight in male (P < .05) but not in female offspring (P = .24). Cultivable aerobes decreased and anaerobes increased in Pb-exposed offspring (P < .005 and P < .05, respectively). Proportions of the 2 predominant phyla (Bacteroidetes and Firmicutes) shifted inversely with Pb exposure, and whole bacterial compositions were significantly different (analysis of molecular variance, P < .05) by Pb exposure without sex bias. In males, changes in gut microbiota were highly associated with adult bodyweight (P = .028; effect size = 2.59). Thus, perinatal Pb exposure results in altered adult gut microbiota regardless of sex, and these changes are highly correlated with increased bodyweight in males. Adult gut microbiota can be shaped by early exposures and may contribute to disease risks in a sex-specific manner. PMID:26962054

  13. Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

    PubMed Central

    Hiolski, Emma M; Kendrick, Preston S; Frame, Elizabeth R; Myers, Mark S; Bammler, Theo K; Beyer, Richard P; Farin, Federico M; Wilkerson, Hui-wen; Smith, Donald R; Marcinek, David J; Lefebvre, Kathi A

    2014-01-01

    Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: 1) identify transcriptional biomarkers of exposure; and 2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly-variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences. PMID:25033243

  14. Alteration of blood glucose levels in the rat following exposure to hyperbaric oxygen.

    PubMed

    Eynan, Mirit; Mullokandov, Michael; Krinsky, Nitzan; Biram, Adi; Arieli, Yehuda

    2015-09-01

    Findings regarding blood glucose level (BGL) on exposure to hyperbaric oxygen (HBO) are contradictory. We investigated the influence of HBO on BGL, and of BGL on latency to central nervous system oxygen toxicity (CNS-OT). The study was conducted on five groups of rats: Group 1, exposure to oxygen at 2.5 atmospheres absolute (ATA), 90 min/day for 7 days; Group 2, exposure to oxygen once a week from 2 to 6 ATA in increments of 1 ATA/wk, for a period of time calculated as 60% of the latency to CNS-OT (no convulsions); Group 3, exposure to 6 ATA breathing a gas mixture with a pO2 of 0.21; Group 4, received 10 U/kg insulin to induce hypoglycemia before exposure to HBO; Group 5, received 33% glucose to induce hyperglycemia before exposure to HBO. Blood samples were drawn before and after exposures for measurement of BGL. No change was observed in BGL after exposure to oxygen at 2.5 ATA, 90 min/day for 7 days. BGL was significantly elevated after exposure to oxygen at 6 ATA until the appearance of convulsions, and following exposure to 4, 5, and 6 ATA without convulsions (P < 0.01). No change was observed in BGL after exposure to 6 ATA breathing a gas mixture with a pO2 of 0.21. Hypoglycemia shortened latency to CNS oxygen toxicity, whereas hyperglycemia had no effect. Our results demonstrate an influence of HBO exposure on elevation of BGL, starting at 4 ATA. This implies that BGL may serve as a marker for the generation of CNS-OT. PMID:26183474

  15. Altered levels of endocrine biomarkers in juvenile barramundi (Lates calcarifer; Bloch) following exposure to commercial herbicide and surfactant formulations.

    PubMed

    Kroon, Frederieke J; Hook, Sharon E; Metcalfe, Suzanne; Jones, Dean

    2015-08-01

    Agricultural pesticides that are known endocrine disrupting chemicals have been detected in waters in the Great Barrier Reef catchment and lagoon. Altered transcription levels of liver vitellogenin (vtg) have been documented in wild populations of 2 Great Barrier Reef fisheries species and were strongly associated with pesticide-containing runoff from sugarcane plantations. The present study examined endocrine and physiological biomarkers in juvenile barramundi (Lates calcarifer) exposed to environmentally relevant concentrations of commercial herbicide (ATRADEX(®) WG Herbicide, DIUREX(®) WG Herbicide) and surfactant (ACTIVATOR(®) 90) formulations commonly used on sugarcane in the Great Barrier Reef catchment. Estrogenic biomarkers (namely, liver vtg messenger RNA and plasma 17β-estradiol) increased following exposure to commercial mixtures but not to the analytical grade chemical, suggesting an estrogenic response to the additives. In contrast, brain aromatase (cyp19a1b) transcription levels, plasma testosterone and 11-ketotestosterone concentrations, and gill ventilation rates were not affected by any of the experimental exposures. These findings support the assertion that exposure to pesticide-containing runoff from sugarcane plantations is a potential causative agent of altered liver vtg transcription levels in wild barramundi. Whether exposure patterns in the Great Barrier Reef catchment and lagoon are sufficient to impair fish sexual and reproductive development and ultimately influence fish population dynamics remains to be determined. These findings highlight the need to consider both active and so-called inert ingredients in commercial pesticide formulations for environmental risk assessments. PMID:25858168

  16. Alteration of extracellular enzymes in pinto bean leaves upon exposure to air pollutants, ozone and sulfur dioxide

    SciTech Connect

    Peters, J.L.; Castillo, F.J.; Heath, R.L. )

    1989-01-01

    Diamine oxidase and peroxidase, associated with the wall in pinto bean (Phaseolus vulgaris L. var Pinto) leaves, can be washed out by vacuum infiltration and assayed without grinding the leaf. The diamine oxidase activity is inhibited in vivo by exposure of the plants to ozone (dose of 0.6 microliters per liter {times} hour), whereas the peroxidase activity associated with the wall space is stimulated. This dose does not cause obvious necrosis or chlorosis of the leaf. These alterations are greater when the dose of ozone exposure is given as a triangular pulse (a slow rise to a peak of 0.24 microliters per liter followed by a slow fall) compared to that given as a constant square wave pulse of 0.15 microliters per liter for the same 4 hour period. Exposure of the plants to sulfur dioxide (at a concentration of 0.4 microliters per liter for 4 hours) does not result in any change in the diamine oxidase or peroxidase activities, yet the total sulfhydryl content of the leaf is increased, demonstrating the entry of sulfur dioxide. These two pollutants, with different chemical reactivities, affect the activities of the extracellular enzymes in different manners. In the case of ozone exposure, the inhibition of extracellular diamine oxidase could profoundly alter the movements of polyamines from cell to cell.

  17. Fetal Liver Bisphenol A Concentrations and Biotransformation Gene Expression Reveal Variable Exposure and Altered Capacity for Metabolism in Humans

    PubMed Central

    Nahar, Muna S.; Liao, Chunyang; Kannan, Kurunthachalam; Dolinoy, Dana C.

    2013-01-01

    Widespread exposure to the endocrine active compound, bisphenol A (BPA), is well documented in humans. A growing body of literature suggests adverse health outcomes associated with varying ranges of exposure to BPA. In the current study, we measured the internal dose of free BPA and conjugated BPA and evaluated gene expression of bio-transformation enzymes specific for BPA metabolism in 50 first- and second-trimester human fetal liver samples. Both free BPA and conjugated BPA concentrations varied widely, with free BPA exhibiting three times higher concentrations than conjugated BPA concentrations. As compared to gender-matched adult liver controls, UDP-glucuronyltransferase, sulfotransferase, and steroid sulfatase genes exhibited reduced expression whereas β-glucuronidase mRNA expression remained unchanged in the fetal tissues. This study provides evidence that there is considerable exposure to BPA during human pregnancy and that the capacity for BPA metabolism is altered in the human fetal liver. PMID:23208979

  18. Maternal Dexamethasone Exposure Alters Synaptic Inputs to Gonadotropin-Releasing Hormone Neurons in the Early Postnatal Rat

    PubMed Central

    Lim, Wei Ling; Idris, Marshita Mohd; Kevin, Felix Suresh; Soga, Tomoko; Parhar, Ishwar S.

    2016-01-01

    Maternal dexamethasone [(DEX); a glucocorticoid receptor agonist] exposure delays pubertal onset and alters reproductive behavior in the adult offspring. However, little is known whether maternal DEX exposure affects the offspring’s reproductive function by disrupting the gonadotropin-releasing hormone (GnRH) neuronal function in the brain. Therefore, this study determined the exposure of maternal DEX on the GnRH neuronal spine development and synaptic cluster inputs to GnRH neurons using transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of GnRH promoter. Pregnant females were administered with DEX (0.1 mg/kg) or vehicle (VEH, water) daily during gestation day 13–20. Confocal imaging was used to examine the spine density of EGFP–GnRH neurons by three-dimensional rendering and synaptic cluster inputs to EGFP–GnRH neurons by synapsin I immunohistochemistry on postnatal day 0 (P0) males. The spine morphology and number on GnRH neurons did not change between the P0 males following maternal DEX and VEH treatment. The number of synaptic clusters within the organum vasculosum of the lamina terminalis (OVLT) was decreased by maternal DEX exposure in P0 males. Furthermore, the number and levels of synaptic cluster inputs in close apposition with GnRH neurons was decreased following maternal DEX exposure in the OVLT region of P0 males. In addition, the postsynaptic marker molecule, postsynaptic density 95, was observed in GnRH neurons following both DEX and VEH treatment. These results suggest that maternal DEX exposure alters neural afferent inputs to GnRH neurons during early postnatal stage, which could lead to reproductive dysfunction during adulthood.

  19. Low-Dose, Gestational Exposure to Atrazine Does Not Alter Postnatal Reproductive Development of Male Offspring

    EPA Science Inventory

    There is growing evidence that xenobiotic exposure during the perinatal period may result in a variety of adverse outcomes when the developing organism attains adulthood. Maternal stress and subsequent exposure of the fetus to excess glucocorticoids may underlie these effects. Pr...

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

    PubMed Central

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

    2015-01-01

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

  1. Early exposure to intermediate-frequency magnetic fields alters brain biomarkers without histopathological changes in adult mice.

    PubMed

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

    2015-04-01

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

  2. Prenatal Bisphenol A Exposure Alters Sex-Specific Estrogen Receptor Expression in the Neonatal Rat Hypothalamus and Amygdala

    PubMed Central

    Patisaul, Heather B.

    2013-01-01

    Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERα) and ESR2 (ERβ) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6–21 with vehicle, 2.5 or 25 μg/kg bw/day BPA, or 5 or 10 μg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naïve control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naïve control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure. PMID:23457122

  3. Repeated exposure to vicarious pain alters electrocortical processing of pain expressions.

    PubMed

    Coll, Michel-Pierre; Grégoire, Mathieu; Prkachin, Kenneth M; Jackson, Philip L

    2016-09-01

    Repeated exposure to others in pain has been shown to bias vicarious pain perception, but the neural correlates of this effect are currently not known. The current study therefore aimed at measuring electrocortical responses to facial expressions of pain following exposure to expressions of pain. To this end, a between-subject design was adopted. Participants in the Exposure group were exposed to facial expressions of intense pain, while the participants in the Control group were exposed to neutral expressions before performing the same pain detection task. As in previous studies, participants in the Exposure group showed a significantly more conservative bias when judging facial expressions pain, meaning that they were less inclined to judge moderate pain expressions as painful compared to participants in the Control group. Event-related potential analyses in response to pain or neutral expressions indicated that this effect was related to a relative decrease in the central late positive potential responses to pain expressions. Furthermore, while the early N170 response was not influenced by repeated exposure to pain expressions, the P100 component showed an adaptation effect in the Control group only. These results suggest that repeated exposure to vicarious pain do not influence early event-related potential responses to pain expressions but decreases the late central positive potential. These results are discussed in terms of changes in the perceived saliency of pain expressions following repeated exposure. PMID:27156101

  4. Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats

    PubMed Central

    Albores-Garcia, Damaris; Hernandez, Alberto J.; Loera, Miriam J.

    2016-01-01

    Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined. PMID:26885512

  5. Continuous exposure to the deterrents cis-jasmone and methyl jasmonate does not alter the behavioural responses of Frankliniella occidentalis

    PubMed Central

    Egger, Barbara; Spangl, Bernhard; Koschier, Elisabeth Helene

    2016-01-01

    Behavioural responses of Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), a generalist, cell sap-feeding insect species with piercing-sucking mouthparts, after continuous exposure to two deterrent secondary plant compounds are investigated. We compared in choice assays on bean leaf discs, the settling, feeding, and oviposition preferences of F. occidentalis females that had no experience with the two fatty acid derivatives methyl jasmonate and cis-jasmone before testing (naïve thrips) vs. females that had been exposed to the deterrent compounds before testing (experienced thrips). The thrips were exposed to the deterrents at low or high concentrations for varied time periods and subsequently tested on bean leaf discs treated with the respective deterrent at either a low or a high concentration. Frankliniella occidentalis females avoided settling on the deterrent-treated bean leaf discs for an observation period of 6 h, independent of their previous experience. Our results demonstrate that feeding and oviposition deterrence of the jasmonates to the thrips were not altered by continuous exposure of the thrips to the jasmonates. Habituation was not induced, neither by exposure to the low concentration of the deterrents nor by exposure to the high concentration. These results indicate that the risk of habituation to two volatile deterrent compounds after repeated exposure is not evident in F. occidentalis. This makes the two compounds potential candidates to be integrated in pest management strategies. PMID:26726263

  6. Pubertal bisphenol A exposure alters murine mammary stem cell function leading to early neoplasia in regenerated glands.

    PubMed

    Wang, Danhan; Gao, Hui; Bandyopadhyay, Abhik; Wu, Anqi; Yeh, I-Tien; Chen, Yidong; Zou, Yi; Huang, Changjiang; Walter, Christi A; Dong, Qiaoxiang; Sun, Lu-Zhe

    2014-04-01

    Perinatal exposure to bisphenol A (BPA) has been shown to cause aberrant mammary gland morphogenesis and mammary neoplastic transformation. Yet, the underlying mechanism is poorly understood. We tested the hypothesis that mammary glands exposed to BPA during a susceptible window may lead to its susceptibility to tumorigenesis through a stem cell-mediated mechanism. We exposed 21-day-old Balb/c mice to BPA by gavage (25 μg/kg/d) during puberty for 3 weeks, and a subset of animals were further challenged with one oral dose (30 mg/kg) of 7,12-dimethylbenz(a)anthracene (DMBA) at 2 months of age. Primary mammary cells were isolated at 6 weeks, and 2 and 4 months of age for murine mammary stem cell (MaSC) quantification and function analysis. Pubertal exposure to the low-dose BPA increased lateral branches and hyperplasia in adult mammary glands and caused an acute increase of MaSC in 6-week-old glands and a delayed increase of luminal progenitors in 4-month-old adult gland. Most importantly, pubertal BPA exposure altered the function of MaSC from different age groups, causing early neoplastic lesions in their regenerated glands similar to those induced by DMBA exposure, which indicates that MaSCs are susceptible to BPA-induced transformation. Deep sequencing analysis on MaSC-enriched mammospheres identified a set of aberrantly expressed genes associated with early neoplastic lesions in patients with human breast cancer. Thus, our study for the first time shows that pubertal BPA exposure altered MaSC gene expression and function such that they induced early neoplastic transformation. PMID:24520039

  7. Paternal BPA exposure in early life alters Igf2 epigenetic status in sperm and induces pancreatic impairment in rat offspring.

    PubMed

    Mao, Zhenxing; Xia, Wei; Chang, Huailong; Huo, Wenqian; Li, Yuanyuan; Xu, Shunqing

    2015-11-01

    Exposure to endocrine disruptors in utero appears to alter epigenetics in the male germ-line and subsequently promote adult-onset disease in subsequent generations. Fetal exposure to bisphenol A (BPA), a highly prevalent endocrine disruptor in environment, has been shown to alter epigenetic modification and result in glucose intolerance in adulthood. However, whether fetal exposure to BPA can induce epigenetic modification and phenotypic changes in their subsequent offspring are still unclear. The present study was designed to investigate whether exposure to BPA in early life induced glucose intolerance in the offspring through male germ line, and the underlying epigenetic molecular basis. F0 pregnant SD rats were received corn oil or 40 μg/kg/day of BPA during gestation and lactation. F1 male rats were maintained to generate F2 offspring by mating with untreated female rats. Both the F1 rats after weaning and the F2 offspring were not received any other treatments. Our results showed that male F2 offspring in the BPA group exhibited glucose intolerance and β-cell dysfunction. Decreased expression of Igf2 and associated hypermethylation of Igf2 were observed in islets of male F2 offspring. In addition, similar effects were observed in female F2 animals, but the effects were more pronounced in males. Moreover, abnormal expression and methylation of Igf2 was observed in sperm of adult F1 male rats, indicating that epigenetic modification in germ cells can be partly progressed to the next generation. Overall, our study suggests that BPA exposure during early life can result in generational transmission of glucose intolerance and β-cell dysfunction in the offspring through male germ line, which is associated with hypermethylation of Igf2 in islets. The changes of epigenetics in germ cells may contribute to this generational transmission. PMID:26276081

  8. VANADIUM EXPOSURE ALTERS SPONTANEOUS BEAT RATE AND GENE EXPRESSION OF CULTURED CARDIAC MYOCYTES

    EPA Science Inventory

    Ambient air pollution particulate matter (PM) exposure is associated with increased morbidity and mortality. Recent toxicological studies report PM-induced changes in a number of cardiac parameters, including heart rate variability, arrhythmias, repolarization, and internal defib...

  9. Developmental Exposure to PCBs Differentially Alters Sensitivity to Audiogenic and Kindling-Induced Seizures in Rats

    EPA Science Inventory

    Previously we reported an increased incidence of audiogenic seizures in offspring of pregnant rats exposed to an environmental mixture of polychlorinated biphenyls (PCBs). This study compares the proconvulsant properties of PCB exposure in audiogenic and electrical kindling seizu...

  10. Identification of neural biomarkers of altered sexual differentiation following gestational exposure###

    EPA Science Inventory

    Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

  11. IDENTIFICATION OF NEURAL BIOMARKERS OF ALTERED SEXUAL DIFFERENTIATION FOLLOWING GESTATIONAL EXPOSURE***

    EPA Science Inventory

    Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

  12. Identification of neural biomarkers of altered sexual differentiation following gestational exposure

    EPA Science Inventory

    Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) during...

  13. Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat: in vivo studies.

    EPA Science Inventory

    Perchlorate, a contaminant found in food and water supplies throughout the USA, blocks iodine uptake into the thyroid gland to reduce circulating levels of thyroid hormone. Neurological function accompanying developmental exposure to perchlorate was evaluated in the present study...

  14. Alteration of Blood Parameters and Histoarchitecture of Liver and Kidney of Silver Barb after Chronic Exposure to Quinalphos

    PubMed Central

    Mohammod Mostakim, Golam; Zahangir, Md. Mahiuddin; Monir Mishu, Mahbuba; Rahman, Md. Khalilur; Islam, M. Sadiqul

    2015-01-01

    Quinalphos (QP) is commonly used for pest control in the agricultural fields surrounding freshwater reservoirs. This study was conducted to evaluate the chronic toxicity of this pesticide on blood parameters and some organs of silver barb, Barbonymus gonionotus. Fish were exposed to two sublethal concentrations, 0.47 ppm and 0.94 ppm, of QP for a period of 28 days. All the blood parameters (red blood cell, hematocrit, and hemoglobin) and blood glucose except for white blood cells decreased with increasing concentration of toxicant and become significantly lower (p < 0.05) at higher concentration when compared with control. The derived hematological indices of mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were equally altered compared to control. Histoarchitectural changes of liver and kidney were observed after exposure to the QP. Hypertrophy of hepatocytes, mild to severe necrosis, ruptured central vein, and vacuolation were observed in the liver of treated groups. Highly degenerated kidney tubules and hematopoietic tissue, degeneration of renal corpuscle, vacuolization, and necrosis were evident in the kidney of treated groups. In conclusion, chronic exposure to QP at sublethal concentrations induced hematological and histological alterations in silver barb and offers a simple tool to evaluate toxicity derived alterations. PMID:26635877

  15. Chronic fetal exposure to caffeine altered resistance vessel functions via RyRs-BKCa down-regulation in rat offspring

    PubMed Central

    Li, Na; Li, Yongmei; Gao, Qinqin; Li, Dawei; Tang, Jiaqi; Sun, Miao; Zhang, Pengjie; Liu, Bailin; Mao, Caiping; Xu, Zhice

    2015-01-01

    Caffeine modifies vascular/cardiac contractility. Embryonic exposure to caffeine altered cardiac functions in offspring. This study determined chronic influence of prenatal caffeine on vessel functions in offspring. Pregnant Sprague-Dawley rats (5-month-old) were exposed to high dose of caffeine, their offspring (5-month-old) were tested for vascular functions in mesenteric arteries (MA) and ion channel activities in smooth muscle cells. Prenatal exposure to caffeine increased pressor responses and vasoconstrictions to phenylephrine, accompanied by enhanced membrane depolarization. Large conductance Ca2+-activated K+ (BKCa) channels in buffering phenylephrine-induced vasoconstrictions was decreased, whole cell BKCa currents and spontaneous transient outward currents (STOCs) were decreased. Single channel recordings revealed reduced voltage/Ca2+ sensitivity of BKCa channels. BKCa α-subunit expression was unchanged, BKCa β1-subunit and sensitivity of BKCa to tamoxifen were reduced in the caffeine offspring as altered biophysical properties of BKCa in the MA. Simultaneous [Ca2+]i fluorescence and vasoconstriction testing showed reduced Ca2+, leading to diminished BKCa activation via ryanodine receptor Ca2+ release channels (RyRs), causing enhanced vascular tone. Reduced RyR1 was greater than that of RyR3. The results suggest that the altered STOCs activity in the caffeine offspring could attribute to down-regulation of RyRs-BKCa, providing new information for further understanding increased risks of hypertension in developmental origins. PMID:26277840

  16. Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

    PubMed

    Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

    2016-04-01

    A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms. PMID:26844865

  17. Sleep alterations following exposure to stress predict fear-associated memory impairments in a rodent model of PTSD.

    PubMed

    Vanderheyden, William M; George, Sophie A; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R

    2015-08-01

    Sleep abnormalities, such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of posttraumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stressor exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops. SPS resulted in acute increases in REM sleep and transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. Reductions in theta (4-10 Hz) and sigma (10-15 Hz) band power during transition to REM sleep also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008

  18. Grapevine Plasticity in Response to an Altered Microclimate: Sauvignon Blanc Modulates Specific Metabolites in Response to Increased Berry Exposure.

    PubMed

    Young, Philip R; Eyeghe-Bickong, Hans A; du Plessis, Kari; Alexandersson, Erik; Jacobson, Dan A; Coetzee, Zelmari; Deloire, Alain; Vivier, Melané A

    2016-03-01

    In this study, the metabolic and physiological impacts of an altered microclimate on quality-associated primary and secondary metabolites in grape (Vitis vinifera) 'Sauvignon Blanc' berries was determined in a high-altitude vineyard. The leaf and lateral shoot removal in the bunch zones altered the microclimate by increasing the exposure of the berries. The physical parameters (berry diameter and weight), primary metabolites (sugars and organic acids), as well as bunch temperature and leaf water potential were predominantly not affected by the treatment. The increased exposure led to higher levels of specific carotenoids and volatile terpenoids in the exposed berries, with earlier berry stages reacting distinctly from the later developmental stages. Plastic/nonplastic metabolite responses could be further classified to identify metabolites that were developmentally controlled and/or responded to the treatment in a predictable fashion (assessed over two consecutive vintages). The study demonstrates that grapevine berries exhibit a degree of plasticity within their secondary metabolites and respond physiologically to the increased exposure by increasing metabolites with potential antioxidant activity. Taken together, the data provide evidence that the underlying physiological responses relate to the maintenance of stress pathways by modulating antioxidant molecules in the berries. PMID:26628747

  19. Sleep Alterations Following Exposure to Stress Predict Fear-Associated Memory Impairments in a Rodent Model of PTSD

    PubMed Central

    Vanderheyden, William M.; George, Sophie A.; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R.

    2015-01-01

    Sleep abnormalities such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of post-traumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating these sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stress exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops in rats. SPS resulted in acutely increased REM sleep, transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. We also report reductions in theta (4–10 Hz) and sigma (10–15 Hz) band power during transition to REM sleep which also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008

  20. Chromosome alterations associated with in vitro exposure of human fibroblasts to chemical or physical carcinogens

    SciTech Connect

    Popescu, N.C.; Amsbaugh, S.C.; Milo, G.; DiPaolo, J.A.

    1986-09-01

    Normal human foreskin fibroblasts treated in vitro with a chemical carcinogen or irradiated with ultraviolet light subsequently acquired anchorage independent growth and an extended but finite capacity for exponential growth. All cell lines were derived from cells recovered from colonies that had grown in semisolid medium; cell lines originally treated with a chemical carcinogen produced nodules after s.c. inoculation into nude mice. G-banding analysis of 10 cell lines (including one ultraviolet light line) revealed that seven were chromosomally abnormal with structural and numerical chromosome alterations, one was characterized by a consistent trisomy, and the other two were normal diploid. Structural alterations consisted of chromosome deletions, translocations, and partial chromosome duplications. Although no common structural or numerical abnormality was detected, several structural alterations were observed involving chromosomes 1, 7, 11, and 22, where fgr, erb-B, H-ras-1, and sis protooncogenes, respectively, are located. In one cell line trisomy 17 was a unique chromosome alteration. The induction of chromosome changes may have influenced the proliferative capacity of the treated cells relative to nontreated cells. However, the two cell lines without detectable chromosome changes also had an increased proliferative life span, suggesting that other submicroscopic genetic alterations may have affected cell multiplication. Although carcinogen induced chromosome abnormalities may represent a step in the process of neoplastic development, additional genetic and/or epigenetic changes, are required for indefinite growth and the expression of malignancy.

  1. Repeated exposure to amphetamine during adolescence alters inhibitory tone in the medial prefrontal cortex following drug re-exposure in adulthood.

    PubMed

    Paul, Kush; Kang, Shuo; Cox, Charles L; Gulley, Joshua M

    2016-08-01

    Behavioral sensitization following repeated amphetamine (AMPH) exposure is associated with changes in GABA function in the medial prefrontal cortex (mPFC). In rats exposed to AMPH during adolescence compared to adulthood, there are unique patterns of sensitization that may reflect age-dependent differences in drug effects on prefrontal GABAergic function. In the current study, we used a sensitizing regimen of repeated AMPH exposure in adolescent and adult rats to determine if a post-withdrawal AMPH challenge would alter inhibitory transmission in the mPFC in a manner that depends on age of exposure. Male Sprague-Dawley rats were treated with saline or 3mg/kg AMPH (i.p.) during adolescence [postnatal day (P) 27-P45] or adulthood (P85- P103) and were sacrificed either at similar ages in adulthood (∼P133; experiment 1) or after similar withdrawal times (3-4 weeks; experiment 2). Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in vitro from deep layer pyramidal cells in the mPFC using the whole-cell configuration. We found no effect of AMPH pre-exposure on baseline sIPSC frequency. Subsequent application of AMPH (25μM) produced a stable increase in sIPSC frequency in controls, suggesting that AMPH increases inhibitory tone in the mPFC. However, AMPH failed to increase sIPSCs in adolescent- or adult-exposed rats. In experiment 2, where withdrawal period was kept similar for both exposure groups, AMPH induced a suppression of sIPSC activity in adolescent-exposed rats. These results suggest that sensitizing treatment with AMPH during adolescence or adulthood dampens inhibitory influences on mPFC pyramidal cells, but potentially through different mechanisms. PMID:27085589

  2. Alteration in Pimephales promelas mucus production after exposure to nanosilver or silver nitrate.

    PubMed

    Hawkins, Adam D; Thornton, Cammi; Steevens, Jeffery A; Willett, Kristine L

    2014-12-01

    The fish gill's ability to produce mucus effectively is a critical part of the stress response and protection against xenobiotic toxicity. Adult fathead minnows were exposed to silver nitrate (0.82 µg/L or 13.2 µg/L), polyvinylpyrrolidone-coated silver nanoparticles (11.1 µg/L or 208 µg/L), and citrate-coated silver nanoparticles (10.1 µg/L or 175 µg/L) for 96 h. Mucus concentrations based on glucose as a surrogate were determined at 0 h, 1 h, 2 h, 3 h, 4 h and 24 h after re-dosing each day. Higher mucus production rates following silver treatment were observed at the beginning as compared to controls and compared to after 3 d of exposure. Control fish produced consistent mucus concentrations throughout the exposure (0.62 mg/L and 0.40 mg/L at 24 h and 96 h, respectively). Following 24 h of exposure, all silver treatment groups produced significantly more mucus than controls. Following 96 h of exposure, mucus concentrations in treatment groups were significantly reduced compared with each respective treatment at 24 h. Reduced mucus production following long-term silver exposure could prevent the gills from removing silver, and thus increase toxicity. PMID:25262928

  3. Developmental timing of sodium perchlorate exposure alters angiogenesis, thyroid follicle proliferation and sexual maturation in stickleback

    PubMed Central

    Furin, Christoff G.; von Hippel, Frank A.; Postlethwait, John H.; Buck, C. Loren; Cresko, William A.; O’Hara, Todd M.

    2015-01-01

    Perchlorate, a common aquatic contaminant, is well known to disrupt homeostasis of the hypothalamus-pituitary-thyroid axis. This study utilizes the threespine stickleback (Gasterosteus aculeatus) fish to determine if perchlorate exposure during certain windows of development has morphological effects on thyroid and gonads. Fish were moved from untreated water to perchlorate-contaminated water (30 and 100 mg/L) starting at 0, 3, 7, 14, 21, 42, 154 and 305 days post fertilization until approximately one year old. A reciprocal treatment (fish in contaminated water switched to untreated water) was conducted on the same schedule. Perchlorate exposure increased angiogenesis and follicle proliferation in thyroid tissue, delayed gonadal maturity, and skewed sex ratios towards males; effects depended on concentration and timing of exposure. This study demonstrates that perchlorate exposure beginning during the first 42 days of development has profound effects on stickleback reproductive and thyroid tissues, and by implication can impact population dynamics. Long-term exposure studies that assess contaminant effects at various stages of development provide novel information to characterize risk to aquatic organisms, to facilitate management of resources, and to determine sensitive developmental windows for further study of underlying mechanisms. PMID:25865142

  4. Exposure to Radiofrequency Radiation Emitted from Common Mobile Phone Jammers Alters the Pattern of Muscle Contractions: an Animal Model Study

    PubMed Central

    Rafati, A.; Rahimi, S.; Talebi, A.; Soleimani, A.; Haghani, M.; Mortazavi, S. M. J.

    2015-01-01

    Introduction The rapid growth of wireless communication technologies has caused public concerns regarding the biological effects of electromagnetic radiations on human health. Some early reports indicated a wide variety of non-thermal effects of electromagnetic radiation on amphibians such as the alterations of the pattern of muscle extractions. This study is aimed at investigating the effects of exposure to radiofrequency (RF) radiation emitted from mobile phone jammers on the pulse height of contractions, the time interval between two subsequent contractions and the latency period of frog’s isolated gastrocnemius muscle after stimulation with single square pulses of 1V (1 Hz). Materials and Methods Frogs were kept in plastic containers in a room. Animals in the jammer group were exposed to radiofrequency (RF) radiation emitted from a common Jammer at a distance of 1m from the jammer’s antenna for 2 hours while the control frogs were only sham exposed. Then animals were sacrificed and isolated gastrocnemius muscles were exposed to on/off jammer radiation for 3 subsequent 10 minute intervals. Isolated gastrocnemius muscles were attached to the force transducer with a string. Using a PowerLab device (26-T), the pattern of muscular contractions was monitored after applying single square pulses of 1V (1 Hz) as stimuli. Results The findings of this study showed that the pulse height of muscle contractions could not be affected by the exposure to electromagnetic fields. However, the latency period was effectively altered in RF-exposed samples. However, none of the experiments could show an alteration in the time interval between two subsequent contractions after exposure to electromagnetic fields. Conclusion These findings support early reports which indicated a wide variety of non-thermal effects of electromagnetic radiation on amphibians including the effects on the pattern of muscle extractions. PMID:26396969

  5. Prenatal Alcohol Exposure and Chronic Mild Stress Differentially Alter Depressive- and Anxiety-Like Behaviors in Male and Female Offspring

    PubMed Central

    Hellemans, Kim G. C.; Verma, Pamela; Yoon, Esther; Yu, Wayne K.; Young, Allan H.; Weinberg, Joanne

    2016-01-01

    Background Fetal Alcohol Spectrum Disorder (FASD) is associated with numerous neuro behavioral alterations, as well as disabilities in a number of domains, including a high incidence of depression and anxiety disorders. Prenatal alcohol exposure (PAE) also alters hypothalamic-pituitary-adrenal (HPA) function, resulting in increased responsiveness to stressors and HPA dysregulation in adulthood. Interestingly, data suggest that pre-existing HPA abnormalities may be a major contributory factor to some forms of depression, particularly when an individual is exposed to stressors later in life. We tested the hypothesis that exposure to stressors in adulthood may unmask an increased vulnerability to depressive- and anxiety-like behaviors in PAE animals. Methods Male and female offspring from prenatal alcohol (PAE), pair-fed (PF), and ad libitumfed control (C) treatment groups were tested in adulthood. Animals were exposed to 10 consecutive days of chronic mild stress (CMS), and assessed in a battery of well-validated tasks sensitive to differences in depressive- and / or anxiety-like behaviors. Results We report here that the combination of PAE and CMS in adulthood increases depressive- and anxiety-like behaviors in a sexually dimorphic manner. PAE males showed impaired hedonic responsivity (sucrose contrast test), locomotor hyperactivity (open field), and alterations in affiliative and nonaffiliative social behaviors (social interaction test) compared to control males. By contrast, PAE and, to a lesser extent, PF, females showed greater levels of “behavioral despair” in the forced swim test, and PAE females showed altered behavior in the final 5 minutes of the social interaction test compared to control females. Conclusions These data support the possibility that stress may be a mediating or contributing factor in the psychopathologies reported in FASD populations. PMID:20102562

  6. Prenatal di-n-butyl phthalate exposure alters reproductive functions at adulthood in male rats.

    PubMed

    Giribabu, Nelli; Sainath, Sri Bhashyam; Sreenivasula Reddy, Pamanji

    2014-05-01

    This study was aimed to investigate the reproductive health in adult male rats exposed to di-n-butyl phthalate (DBP) during embryonic development. Pregnant rats were injected with DBP and F1 male rats were weaned and on postnatal day 100, used for mating with normal cycling females to assess reproductive performance. After completion of cohabitation period, rats were analyzed for other reproductive end points. Transplacental exposure to DBP significantly decreased fertility in adult male rats. Prenatal exposure to DBP significantly decreased sperm density, number of motile sperms, viable sperms, and hypoosmotic swelling tail coiled sperms with an increase in morphological abnormalities in sperms. Testicular steroidogenic enzyme activity levels and serum testosterone levels were significantly decreased in rats exposed to DBP during embryonic development. In conclusion, transplacental exposure to DBP impairs male reproductive performance by decreasing steroidogenesis and spermatogenesis. PMID:22489061

  7. EXPOSURE TO CONCENTRATED AMBIENT PARTICLES IN DETROIT ALTERS HEART RATE VARIABILITY IN SPONTANEOUSLY HYPERTENSIVE RATS

    EPA Science Inventory

    Elevations in airborne particulate matter (PM) are linked to increased mortality and morbidity in humans with cardiopulmonary disease. Clinical studies show that PM is associated with altered heart rate variability (HRV) and suggests that loss of autonomic control may underlie ca...

  8. POTENTIAL ALTERATIONS IN GENE EXPRESSION ASSOCIATED WITH CARCINOGEN EXPOSURE IN MYA ARENARIA

    EPA Science Inventory

    Gonadal cancers in soft-shell clams (Mya arenaria) have been found at high prevalences (20-40%) in populations in eastern Maine. The aetiology of these tumours is unknown. We hypothesized that gene expression would be altered in gonadal tumours and that examination of gene expres...

  9. [Alteration of thyroid hormone secretion after long-term exposure to low doses of endocrine disruptor DDT].

    PubMed

    Iaglova, N V; Iaglov, V V

    2014-01-01

    Endocrine disruptors are exogenous substances that exhibit hormone-like action and consequently disrupt homeostatic action of endogenous hormones. DDT is the most common disruptor. The objective was to evaluate changes in thyroid hormone secretion after long-term exposure to low doses of DDT. The experiment was performed on male Wistar rats. The rats were given DDT at doses of 1.89±0.86 мg/kg/day and 7.77±0.17 мg/kg/day for 6 and 10 weeks. Dose dependent increase of serum total thyroxine, total triiodthyronine, and thyroid peroxidase was revealed after 6 weeks exposure. After 10 weeks free thyroxine secretion was reduced. Such alterations of the thyroid status are typical for iodine deficient goiter. The data obtained indicate that the main mechanism of DDT action includes disruption of thyroxine secretion by thyrocytes, but not inhibition of deiodinase activity and decrease of blood thyroid binding proteins. PMID:25552505

  10. Long-term exposure of 3T3 fibroblast cells to endocrine disruptors alters sensitivity to oxidative injury.

    PubMed

    Nishimura, Yuka; Nakai, Yasuyoshi; Tanaka, Aiko; Nagao, Tetsuji; Fukushima, Nobuyuki

    2014-07-01

    When Swiss 3T3 fibroblasts were exposed to bisphenol A (BPA) or nonylphenol (NP) within a range of 0.1-100 nM for 30-45 days, increased resistance to oxidative injury was found. Western blot analysis indicated concomitant increased expression of bcl-2 protein and reduced histone methylation levels in cells after BPA or NP exposure. Using a heterologous expression system, both chemicals could stimulate G protein-coupled receptor 30 (GPR30), a transmembrane estrogen receptor predominantly expressed in 3T3 cells, at lower concentrations, which gave increased survival. Taken together, these results suggest that BPA or NP exposure might cause alterations in cellular activity against oxidative stress, possibly through GPR30. PMID:24604882

  11. Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/beta-catenin signaling in the thymus resulting in altered thymocyte development

    SciTech Connect

    Hanson, Miranda L.; Brundage, Kathleen M.; Schafer, Rosana; Tou, Janet C.; Barnett, John B.

    2010-01-15

    Cadmium (Cd) is both an environmental pollutant and a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/beta-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/beta-catenin pathways. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways were assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4{sup +} cells and a subpopulation of double-negative cells (DN; CD4{sup -}CD8{sup -}), DN4 (CD44{sup -}CD25{sup -}). Shh and Wnt/beta-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/beta-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.

  12. Exposure to a Social Stressor Alters the Structure of the Intestinal Microbiota: Implications for Stressor-Induced Immunomodulation

    PubMed Central

    Bailey, Michael T.; Dowd, Scot E.; Galley, Jeffrey D.; Hufnagle, Amy R.; Allen, Rebecca G.; Lyte, Mark

    2010-01-01

    The bodies of most animals are populated by highly complex and genetically diverse communities of microorganisms. The majority of these microbes reside within the intestines in largely stable but dynamically interactive climax communities that positively interact with their host. Studies from this laboratory have shown that stressor exposure impacts the stability of the microbiota and leads to bacterial translocation. The biological importance of these alterations, however, is not well understood. To determine whether the microbiome contributes to stressor-induced immunoenhancement, mice were exposed to a social stressor called social disruption (SDR), that increases circulating cytokines and primes the innate immune system for enhanced reactivity. Bacterial populations in the cecum were characterized using bacterial tag-encoded FLX amplicon pyrosequencing. Stressor exposure significantly changed the community structure of the microbiota, particularly when the microbiota were assessed immediately after stressor exposure. Most notably, stressor exposure decreased the relative abundance of bacteria in the genus Bacteroides, while increasing the relative abundance of bacteria in the genus Clostridium. The stressor also increased circulating levels of IL-6 and MCP-1, which were significantly correlated with stressor-induced changes to three bacterial genera (i.e., Coprococcus, Pseudobutyrivibrio, and Dorea). In follow up experiments, mice were treated with an antibiotic cocktail to determine whether reducing the microbiota would abrogate the stressor-induced increases in circulating cytokines. Exposure to SDR failed to increase IL-6 and MCP-1 in the antibiotic treated mice. These data show that exposure to SDR significantly affects bacterial populations in the intestines, and remarkably also suggest that the microbiota are necessary for stressor-induced increases in circulating cytokines. PMID:21040780

  13. Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction.

    PubMed

    Massa, Christopher B; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L; Gow, Andrew J

    2014-07-01

    Acute Cl2 exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl2 inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60ppm-hour Cl2 dose, and were euthanized 3, 24 and 48h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24h. Cl2 exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO3(-) or NO2(-). Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl2 exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl2 inhalation. PMID:24582687

  14. Acute Chlorine Gas Exposure Produces Transient Inflammation and a Progressive Alteration in Surfactant Composition with Accompanying Mechanical Dysfunction

    PubMed Central

    Massa, Christopher B; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L; Gow, Andrew J

    2014-01-01

    Acute Cl2 exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl2 inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl2 dose, and were sacrificed 3, 24 and 48 hours later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 hours, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 hours. Cl2 exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO3− or NO2−. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl2 exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 hours, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl2 inhalation. PMID:24582687

  15. Developmental neurotoxicity of organophosphorous pesticides: fetal and neonatal exposure to chlorpyrifos alters sex-specific behaviors at adulthood in mice.

    PubMed

    Ricceri, Laura; Venerosi, Aldina; Capone, Francesca; Cometa, Maria Francesca; Lorenzini, Paola; Fortuna, Stefano; Calamandrei, Gemma

    2006-09-01

    Developmental exposure to the organophosphorous insecticide chlorpyrifos (CPF) induces long-term effects on brain and behavior in laboratory rodents. We evaluated in adult mice the behavioral effects of either fetal and/or neonatal CPF exposure at doses not inhibiting fetal and neonatal brain cholinesterase. CPF (3 or 6 mg/kg) was given by oral treatment to pregnant females on gestational days 15-18 and offspring were treated sc (1 or 3 mg/kg) on postnatal days (PNDs) 11-14. Serum and brain acetylcholinesterase (AChE) activity was evaluated at birth and 24 h from termination of postnatal treatments. On PND 70, male mice were assessed for spontaneous motor activity in an open-field test and in a socioagonistic encounter with an unfamiliar conspecific. Virgin females underwent a maternal induction test following presentation of foster pups. Both sexes were subjected to a plus-maze test to evaluate exploration and anxiety levels. Gestational and postnatal CPF exposure (higher doses) affected motor activity in the open field and enhanced synergically agonistic behavior. Postnatal CPF exposure increased maternal responsiveness toward pups in females. Mice of both sexes exposed to postnatal CPF showed reduced anxiety response in the plus-maze, an effect greater in females. Altogether, developmental exposure to CPF at doses that do not cause brain AChE inhibition induces long-term alterations in sex-specific behavior patterns of the mouse species. Late neonatal exposure on PNDs 11-14 was the most effective in causing behavioral changes. These findings support the hypothesis that developmental CPF may represent a risk factor for increased vulnerability to neurodevelopmental disorders in humans. PMID:16760416

  16. Exposure to N-Ethyl-N-Nitrosourea in Adult Mice Alters Structural and Functional Integrity of Neurogenic Sites

    PubMed Central

    Capilla-Gonzalez, Vivian; Gil-Perotin, Sara; Ferragud, Antonio; Bonet-Ponce, Luis; Canales, Juan Jose; Garcia-Verdugo, Jose Manuel

    2012-01-01

    Background Previous studies have shown that prenatal exposure to the mutagen N-ethyl-N-nitrosourea (ENU), a N-nitroso compound (NOC) found in the environment, disrupts developmental neurogenesis and alters memory formation. Previously, we showed that postnatal ENU treatment induced lasting deficits in proliferation of neural progenitors in the subventricular zone (SVZ), the main neurogenic region in the adult mouse brain. The present study is aimed to examine, in mice exposed to ENU, both the structural features of adult neurogenic sites, incorporating the dentate gyrus (DG), and the behavioral performance in tasks sensitive to manipulations of adult neurogenesis. Methodology/Principal Findings 2-month old mice received 5 doses of ENU and were sacrificed 45 days after treatment. Then, an ultrastructural analysis of the SVZ and DG was performed to determine cellular composition in these regions, confirming a significant alteration. After bromodeoxyuridine injections, an S-phase exogenous marker, the immunohistochemical analysis revealed a deficit in proliferation and a decreased recruitment of newly generated cells in neurogenic areas of ENU-treated animals. Behavioral effects were also detected after ENU-exposure, observing impairment in odor discrimination task (habituation-dishabituation test) and a deficit in spatial memory (Barnes maze performance), two functions primarily related to the SVZ and the DG regions, respectively. Conclusions/Significance The results demonstrate that postnatal exposure to ENU produces severe disruption of adult neurogenesis in the SVZ and DG, as well as strong behavioral impairments. These findings highlight the potential risk of environmental NOC-exposure for the development of neural and behavioral deficits. PMID:22238669

  17. The characteristics of coarse particulate matter air pollution associated with alterations in blood pressure and heart rate during controlled exposures

    PubMed Central

    Morishita, Masako; Bard, Robert L.; Wang, Lu; Das, Ritabrata; Dvonch, J. Timothy; Spino, Catherine; Mukherjee, Bhramar; Sun, Qinghua; Harkema, Jack R.; Rajagopalan, Sanjay; Brook, Robert D.

    2015-01-01

    Although fine particulate matter (PM) air pollution <2.5 μm in aerodynamic diameter (PM2.5) is a leading cause of global morbidity and mortality, the potential health effects of coarse PM (2.5–10 μm in aerodynamic diameter; PM10–2.5) remain less clearly understood. We aimed to elucidate the components within coarse PM most likely responsible for mediating these hemodynamic alterations. Thirty-two healthy adults (25.9 ± 6.6 years) were exposed to concentrated ambient coarse PM (CAP) (76.2 ± 51.5 μg/m3) and filtered air (FA) for 2 h in a rural location in a randomized double-blind crossover study. The particle constituents (24 individual elements, organic and elemental carbon) were analyzed from filter samples and associated with the blood pressure (BP) and heart rate (HR) changes occurring throughout CAP and FA exposures in mixed model analyses. Total coarse PM mass along with most of the measured elements were positively associated with similar degrees of elevations in both systolic BP and HR. Conversely, total PM mass was unrelated, whereas only two elements (Cu and Mo) were positively associated with and Zn was inversely related to diastolic BP changes during exposures. Inhalation of coarse PM from a rural location rapidly elevates systolic BP and HR in a concentration-responsive manner, whereas the particulate composition does not appear to be an important determinant of these responses. Conversely, exposure to certain PM elements may be necessary to trigger a concomitant increase in diastolic BP. These findings suggest that particulate mass may be an adequate metric of exposure to predict some, but not all, hemodynamic alterations induced by coarse PM mass. PMID:25227729

  18. Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats.

    PubMed

    Cohen, Ori S; Varlinskaya, Elena I; Wilson, Carey A; Glatt, Stephen J; Mooney, Sandra M

    2013-12-01

    Prenatal exposure to moderate doses of valproic acid (VPA) produces brainstem abnormalities, while higher doses of this teratogen elicit social deficits in the rat. In this pilot study, we examined effects of prenatal exposure to a moderate dose of VPA on behavior and on transcriptomic expression in three brain regions that mediate social behavior. Pregnant Long Evans rats were injected with 350 mg/kg VPA or saline on gestational day 13. A modified social interaction test was used to assess social behavior and social preference/avoidance during early and late adolescence and in adulthood. VPA-exposed animals demonstrated more social investigation and play fighting than control animals. Social investigation, play fighting, and contact behavior also differed as a function of age; the frequency of these behaviors increased in late adolescence. Social preference and locomotor activity under social circumstances were unaffected by treatment or age. Thus, a moderate prenatal dose of VPA produces behavioral alterations that are substantially different from the outcomes that occur following exposure to a higher dose. At adulthood, VPA-exposed subjects exhibited transcriptomic abnormalities in three brain regions: anterior amygdala, cerebellar vermis, and orbitofrontal cortex. A common feature among the proteins encoded by the dysregulated genes was their ability to be modulated by acetylation. Analysis of the expression of individual exons also revealed that genes involved in post-translational modification and epigenetic regulation had particular isoforms that were ubiquitously dysregulated across brain regions. The vulnerability of these genes to the epigenetic effects of VPA may highlight potential mechanisms by which prenatal VPA exposure alters the development of social behavior. PMID:24055786

  19. Environmental enrichment alters structural plasticity of the adolescent brain but does not remediate the effects of prenatal nicotine exposure.

    PubMed

    Mychasiuk, Richelle; Muhammad, Arif; Kolb, Bryan

    2014-07-01

    Exposure to both drugs of abuse and environmental enrichment (EE) are widely studied experiences that induce large changes in dendritic morphology and synaptic connectivity. As there is an abundance of literature using EE as a treatment strategy for drug addiction, we sought to determine whether EE could remediate the effects of prenatal nicotine (PN) exposure. Using Golgi-Cox staining, we examined eighteen neuroanatomical parameters in four brain regions [medial prefrontal cortex (mPFC), orbital frontal cortex (OFC), nucleus accumben, and Par1] of Long-Evans rats. EE in adolescence dramatically altered structural plasticity in the male and female brain, modifying 60% of parameters investigated. EE normalized three parameters (OFC spine density and dendritic branching and mPFC dendritic branching) in male offspring exposed to nicotine prenatally but did not remediate any measures in female offspring. PN exposure interfered with adolescent EE-induced changes in five neuroanatomical measurements (Par1 spine density and dendritic branching in both male and female offspring, and mPFC spine density in male offspring). And in four neuroanatomical parameters examined, PN exposure and EE combined to produce additive effects [OFC spine density in females and mPFC dendritic length (apical and basilar) and branching in males]. Despite demonstrated efficacy in reversing drug addiction, EE was not able to reverse many of the PN-induced changes in neuronal morphology, indicating that modifications in neural circuitry generated in the prenatal period may be more resistant to change than those generated in the adult brain. PMID:24616009

  20. Exposure of fluid milk to LED light negatively affects consumer perception and alters underlying sensory properties.

    PubMed

    Martin, Nicole; Carey, Nancy; Murphy, Steven; Kent, David; Bang, Jae; Stubbs, Tim; Wiedmann, Martin; Dando, Robin

    2016-06-01

    Fluid milk consumption per capita in the United States has been steadily declining since the 1940s. Many factors have contributed to this decline, including the increasing consumption of carbonated beverages and bottled water. To meet the challenge of stemming the decline in consumption of fluid milk, the dairy industry must take a systematic approach to identifying and correcting for factors that negatively affect consumers' perception of fluid milk quality. To that end, samples of fluid milk were evaluated to identify factors, with a particular focus on light-emitting diode (LED) light exposure, which negatively affect the perceived sensory quality of milk, and to quantify their relative effect on the consumer's experience. Fluid milk samples were sourced from 3 processing facilities with varying microbial postprocessing contamination patterns based on historical testing. The effect of fat content, light exposure, age, and microbiological content were assayed across 23 samples of fluid milk, via consumer, descriptive sensory, and instrumental analyses. Most notably, light exposure resulted in a broad negative reaction from consumers, more so than samples with microbiological contamination exceeding 20,000 cfu/mL on days approaching code. The predominant implication of the study is that a component of paramount importance in ensuring the success of the dairy industry would be to protect fluid milk from all sources of light exposure, from processing plant to consumer. PMID:27060830

  1. PERINATAL EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS: POTENTIAL ROLE OF HORMONAL ALTERATIONS IN INITIATING ADULT REPRODUCTIVE ANOMALIES

    EPA Science Inventory

    The primary hypothesis to be tested in this series of studies is whether or not exposure to environmental agents, during certain key periods of development, will increase the risk of specific anomalies of the reproductive system. Embedded in this hypothesis is the assumption that...

  2. Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure

    PubMed Central

    Goss, Kara N.; Cucci, Anthony R.; Fisher, Amanda J.; Albrecht, Marjorie; Frump, Andrea; Tursunova, Roziya; Gao, Yong; Brown, Mary Beth; Petrache, Irina; Tepper, Robert S.; Ahlfeld, Shawn K.

    2015-01-01

    The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0–4 or 0–10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults. PMID:25659904

  3. Developmental Exposure to a Dopaminergic Toxicant Produces Altered Locomotor Activity in Larval Zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after developmental exposure to various classes of prototypic drugs that act on the central nervous system. ...

  4. Exposure to hyperoxia in the neonatal period alters bone marrow function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxygen is often life saving in preterm infants, however, excessive exposure may lead to blood vessel and tissue injury in the lung and retina. Oxygen-treated neonates often exhibit bone marrow (BM) suppression requiring blood product transfusions. However, we do not know whether oxygen is directly t...

  5. Perinatal ethanol exposure alters met-enkephalin levels of male and female rats.

    PubMed

    Lugo, Joaquin N; Wilson, Marlene A; Kelly, Sandra J

    2006-01-01

    This study used a rat model of Fetal Alcohol Syndrome to investigate whether combined prenatal and postnatal ethanol exposure affects met-enkephalin levels in the brains of male and female Long-Evans adult rats. Intragastric ethanol was administered to a group of rats (ET) from gestational day (GD) 1 through 22 and from postnatal day (PD) 2 through 10. The control groups consisted of a nontreated control group (NTC) and an intubated control group (IC) that received the intragastric intubation procedure but no exposure to ethanol. We measured met-enkephalin levels in the prefrontal cortex, nucleus accumbens, hypothalamus, central and basolateral nucleus of amygdala and ventral tegmental area. Met-enkephalin levels in the hypothalamus of male and female ET animals were significantly higher than those in either the NTC or IC animals. Met-enkephalin levels in the central nucleus of the amygdala of male and female ET animals were significantly lower than the levels in the NTC animals. Met-enkephalin levels in the nucleus accumbens of ET females were significantly greater than those in the IC females. These results demonstrate that the combination of prenatal and postnatal ethanol exposure affects basal met-enkephalin levels in specific regions in a sex-specific manner. These changes in met-enkephalin levels may explain how early ethanol exposure affects opioid-regulated behaviors such as social play, sexual behavior, and other social behaviors. PMID:16457985

  6. GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE PERMANENTLY ALTERS REPRODUCTIVE COMPETENCE IN THE CD-1 MOUSE

    EPA Science Inventory

    While the adult mouse Leydig cell (LC) has been considered refractory to cytotoxic destruction by ethane dimethanesulfonate (EDS), the potential consequences of exposure during reproductive development in this species are unknown. Herein pregnant CD-1 mice were treated with 160 m...

  7. Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure.

    PubMed

    Goss, Kara N; Cucci, Anthony R; Fisher, Amanda J; Albrecht, Marjorie; Frump, Andrea; Tursunova, Roziya; Gao, Yong; Brown, Mary Beth; Petrache, Irina; Tepper, Robert S; Ahlfeld, Shawn K; Lahm, Tim

    2015-04-15

    The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0-4 or 0-10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults. PMID:25659904

  8. Tracheal Morphologic and Protein Alterations FollowingShort-Term Cigarette Mainstream Smoke Exposure to Rats.

    PubMed

    Carter, Charleata A; Misra, Manoj; Maronpot, Robert R

    2012-09-01

    A short-term 5-day nose-only cigarette smoke exposure study was conducted in Fisher 344 rats to identify smoke-induced tracheal protein changes. Groups of 10 male and female 5 week old rats were assigned to 1 of 4 exposure groups. Animals received filtered air, or 75, 200 or 400 mg total particulate matter (TPM)/m(3) of diluted 3R4F Kentucky reference cigarette mainstream smoke. Exposures were conducted for 3 hrs/day, for 5 consecutive days. Tracheas from half the rats were processed for pathology, and tracheas from the other half of the rats frozen immediately for proteomics. We hypothesized that smoke will activate tracheal inflammatory, apoptotic, proliferative, and stress-induced pathways. Mucosal epithelial toxicity from the inhaled material was evidenced by cilia shortening and loss of tracheal mucosal epithelium in smoke-exposed animals. Mucosal thinning occurred in all smoke-exposed groups with hyperplastic reparative responses in the 200 and 400 mg TPM/m(3) groups. Tracheal lysates from control vs. treated animals were screened for 800 proteins using antibody-based microarray technology and subsequently the most changed proteins evaluated by Western blot. Tracheal proteins expressed at high levels that were markedly increased or decreased by smoke exposure depended on dose and gender and included caspase 5, ERK 1/2 and p38. Signaling pathways common between the morphologic and protein changes were stress, apoptosis, cell cycle control, cell proliferation and survival. Changes in identified proteins affected by smoke exposure were associated with tracheal mucosal pathology, may induce functional tracheal changes, and could serve as early indicators of tracheal damage and associated disease. PMID:22988338

  9. Temperature, hydric environment, and prior pathogen exposure alter the experimental severity of chytridiomycosis in boreal toads

    USGS Publications Warehouse

    Murphy, Peter J.; St-Hilaire, Sophie; Corn, Paul Stephen

    2011-01-01

    Prevalence of the pathogen Batrachochytrium dendrobatidis (Bd), implicated in amphibian population declines worldwide, is associated with habitat moisture and temperature, but few studies have varied these factors and measured the response to infection in amphibian hosts. We evaluated how varying humidity, contact with water, and temperature affected the manifestation of chytridiomycosis in boreal toads Anaxyrus (Bufo) boreas boreas and how prior exposure to Bd affects the likelihood of survival after re-exposure, such as may occur seasonally in long-lived species. Humidity did not affect survival or the degree of Bd infection, but a longer time in contact with water increased the likelihood of mortality. After exposure to ~106 Bd zoospores, all toads in continuous contact with water died within 30 d. Moreover, Bd-exposed toads that were disease-free after 64 d under dry conditions, developed lethal chytridiomycosis within 70 d of transfer to wet conditions. Toads in unheated aquaria (mean = 15°C) survived less than 48 d, while those in moderately heated aquaria (mean = 18°C) survived 115 d post-exposure and exhibited behavioral fever, selecting warmer sites across a temperature gradient. We also found benefits of prior Bd infection: previously exposed toads survived 3 times longer than Bd-naïve toads after re-exposure to 106 zoospores (89 vs. 30 d), but only when dry microenvironments were available. This study illustrates how the outcome of Bd infection in boreal toads is environmentally dependent: when continuously wet, high reinfection rates may overwhelm defenses, but periodic drying, moderate warming, and previous infection may allow infected toads to extend their survival.

  10. Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction

    SciTech Connect

    Massa, Christopher B.; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L.; Gow, Andrew J.

    2014-07-01

    Acute Cl{sub 2} exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl{sub 2} inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl{sub 2} dose, and were euthanized 3, 24 and 48 h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 h. Cl{sub 2} exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO{sub 3}{sup −} or NO{sub 2}{sup −}. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl{sub 2} exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl{sub 2} inhalation. - Highlights: • Effect of 60 ppm*hr Cl{sub 2} gas on lung inflammation and mechanical function examined. • Pulmonary inflammation is transient and minor.

  11. Previous exposure of predatory fish to a pesticide alters palatability of larval amphibian prey.

    PubMed

    Hanlon, Shane M; Parris, Matthew J

    2013-12-01

    Habitat preferences of organisms are reliant on a variety of factors. For amphibians specifically, preferences can depend on factors such as food availability, water quality, and the presence of potential predators. Because some amphibians breed in permanent bodies of water (e.g., ponds), the threat of predation (e.g., from fish) is constant. Thus, some amphibians are unpalatable to many predators, allowing them to coexist in the same habitats. However, the addition of anthropogenic stressors (i.e., pesticides) may alter the perceived palatability of prey items to predators. The authors tested the hypothesis that bluegill fish (Lepomis macrochirus), previously exposed to the pesticide carbaryl, would consume more unpalatable prey (Fowler's toad [Anaxyrus fowleri] tadpoles) than unexposed predators. Carbaryl is a pesticide that attacks the nervous system and is linked to taste sense in organisms. Moreover, the authors conducted an identical test using palatable prey (gray treefrog [Hyla versicolor] tadpoles) and predicted that no change in preference would be observed. In support of the primary hypothesis, bluegill exposed to the highest concentration of carbaryl consumed more A. fowleri tadpoles compared with those exposed to carbaryl at the lowest concentration or water control. Moreover, an effect of carbaryl on predation success on H. versicolor tadpoles was not observed. The present study shows that an anthropogenic stressor (carbaryl) can alter the perceived palatability of noxious prey to fish predators, potentially altering predator-prey relationships in natural settings. PMID:24383102

  12. Previous exposure of predatory fish to a pesticide alters palatability of larval amphibian prey.

    PubMed

    Hanlon, Shane M; Parris, Matthew J

    2013-09-01

    Habitat preferences of organisms are reliant upon a variety of factors. Specifically with amphibians, preferences can depend on factors such as food availability, water quality, or the presence of potential predators. Because some amphibians breed in permanent bodies of water (e.g., ponds), the threat of predation (e.g., from fish) is constant. Thus, some amphibians are unpalatable to many predators, allowing them to coexist in the same habitats. However, the addition of anthropogenic stressors (i.e., pesticides) may alter the perceived palatability of prey items to predators. We tested the hypothesis that bluegill fish (Lepomis macrochirus), previously exposed to the pesticide carbaryl, would consume more unpalatable prey (Fowler's toad [Anaxyrus fowleri] tadpoles) than unexposed predators. Carbaryl is a pesticide that attacks the nervous system and is linked to taste sense in organisms. Moreover, we conducted an identical test using palatable prey (gray treefrog [Hyla versicolor] tadpoles) and predicted that no change in preference would be observed. In support of our primary hypothesis, bluegill exposed to the highest concentration of carbaryl consumed more A. folweri tadpoles compared to those exposed to carbaryl at the lowest concentration or water control. Moreover, an effect of carbaryl on predation success on H. versicolor tadpoles was not observed. Our study shows that an anthropogenic stressor (carbaryl) can alter the perceived palatability of noxious prey to fish predators, potentially altering predator-prey relationships in natural settings. Environ Toxicol Chem © 2013 SETAC. PMID:23996644

  13. Low-frequency pulsed electromagnetic field exposure can alter neuroprocessing in humans

    PubMed Central

    Robertson, John A.; Théberge, Jean; Weller, Julie; Drost, Dick J.; Prato, Frank S.; Thomas, Alex W.

    2010-01-01

    Extremely low-frequency magnetic fields (from DC to 300 Hz) have been shown to affect pain sensitivity in snails, rodents and humans. Here, a functional magnetic resonance imaging study demonstrates how the neuromodulation effect of these magnetic fields influences the processing of acute thermal pain in normal volunteers. Significant interactions were found between pre- and post-exposure activation between the sham and exposed groups for the ipsilateral (right) insula, anterior cingulate and bilateral hippocampus/caudate areas. These results show, for the first time, that the neuromodulation induced by exposure to low-intensity low-frequency magnetic fields can be observed in humans using functional brain imaging and that the detection mechanism for these effects may be different from those used by animals for orientation and navigation. Magnetoreception may be more common than presently thought. PMID:19656823

  14. Dietary exposure to Aroclor 1254 alters gene expression in Xenopus laevis frogs.

    PubMed

    Jelaso, Anna M; DeLong, Cari; Means, Jay; Ide, Charles F

    2005-05-01

    Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that contribute to worldwide health problems. Despite data associating PCBs with adverse health effects, decisions to clean up contaminated sites remain controversial. Cleanup decisions are typically based on risk assessment methods that are not sensitive enough to detect subtle changes in health. We have recently shown that gene expression signatures can serve as sensitive molecular biomarkers of exposure and related health effects. Our initial studies were carried out with developing Xenopus laevis tadpoles that were exposed to the PCB mixture Aroclor 1254 (A1254) for 2 days. A1254 was dissolved in dimethyl sulfoxide and added to the aquarium water for rapid loading of PCBs into the tadpole tissue. These studies showed that increases in the expression of specific genes occurred independent of adverse health effects, and decreases in specific genes correlated with the appearance of observable health effects, including decreased survival and gross morphological and behavioral abnormalities. In this report, we extend our previous work to test the use of gene expression signatures as biomarkers in frogs exposed to PCBs through the diet from early tadpole stages through metamorphosis. This work showed that chronic low-dose exposure to A1254 (24 ppm) in food produced tissue levels of 17 ppm and increased gene expression of nerve growth factor and proopiomelanocortin independent of adverse health effects. Exposure to higher doses of A1254 (200 ppm) produced tissue levels of 80 ppm and increased expression of p450 1A1, also, independent of adverse health effects. This work provides further evidence for the use of gene expression changes as biomarkers of exposure to PCBs. PMID:15721885

  15. Subacute Microcystin-LR Exposure Alters the Metabolism of Thyroid Hormones in Juvenile Zebrafish (Danio Rerio)

    PubMed Central

    Liu, Zidong; Tang, Rong; Li, Dapeng; Hu, Qing; Wang, Ying

    2015-01-01

    Microcystin-LR (MC-LR) has been detected extensively in the aquatic environment and has the potential to disturb the thyroid endocrine system. However, limited information is available on the effects of subacute MC-LR exposure on fish thyroid hormone (TH) metabolism. In the present study, juvenile zebrafish (Danio rerio) were exposed to MC-LR at environmentally relevant concentrations (0, 1, 5, and 25 μg/L) for 28 days. Whole-body TH content and thyroid follicle histology were used as direct endpoints to assess thyroid disruption. The activities of iodothyronine deiodinases (IDs) and the transcription of selected genes associated with TH synthesis were also investigated to study the underlying mechanisms of endocrine disruption. Exposure of zebrafish to MC-LR significantly increased whole-body thyroxine (T4) content but decreased whole-body triiodothyronine (T3) content. We also observed hypertrophy and hyperplasia of the thyroid follicle epithelial cells, as well as up-regulation of corticotropin-releasing hormone (CRH), thyroid-stimulating hormone (TSH), thyroid peroxidase (TPO), and transthyretin (TTR) genes. The decreases in ID1 and ID2 activities coupled with an increase in ID3 activity were observed in MC-LR treatment groups. These results demonstrate that exposure to MC-LR at environmental concentrations results in the disturbance of TH homeostasis by disrupting the synthesis and conversion of THs. PMID:25647779

  16. Developmental lead exposure alters gene expression of metabotropic glutamate receptors in rat hippocampal neurons.

    PubMed

    Xu, Jian; Yan, Chong-Huai; Wu, Sheng-Hu; Yu, Xiao-Dan; Yu, Xiao-Gang; Shen, Xiao-Ming

    2007-02-21

    Exposure to lead in utero and in infancy is associated with a risk of impaired cognitive development. Increasing evidence suggests that the family of metabotropic glutamate receptors (mGluRs) plays an important role in synaptic plasticity and memory formation. We determined whether mGluRs subtypes 1, 3, and 7 (mGluR1, mGluR3, and mGluR7) were involved in developmental neurotoxicity due to lead. Embryonic rat hippocampal neurons were cultured for 21 days and exposed to lead chloride beginning on the fourth day of incubation. We investigated levels of mGluR1, mGluR3, and mGluR7 mRNA expression by using quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) with lead exposure at 10 nM, 1 microM, and 100 microM. Lead exposure in vitro downregulated the expression of mGluR1 mRNA and upregulated the expression of mGluR3 and mGluR7 mRNA in a dose-dependent manner. We speculate that mGluRs may be involved in lead neurotoxicity. Pathways that likely contribute to lead neurotoxicity by means of mGluRs are impairment of long-term potentiation, effects on N-methyl-D-aspartate (NMDA) receptor functions, and depotentiation. PMID:17267122

  17. Subacute microcystin-LR exposure alters the metabolism of thyroid hormones in juvenile zebrafish (Danio Rerio).

    PubMed

    Liu, Zidong; Tang, Rong; Li, Dapeng; Hu, Qing; Wang, Ying

    2015-02-01

    Microcystin-LR (MC-LR) has been detected extensively in the aquatic environment and has the potential to disturb the thyroid endocrine system. However, limited information is available on the effects of subacute MC-LR exposure on fish thyroid hormone (TH) metabolism. In the present study, juvenile zebrafish (Danio rerio) were exposed to MC-LR at environmentally relevant concentrations (0, 1, 5, and 25 μg/L) for 28 days. Whole-body TH content and thyroid follicle histology were used as direct endpoints to assess thyroid disruption. The activities of iodothyronine deiodinases (IDs) and the transcription of selected genes associated with TH synthesis were also investigated to study the underlying mechanisms of endocrine disruption. Exposure of zebrafish to MC-LR significantly increased whole-body thyroxine (T4) content but decreased whole-body triiodothyronine (T3) content. We also observed hypertrophy and hyperplasia of the thyroid follicle epithelial cells, as well as up-regulation of corticotropin-releasing hormone (CRH), thyroid-stimulating hormone (TSH), thyroid peroxidase (TPO), and transthyretin (TTR) genes. The decreases in ID1 and ID2 activities coupled with an increase in ID3 activity were observed in MC-LR treatment groups. These results demonstrate that exposure to MC-LR at environmental concentrations results in the disturbance of TH homeostasis by disrupting the synthesis and conversion of THs. PMID:25647779

  18. Histopathologic alterations associated with global gene expression due to chronic dietary TCDD exposure in juvenile zebrafish.

    PubMed

    Liu, Qing; Spitsbergen, Jan M; Cariou, Ronan; Huang, Chun-Yuan; Jiang, Nan; Goetz, Giles; Hutz, Reinhold J; Tonellato, Peter J; Carvan, Michael J

    2014-01-01

    The goal of this project was to investigate the effects and possible developmental disease implication of chronic dietary TCDD exposure on global gene expression anchored to histopathologic analysis in juvenile zebrafish by functional genomic, histopathologic and analytic chemistry methods. Specifically, juvenile zebrafish were fed Biodiet starter with TCDD added at 0, 0.1, 1, 10 and 100 ppb, and fish were sampled following 0, 7, 14, 28 and 42 d after initiation of the exposure. TCDD accumulated in a dose- and time-dependent manner and 100 ppb TCDD caused TCDD accumulation in female (15.49 ppb) and male (18.04 ppb) fish at 28 d post exposure. Dietary TCDD caused multiple lesions in liver, kidney, intestine and ovary of zebrafish and functional dysregulation such as depletion of glycogen in liver, retrobulbar edema, degeneration of nasal neurosensory epithelium, underdevelopment of intestine, and diminution in the fraction of ovarian follicles containing vitellogenic oocytes. Importantly, lesions in nasal epithelium and evidence of endocrine disruption based on alternatively spliced vasa transcripts are two novel and significant results of this study. Microarray gene expression analysis comparing vehicle control to dietary TCDD revealed dysregulated genes involved in pathways associated with cardiac necrosis/cell death, cardiac fibrosis, renal necrosis/cell death and liver necrosis/cell death. These baseline toxicological effects provide evidence for the potential mechanisms of developmental dysfunctions induced by TCDD and vasa as a biomarker for ovarian developmental disruption. PMID:24988445

  19. Histopathologic Alterations Associated with Global Gene Expression Due to Chronic Dietary TCDD Exposure in Juvenile Zebrafish

    PubMed Central

    Liu, Qing; Spitsbergen, Jan M.; Cariou, Ronan; Huang, Chun-Yuan; Jiang, Nan; Goetz, Giles; Hutz, Reinhold J.; Tonellato, Peter J.; Carvan, Michael J.

    2014-01-01

    The goal of this project was to investigate the effects and possible developmental disease implication of chronic dietary TCDD exposure on global gene expression anchored to histopathologic analysis in juvenile zebrafish by functional genomic, histopathologic and analytic chemistry methods. Specifically, juvenile zebrafish were fed Biodiet starter with TCDD added at 0, 0.1, 1, 10 and 100 ppb, and fish were sampled following 0, 7, 14, 28 and 42 d after initiation of the exposure. TCDD accumulated in a dose- and time-dependent manner and 100 ppb TCDD caused TCDD accumulation in female (15.49 ppb) and male (18.04 ppb) fish at 28 d post exposure. Dietary TCDD caused multiple lesions in liver, kidney, intestine and ovary of zebrafish and functional dysregulation such as depletion of glycogen in liver, retrobulbar edema, degeneration of nasal neurosensory epithelium, underdevelopment of intestine, and diminution in the fraction of ovarian follicles containing vitellogenic oocytes. Importantly, lesions in nasal epithelium and evidence of endocrine disruption based on alternatively spliced vasa transcripts are two novel and significant results of this study. Microarray gene expression analysis comparing vehicle control to dietary TCDD revealed dysregulated genes involved in pathways associated with cardiac necrosis/cell death, cardiac fibrosis, renal necrosis/cell death and liver necrosis/cell death. These baseline toxicological effects provide evidence for the potential mechanisms of developmental dysfunctions induced by TCDD and vasa as a biomarker for ovarian developmental disruption. PMID:24988445

  20. Chronic fluoxetine exposure alters movement and burrowing in adult freshwater mussels.

    PubMed

    Hazelton, Peter D; Du, Bowen; Haddad, Samuel P; Fritts, Andrea K; Chambliss, C Kevin; Brooks, Bryan W; Bringolf, Robert B

    2014-06-01

    The antidepressant fluoxetine is commonly found in aquatic fauna living near or downstream from point-sources of municipal waste effluent. Continuous release of fluoxetine results in increased effective exposure duration in surface waters, resulting in a chronic exposure for animals downstream, particularly in effluent dominated ecosystems. Fluoxetine is known to cause disruptions in reproductive behavior of freshwater mussels (order Unionoida), including stimulating release of gametes, parturition of glochidia (larvae), and changes in lure display and foot protrusion. However, the ecological relevance of these effects at environmental concentrations is unknown. We conducted a 67-d exposure of adult Lampsilis fasciola to fluoxetine concentrations of 0, 0.5, 2.5, and 22.3μg/L and assessed impacts on behavior (lateral movement, burrowing, and filtering) and metabolism (glycogen storage and respiration). Mussels treated with 2.5 and 22.3μg/L fluoxetine displayed mantle lures significantly (p<0.05) more than controls. Animals treated with 22.3μg/L fluoxetine were statistically more likely to have shorter time-to-movement, greater total movement, and initiate burrowing sooner than control animals. These observations suggest that increased activity of mussels exposed to fluoxetine may result in increased susceptibility to predators and may lead to a reduction in energy stores. PMID:24438840

  1. Traffic pollution exposure is associated with altered brain connectivity in school children.

    PubMed

    Pujol, Jesus; Martínez-Vilavella, Gerard; Macià, Dídac; Fenoll, Raquel; Alvarez-Pedrerol, Mar; Rivas, Ioar; Forns, Joan; Blanco-Hinojo, Laura; Capellades, Jaume; Querol, Xavier; Deus, Joan; Sunyer, Jordi

    2016-04-01

    Children are more vulnerable to the effects of environmental elements due to their active developmental processes. Exposure to urban air pollution has been associated with poorer cognitive performance, which is thought to be a result of direct interference with brain maturation. We aimed to assess the extent of such potential effects of urban pollution on child brain maturation using general indicators of vehicle exhaust measured in the school environment and a comprehensive imaging evaluation. A group of 263 children, aged 8 to 12years, underwent MRI to quantify regional brain volumes, tissue composition, myelination, cortical thickness, neural tract architecture, membrane metabolites, functional connectivity in major neural networks and activation/deactivation dynamics during a sensory task. A combined measurement of elemental carbon and NO2 was used as a putative marker of vehicle exhaust. Air pollution exposure was associated with brain changes of a functional nature, with no evident effect on brain anatomy, structure or membrane metabolites. Specifically, a higher content of pollutants was associated with lower functional integration and segregation in key brain networks relevant to both inner mental processes (the default mode network) and stimulus-driven mental operations. Age and performance (motor response speed) both showed the opposite effect to that of pollution, thus indicating that higher exposure is associated with slower brain maturation. In conclusion, urban air pollution appears to adversely affect brain maturation in a critical age with changes specifically concerning the functional domain. PMID:26825441

  2. Chronic diclofenac (DCF) exposure alters both enzymatic and haematological profile of African catfish, Clarias gariepinus.

    PubMed

    Ajima, Malachy N O; Ogo, Ogo A; Audu, Bala S; Ugwoegbu, Kyrian C

    2015-10-01

    Pharmaceuticals are used extensively in human and veterinary medicine to eradicate or prevent diseases. The residues of these drugs have been detected in aquatic ecosystem; nevertheless, their toxicological effects on Clarias gariepinus have not been critically investigated. In this study, the toxic effects of diclofenac (DCF), a non-steroid anti-inflammatory drug, were studied in C. gariepinus by acute and chronic static renewable bioassay. The 96 h LC50 of DCF to C. gariepinus was 25.12 mg/L. Exposure to acute toxicity resulted in abnormal behavior and mortality of some fish. Compared with the control, chronic exposure of the fish to concentration (1.57, 3.14 and 6.28 mg/L) showed significantly higher mean corpuscular haemoglobin concentration (MCHC), mean corpuscular volume (MCV) and white blood cell (WBC), with significantly lower haemoglobin (Hb), haematocrit, red blood cell (RBC) and mean corpuscular haemoglobin (MCH) with increase in the concentration of the drug. Furthermore, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and glucose values significantly increased while protein levels were reduced (p < 0.05) in serum and gills throughout the 42-day exposure period. The study reports that DCF-induced enzymatic and haematological changes in the fish and recommends that these parameters be used as potential biomarkers for assessing residual pharmaceuticals available in aquatic ecosystem. PMID:25367777

  3. Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area.

    PubMed

    Sarti, Federica; Borgland, Stephanie L; Kharazia, Viktor N; Bonci, Antonello

    2007-08-01

    Growing evidence indicates that the expression of synaptic plasticity in the central nervous system results in dendritic reorganization and spine remodeling. Although long-term potentiation of glutamatergic synapses after cocaine exposure in the ventral tegmental area (VTA) has been proposed as a cellular mechanism underlying addictive behaviors, the relationship between long-term potentiation and dendritic remodeling induced by cocaine on the dopaminergic neurons of the VTA has not been demonstrated. Here we report that rat VTA cells classified as type I and II showed distinct morphological responses to cocaine, as a single cocaine exposure significantly increased dendritic spine density in type I but not in type II cells. Further, only type I cells had a significant increase in the AMPA receptor:NMDA receptor ratio after a single cocaine exposure. Taken together, our data provide evidence that increased spine density and synaptic plasticity are coexpressed within the same VTA neuronal population and that only type I neurons are structurally and synaptically modified by cocaine. PMID:17686047

  4. Time Course of Behavioral Alteration and mRNA Levels of Neurotrophic Factor Following Stress Exposure in Mouse.

    PubMed

    Hashikawa, Naoya; Ogawa, Takumi; Sakamoto, Yusuke; Ogawa, Mami; Matsuo, Yumi; Zamami, Yoshito; Hashikawa-Hobara, Narumi

    2015-08-01

    Stress is known to affect neurotrophic factor expression, which induces depression-like behavior. However, whether there are time-dependent changes in neurotrophic factor mRNA expression following stress remains unclear. In the present study, we tested whether chronic stress exposure induces long-term changes in depression-related behavior, serum corticosterone, and hippocampal proliferation as well as neurotrophic factor family mRNA levels, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and ciliary neurotrophic factor (CNTF), in the mouse hippocampus. The mRNA level of neurotrophic factors (BDNF, NGF, NT-3, and CNTF) was measured using the real-time PCR. The serum corticosterone level was evaluated by enzyme-linked immunosorbent assay, and, for each subject, the hippocampal proliferation was examined by 5-bromo-2-deoxyuridine immunostaining. Mice exhibited depression-like behavior in the forced-swim test (FST) and decreased BDNF mRNA and hippocampal proliferation in the middle of the stress exposure. After 15 days of stress exposure, we observed increased immobility in the FST, serum corticosterone levels, and BDNF mRNA levels and degenerated hippocampal proliferation, maintained for at least 2 weeks. Anhedonia-like behavior in the sucrose preference test and NGF mRNA levels were decreased following 15 days of stress. NGF mRNA levels were significantly higher 1 week after stress exposure. The current data demonstrate that chronic stress exposure induces prolonged BDNF and NGF mRNA changes and increases corticosterone levels and depression-like behavior in the FST, but does not alter other neurotrophic factors or performance in the sucrose preference test. PMID:25820756

  5. Altered resistance to Trichinella spiralis infection following subchronic exposure of adult mice to chemicals of environmental concern

    SciTech Connect

    Luebke, R.W.

    1981-01-01

    The effects of subchronic chemical exposure on expulsion of adult Trichinella spiralis from the small intestine of mice and encystment of newborn larvae in the host's musculature were investigated. Exposure to diethylstilbestrol, benzo(a)pyrene, tris-(1,3-dichloro-2-propyl) phosphate, cyclophosphamide, phorbol myristate acetate, and dimethylvinylchloride prior to infection of mice with 200 infective larvae resulted in larger worm burdens in treated animals than in controls 14 days after infection. Worm expulsion was not affected by exposure to tris-(2,3-dibromopropyl)phosphate, orthophenylphenol, and indomethacin. Increased burdens of muscle-phase larvae were found in animals that maintained significant numbers of adult worms in the gut at 14 days, except in mice administered diethylstilbestrol and dimethylvinylchloride. Exposure to diethylstilbestrol and cyclophosphamide resulted in decreased inflammatory reactions in the tissues of the small intestine and development of bone marrow eosinophilia in infected mice. Marrow eosinophilia was likewise decreased in mice given tris-(1,3-dichloro-2-propyl)phosphate before infection. Additional studies with diethylstilbestrol administered either before, at the time of, or after infection showed inhibition of worm expulsion. Drug exposure during a primary infection inhibited the expulsion of a second T. spiralis infection, but did not affect worm elimination when given during a second infection. Treatment with diethylstilbestrol after artificial sensitization of mice with Trichinella antigens decreased delayed hypersensitivity responses to the sensitizing antigen. Immune functions, assessed by lymphoproliferative responses to mitogens and antibody responses to sheep red blood cells, generally correlated with altered host resistance to T. spiralis infection.

  6. Prenatal exposure to dexamethasone in the mouse alters cardiac growth patterns and increases pulse pressure in aged male offspring.

    PubMed

    O'Sullivan, Lee; Cuffe, James S M; Paravicini, Tamara M; Campbell, Sally; Dickinson, Hayley; Singh, Reetu R; Gezmish, Oksan; Black, M Jane; Moritz, Karen M

    2013-01-01

    Exposure to synthetic glucocorticoids during development can result in later cardiovascular and renal disease in sheep and rats. Although prenatal glucocorticoid exposure is associated with impaired renal development, less is known about effects on the developing heart. This study aimed to examine the effects of a short-term exposure to dexamethasone (60 hours from embryonic day 12.5) on the developing mouse heart, and cardiovascular function in adult male offspring. Dexamethasone (DEX) exposed fetuses were growth restricted compared to saline treated controls (SAL) at E14.5, but there was no difference between groups at E17.5. Heart weights of the DEX fetuses also tended to be smaller at E14.5, but not different at E17.5. Cardiac AT1aR, Bax, and IGF-1 mRNA expression was significantly increased by DEX compared to SAL at E17.5. In 12-month-old offspring DEX exposure caused an increase in basal blood pressure of ~3 mmHg. In addition, DEX exposed mice had a widened pulse pressure compared to SAL. DEX exposed males at 12 months had an approximate 25% reduction in nephron number compared to SAL, but no difference in cardiomyocyte number. Exposure to DEX in utero appears to adversely impact on nephrogenesis and heart growth but is not associated with a cardiomyocyte deficit in male mice in adulthood, possibly due to compensatory growth of the myocardium following the initial insult. However, the widened pulse pressure may be indicative of altered vascular compliance. PMID:23935943

  7. Prenatal Exposure to Dexamethasone in the Mouse Alters Cardiac Growth Patterns and Increases Pulse Pressure in Aged Male Offspring

    PubMed Central

    O'Sullivan, Lee; Cuffe, James S. M.; Paravicini, Tamara M.; Campbell, Sally; Dickinson, Hayley; Singh, Reetu R.; Gezmish, Oksan; Black, M. Jane; Moritz, Karen M.

    2013-01-01

    Exposure to synthetic glucocorticoids during development can result in later cardiovascular and renal disease in sheep and rats. Although prenatal glucocorticoid exposure is associated with impaired renal development, less is known about effects on the developing heart. This study aimed to examine the effects of a short-term exposure to dexamethasone (60 hours from embryonic day 12.5) on the developing mouse heart, and cardiovascular function in adult male offspring. Dexamethasone (DEX) exposed fetuses were growth restricted compared to saline treated controls (SAL) at E14.5, but there was no difference between groups at E17.5. Heart weights of the DEX fetuses also tended to be smaller at E14.5, but not different at E17.5. Cardiac AT1aR, Bax, and IGF-1 mRNA expression was significantly increased by DEX compared to SAL at E17.5. In 12-month-old offspring DEX exposure caused an increase in basal blood pressure of ∼3 mmHg. In addition, DEX exposed mice had a widened pulse pressure compared to SAL. DEX exposed males at 12 months had an approximate 25% reduction in nephron number compared to SAL, but no difference in cardiomyocyte number. Exposure to DEX in utero appears to adversely impact on nephrogenesis and heart growth but is not associated with a cardiomyocyte deficit in male mice in adulthood, possibly due to compensatory growth of the myocardium following the initial insult. However, the widened pulse pressure may be indicative of altered vascular compliance. PMID:23935943

  8. Alteration of the Carbon and Nitrogen Isotopic Composition in the Martian Surface Rocks Due to Cosmic Ray Exposure

    NASA Technical Reports Server (NTRS)

    Pavlov, A. A.; Pavlov, A. K.; Ostryakov, V. M.; Vasilyev, G. I.; Mahaffy, P.; Steele, A.

    2014-01-01

    C-13/C-12 and N-15/N-14 isotopic ratios are pivotal for our understanding of the Martian carbon cycle, history of the Martian atmospheric escape, and origin of the organic compounds on Mars. Here we demonstrate that the carbon and nitrogen isotopic composition of the surface rocks on Mars can be significantly altered by the continuous exposure of Martian surface to cosmic rays. Cosmic rays can effectively produce C-13 and N-15 isotopes via spallation nuclear reactions on oxygen atoms in various Martian rocks. We calculate that in the top meter of the Martian rocks, the rates of production of both C-13 and N-15 due to galactic cosmic rays (GCRs) exposure can vary within 1.5-6 atoms/cm3/s depending on rocks' depth and chemical composition. We also find that the average solar cosmic rays can produce carbon and nitrogen isotopes at a rate comparable to GCRs in the top 5-10 cm of the Martian rocks. We demonstrate that if the total carbon content in a surface Martian rock is <10 ppm, then the "light," potentially "biological" C-13/C-12 ratio would be effectively erased by cosmic rays over 3.5 billion years of exposure. We found that for the rocks with relatively short exposure ages (e.g., 100 million years), cosmogenic changes in N-15/N-14 ratio are still very significant. We also show that a short exposure to cosmic rays of Allan Hills 84001 while on Mars can explain its high-temperature heavy nitrogen isotopic composition (N-15/N-14). Applications to Martian meteorites and the current Mars Science Laboratory mission are discussed.

  9. Repeated exposure to neurotoxic levels of chlorpyrifos alters hippocampal expression of neurotrophins and neuropeptides.

    PubMed

    Lee, Young S; Lewis, John A; Ippolito, Danielle L; Hussainzada, Naissan; Lein, Pamela J; Jackson, David A; Stallings, Jonathan D

    2016-01-18

    Chlorpyrifos (CPF), an organophosphorus pesticide (OP), is one of the most widely used pesticides in the world. Subchronic exposures to CPF that do not cause cholinergic crisis are associated with problems in cognitive function (i.e., learning and memory deficits), but the biological mechanism(s) underlying this association remain speculative. To identify potential mechanisms of subchronic CPF neurotoxicity, adult male Long Evans (LE) rats were administered CPF at 3 or 10mg/kg/d (s.c.) for 21 days. We quantified mRNA and non-coding RNA (ncRNA) expression profiles by RNA-seq, microarray analysis and small ncRNA sequencing technology in the CA1 region of the hippocampus. Hippocampal slice immunohistochemistry was used to determine CPF-induced changes in protein expression and localization patterns. Neither dose of CPF caused overt clinical signs of cholinergic toxicity, although after 21 days of exposure, cholinesterase activity was decreased to 58% or 13% of control levels in the hippocampus of rats in the 3 or 10mg/kg/d groups, respectively. Differential gene expression in the CA1 region of the hippocampus was observed only in the 10mg/kg/d dose group relative to controls. Of the 1382 differentially expressed genes identified by RNA-seq and microarray analysis, 67 were common to both approaches. Differential expression of six of these genes (Bdnf, Cort, Crhbp, Nptx2, Npy and Pnoc) was verified in an independent CPF exposure study; immunohistochemistry demonstrated that CRHBP and NPY were elevated in the CA1 region of the hippocampus at 10mg/kg/d CPF. Gene ontology enrichment analysis suggested association of these genes with receptor-mediated cell survival signaling pathways. miR132/212 was also elevated in the CA1 hippocampal region, which may play a role in the disruption of neurotrophin-mediated cognitive processes after CPF administration. These findings identify potential mediators of CPF-induced neurobehavioral deficits following subchronic exposure to CPF at

  10. Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny.

    PubMed

    Haddad, Rami; Kasneci, Amanda; Mepham, Kathryn; Sebag, Igal A; Chalifour, Lorraine E

    2013-01-01

    Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5-14.5. At 3months, male progeny were left sedentary or were swim trained for 4weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. PMID:23142472

  11. Maternal exposure to fish oil primes offspring to harbor intestinal pathobionts associated with altered immune cell balance.

    PubMed

    Gibson, D L; Gill, S K; Brown, K; Tasnim, N; Ghosh, S; Innis, S; Jacobson, K

    2015-01-01

    Our previous studies revealed that offspring from rat dams fed fish oil (at 8% and 18% energy), developed impaired intestinal barriers sensitizing the colon to exacerbated injury later in life. To discern the mechanism, we hypothesized that in utero exposure to fish oil, rich in n-3 polyunsaturated fatty acid (PUFA), caused abnormal intestinal reparative responses to mucosal injury through differences in intestinal microbiota and the presence of naïve immune cells. To identify such mechanisms, gut microbes and naïve immune cells were compared between rat pups born to dams fed either n-6 PUFA, n-3 PUFA or breeder chow. Maternal exposure to either of the PUFA rich diets altered the development of the intestinal microbiota with an overall reduction in microbial density. Using qPCR, we found that each type of PUFA differentially altered the major gut phyla; fish oil increased Bacteroidetes and safflower oil increased Firmicutes. Both PUFA diets reduced microbes known to dominate the infant gut like Enterobacteriaceae and Bifidobacteria spp. when compared to the chow group. Uniquely, maternal fish oil diets resulted in offspring showing blooms of opportunistic pathogens like Bilophila wadsworthia, Enterococcus faecium and Bacteroides fragilis in their gut microbiota. As well, fish oil groups showed a reduction in colonic CD8+ T cells, CD4+ Foxp3+ T cells and arginase+ M2 macrophages. In conclusion, fish oil supplementation in pharmacological excess, at 18% by energy as shown in this study, provides an example where excess dosing in utero can prime offspring to harbor intestinal pathobionts and alter immune cell homeostasis. PMID:25559197

  12. Acute effects of tetracycline exposure in the freshwater fish Gambusia holbrooki: antioxidant effects, neurotoxicity and histological alterations.

    PubMed

    Nunes, B; Antunes, S C; Gomes, R; Campos, J C; Braga, M R; Ramos, A S; Correia, A T

    2015-02-01

    A large body of evidence was compiled in the recent decades showing a noteworthy increase in the detection of pharmaceutical drugs in aquatic ecosystems. Due to its ubiquitous presence, chemical nature, and practical purpose, this type of contaminant can exert toxic effects in nontarget organisms. Exposure to pharmaceutical drugs can result in adaptive alterations, such as changes in tissues, or in key homeostatic mechanisms, such as antioxidant mechanisms, biochemical/physiological pathways, and cellular damage. These alterations can be monitored to determine the impact of these compounds on exposed aquatic organisms. Among pharmaceutical drugs in the environment, antibiotics are particularly important because they include a variety of substances widely used in medical and veterinary practice, livestock production, and aquaculture. This wide use constitutes a decisive factor contributing for their frequent detection in the aquatic environment. Tetracyclines are the individual antibiotic subclass with the second highest frequency of detection in environmental matrices. The characterization of the potential ecotoxicological effects of tetracycline is a much-required task; to attain this objective, the present study assessed the acute toxic effects of tetracycline in the freshwater fish species Gambusia holbrooki by the determination of histological changes in the gills and liver, changes in antioxidant defense [glutathione S-transferase (GST), catalase (CAT), and lipoperoxidative damage] as well as potential neurotoxicity (acetylcholinesterase activity). The obtained results suggest the existence of a cause-and-effect relationship between the exposure to tetracycline and histological alterations (more specifically in gills) and enzymatic activity (particularly the enzyme CAT in liver and GST in gills) indicating that this compound can exert a pro-oxidative activity. PMID:25475590

  13. Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp

    PubMed Central

    2014-01-01

    Background Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Results Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. Conclusions These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate. PMID:24655547

  14. Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab.

    PubMed

    Sharieh, Elham Abu; Awidi, Abdulla S; Ahram, Mamoun; Zihlif, Malek A

    2016-01-10

    Development of resistance against cancer therapeutic agents is a common problem in cancer management. Trastuzumab resistance is one of the challenges in management of HER-2-positive breast cancer patients resulting in breast cancer progression, metastasis, and patient poor outcome. The aim of this study is to determine the alteration in gene expression in response to Trastuzumab resistance after long-term exposure to Trastuzumab. The Trastuzumab-resistant MDA-MB-453 (MDA-MB-453/TR) cell line was developed by exposing cells to 10 μM Trastuzumab continuously for 6 months. Sensitivity toward Trastuzumab was tested using cell viability assays. The acquisition of an epithelial-to mesenchymal transition (EMT) phenotype was also observed in parallel with the development of resistance. Based on the real-time-based PCR array technology, several genes were altered affecting multiple networks. The most up-regulated genes were TGF-β1 and EGF, and IGFBP-3. These genes are known to have a critical role in Trastuzumab resistance in breast cancer cell lines and/or in the acquisition of EMT. They are also recognized for their role in cancer progression and metastasis. These alterations indicate that the development of Trastuzumab resistance is multifactorial and involves a development of a mesenchymal like phenotype. PMID:26367328

  15. Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome.

    PubMed

    Duncan, Jhodie R; Garland, Marianne; Myers, Michael M; Fifer, William P; Yang, May; Kinney, Hannah C; Stark, Raymond I

    2009-11-01

    During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors. PMID:19729586

  16. Exposure to a glyphosate-based herbicide during pregnancy and lactation induces neurobehavioral alterations in rat offspring.

    PubMed

    Gallegos, Cristina E; Bartos, Mariana; Bras, Cristina; Gumilar, Fernanda; Antonelli, Marta C; Minetti, Alejandra

    2016-03-01

    The impact of sub-lethal doses of herbicides on human health and the environment is a matter of controversy. Due to the fact that evidence particularly of the effects of glyphosate on the central nervous system of rat offspring by in utero exposure is scarce, the purpose of the present study was to assess the neurobehavioral effects of chronic exposure to a glyphosate-containing herbicide during pregnancy and lactation. To this end, pregnant Wistar rats were exposed through drinking water to 0.2% or 0.4% of a commercial formulation of glyphosate (corresponding to a concentration of 0.65 or 1.30g/L of glyphosate, respectively) during pregnancy and lactation and neurobehavioral alterations in offspring were analyzed. The postnatal day on which each pup acquired neonatal reflexes (righting, cliff aversion and negative geotaxis) and that on which eyes and auditory canals were fully opened were recorded for the assessment of sensorimotor development. Locomotor activity and anxiety levels were monitored via open field test and plus maze test, respectively, in 45- and 90-day-old offspring. Pups exposed to a glyphosate-based herbicide showed early onset of cliff aversion reflex and early auditory canal opening. A decrease in locomotor activity and in anxiety levels was also observed in the groups exposed to a glyphosate-containing herbicide. Findings from the present study reveal that early exposure to a glyphosate-based herbicide affects the central nervous system in rat offspring probably by altering mechanisms or neurotransmitter systems that regulate locomotor activity and anxiety. PMID:26632987

  17. Early life exposure to environmental tobacco smoke alters immune response to asbestos via a shift in inflammatory phenotype resulting in increased disease development.

    PubMed

    Brown, Traci Ann; Holian, Andrij; Pinkerton, Kent E; Lee, Joong Won; Cho, Yoon Hee

    2016-07-01

    Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual's lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development. PMID:27138493

  18. Chronic cigarette smoke exposure adversely alters /sup 14/C-arachidonic acid metabolism in rat lungs, aortas and platelets

    SciTech Connect

    Lubawy, W.C.; Valentovic, M.A.; Atkinson, J.E.; Gairola, G.C.

    1983-08-08

    Male rats were exposed to freshly generated cigarette smoke once daily, 5 times a week for 10 weeks. Inhalation of smoke was verified by elevated carboxyhemoglobin in blood sampled immediately after smoke exposure and by increased lung aryl hydrocarbon hydroxylase activity 24 hours after the last smoke exposure. Aortic rings isolated from smoke-exposed rats synthesized less prostacyclin (PGI2) from /sup 14/C-arachidonic acid than rings from sham rats. Platelets from smoke-exposed rats synthesized more thromboxane (TXA2) from /sup 14/C-arachidonic acid than platelets from room controls but not those from sham rats. Lung microsomes from smoke-exposed rats synthesized more TXA2 and had a lower PGI2/TXA2 ratio than lung microsomes from room controls and shams. It is concluded that chronic cigarette smoke exposure alters arachidonic acid metabolism in aortas, platelets and lungs in a manner resulting in decreased PGI2 and increased TXA2, thereby creating a condition favoring platelet aggregation and a variety of cardiovascular diseases.

  19. Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring.

    PubMed

    Zumbrun, Elizabeth E; Sido, Jessica M; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2015-06-01

    Use of marijuana during pregnancy is fairly commonplace and can be expected increase in frequency as more states legalize its recreational use. The cannabinoids present in marijuana have been shown to be immunosuppressive, yet the effect of prenatal exposure to cannabinoids on the immune system of the developing fetus, its long term consequences during adult stage of life, and transgenerational effects have not been well characterized. Confounding factors such as co-existing drug use make the impact of cannabis use on progeny inherently difficult to study in a human population. Data from various animal models suggests that in utero exposure to cannabinoids results in profound T cell dysfunction and a greatly reduced immune response to viral antigens. Furthermore, evidence from animal studies indicates that the immunosuppressive effects of cannabinoids can be mediated through epigenetic mechanisms such as altered microRNA, DNA methylation and histone modification profiles. Such studies support the hypothesis that that parental or prenatal exposure to cannabis can trigger epigenetic changes that could have significant immunological consequences for offspring as well as long term transgenerational effects. PMID:25618446

  20. Short-term exposure of arsenite disrupted thyroid endocrine system and altered gene transcription in the HPT axis in zebrafish.

    PubMed

    Sun, Hong-Jie; Li, Hong-Bo; Xiang, Ping; Zhang, Xiaowei; Ma, Lena Q

    2015-10-01

    Arsenic (As) pollution in aquatic environment may adversely impact fish health by disrupting their thyroid hormone homeostasis. In this study, we explored the effect of short-term exposure of arsenite (AsIII) on thyroid endocrine system in zebrafish. We measured As concentrations, As speciation, and thyroid hormone thyroxine levels in whole zebrafish, oxidative stress (H2O2) and damage (MDA) in the liver, and gene transcription in hypothalamic-pituitary-thyroid (HPT) axis in the brain and liver tissues of zebrafish after exposing to different AsIII concentrations for 48 h. Result indicated that exposure to AsIII increased inorganic As in zebrafish to 0.46-0.72 mg kg(-1), induced oxidative stress with H2O2 being increased by 1.4-2.5 times and caused oxidative damage with MDA being augmented by 1.6 times. AsIII exposure increased thyroxine levels by 1.3-1.4 times and modulated gene transcription in HPT axis. Our study showed AsIII caused oxidative damage, affected thyroid endocrine system and altered gene transcription in HPT axis in zebrafish. PMID:26057477

  1. Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring

    PubMed Central

    Zumbrun, Elizabeth E.; Sido, Jessica M.; Nagarkatti, Prakash S.

    2015-01-01

    Use of marijuana during pregnancy is fairly commonplace and can be expected increase in frequency as more states legalize its recreational use. The cannabinoids present in marijuana have been shown to be immunosuppressive, yet the effect of prenatal exposure to cannabinoids on the immune system of the developing fetus, its long term consequences during adult stage of life, and transgenerational effects have not been well characterized. Confounding factors such as coexisting drug use make the impact of cannabis use on progeny inherently difficult to study in a human population. Data from various animal models suggests that in utero exposure to cannabinoids results in profound T cell dysfunction and a greatly reduced immune response to viral antigens. Furthermore, evidence from animal studies indicates that the immunosuppressive effects of cannabinoids can be mediated through epigenetic mechanisms such as altered microRNA, DNA methylation and histone modification profiles. Such studies support the hypothesis that that parental or prenatal exposure to cannabis can trigger epigenetic changes that could have significant immunological consequences for offspring as well as long term transgenerational effects. PMID:25618446

  2. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A.

    PubMed

    Yaoi, Takeshi; Itoh, Kyoko; Nakamura, Keiko; Ogi, Hiroshi; Fujiwara, Yasuhiro; Fushiki, Shinji

    2008-11-21

    Bisphenol A (BPA) is one of endocrine disrupting chemicals, being distributed widely in the environment. We have been studying the low dose effects of BPA on murine forebrain development. Here, we have investigated the genome-wide effect of maternal exposure to BPA on the epigenome in mouse forebrain at E12.5 and at E14.5. We scanned CpG methylation status in 2500 NotI loci, representing 48 (de)methylated unique loci. Methylation status in most of them was primarily developmental stage-dependent. Each of almost all cloned NotI loci was located in a CpG island (CGI) adjacent to 5' end of the transcriptional unit. The mRNA expression of two functionally related genes changed with development as well as the exposure to BPA. In both genes, changes at the transcriptional level correlated well with the changes in NotI methylation status. Taken together, epigenetic alterations in promoter-associated CGIs after exposure to BPA may underlie some effects on brain development. PMID:18804091

  3. Metabolic and feeding behavior alterations provoked by prenatal exposure to aspartame.

    PubMed

    von Poser Toigo, E; Huffell, A P; Mota, C S; Bertolini, D; Pettenuzzo, L F; Dalmaz, C

    2015-04-01

    The use of artificial sweeteners has increased together with the epidemic growth of obesity. In addition to their widespread use in sodas, artificial sweeteners are added to nearly 6000 other products sold in the US, including baby foods, frozen dinners and even yogurts. It has been suggested that the use of nonnutritive sweeteners can lead to body weight gain and an altered metabolic profile. However, very few studies have evaluated the effects of maternal consumption of artificial non-caloric sweeteners on body weight, feeding behavior or the metabolism of offspring in adult life. In this study, we found that animals exposed to aspartame during the prenatal period presented a higher consumption of sweet foods during adulthood and a greater susceptibility to alterations in metabolic parameters, such as increased glucose, LDL and triglycerides. These effects were observed in both males and females, although they were more pronounced in males. Despite the preliminary nature of this study, and the need for further confirmation of these effects, our data suggest that the consumption of sweeteners during gestation may have deleterious long-term effects and should be used with caution. PMID:25543075

  4. Skin alterations induced by long-term exposure to uranium and their effect on permeability.

    PubMed

    Ubios, A M; Marzorati, M; Cabrini, R L

    1997-05-01

    The skin is a probable route of incorporation of uranium by percutaneous absorption. The changes in epidermal thickness and their effect on skin permeability after uranium exposure are reported herein. Two experiments (A and B) were performed in Wistar rats weighing 60 g. In experiment A the animals were exposed to U3O8 (0.012 g d(-1)) in 30 daily topical applications. In experiment B the animals were treated as in experiment A, followed by a period of non-exposure of 60 d. Samples of the treated area of skin were taken for histologic studies and for the study of the skin permeability. The epidermal thickness was measured on the histological sections. Epidermis was thinner in experimental than in control animals in both experiments. The values in the control groups were 41.05 +/- 14.03 microm (A) and 38.92 +/- 16.50 microm (B) and 21.35 +/- 10.29 microm (A) and 24.06 +/- 16.50 microm (B) in the experimental groups, the differences being statistically significant. Skin permeability was measured placing skin samples in a diffusion cell, in which the upper compartment was filled with a staining solution. The determinations were made with a spectrophotometer. The results revealed that the skin permeability in both experimental groups was higher than in the respective controls, 65% in experiment A and 77% in experiment B. The results revealed that a long term uranium exposure leads to an epidermal atrophy which in turn results in an increased permeability of the skin. PMID:9106712

  5. Alterations in Rat Fetal Morphology Following Abuse Patterns of Toluene Exposure

    PubMed Central

    Bowen, Scott E.; Irtenkauf, Susan; Hannigan, John H.; Stefanski, Adrianne L.

    2009-01-01

    Toluene is a commonly abused organic solvent. Inhalant abusers are increasingly women in their prime childbearing years. Children born to mothers who abused solvents during pregnancy may exhibit characteristics of a “fetal solvent syndrome” which may include dysmorphic features. This study examined the teratological effects of an abuse pattern of binge toluene exposure during gestation on skeletal and soft tissue abnormalities, body weight, and body size in fetal rats. Pregnant Sprague–Dawley rats were exposed for 30 min, twice daily, from gestational day (GD) 8 through GD20 to either air (0 ppm), 8,000 ppm, 12,000 ppm, or 16,000 ppm toluene. Two-thirds of each litter was prepared for skeletal examination using Alizarin Red S staining while the remaining third of each litter was fixed in Bouin’s solution for Wilson’s soft tissue evaluation. Exposure to toluene at all levels significantly reduced growth, including decreases in placental weight, fetal weight, and crown-rump length. In addition, numerous gross morphological anomalies were observed such as short or missing digits and missing limbs. Skeletal examination revealed that ossification of the extremities was significantly reduced as a result of toluene exposure at all levels. Specific skeletal defects included misshapen scapula, missing and supernumerary vertebrae and ribs, and fused digits. Soft tissue anomalies were also observed at all toluene levels and there was a dose-dependent increase in the number of anomalies which included cryptorchidism, displaced abdominal organs, gastromegaly, distended/hypoplastic bladder, and delayed cardiac development, among others. These results indicate that animals exposed prenatally to levels and patterns of toluene typical of inhalant abuse are at increased risk for skeletal and soft tissue abnormalities. PMID:19429395

  6. Developmental exposure to bisphenol A (BPA) alters sexual differentiation in painted turtles (Chrysemys picta)

    USGS Publications Warehouse

    Jandegian, Caitlin M.; Deem, Sharon L.; Bhandari, Ramji K.; Holliday, Casey M.; Nicks, Diane; Rosenfeld, Cheryl S.; Selcer, Kyle; Tillitt, Donald E.; vom Saal, Fredrick S.; Velez, Vanessa; Yang, Ying; Holliday, Dawn K.

    2015-01-01

    Environmental chemicals can disrupt endocrine signaling and adversely impact sexual differentiation in wildlife. Bisphenol A (BPA) is an estrogenic chemical commonly found in a variety of habitats. In this study, we used painted turtles (Chrysemys picta), which have temperature-dependent sex determination (TSD), as an animal model for ontogenetic endocrine disruption by BPA. We hypothesized that BPA would override TSD and disrupt sexual development. We incubated farm-raised turtle eggs at the male-producing temperature (26 °C), randomly assigned individuals to treatment groups: control, vehicle control, 17β-estradiol (E2, 20 ng/g-egg) or 0.01, 1.0, 100 μg BPA/g-egg and harvested tissues at hatch. Typical female gonads were present in 89% of the E2-treated “males”, but in none of the control males (n = 35). Gonads of BPA-exposed turtles had varying amounts of ovarian-like cortical (OLC) tissue and disorganized testicular tubules in the medulla. Although the percentage of males with OLCs increased with BPA dose (BPA-low = 30%, BPA-medium = 33%, BPA-high = 39%), this difference was not significant (p = 0.85). In all three BPA treatments, SOX9 patterns revealed disorganized medullary testicular tubules and β-catenin expression in a thickened cortex. Liver vitellogenin, a female-specific liver protein commonly used as an exposure biomarker, was not induced by any of the treatments. Notably, these results suggest that developmental exposure to BPA disrupts sexual differentiation in painted turtles. Further examination is necessary to determine the underlying mechanisms of sex reversal in reptiles and how these translate to EDC exposure in wild populations.

  7. Manganese exposure among smelting workers: relationship between blood manganese-iron ratio and early onset neurobehavioral alterations.

    PubMed

    Cowan, Dallas M; Zheng, Wei; Zou, Yan; Shi, Xiujuan; Chen, Jian; Rosenthal, Frank S; Fan, Qiyuan

    2009-11-01

    A biomarker for detection of early onset neurobehavioral alterations in manganism remains unknown. The purpose of this study was to use a neurobehavioral test battery to identify subtle changes in Mn-induced motor and memory dysfunction and to relate the quantifiable neurological dysfunction to an established Mn-exposure index such as blood manganese-iron ratio (MIR). A total of 323 subjects were recruited to control (n=106), low-exposure (122), and high-exposure (95) groups. The test battery consisted of standard testing procedures including the nine-hole and groove-type steadiness tester, Benton visual retention test, and Purdue pegboard coordination test. No significant health problems or clinically diagnosed neurological dysfunctions were observed. Benton test did not reveal any abnormal memory deficits among Mn-exposed smelters, nor did the groove and nine-hole tests detect any abnormality in dynamic and static steadiness in tested subjects. Purdue pegboard test showed a remarkable age-related decline in fine movement coordination among all study participants regardless of the Mn-exposure condition. Mn exposure significantly exacerbated this age-related deterioration. Statistical modeling revealed that the plasma and erythrocyte MIR (i.e., pMIR and eMIR, respectively) were associated with Purdue pegboard scores. Among all subjects whose MIR were above the cut-off value (COV), pMIR was significantly correlated with pegboard scores (r=-0.261, p=0.002), whereas for those subjects over the age of 40, the eMIR, but not pMIR, was associated with declined pegboard performance (r=-0.219, p=0.069). When both factors were taken into account (i.e., age>40 and MIR>the COV), only pMIR was inversely associated with pegboard scores. Combining their usefulness in Mn-exposure assessment, we recommend that the blood Mn-Fe ratio may serve as a reasonable biomarker not only for assessment of Mn exposure but also for health risk assessment. PMID:19963104

  8. Short-duration exposure to radiofrequency electromagnetic radiation alters the chlorophyll fluorescence of duckweeds (Lemna minor).

    PubMed

    Senavirathna, Mudalige Don Hiranya Jayasanka; Takashi, Asaeda; Kimura, Yuichi

    2014-12-01

    Plants growing in natural environments are exposed to radiofrequency electromagnetic radiation (EMR) emitted by various communication network base stations. The environmental concentration of this radiation is increasing rapidly with the congested deployment of base stations. Although numerous scientific studies have been conducted to investigate the effects of EMR on the physiology of humans and animals, there have been few attempts to investigate the effects of EMR on plants. In this study, we attempted to evaluate the effects of EMR on photosynthesis by investigating the chlorophyll fluorescence (ChF) parameters of duckweed fronds. During the experiment, the fronds were tested with 2, 2.5, 3.5, 5.5 and 8 GHz EMR frequencies, which are not widely studied even though there is a potentially large concentration of these frequencies in the environment. The duckweed fronds were exposed to EMR for 30 min, 1 h and 24 h durations with electric field strength of 45-50 V/m for each frequency. The results indicated that exposure to EMR causes a change in the non-photochemical quenching of the duckweeds. The changes varied with the frequency of the EMR and were time-varying within a particular frequency. The temperature remained unchanged in the duckweed fronds upon exposure to EMR, which confirms that the effect is non-thermal. PMID:24131393

  9. Acute fluoxetine exposure alters crab anxiety-like behaviour, but not aggressiveness

    PubMed Central

    Hamilton, Trevor James; Kwan, Garfield T.; Gallup, Joshua; Tresguerres, Martin

    2016-01-01

    Aggression and responsiveness to noxious stimuli are adaptable traits that are ubiquitous throughout the animal kingdom. Like vertebrate animals, some invertebrates have been shown to exhibit anxiety-like behaviour and altered levels of aggression that are modulated by the neurotransmitter serotonin. To investigate whether this influence of serotonin is conserved in crabs and whether these behaviours are sensitive to human antidepressant drugs; the striped shore crab, Pachygrapsus crassipes, was studied using anxiety (light/dark test) and aggression (mirror test) paradigms. Crabs were individually exposed to acute doses of the selective serotonin reuptake inhibitor, fluoxetine (5 or 25 mg/L), commonly known as Prozac®, followed by behavioural testing. The high dose of fluoxetine significantly decreased anxiety-like behaviour but had no impact on mobility or aggression. These results suggest that anxiety-like behaviour is more sensitive to modulation of serotonin than is aggressiveness in the shore crab. PMID:26806870

  10. Sensorimotor learning in children and adults: Exposure to frequency-altered auditory feedback during speech production.

    PubMed

    Scheerer, N E; Jacobson, D S; Jones, J A

    2016-02-01

    Auditory feedback plays an important role in the acquisition of fluent speech; however, this role may change once speech is acquired and individuals no longer experience persistent developmental changes to the brain and vocal tract. For this reason, we investigated whether the role of auditory feedback in sensorimotor learning differs across children and adult speakers. Participants produced vocalizations while they heard their vocal pitch predictably or unpredictably shifted downward one semitone. The participants' vocal pitches were measured at the beginning of each vocalization, before auditory feedback was available, to assess the extent to which the deviant auditory feedback modified subsequent speech motor commands. Sensorimotor learning was observed in both children and adults, with participants' initial vocal pitch increasing following trials where they were exposed to predictable, but not unpredictable, frequency-altered feedback. Participants' vocal pitch was also measured across each vocalization, to index the extent to which the deviant auditory feedback was used to modify ongoing vocalizations. While both children and adults were found to increase their vocal pitch following predictable and unpredictable changes to their auditory feedback, adults produced larger compensatory responses. The results of the current study demonstrate that both children and adults rapidly integrate information derived from their auditory feedback to modify subsequent speech motor commands. However, these results also demonstrate that children and adults differ in their ability to use auditory feedback to generate compensatory vocal responses during ongoing vocalization. Since vocal variability also differed across the children and adult groups, these results also suggest that compensatory vocal responses to frequency-altered feedback manipulations initiated at vocalization onset may be modulated by vocal variability. PMID:26628403

  11. Ethanol exposure alters early cardiac function in the looping heart: a mechanism for congenital heart defects?

    PubMed Central

    Gu, Shi; Doughman, Yong Qiu; Peterson, Lindsy M.; Mai, Katherine; McHale, Quinn; Jenkins, Michael W.; Linask, Kersti K.; Rollins, Andrew M.; Watanabe, Michiko

    2013-01-01

    Alcohol-induced congenital heart defects are frequently among the most life threatening and require surgical correction in newborns. The etiology of these defects, collectively known as fetal alcohol syndrome, has been the focus of much study, particularly involving cellular and molecular mechanisms. Few studies have addressed the influential role of altered cardiac function in early embryogenesis because of a lack of tools with the capability to assay tiny beating hearts. To overcome this gap in our understanding, we used optical coherence tomography (OCT), a nondestructive imaging modality capable of micrometer-scale resolution imaging, to rapidly and accurately map cardiovascular structure and hemodynamics in real time under physiological conditions. In this study, we exposed avian embryos to a single dose of alcohol/ethanol at gastrulation when the embryo is sensitive to the induction of birth defects. Late-stage hearts were analyzed using standard histological analysis with a focus on the atrio-ventricular valves. Early cardiac function was assayed using Doppler OCT, and structural analysis of the cardiac cushions was performed using OCT imaging. Our results indicated that ethanol-exposed embryos developed late-stage valvuloseptal defects. At early stages, they exhibited increased regurgitant flow and developed smaller atrio-ventricular cardiac cushions, compared with controls (uninjected and saline-injected embryos). The embryos also exhibited abnormal flexion/torsion of the body. Our evidence suggests that ethanol-induced alterations in early cardiac function have the potential to contribute to late-stage valve and septal defects, thus demonstrating that functional parameters may serve as early and sensitive gauges of cardiac normalcy and abnormalities. PMID:24271490

  12. Ethanol exposure alters early cardiac function in the looping heart: a mechanism for congenital heart defects?

    PubMed

    Karunamuni, Ganga; Gu, Shi; Doughman, Yong Qiu; Peterson, Lindsy M; Mai, Katherine; McHale, Quinn; Jenkins, Michael W; Linask, Kersti K; Rollins, Andrew M; Watanabe, Michiko

    2014-02-01

    Alcohol-induced congenital heart defects are frequently among the most life threatening and require surgical correction in newborns. The etiology of these defects, collectively known as fetal alcohol syndrome, has been the focus of much study, particularly involving cellular and molecular mechanisms. Few studies have addressed the influential role of altered cardiac function in early embryogenesis because of a lack of tools with the capability to assay tiny beating hearts. To overcome this gap in our understanding, we used optical coherence tomography (OCT), a nondestructive imaging modality capable of micrometer-scale resolution imaging, to rapidly and accurately map cardiovascular structure and hemodynamics in real time under physiological conditions. In this study, we exposed avian embryos to a single dose of alcohol/ethanol at gastrulation when the embryo is sensitive to the induction of birth defects. Late-stage hearts were analyzed using standard histological analysis with a focus on the atrio-ventricular valves. Early cardiac function was assayed using Doppler OCT, and structural analysis of the cardiac cushions was performed using OCT imaging. Our results indicated that ethanol-exposed embryos developed late-stage valvuloseptal defects. At early stages, they exhibited increased regurgitant flow and developed smaller atrio-ventricular cardiac cushions, compared with controls (uninjected and saline-injected embryos). The embryos also exhibited abnormal flexion/torsion of the body. Our evidence suggests that ethanol-induced alterations in early cardiac function have the potential to contribute to late-stage valve and septal defects, thus demonstrating that functional parameters may serve as early and sensitive gauges of cardiac normalcy and abnormalities. PMID:24271490

  13. Exposure and Figure Out of Climate Induced Alterations in the Wetlands of Banglades

    NASA Astrophysics Data System (ADS)

    Siddiquee, S. A.; Rahman, M. Z.

    2015-12-01

    Unique geographic location and geo-morphological conditions of Bangladesh have made the wetlands of this country one of the most vulnerable to climate change. Wetland plays a crucial role in maintaining the ecological balance of ecosystems and cultural figures and which occupy around 50% of the area. Drought, excessive temperature, mountain snowfields and glaciers melting, riverbank erosion, salinity intrusion, flashflood, storm surges, higher water temperatures, precipitation anomalies, coastal cyclones, seasonal anomalies and extremes are main threats to the wetland ecosystem. Enhanced UV-B radiation and increased summer precipitation will significantly increase dissolved organic carbon concentrations altering major biogeochemical cycles and also will result into the expansion of range for many invasive aquatic weeds. Generally, rising temperature will lower water quality through a fall in oxygen concentrations, release of phosphorus from sediments, increased thermal stability, and altered mixing patterns. As a result biodiversity is getting degraded, many species of flora and fauna are getting threatened, and wetland-based ecosystem is getting degenerated. At the same time, the living conditions of local people are deteriorating as livelihoods, socioeconomic institutions, and extensive cultural values as well. For conserving and managing wetlands technology, legislation, educational knowledge, action plan strategy and restoration practices are required. In order to address the human needs in the changing climate community-based adaptation approaches and wetland restoration, practices had been taken in almost every type of wetlands in Bangladesh. Therefore, Bangladesh now needs a comprehensive strategy and integrated system combining political, economic, social, technological approaches and institutional supports to address sustainable wetland restoration, conservation and the newly added crisis, climate change.

  14. Juvenile exposure to a high fat diet promotes behavioral and limbic alterations in the absence of obesity.

    PubMed

    Vinuesa, Angeles; Pomilio, Carlos; Menafra, Martin; Bonaventura, Maria Marta; Garay, Laura; Mercogliano, María Florencia; Schillaci, Roxana; Lux Lantos, Victoria; Brites, Fernando; Beauquis, Juan; Saravia, Flavia

    2016-10-01

    The incidence of metabolic disorders including obesity, type 2 diabetes and metabolic syndrome have seriously increased in the last decades. These diseases - with growing impact in modern societies - constitute major risk factors for neurodegenerative disorders such as Alzheimer's disease (AD), sharing insulin resistance, inflammation and associated cognitive impairment. However, cerebral cellular and molecular pathways involved are not yet clearly understood. Thus, our aim was to study the impact of a non-severe high fat diet (HFD) that resembles western-like alimentary habits, particularly involving juvenile stages where the brain physiology and connectivity are in plain maturation. To this end, one-month-old C57BL/6J male mice were given either a control diet or HFD during 4 months. Exposure to HFD produced metabolic alterations along with changes in behavioral and central parameters, in the absence of obesity. Two-month-old HFD mice showed increased glycemia and plasmatic IL1β but these values normalized at the end of the HFD protocol at 5 months of age, probably representing an acute response that is compensated at later stages. After four months of HFD exposure, mice presented dyslipidemia, increased Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, hepatic insulin resistance and inflammation. Alterations in the behavioral profile of the HFD group were shown by the impediment in nest building behavior, deficiencies in short and mid-term spatial memories, anxious and depressive- like behavior. Regarding the latter disruptions in emotional processing, we found an increased neural activity in the amygdala, shown by a greater number of c-Fos+ nuclei. We found that hippocampal adult neurogenesis was decreased in HFD mice, showing diminished cell proliferation measured as Ki67+ cells and neuronal differentiation in SGZ by doublecortin labeling. These phenomena were accompanied by a neuroinflammatory and insulin-resistant state in the hippocampus

  15. Adolescent Δ(9)-Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats.

    PubMed

    Scherma, Maria; Dessì, Christian; Muntoni, Anna Lisa; Lecca, Salvatore; Satta, Valentina; Luchicchi, Antonio; Pistis, Marco; Panlilio, Leigh V; Fattore, Liana; Goldberg, Steven R; Fratta, Walter; Fadda, Paola

    2016-04-01

    Cannabis is the most commonly used illicit drug worldwide, and use is typically initiated during adolescence. The endocannabinoid system has an important role in formation of the nervous system, from very early development through adolescence. Cannabis exposure during this vulnerable period might lead to neurobiological changes that affect adult brain functions and increase the risk of cannabis use disorder. The aim of this study was to investigate whether exposure to Δ(9)-tetrahydrocannabinol (THC) in adolescent rats might enhance reinforcing effects of cannabinoids in adulthood. Male adolescent rats were treated with increasing doses of THC (or its vehicle) twice/day for 11 consecutive days (PND 45-55). When the animals reached adulthood, they were tested by allowing them to intravenously self-administer the cannabinoid CB1-receptor agonist WIN55,212-2. In a separate set of animals given the same THC (or vehicle) treatment regimen, electrophysiological and neurochemical experiments were performed to assess possible modifications of the mesolimbic dopaminergic system, which is critically involved in cannabinoid-induced reward. Behavioral data showed that acquisition of WIN55,212-2 self-administration was enhanced in THC-exposed rats relative to vehicle-exposed controls. Neurophysiological data showed that THC-exposed rats displayed a reduced capacity for WIN55,212-2 to stimulate firing of dopamine neurons in the ventral tegmental area and to increase dopamine levels in the nucleus accumbens shell. These findings-that early, passive exposure to THC can produce lasting alterations of the reward system of the brain and subsequently increase cannabinoid self-administration in adulthood-suggest a mechanism by which adolescent cannabis exposure could increase the risk of subsequent cannabis dependence in humans. PMID:26388146

  16. Atrazine-induced reproductive tract alterations after transplacental and/or lactational exposure in male Long-Evans rats

    SciTech Connect

    Rayner, Jennifer L.; Enoch, Rolondo R.; Wolf, Douglas C.; Fenton, Suzanne E. . E-mail: fenton.suzanne@epa.gov

    2007-02-01

    Studies showed that early postnatal exposure to the herbicide atrazine (ATR) delayed preputial separation (PPS) and increased incidence of prostate inflammation in adult Wistar rats. A cross-fostering paradigm was used in this study to determine if gestational exposure to ATR would also result in altered puberty and reproductive tissue effects in the male rat. Timed-pregnant Long-Evans (LE) rats were dosed by gavage on gestational days (GD) 15-19 with 100 mg ATR/kg body weight (BW) or 1% methylcellulose (controls, C). On postnatal day (PND)1, half litters were cross-fostered, creating 4 treatment groups; C-C, ATR-C, C-ATR, and ATR-ATR (transplacental-milk as source, respectively). On PND4, male offspring in the ATR-ATR group weighed significantly less than the C-C males. ATR-ATR male pups had significantly delayed preputial separation (PPS). BWs at PPS for C-ATR and ATR-ATR males were reduced by 6% and 9%, respectively, from that of C-C. On PND120, lateral prostate weights of males in the ATR-ATR group were significantly increased over C-C. Histological examination of lateral and ventral prostates identified an increased distribution of inflammation in the lateral prostates of C-ATR males. By PND220, lateral prostate weights were significantly increased for ATR-C and ATR-ATR, but there were no significant changes in inflammation in either the lateral or ventral prostate. These results suggest that in LE rats, gestational ATR exposure delays PPS when male offspring suckle an ATR dam, but leads to increased lateral prostate weight via transplacental exposure alone. Inflammation present at PND120 does not increase in severity with time.

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

    PubMed

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

    2013-09-01

    Alcohol consumption during pregnancy has deleterious effects on the developing foetus ranging from subtle physical deficits to severe behavioural abnormalities and is encompassed under a broad umbrella term, foetal alcohol spectrum disorders (FASD). High levels of exposure show distinct effects, whereas the consequences of moderate exposures have been less well studied. The aim of this study was to examine the effects of a moderate dose ethanol exposure using an ad libitum drinking procedure during the first eight days of gestation in mice on the behavioural phenotype of adult offspring. Adult female C57Bl/6J mice were mated and exposed to either 10% (v/v) ethanol or water for the first 8 days of gestation (GD 0-8), and then offered water for the rest of gestation. Early developmental milestone achievement was assessed in offspring at postnatal days (P) 7, 14 and 21. Adult offspring underwent a comprehensive battery of behavioural tests to examine a range of behavioural domains including locomotion, exploration, anxiety, social behaviour, learned helplessness, sensorimotor gating, and nociception, as well as spatial memory in a water maze. Ethanol-exposed mice had similar postnatal developmental trajectories to water-exposed mice. However, the ethanol-exposed mice showed increased hyperlocomotion at P 14, 21 and 70 (p<0.05). Increased exploration and heightened motivation were also observed in adult mice. Furthermore, ethanol-exposed mice showed a significant improvement in memory in the water maze. The main findings were that mice had persistent and long lasting alterations in behaviour, including hyperactivity and enhanced spatial memory. These data suggest that even moderate dose ethanol exposure in early gestation has long term consequences on brain function and behaviour in mice. PMID:23756143

  18. Sublethal exposure to azamethiphos causes neurotoxicity, altered energy allocation and high mortality during simulated live transport in American lobster.

    PubMed

    Couillard, C M; Burridge, L E

    2015-05-01

    In the Bay of Fundy, New Brunswick, sea lice outbreaks in caged salmon are treated with pesticides including Salmosan(®), applied as bath treatments and then released into the surrounding seawater. The effect of chronic exposure to low concentrations of this pesticide on neighboring lobster populations is a concern. Adult male lobsters were exposed to 61 ngL(-1) of azamethiphos (a.i. in Salmosan(®) formulation) continuously for 10 days. In addition to the direct effects of pesticide exposure, effects on the ability to cope with shipping conditions and the persistence of the effects after a 24h depuration period in clean seawater were assessed. Indicators of stress and hypoxia (serum total proteins, hemocyanin and lactate), oxidative damage (protein carbonyls in gills and serum) and altered energy allocation (hepatosomatic and gonadosomatic indices, hepatopancreas lipids) were assessed in addition to neurotoxicity (chlolinesterase activity in muscle). Directly after exposure, azamethiphos-treated lobsters had inhibition of muscle cholinesterase, reduced gonadosomatic index and enhanced hepatosomatic index and hepatopancreas lipid content. All these responses persisted after 24-h depuration, increasing the risk of cumulative impacts with further exposure to chemical or non-chemical stressors. In both control and treated lobsters exposed to simulated shipment conditions, concentrations of protein and lactate in serum, and protein carbonyls in gills increased. However, mortality rate was higher in azamethiphos-treated lobsters (33 ± 14%) than in controls (2.6 ± 4%). Shipment and azamethiphos had cumulative impacts on serum proteins. Both direct effects on neurological function and energy allocation and indirect effect on ability to cope with shipping stress could have significant impacts on lobster population and/or fisheries. PMID:25499691

  19. Lead Exposure Impairs Hippocampus Related Learning and Memory by Altering Synaptic Plasticity and Morphology During Juvenile Period.

    PubMed

    Wang, Tao; Guan, Rui-Li; Liu, Ming-Chao; Shen, Xue-Feng; Chen, Jing Yuan; Zhao, Ming-Gao; Luo, Wen-Jing

    2016-08-01

    Lead (Pb) is an environmental neurotoxic metal. Pb exposure may cause neurobehavioral changes, such as learning and memory impairment, and adolescence violence among children. Previous animal models have largely focused on the effects of Pb exposure during early development (from gestation to lactation period) on neurobehavior. In this study, we exposed Sprague-Dawley rats during the juvenile stage (from juvenile period to adult period). We investigated the synaptic function and structural changes and the relationship of these changes to neurobehavioral deficits in adult rats. Our results showed that juvenile Pb exposure caused fear-conditioned memory impairment and anxiety-like behavior, but locomotion and pain behavior were indistinguishable from the controls. Electrophysiological studies showed that long-term potentiation induction was affected in Pb-exposed rats, and this was probably due to excitatory synaptic transmission impairment in Pb-exposed rats. We found that NMDA and AMPA receptor-mediated current was inhibited, whereas the GABA synaptic transmission was normal in Pb-exposed rats. NR2A and phosphorylated GluR1 expression decreased. Moreover, morphological studies showed that density of dendritic spines declined by about 20 % in the Pb-treated group. The spine showed an immature form in Pb-exposed rats, as indicated by spine size measurements. However, the length and arborization of dendrites were unchanged. Our results suggested that juvenile Pb exposure in rats is associated with alterations in the glutamate receptor, which caused synaptic functional and morphological changes in hippocampal CA1 pyramidal neurons, thereby leading to behavioral changes. PMID:26141123

  20. Caffeine exposure alters adenosine system and neurochemical markers during retinal development.

    PubMed

    Brito, Rafael; Pereira-Figueiredo, Danniel; Socodato, Renato; Paes-de-Carvalho, Roberto; Calaza, Karin C

    2016-08-01

    Evidence points to beneficial properties of caffeine in the adult central nervous system, but teratogenic effects have also been reported. Caffeine exerts most of its effects by antagonizing adenosine receptors, especially A1 and A2A subtypes. In this study, we evaluated the role of caffeine on the expression of components of the adenosinergic system in the developing avian retina and the impact of caffeine exposure upon specific markers for classical neurotransmitter systems. Caffeine exposure (5-30 mg/kg by in ovo injection) to 14-day-old chick embryos increased the expression of A1 receptors and concomitantly decreased A2A adenosine receptors expression after 48 h. Accordingly, caffeine (30 mg/kg) increased [(3) H]-8-cyclopentyl-1,3-dipropylxanthine (A1 antagonist) binding and reduced [(3) H]-ZM241385 (A2A antagonist) binding. The caffeine time-response curve demonstrated a reduction in A1 receptors 6 h after injection, but an increase after 18 and 24 h. In contrast, caffeine exposure increased the expression of A2A receptors from 18 and 24 h. Kinetic assays of [(3) H]-S-(4-nitrobenzyl)-6-thioinosine binding to the equilibrative adenosine transporter ENT1 revealed an increase in Bmax with no changes in Kd , an effect accompanied by an increase in adenosine uptake. Immunohistochemical analysis showed a decrease in retinal content of tyrosine hydroxylase, calbindin and choline acetyltransferase, but not Brn3a, after 48 h of caffeine injection. Furthermore, retinas exposed to caffeine had increased levels of phosphorylated extracellular signal-regulated kinase and cAMP-response element binding protein. Overall, we show an in vivo regulation of the adenosine system, extracellular signal-regulated kinase and cAMP-response element binding protein function and protein expression of specific neurotransmitter systems by caffeine in the developing retina. The beneficial or maleficent effects of caffeine have been demonstrated by the work of different studies. It

  1. Gene expression and pathologic alterations in juvenile rainbow trout due to chronic dietary TCDD exposure

    PubMed Central

    Liu, Qing; Rise, Matthew L.; Spitsbergen, Jan M.; Hori, Tiago S.; Mieritz, Mark; Geis, Steven; McGraw, Joseph E.; Goetz, Giles; Larson, Jeremy; Hutz, Reinhold J.; Carvan, Michael J.

    2013-01-01

    The goal of this project was to use functional genomic methods to identify molecular biomarkers as indicators of the impact of TCDD exposure in rainbow trout. Specifically, we investigated the effects of chronic dietary TCDD exposure on whole juvenile rainbow trout global gene expression associated with histopathological analysis. Juvenile rainbow trout were fed Biodiet starter with TCDD added at 0, 0.1, 1, 10 and 100 ppb (ng TCDD / g food), and fish were sampled from each group at 7, 14, 28 and 42 days (d) after initiation of feeding. 100 ppb TCDD caused 100% mortality at 39 d. Fish fed with 100 ppb TCDD food had TCDD accumulation of 47.37 ppb (ng TCDD / g fish) in whole fish at 28 d. Histological analysis from TCDD-treated trout sampled from 28 d and 42 d revealed that obvious lesions were found in skin, oropharynx, liver, gas bladder, intestine, pancreas, nose and kidney. In addition, TCDD caused anemia in peripheral blood, decreases in abdominal fat, increases of remodeling of fin rays, edema in pericardium and retrobulbar hemorrhage in the 100 ppb TCDD-treated rainbow trout compared to the control group at 28 d. Dose- and time-dependent global gene expression analyses were performed using the cGRASP 16,000 (16K) cDNA microarray. TCDD-responsive whole body transcripts identified in the microarray experiments have putative functions involved in various biological processes including growth, cell proliferation, metabolic process, and immune system processes. Nine microarray-identified genes were selected for QPCR validation. CYP1A3 and CYP1A1 were common up-regulated genes and HBB1 was a common down-regulated gene among each group based on microarray data, and their QPCR validations are consistent with microarray data for the 10 and 100 ppb TCDD treatment groups after 28-d exposure (p< 0.05). In addition, in the 100 ppb group at 28d, expression of complement component C3-1 and trypsin-1 precursor have a more than 10-fold induction from the microarray experiments

  2. Altering genomic integrity: heavy metal exposure promotes trans-posable element-mediated damage

    PubMed Central

    Morales, Maria E.; Servant, Geraldine; Ade, Catherine; Roy-Enge, Astrid M.

    2015-01-01

    Maintenance of genomic integrity is critical for cellular homeostasis and survival. The active transposable elements (TEs) composed primarily of three mobile element lineages LINE-1, Alu, and SVA comprise approximately 30% of the mass of the human genome. For the past two decades, studies have shown that TEs significantly contribute to genetic instability and that TE-caused damages are associated with genetic diseases and cancer. Different environmental exposures, including several heavy metals, influence how TEs interact with its host genome increasing their negative impact. This mini-review provides some basic knowledge on TEs, their contribution to disease and an overview of the current knowledge on how heavy metals influence TE-mediated damage. PMID:25774044

  3. Exposure to the BPA-Substitute Bisphenol S Causes Unique Alterations of Germline Function

    PubMed Central

    Chen, Yichang; Qiu, Zhiqun; Lee, Dong Yeon; Telesca, Donatello; Yang, Xia; Allard, Patrick

    2016-01-01

    Concerns about the safety of Bisphenol A, a chemical found in plastics, receipts, food packaging and more, have led to its replacement with substitutes now found in a multitude of consumer products. However, several popular BPA-free alternatives, such as Bisphenol S, share a high degree of structural similarity with BPA, suggesting that these substitutes may disrupt similar developmental and reproductive pathways. We compared the effects of BPA and BPS on germline and reproductive functions using the genetic model system Caenorhabditis elegans. We found that, similarly to BPA, BPS caused severe reproductive defects including germline apoptosis and embryonic lethality. However, meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast data mining all indicate that these effects are partly achieved via mechanisms distinct from BPAs. These findings therefore raise new concerns about the safety of BPA alternatives and the risk associated with human exposure to mixtures. PMID:27472198

  4. Altered excitability of cultured chromaffin cells following exposure to multi-walled carbon nanotubes.

    PubMed

    Gavello, Daniela; Vandael, David H F; Cesa, Roberta; Premoselli, Federica; Marcantoni, Andrea; Cesano, Federico; Scarano, Domenica; Fubini, Bice; Carbone, Emilio; Fenoglio, Ivana; Carabelli, Valentina

    2012-02-01

    We studied the effects of multi-walled carbon nanotubes (MWCNTs) on the electrophysiological properties of cultured mouse chromaffin cells, a model of spontaneously firing cells. The exposure of chromaffin cells to MWCNTs at increasing concentrations (30-263 μg/ml) for 24 h reduced, in a dose-dependent way, both the cell membrane input resistance and the number of spontaneously active cells (from 80-52%). Active cells that survived from the toxic effects of MWCNTs exhibited more positive resting potentials, higher firing frequencies and unaltered voltage-gated Ca(2+), Na(+) and K+ current amplitudes. MWCNTs slowed down the inactivation kinetics of Ca(2+)-dependent BK channels. These electrophysiological effects were accompanied by MWCNTs internalization, as confirmed by transmission electron microscopy, indicating that most of the toxic effects derive from a dose-dependent MWCNTs-cell interaction that damages the spontaneous cell activity. PMID:21322767

  5. Exposure to the BPA-Substitute Bisphenol S Causes Unique Alterations of Germline Function.

    PubMed

    Chen, Yichang; Shu, Le; Qiu, Zhiqun; Lee, Dong Yeon; Settle, Sara J; Que Hee, Shane; Telesca, Donatello; Yang, Xia; Allard, Patrick

    2016-07-01

    Concerns about the safety of Bisphenol A, a chemical found in plastics, receipts, food packaging and more, have led to its replacement with substitutes now found in a multitude of consumer products. However, several popular BPA-free alternatives, such as Bisphenol S, share a high degree of structural similarity with BPA, suggesting that these substitutes may disrupt similar developmental and reproductive pathways. We compared the effects of BPA and BPS on germline and reproductive functions using the genetic model system Caenorhabditis elegans. We found that, similarly to BPA, BPS caused severe reproductive defects including germline apoptosis and embryonic lethality. However, meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast data mining all indicate that these effects are partly achieved via mechanisms distinct from BPAs. These findings therefore raise new concerns about the safety of BPA alternatives and the risk associated with human exposure to mixtures. PMID:27472198

  6. Chronic cocaine or ethanol exposure during adolescence alters novelty-related behaviors in adulthood.

    PubMed

    Stansfield, Kirstie H; Kirstein, Cheryl L

    2007-04-01

    Adolescence is a time of high-risk behavior and increased exploration. This developmental period is marked by a greater probability to initiate drug use and is associated with an increased risk to develop addiction and adulthood dependency and drug use at this time is associated with an increased risk. Human adolescents are predisposed toward an increased likelihood of risk-taking behaviors [Zuckerman M. Sensation seeking and the endogenous deficit theory of drug abuse. NIDA Res Monogr 1986;74:59-70.], including drug use or initiation. In the present study, adolescent animals were exposed to twenty days of either saline (0.9% sodium chloride), cocaine (20 mg/kg) or ethanol (1 g/kg) i.p. followed by a fifteen-day washout period. All animals were tested as adults on several behavioral measures including locomotor activity induced by a novel environment, time spent in the center of an open field, novelty preference and novel object exploration. Animals exposed to cocaine during adolescence and tested as adults exhibited a greater locomotor response in a novel environment, spent less time in the center of the novel open field and spent less time with a novel object, results that are indicative of a stress or anxiogenic response to novelty or a novel situation. Adolescent animals chronically administered ethanol and tested as adults, unlike cocaine-exposed were not different from controls in a novel environment, indicated by locomotor activity or time spent with a novel object. However, ethanol-exposed animals approached the novel object more, suggesting that exposure to ethanol during development may result in less-inhibited behaviors during adulthood. The differences in adult behavioral responses after drug exposure during adolescence are likely due to differences in the mechanisms of action of the drugs and subsequent reward and/or stress responsivity. Future studies are needed to determine the neural substrates of these long lasting drug-induced changes. PMID

  7. Gestational Exposure to Low Dose Bisphenol A Alters Social Behavior in Juvenile Mice

    PubMed Central

    Wolstenholme, Jennifer T.; Taylor, Julia A.; Shetty, Savera R. J.; Edwards, Michelle; Connelly, Jessica J.; Rissman, Emilie F.

    2011-01-01

    Bisphenol A (BPA) is a man-made compound used to make polycarbonate plastics and epoxy resins; public health concerns have been fueled by findings that BPA exposure can reduce sex differences in brain and some behaviors. We asked if a low BPA dose, within the range measured in humans, ingested during pregnancy, would affect social behaviors in prepubertal mice. We noted sex differences in social interactions whereby females spent more time sitting side-by-side, while males engaged in more exploring and sitting alone. In addition BPA increased display of nose-to-nose contacts, play solicitations and approaches in both sexes. Interactions between sex and diet were found for self grooming, social interactions while sitting side-by-side and following the other mouse. In all these cases interactions were produced by differences between control and BPA females. We examined brains from embryos during late gestation to determine if gene expression differences might be correlated with some of the sexually dimorphic or BPA affected behaviors we observed. Because BPA treatments ended at birth we took the brains during embryogenesis to increase the probability of discovering BPA mediated effects. We also selected this embryonic age (E18.5) because it coincides with the onset of sexual differentiation of the brain. Interestingly, mRNA for the glutamate transporter, Slc1a1, was enhanced by exposure to BPA in female brains. Also we noted that BPA changed the expression of two of the three DNA methyltransferase genes, Dnmt1 and Dnmt3a. We propose that BPA affects DNA methylation of Sc1a1 during neural development. Sex differences in juvenile social interactions are affected by BPA and in particular this compound modifies behavior in females. PMID:21980460

  8. Developmental Exposure to Perchlorate Alters Synaptic Transmission in Hippocampus of the Adult Rat

    PubMed Central

    Gilbert, Mary E.; Sui, Li

    2008-01-01

    Background Perchlorate is an environmental contaminant that blocks iodine uptake into the thyroid gland and reduces thyroid hormones. This action of perchlorate raises significant concern over its effects on brain development. Objectives The purpose of this study was to evaluate neurologic function in rats after developmental exposure to perchlorate. Methods Pregnant rats were exposed to 0, 30, 300, or 1,000 ppm perchlorate in drinking water from gestational day 6 until weaning. Adult male offspring were evaluated on a series of behavioral tasks and neurophysiologic measures of synaptic function in the hippocampus. Results At the highest perchlorate dose, triiodothyronine (T3) and thyroxine (T4) were reduced in pups on postnatal day 21. T4 in dams was reduced relative to controls by 16%, 28%, and 60% in the 30-, 300-, and 1,000-ppm dose groups, respectively. Reductions in T4 were associated with increases in thyroid-stimulating hormone in the high-dose group. No changes were seen in serum T3. Perchlorate did not impair motor activity, spatial learning, or fear conditioning. However, significant reductions in baseline synaptic transmission were observed in hippocampal field potentials at all dose levels. Reductions in inhibitory function were evident at 300 and 1,000 ppm, and augmentations in long-term potentiation were observed in the population spike measure at the highest dose. Conclusions Dose-dependent deficits in hippocampal synaptic function were detectable with relatively minor perturbations of the thyroid axis, indicative of an irreversible impairment in synaptic transmission in response to developmental exposure to perchlorate. PMID:18560531

  9. Mainstream cigarette smoke exposure alters cytochrome P4502G1 expression in F344 rat olfactory mucosa

    SciTech Connect

    Hotchkiss, J.A.; Nikula, K.J.; Lewis, J.L.; Finch, G.L.; Belinsky, S.A.; Dahl, A.R.

    1994-11-01

    Inhalation of mainstream cigarette smoke (MCS) by rats results in multifocal rhinitis, mucous hypersecretion, nasal epithelial hyperplasia and metaplasia, and focal olfactory mucosal atrophy. In humans, cigarette smoking causes long-term, dose-related alterations in olfactory function in both current and former smokers. An olfactory-specific cytochrome P450 has been identified in rabbits and rats. The presence of olfactory-specific P450s, as well as relatively high levels of other biotransformation enzymes, such as NADPH-cytochrome P450 reductase and UDP-glucuronosyl transferase, in the olfactory neuroepithelium suggest that these enzyme systems may play a role in olfaction. This hypothesis is strengthened by the observation that, in rats, the temporal gene activation of P4502G1 coincides with the postnatal increase in the sensitivity of olfactory response to odorants. The purpose of this investigation was to examine the effect of MCS exposure on P4502G1 protein expression.

  10. Developmental Exposure to Aroclor 1254 Alters Migratory Behavior in Juvenile European Starlings (Sturnus vulgaris).

    PubMed

    Flahr, Leanne M; Michel, Nicole L; Zahara, Alexander R D; Jones, Paul D; Morrissey, Christy A

    2015-05-19

    Birds exposed to endocrine disrupting chemicals during development could be susceptible to neurological and other physiological changes affecting migratory behaviors. We investigated the effects of ecologically relevant levels of Aroclor 1254, a polychlorinated biphenyl (PCB) mixture, on moult, fattening, migratory activity, and orientation in juvenile European starlings (Sturnus vulgaris). Birds were orally administered 0 (control), 0.35 (low), 0.70 (intermediate), or 1.05 (high) μg Aroclor 1254/g-body weight by gavage from 1 through 18 days posthatch and later exposed in captivity to a photoperiod shift simulating an autumn migration. Migratory activity and orientation were examined using Emlen funnel trials. Across treatments, we found significant increases in mass, fat, and moulting and decreasing plasma thyroid hormones over time. We observed a significant increase in activity as photoperiod was shifted from 13L:11D (light:dark) to 12L:12D, demonstrating that migratory condition was induced in captivity. At 12L:12D, control birds oriented to 155.95° (South-Southeast), while high-dosed birds did not. High-dosed birds showed a delayed orientation to 197.48° (South-Southwest) under 10L:14D, concomitant with apparent delays in moult. These findings demonstrate how subtle contaminant-induced alterations during development could lead to longer-scale effects, including changes in migratory activity and orientation, which could potentially result in deleterious effects on fitness and survival. PMID:25893686

  11. Geniohyoid muscle properties and myosin heavy chain composition are altered after short-term intermittent hypoxic exposure.

    PubMed

    Pae, Eung-Kwon; Wu, Jennifer; Nguyen, Daniel; Monti, Ryan; Harper, Ronald M

    2005-03-01

    Patients with obstructive sleep apnea (OSA) often exhibit fatigued or inefficient upper airway dilator and constrictor muscles; an upper airway dilator, the geniohyoid (GH) muscle, is a particular example. Intermittent hypoxia (IH) is a frequent concomitant of OSA, and it may trigger muscle fiber composition changes that are characteristic of a fatigable nature. We examined effects of short-term IH on diaphragmatic and GH muscle fiber composition and fatigue properties by exposing 24 rats to alternating 10.3% O(2)-balance N(2) and room air every 480 s (240 s duty cycle) for a total duration of 5, 10, 15, 20, or 30 h. Sternohyoid fiber composition was also examined. Control animals were exposed to room air on the same schedule. Single-fiber analyses showed that GH muscle fiber types changed completely from myosin heavy chain (MHC) type 2A to MHC type 2B after 10 h of exposure, and the conversion was maintained for at least 30 h. Sternohyoid muscle fibers showed a delayed transition from MHC type 2A/2B to MHC type 2B. In contrast, major fiber types of the diaphragm were not significantly altered. The GH muscles showed similar tension-frequency relationships in all groups, but an increased fatigability developed, proportional to the duration of IH treatment. We conclude that short-term IH exposure alters GH muscle composition and physical properties toward more fatigable, fast-twitch types and that it may account for the fatigable upper airway fiber types found in sleep-disturbed breathing. PMID:15557011

  12. Prenatal exposure to aflatoxin B1: developmental, behavioral, and reproductive alterations in male rats

    NASA Astrophysics Data System (ADS)

    Supriya, Ch.; Reddy, P. Sreenivasula

    2015-06-01

    Previous studies have shown that aflatoxin B1 (AfB1) inhibits androgen biosynthesis as a result of its ability to form a high-affinity complex with the steroidogenic acute regulatory protein. The results of the present study demonstrate the postnatal effects of in utero exposure to AfB1 in the rat. Pregnant Wistar rats were given 10, 20, or 50 μg AfB1/kg body weight daily from gestation day (GD) 12 to GD 19. At parturition, newborns were observed for clinical signs and survival. All animals were born alive and initially appeared to be active. Male pups from control and AfB1-exposed animals were weaned and maintained up to postnatal day (PD) 100. Litter size, birth weight, sex ratio, survival rate, and crown-rump length of the pups were significantly decreased in AfB1-exposed rats when compared to controls. Elapsed time (days) for testes to descend into the scrotal sac was significantly delayed in experimental pups when compared to control pups. Behavioral observations such as cliff avoidance, negative geotaxis, surface rightening activity, ascending wire mesh, open field behavior, and exploratory and locomotory activities were significantly impaired in experimental pups. Body weights and the indices of testis, cauda epididymis, prostate, seminal vesicles, and liver were significantly reduced on PD 100 in male rats exposed to AfB1 during embryonic development when compared with controls. Significant reduction in the testicular daily sperm production, epididymal sperm count, and number of viable, motile, and hypo-osmotic tail coiled sperm was observed in experimental rats. The levels of serum testosterone and activity levels of testicular hydroxysteroid dehydrogenases were significantly decreased in a dose-dependent manner with a significant increase in the serum follicle-stimulating hormone and luteinizing hormone in experimental rats. Deterioration in the testicular and cauda epididymal architecture was observed in experimental rats. The results of fertility

  13. Prenatal exposure to aflatoxin B1: developmental, behavioral, and reproductive alterations in male rats.

    PubMed

    Supriya, Ch; Reddy, P Sreenivasula

    2015-06-01

    Previous studies have shown that aflatoxin B1 (AfB1) inhibits androgen biosynthesis as a result of its ability to form a high-affinity complex with the steroidogenic acute regulatory protein. The results of the present study demonstrate the postnatal effects of in utero exposure to AfB1 in the rat. Pregnant Wistar rats were given 10, 20, or 50 μg AfB1/kg body weight daily from gestation day (GD) 12 to GD 19. At parturition, newborns were observed for clinical signs and survival. All animals were born alive and initially appeared to be active. Male pups from control and AfB1-exposed animals were weaned and maintained up to postnatal day (PD) 100. Litter size, birth weight, sex ratio, survival rate, and crown-rump length of the pups were significantly decreased in AfB1-exposed rats when compared to controls. Elapsed time (days) for testes to descend into the scrotal sac was significantly delayed in experimental pups when compared to control pups. Behavioral observations such as cliff avoidance, negative geotaxis, surface rightening activity, ascending wire mesh, open field behavior, and exploratory and locomotory activities were significantly impaired in experimental pups. Body weights and the indices of testis, cauda epididymis, prostate, seminal vesicles, and liver were significantly reduced on PD 100 in male rats exposed to AfB1 during embryonic development when compared with controls. Significant reduction in the testicular daily sperm production, epididymal sperm count, and number of viable, motile, and hypo-osmotic tail coiled sperm was observed in experimental rats. The levels of serum testosterone and activity levels of testicular hydroxysteroid dehydrogenases were significantly decreased in a dose-dependent manner with a significant increase in the serum follicle-stimulating hormone and luteinizing hormone in experimental rats. Deterioration in the testicular and cauda epididymal architecture was observed in experimental rats. The results of fertility

  14. Chronic prenatal ethanol exposure alters expression of central and peripheral insulin signaling molecules in adult guinea pig offspring.

    PubMed

    Dobson, Christine C; Thevasundaram, Kersh; Mongillo, Daniel L; Winterborn, Andrew; Holloway, Alison C; Brien, James F; Reynolds, James N

    2014-11-01

    Maternal ethanol consumption during pregnancy can produce a range of teratogenic outcomes in offspring. The mechanism of ethanol teratogenicity is multi-faceted, but may involve alterations in insulin and insulin-like growth factor (IGF) signaling pathways. These pathways are not only important for metabolism, but are also critically involved in neuronal survival and plasticity, and they can be altered by chronic prenatal ethanol exposure (CPEE). The objective of this study was to test the hypothesis that CPEE alters expression of insulin and IGF signaling molecules in the prefrontal cortex and liver of adult guinea pig offspring. Pregnant Dunkin-Hartley-strain guinea pigs received ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (nutritional control) throughout gestation. Fasting blood glucose concentration was measured in male and female offspring at postnatal day 150-200, followed by euthanasia, collection of prefrontal cortex and liver, and RNA extraction. IGF-1, IGF-1 receptor (IGF-1R), IGF-2, IGF-2 receptor (IGF-2R), insulin receptor substrate (IRS)-1, IRS-2, and insulin receptor (INSR) mRNA expression levels were measured in tissues using quantitative real-time PCR. The mean maternal blood ethanol concentration was 281 ± 15 mg/dL at 1 h after the second divided dose of ethanol on GD 57. CPEE resulted in increased liver weight in adult offspring, but produced no difference in fasting blood glucose concentration compared with nutritional control. In the liver, CPEE decreased mRNA expression of IGF-1, IGF-1R, and IGF-2, and increased IRS-2 mRNA expression in male offspring only compared with nutritional control. Female CPEE offspring had decreased INSR hepatic mRNA expression compared with male CPEE offspring. In the prefrontal cortex, IRS-2 mRNA expression was increased in CPEE offspring compared with nutritional control. The data demonstrate that CPEE alters both central and peripheral expression of insulin and IGF signaling

  15. Estradiol Exposure Differentially Alters Monolayer versus Microtissue MCF-7 Human Breast Carcinoma Cultures.

    PubMed

    Vantangoli, Marguerite M; Madnick, Samantha J; Wilson, Shelby; Boekelheide, Kim

    2016-01-01

    The development of three-dimensional (3D) cultures is increasing, as they are able to provide the utility of in vitro models and the strength of testing in physiologically relevant systems. When cultured in a scaffold-free agarose hydrogel system, MCF-7 human breast carcinoma cells organize and develop into microtissues that contain a luminal space, in stark contrast to the flat morphology of MCF-7 two-dimensional (2D) monolayer cultures. Following exposure to 1nM E2, expression of typical estrogen-responsive genes, including progesterone receptor (PGR), PDZ containing domain 1 (PDZK1) and amphiregulin (AREG) is increased in both 2D and 3D cultures. When examining expression of other genes, particularly those involved in cell adhesion, there were large changes in 3D MCF-7 microtissues, with little to no change observed in the MCF-7 monolayer cultures. Together, these results indicate that while the initial estrogen-regulated transcriptional targets respond similarly in 2D and 3D cultures, there are large differences in activation of other pathways related to cell-cell interactions. PMID:27379522

  16. Proteomics study revealed altered proteome of Dichogaster curgensis upon exposure to fly ash.

    PubMed

    Markad, Vijaykumar L; Adav, Sunil S; Ghole, Vikram S; Sze, Siu Kwan; Kodam, Kisan M

    2016-10-01

    Fly ash is toxic and its escalating use as a soil amendment and disposal by dumping into environment is receiving alarming attention due to its impact on environment. Proteomics technology is being used for environmental studies since proteins respond rapidly when an organism is exposed to a toxicant, and hence soil engineers such as earthworms are used as model organisms to assess the toxic effects of soil toxicants. This study adopted proteomics technology and profiled proteome of earthworm Dichogaster curgensis that was exposed to fly ash, with main aim to elucidate fly ash effects on cellular and metabolic pathways. The functional classification of identified proteins revealed carbohydrate metabolism (14.36%), genetic information processing (15.02%), folding, sorting and degradation (10.83%), replication and repair (3.95%); environmental information processing (2.19%), signal transduction (9.61%), transport and catabolism (17.27%), energy metabolism (6.69%), etc. in the proteome. Proteomics data and functional assays revealed that the exposure of earthworm to fly ash induced protein synthesis, up-regulation of gluconeogenesis, disturbed energy metabolism, oxidative and cellular stress, and mis-folding of proteins. The regulation of ubiquitination, proteasome and modified alkaline comet assay in earthworm coelomocytes suggested DNA-protein cross link affecting chromatin remodeling and protein folding. PMID:27371791

  17. Estradiol Exposure Differentially Alters Monolayer versus Microtissue MCF-7 Human Breast Carcinoma Cultures

    PubMed Central

    Madnick, Samantha J.; Wilson, Shelby; Boekelheide, Kim

    2016-01-01

    The development of three-dimensional (3D) cultures is increasing, as they are able to provide the utility of in vitro models and the strength of testing in physiologically relevant systems. When cultured in a scaffold-free agarose hydrogel system, MCF-7 human breast carcinoma cells organize and develop into microtissues that contain a luminal space, in stark contrast to the flat morphology of MCF-7 two-dimensional (2D) monolayer cultures. Following exposure to 1nM E2, expression of typical estrogen-responsive genes, including progesterone receptor (PGR), PDZ containing domain 1 (PDZK1) and amphiregulin (AREG) is increased in both 2D and 3D cultures. When examining expression of other genes, particularly those involved in cell adhesion, there were large changes in 3D MCF-7 microtissues, with little to no change observed in the MCF-7 monolayer cultures. Together, these results indicate that while the initial estrogen-regulated transcriptional targets respond similarly in 2D and 3D cultures, there are large differences in activation of other pathways related to cell-cell interactions. PMID:27379522

  18. Altered Microbiota Contributes to Reduced Diet-Induced Obesity upon Cold Exposure.

    PubMed

    Ziętak, Marika; Kovatcheva-Datchary, Petia; Markiewicz, Lidia H; Ståhlman, Marcus; Kozak, Leslie P; Bäckhed, Fredrik

    2016-06-14

    Maintenance of body temperature in cold-exposed animals requires induction of thermogenesis and management of fuel. Here, we demonstrated that reducing ambient temperature attenuated diet-induced obesity (DIO), which was associated with increased iBAT thermogenesis and a plasma bile acid profile similar to that of germ-free mice. We observed a marked shift in the microbiome composition at the phylum and family levels within 1 day of acute cold exposure and after 4 weeks at 12°C. Gut microbiota was characterized by increased levels of Adlercreutzia, Mogibacteriaceae, Ruminococcaceae, and Desulfovibrio and reduced levels of Bacilli, Erysipelotrichaceae, and the genus rc4-4. These genera have been associated with leanness and obesity, respectively. Germ-free mice fed a high-fat diet at room temperature gained less adiposity and improved glucose tolerance when transplanted with caecal microbiota of mice housed at 12°C compared to mice transplanted with microbiota from 29°C. Thus, a microbiota-liver-BAT axis may mediate protection against obesity at reduced temperature. PMID:27304513

  19. Prenatal nicotine exposure alters postnatal cardiorespiratory integration in young male but not female rats

    PubMed Central

    Boychuk, Carie R.; Hayward, Linda F.

    2011-01-01

    The present study tested the hypothesis that prenatal nicotine exposure (PNE) induces sex specific alternations in indices of cardiorespiratory coupling during early development. Rat pups exposed to either nicotine (6mg/kg/day) or saline (control) in utero were chronically instrumented with ECG electrodes for measurement of heart rate (HR) and respiratory frequency (RF) was monitored by whole body plethysmography on postnatal days (P)13, P16 and P26. PNE had no identifiable effect on resting respiratory frequency (RF) in either sex. There was however a strong trend (p=0.057) for resting HR to be elevated by PNE in male offspring only. Alternatively, the HR response to hypoxia (10% O2), was significantly blunted at P13 but significantly elevated at P26 s in the absence of any significant change in RF in PNE males only. Indicators of respiratory sinus arrhythmia (RSA) were also significantly reduced in P26 PNE males. No significant effects of PNE on HR, RF or RSA were identified in female offspring at any age. Our results demonstrate that PNE induces very specific changes in cardiorespiratory integration at select postnatal ages and these changes are more prominent in males. Additionally, alternations in cardiorespiratory integration appear to persist into later development in males only, potentially increasing the risk for cardiovascular diseases such as hypertension later in life. PMID:21945005

  20. Early Alterations in Cytokine Expression in Adult Compared to Developing Lung in Mice after Radiation Exposure

    PubMed Central

    Johnston, Carl J.; Hernady, Eric; Reed, Christina; Thurston, Sally W.; Finkelstein, Jacob N.; Williams, Jacqueline P.

    2010-01-01

    To assess early changes in the lung after low-dose radiation exposure that may serve as targets for mitigation of lung injury in the aftermath of a terrorist event, we analyzed cytokine expression after irradiation. Adult mice were studied after whole-lung or total-body irradiation. Mouse pups of different ages were also investigated after total-body irradiation. mRNA abundance was analyzed in tissue and plasma, and pathological changes were assessed. In lung tissue, dose-related changes were seen in IL1B, IL1R2 and CXCR2 mRNA expression at 1 and 6 h after irradiation, concurrent with increases in plasma protein levels of KC/CXCL1 and IL6. However, in the pups, changes in IL1 abundance were not detected until 28 days of age, coincident with the end of postnatal lung growth, although apoptosis was detected at all ages. In conclusion, although cytokines were expressed after low doses of radiation, their role in the progression of tissue response is yet to be determined. They may be candidates for use in marker-based biodosimetry. However, the lack of cytokine induction in early life suggests that different end points (and mitigating treatments) may be required for children. PMID:20334525

  1. Utility of biological membranes as indicators for radiation exposure: alterations in membrane structure and function over time.

    PubMed

    Dainiak, N; Tan, B J

    1995-05-01

    In addition to interacting with genomic DNA, ionizing radiation may directly and indirectly alter the structure and function of components of the plasma membrane of eukaryotic cells. Water radiolysis generates reactive species, including superoxide, hypochlorous acid and chloride radicals that may in turn react with biological membranes, as well as with cellular DNA. Reaction of plasma membrane lipids with molecular oxygen results in lipid peroxidation of both reconstituted membranes and biological membranes, an effect that increases with decreasing dose rate. Both ionizing radiation and ultraviolet light alter functions of membrane-anchored molecules, including adhesion molecules, histocompatibility complex antigens and membrane-bound growth factors. The latter growth factors represent a repertoire of growth and differentiation signals that are expressed in a nondiffusible fashion at the cell surface, and in soluble forms appearing after cleavage of their extracellular domain. The importance of cell-cell signaling via the membrane-anchored form of growth factors is becoming increasingly recognized. Expression of membrane-bound hematopoietic cytokines by eukaryotic cells is impaired after exposure to ultraviolet light, a defect in cell-cell signaling that may lead to impaired hematopoiesis. While studies suggest that permanent changes in membrane structure and function may result from radiation-induced injury to the plasma membrane and reconstituted "pure" membranes, reversibility of these defects over time requires additional study. PMID:7488940

  2. Rotating wall vessel exposure alters protein secretion and global gene expression in Staphylococcus aureus

    NASA Astrophysics Data System (ADS)

    Rosado, Helena; O'Neill, Alex J.; Blake, Katy L.; Walther, Meik; Long, Paul F.; Hinds, Jason; Taylor, Peter W.

    2012-04-01

    Staphylococcus aureus is routinely recovered from air and surface samples taken aboard the International Space Station (ISS) and poses a health threat to crew. As bacteria respond to the low shear forces engendered by continuous rotation conditions in a Rotating Wall Vessel (RWV) and the reduced gravitational field of near-Earth flight by altering gene expression, we examined the effect of low-shear RWV growth on protein secretion and gene expression by three S. aureus isolates. When cultured under 1 g, the total amount of protein secreted by these strains varied up to fourfold; under continuous rotation conditions, protein secretion by all three strains was significantly reduced. Concentrations of individual proteins were differentially reduced and no evidence was found for increased lysis. These data suggest that growth under continuous rotation conditions reduces synthesis or secretion of proteins. A limited number of changes in gene expression under continuous rotation conditions were noted: in all isolates vraX, a gene encoding a polypeptide associated with cell wall stress, was down-regulated. A vraX deletion mutant of S. aureus SH1000 was constructed: no differences were found between SH1000 and ΔvraX with respect to colony phenotype, viability, protein export, antibiotic susceptibility, vancomycin kill kinetics, susceptibility to cold or heat and gene modulation. An ab initio protein-ligand docking simulation suggests a major binding site for β-lactam drugs such as imipenem. If such changes to the bacterial phenotype occur during spaceflight, they will compromise the capacity of staphylococci to cause systemic infection and to circumvent antibacterial chemotherapy.

  3. Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics.

    PubMed

    Caffino, Lucia; Giannotti, Giuseppe; Malpighi, Chiara; Racagni, Giorgio; Fumagalli, Fabio

    2015-10-01

    Although glucocorticoid receptors (GRs) contribute to the action of cocaine, their role following developmental exposure to the psychostimulant is still unknown. To address this issue, we exposed adolescent male rats to cocaine (20mg/kg/day) from post-natal day (PND) 28 to PND 42 and sacrificed them at PND 45 or 90. We studied the medial prefrontal cortex (mPFC), a brain region that is still developing during adolescence. In PND 45 rats we found enhanced GR transcription and translation as well as increased trafficking toward the nucleus of the receptor, with no alteration in plasma corticosterone levels. We also showed reduced expression of the GR co-chaperone FKBP51, that normally keeps the receptor in the cytoplasm, and increased expression of Src1, which cooperates in the activation of GR transcriptional activity, revealing that short withdrawal alters the finely tuned mechanisms regulating GR action. Since activation of GRs regulate dendritic spine morphology, we next investigated spine dynamics in cocaine-withdrawn rats. We found that PSD95, cofilin and F-actin, molecules regulating spine actin network, are reduced in the mPFC of PND 45 rats suggesting reduced spine density, confirmed by confocal imaging. Further, formation of filopodia, i.e. the inactive spines, is enhanced suggesting the formation of non-functional spines. Of note, no changes were found in molecules related to GR machinery or spine dynamics following long-term abstinence, i.e. in adult rats (PND 90). These findings demonstrate that short withdrawal promotes plastic changes in the developing brain via the dysregulation of the GR system and alterations in the spine network. PMID:26004981

  4. Chronic anabolic androgenic steroid exposure alters corticotropin releasing factor expression and anxiety-like behaviors in the female mouse.

    PubMed

    Costine, Beth A; Oberlander, Joseph G; Davis, Matthew C; Penatti, Carlos A A; Porter, Donna M; Leaton, Robert N; Henderson, Leslie P

    2010-11-01

    In the past several decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit use of these drugs by elite athletes and a growing number of adolescents to enhance performance and body image. As with adults, AAS use by adolescents is associated with a range of behavioral effects, including increased anxiety and altered responses to stress. It has been suggested that adolescents, especially adolescent females, may be particularly susceptible to the effects of these steroids, but few experiments in animal models have been performed to test this assertion. Here we show that chronic exposure of adolescent female mice to a mixture of three commonly abused AAS (testosterone cypionate, nandrolone decanoate and methandrostenolone; 7.5 mg/kg/day for 5 days) significantly enhanced anxiety-like behavior as assessed by the acoustic startle response (ASR), but did not augment the fear-potentiated startle response (FPS) or alter sensorimotor gating as assessed by prepulse inhibition of the acoustic startle response (PPI). AAS treatment also significantly increased the levels of corticotropin releasing factor (CRF) mRNA and somal-associated CRF immunoreactivity in the central nucleus of the amygdala (CeA), as well as neuropil-associated immunoreactivity in the dorsal aspect of the anterolateral division of the bed nucleus of the stria terminalis (dBnST). AAS treatment did not alter CRF receptor 1 or 2 mRNA in either the CeA or the dBnST; CRF immunoreactivity in the ventral BnST, the paraventricular nucleus (PVN) or the median eminence (ME); or peripheral levels of corticosterone. These results suggest that chronic AAS treatment of adolescent female mice may enhance generalized anxiety, but not sensorimotor gating or learned fear, via a mechanism that involves increased CRF-mediated signaling from CeA neurons projecting to the dBnST. PMID:20537804

  5. Chronic Anabolic Androgenic Steroid Exposure Alters Corticotropin Releasing Factor Expression and Anxiety-Like Behaviors in the Female Mouse

    PubMed Central

    Costine, Beth A; Oberlander, Joseph G; Davis, Matthew C; Penatti, Carlos A A; Porter, Donna M; Leaton, Robert N; Henderson, Leslie P

    2010-01-01

    Summary In the past several decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit use of these drugs by elite athletes and a growing number of adolescents to enhance performance and body image. As with adults, AAS use by adolescents is associated with a range of behavioral effects, including increased anxiety and altered responses to stress. It has been suggested that adolescents, especially adolescent females, may be particularly susceptible to the effects of these steroids, but few experiments in animal models have been performed to test this assertion. Here we show that chronic exposure of adolescent female mice to a mixture of three commonly abused AAS (testosterone cypionate, nandrolone decanoate and methandrostenolone; 7.5 mg/kg/day for 5 days) significantly enhanced anxiety-like behavior as assessed by the acoustic startle response (ASR), but did not augment the fear-potentiated startle response (FPS) or alter sensorimotor gating as assessed by prepulse inhibition of the acoustic startle response (PPI). AAS treatment also significantly increased the levels of corticotropin releasing factor (CRF) mRNA and somal-associated CRF immunoreactivity in the central amygdala (CeA), as well as neuropil-associated immunoreactivity in the dorsal aspect of the anterolateral division of the bed nucleus of the stria terminalis (dBnST). AAS treatment did not alter CRF receptor 1 or 2 mRNA in either the CeA or the dBnST; CRF immunoreactivity in the ventral BNST, the paraventricular nucleus (PVN) or the median eminence (ME); or peripheral levels of corticosterone. These results suggest that chronic AAS treatment of adolescent female mice may enhance generalized anxiety, but not sensorimotor gating or learned fear, via a mechanism that involves increased CRF-mediated signaling from CeA neurons projecting to the dBnST. PMID:20537804

  6. Fetal exposure to HIV-1 alters chemokine receptor expression by CD4+T cells and increases susceptibility to HIV-1.

    PubMed

    Bunders, Madeleine J; van Hamme, John L; Jansen, Machiel H; Boer, Kees; Kootstra, Neeltje A; Kuijpers, Taco W

    2014-01-01

    Absolute numbers of lymphocytes are decreased in uninfected infants born to HIV-1-infected women (HIV-1-exposed). Although the exact mechanism is unknown, fetal exposure to maternal HIV-1-infection could prime the immune system and affect T cell trafficking. We compared the expression of chemokine receptors on cord blood CD4(+) T cells from HIV-1-exposed children and healthy controls. At baseline CD4(+) T cells had a largely naïve phenotype. However, stimulation with cytokines resulted in an upregulation of inflammatory response-related chemokine receptors on CD4(+) T cells, with HIV-1-exposed infants having a significantly higher frequency of CD4(+) T cells expressing, in particularly Th2 associated chemokine receptors (CCR3 p < 0.01, CCR8 p = 0.03). Numbers of naive CCR7(+) CD4(+) T cells were reduced (p = 0.01) in HIV-1-exposed infants. We further assessed whether the inflammatory phenotype was associated with susceptibility to HIV-1 and detected higher levels of p24 upon in in vitro infection of stimulated CD4(+) T cells of HIV-1-exposed infants. In summary, fetal exposure to HIV-1 primes the immune system in the infant leading to an enhanced immune activation and altered T cell homing, with potential ramifications regarding T cell responses and the acquisition of HIV-1 as an infant. PMID:25341640

  7. Cadmium exposure activates the ERK signaling pathway leading to altered osteoblast gene expression and apoptotic death in Saos-2 cells

    PubMed Central

    Arbon, Kate S.; Christensen, Cody M.; Harvey, Wendy A.; Heggland, Sara J.

    2012-01-01

    Recent reports of cadmium in electronic waste and jewelry have increased public awareness regarding this toxic metal. Human exposure to cadmium is associated with the development of osteoporosis. We previously reported cadmium induces apoptosis in human tumor-derived Saos-2 osteoblasts. In this study, we examine the extracellular signal-regulated protein kinase (ERK) and protein kinase C (PKC) pathways in cadmium-induced apoptosis and altered osteoblast gene expression. Saos-2 osteoblasts were cultured in the presence or absence of 10 μM CdCl2 for 2–72 hours. We detected significant ERK activation in response to CdCl2 and pretreatment with the ERK inhibitor PD98059 attenuated cadmium-induced apoptosis. However, PKCα activation was not observed after exposure to CdCl2 and pretreatment with the PKC inhibitor, Calphostin C, was unable to rescue cells from cadmium-induced apoptosis. Gene expression studies were conducted using qPCR. Cells exposed to CdCl2 exhibited a significant decrease in the bone-forming genes osteopontin (OPN) and alkaline phosphatase (ALP) mRNA. In contrast, SOST, whose protein product inhibits bone formation, significantly increased in response to CdCl2. Pretreatment with PD98059 had a recovery effect on cadmium-induced changes in gene expression. This research demonstrates cadmium can directly inhibit osteoblasts via ERK signaling pathway and identifies SOST as a target for cadmium-induced osteotoxicity. PMID:22019892

  8. Long-term exposure of polychaetes to caffeine: Biochemical alterations induced in Diopatra neapolitana and Arenicola marina.

    PubMed

    Pires, Adília; Almeida, Ângela; Calisto, Vânia; Schneider, Rudolf J; Esteves, Valdemar I; Wrona, Frederick J; Soares, Amadeu M V M; Figueira, Etelvina; Freitas, Rosa

    2016-07-01

    In the last decade studies have reported the presence of several pharmaceutical drugs in aquatic environments worldwide and an increasing effort has been done to understand the impacts induced on wildlife. Among the most abundant drugs in the environment is caffeine, which has been reported as an effective chemical anthropogenic marker. However, as for the majority of pharmaceuticals, scarce information is available on the adverse effects of caffeine on marine benthic organisms, namely polychaetes which are the most abundant group of organisms in several aquatic ecossystems. Thus, the present study aimed to evaluate the biochemical alterations induced by environmentally relevant concentrations of caffeine on the polychaete species Diopatra neapolitana and Arenicola marina. The results obtained demonstrated that after 28 days exposure oxidative stress was induced in both species, especially noticed in A. marina, resulting from the incapacity of antioxidant and biotransformation enzymes to prevent cells from lipid peroxidation. The present study further revealed that D. neapolitana used glycogen and proteins as energy to develop defense mechanisms while in A. marina these reserves were maintained independently on the exposure concentration, reinforcing the low capacity of this species to fight against oxidative stress. PMID:27112728

  9. Age at First Exposure to Football Is Associated with Altered Corpus Callosum White Matter Microstructure in Former Professional Football Players.

    PubMed

    Stamm, Julie M; Koerte, Inga K; Muehlmann, Marc; Pasternak, Ofer; Bourlas, Alexandra P; Baugh, Christine M; Giwerc, Michelle Y; Zhu, Anni; Coleman, Michael J; Bouix, Sylvain; Fritts, Nathan G; Martin, Brett M; Chaisson, Christine; McClean, Michael D; Lin, Alexander P; Cantu, Robert C; Tripodis, Yorghos; Stern, Robert A; Shenton, Martha E

    2015-11-15

    Youth football players may incur hundreds of repetitive head impacts (RHI) in one season. Our recent research suggests that exposure to RHI during a critical neurodevelopmental period prior to age 12 may lead to greater later-life mood, behavioral, and cognitive impairments. Here, we examine the relationship between age of first exposure (AFE) to RHI through tackle football and later-life corpus callosum (CC) microstructure using magnetic resonance diffusion tensor imaging (DTI). Forty retired National Football League (NFL) players, ages 40-65, were matched by age and divided into two groups based on their AFE to tackle football: before age 12 or at age 12 or older. Participants underwent DTI on a 3 Tesla Siemens (TIM-Verio) magnet. The whole CC and five subregions were defined and seeded using deterministic tractography. Dependent measures were fractional anisotropy (FA), trace, axial diffusivity, and radial diffusivity. Results showed that former NFL players in the AFE <12 group had significantly lower FA in anterior three CC regions and higher radial diffusivity in the most anterior CC region than those in the AFE ≥12 group. This is the first study to find a relationship between AFE to RHI and later-life CC microstructure. These results suggest that incurring RHI during critical periods of CC development may disrupt neurodevelopmental processes, including myelination, resulting in altered CC microstructure. PMID:26200068

  10. Global Gene Expression Alterations as a Crucial Constituent of Human Cell Response to Low Doses of Ionizing Radiation Exposure

    PubMed Central

    Sokolov, Mykyta; Neumann, Ronald

    2015-01-01

    Exposure to ionizing radiation (IR) is inevitable to humans in real-life scenarios; the hazards of IR primarily stem from its mutagenic, carcinogenic, and cell killing ability. For many decades, extensive research has been conducted on the human cell responses to IR delivered at a low dose/low dose (LD) rate. These studies have shown that the molecular-, cellular-, and tissue-level responses are different after low doses of IR (LDIR) compared to those observed after a short-term high-dose IR exposure (HDIR). With the advent of high-throughput technologies in the late 1990s, such as DNA microarrays, changes in gene expression have also been found to be ubiquitous after LDIR. Very limited subset of genes has been shown to be consistently up-regulated by LDIR, including CDKN1A. Further research on the biological effects and mechanisms induced by IR in human cells demonstrated that the molecular and cellular processes, including transcriptional alterations, activated by LDIR are often related to protective responses and, sometimes, hormesis. Following LDIR, some distinct responses were observed, these included bystander effects, and adaptive responses. Changes in gene expression, not only at the level of mRNA, but also miRNA, have been found to crucially underlie these effects having implications for radiation protection purposes. PMID:26729107

  11. Effects of brief stress exposure during early postnatal development in Balb/CByJ mice: II. Altered cortical morphology.

    PubMed

    Hohmann, C F; Beard, N A; Kari-Kari, P; Jarvis, N; Simmons, Q

    2012-11-01

    Early life experience can significantly determine later mental health status and cognitive function. Neonatal stress, in particular, has been linked to the etiology of mental health disorders as divergent as mood disorder, schizophrenia, and autism. Our study uses a Balb/CByJ mouse model to test the hypothesis, that neonatal stress will alter development and subsequent environmental modulation of neocortex. Using a split litter design, we generated stressed mice (STR) and within litter controls (LMC) along with age-matched, untreated animals (AMC), to serve as across litter controls. Short, daily exposure to a psychosocial/physical stressor, during the first week of life, resulted by adulthood in significant changes in neocortical thickness and architecture, which were further modulated by exposure to behavioral testing. Surprisingly, cortical size in LMC mice was also affected. These observations were compared to the effects of environmental enrichment in the same mouse strain. Our data indicate that LMC and STR males share with environmentally enriched males, an increase in thickness in infra-granular cortical layers, while STR also display a stress selective decrease in supragranular layers, in response to behavioral training as adults. PMID:22488100

  12. Repeated Exposure of Adult Rats to Transient Oxidative Stress Induces Various Long-Lasting Alterations in Cognitive and Behavioral Functions

    PubMed Central

    Iguchi, Yoshio; Kosugi, Sakurako; Nishikawa, Hiromi; Lin, Ziqiao; Minabe, Yoshio; Toda, Shigenobu

    2014-01-01

    Exposure of neonates to oxidative stress may increase the risk of psychiatric disorders such as schizophrenia in adulthood. However, the effects of moderate oxidative stress on the adult brain are not completely understood. To address this issue, we systemically administrated 2-cyclohexen-1-one (CHX) to adult rats to transiently reduce glutathione levels. Repeated administration of CHX did not affect the acquisition or motivation of an appetitive instrumental behavior (lever pressing) rewarded by a food outcome under a progressive ratio schedule. In addition, response discrimination and reversal learning were not affected. However, acute CHX administration blunted the sensitivity of the instrumental performance to outcome devaluation, and this effect was prolonged in rats with a history of repeated CHX exposure, representing pro-depression-like phenotypes. On the other hand, repeated CHX administration reduced immobility in forced swimming tests and blunted acute cocaine-induced behaviors, implicating antidepressant-like effects. Multivariate analyses segregated a characteristic group of behavioral variables influenced by repeated CHX administration. Taken together, these findings suggest that repeated administration of CHX to adult rats did not cause a specific mental disorder, but it induced long-term alterations in behavioral and cognitive functions, possibly related to specific neural correlates. PMID:25489939

  13. Repeated exposure of adult rats to transient oxidative stress induces various long-lasting alterations in cognitive and behavioral functions.

    PubMed

    Iguchi, Yoshio; Kosugi, Sakurako; Nishikawa, Hiromi; Lin, Ziqiao; Minabe, Yoshio; Toda, Shigenobu

    2014-01-01

    Exposure of neonates to oxidative stress may increase the risk of psychiatric disorders such as schizophrenia in adulthood. However, the effects of moderate oxidative stress on the adult brain are not completely understood. To address this issue, we systemically administrated 2-cyclohexen-1-one (CHX) to adult rats to transiently reduce glutathione levels. Repeated administration of CHX did not affect the acquisition or motivation of an appetitive instrumental behavior (lever pressing) rewarded by a food outcome under a progressive ratio schedule. In addition, response discrimination and reversal learning were not affected. However, acute CHX administration blunted the sensitivity of the instrumental performance to outcome devaluation, and this effect was prolonged in rats with a history of repeated CHX exposure, representing pro-depression-like phenotypes. On the other hand, repeated CHX administration reduced immobility in forced swimming tests and blunted acute cocaine-induced behaviors, implicating antidepressant-like effects. Multivariate analyses segregated a characteristic group of behavioral variables influenced by repeated CHX administration. Taken together, these findings suggest that repeated administration of CHX to adult rats did not cause a specific mental disorder, but it induced long-term alterations in behavioral and cognitive functions, possibly related to specific neural correlates. PMID:25489939

  14. Estrogen-induced breast cancer: Alterations in breast morphology and oxidative stress as a function of estrogen exposure

    SciTech Connect

    Mense, Sarah M.; Remotti, Fabrizio; Bhan, Ashima; Singh, Bhupendra; El-Tamer, Mahmoud; Hei, Tom K.; Bhat, Hari K.

    2008-10-01

    mammary tissue from age-matched animals. Similarly, alterations in glutathione peroxidase and superoxide dismutase activities were detected in both mammary and tumor tissue from E{sub 2}-treated rats. Taken together, our data reveal that proliferative changes in the breast tissue of ACI rats are associated with increases in 8-isoPGF{sub 2{alpha}} formation as well as changes in the activities of antioxidant enzymes. These oxidative changes appear to be a function of E{sub 2} exposure and occur prior to tumor development.

  15. Prenatal Exposure to Soy Isoflavones Altered the Immunological Parameters in Female Rats.

    PubMed

    Ebaid, Hala M; Elgawish, Rania Abdel Rahman; Abdelrazek, Heba M A; Gaffer, Ghada; Tag, Hend M

    2016-05-01

    Information on the effects of phytoestrogens on animals has increased recently; however, there were only few studies on prenatal exposure on cellular immune response. Pregnant rats were assigned to 3 groups (12 rats per group), the first was fed control diet, the second was fed low-dose (6.5 g/100 g of diet) soy isoflavones, while the third was fed high-dose (26 g/100 g of diet) soy isoflavones. The female offspring cell-mediated immune response was determined using phytohemagglutinin (PHA) injection, and intumesce index was calculated on postnatal day 50. After 24 hours of PHA injection, blood samples were collected for tumor necrosis factor α, interferon γ (IFN-γ), and interleukin (IL)-12 determination. Spleen, thymus, and PHA-injected footpads were fixed for histopathology. Intumesce index was significantly (P < 0.05) reduced in rats' offspring born from dams fed low- and high-dietary soy isoflavones than that in control groups. Thymic relative weights in offspring of rats fed high-dietary soy isoflavones showed a significant (P < 0.05) decrease compared to that in the control group. Female offspring where low and high-dietary soy isoflavones were fed to their dams showed a significant (P < 0.05) decrease in IFN-γ and IL-12 than that in control ones. Spleen of rats born from dams fed high dose of dietary soy isoflavones showed lymphocytic depletion in white pulp. Taking together, it is clear that dietary soy isoflavones at prenatal period had immunosuppressive effect on female offspring after PHA stimulation. This effect was mediated through reduced IFN-γ that interplayed in IL-12 production pathway thus reducing its level. PMID:26758869

  16. Early exposure to dynamic environments alters patterns of motor exploration throughout the lifespan.

    PubMed

    Hong, S Lee; Estrada-Sánchez, Ana María; Barton, Scott J; Rebec, George V

    2016-04-01

    We assessed early rearing conditions on aging-related changes in mouse behavior. Two isolated-housing groups, running wheel (IHRW) and empty cage (IHEC), were compared against two enriched environments, static (EEST) and dynamic (EEDY), both of which included toys and other mice. For EEDY, the location of toys and sources of food and water changed daily, but remained constant for EEST. All mice, randomly assigned to one of the four groups at ∼4 weeks of age, remained in their respective environments for 25 weeks followed by single housing in empty cages. Beginning at ∼40 weeks of age, all mice were tested at monthly intervals in a plus-shaped maze in which we measured the number of arm entries and the probability of entering a perpendicular arm. Despite making significantly more arm entries than any other group, IHEC mice also were less likely to turn into the left or right arm, a sign of motor inflexibility. Both EEDY and EEST mice showed enhanced turning relative to IHRW and IHEC groups, but only EEDY mice maintained their turning performance for up to ∼100 weeks of age. EEDY and EEST mice also were unique in showing an increase in expression of the major glutamate transporter (GLT1) in striatum, but a decrease in motor cortex, suggesting a need for further assessment of environmental manipulations on long-term changes in forebrain glutamate transmission. Our behavioral results indicate that early exposure to continually changing environments, rather than socialization or exercise alone, results in life-long changes in patterns of motor exploration. PMID:26778790

  17. Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny

    SciTech Connect

    Haddad, Rami; Kasneci, Amanda; Mepham, Kathryn; Sebag, Igal A.; and others

    2013-01-01

    Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0 μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5–14.5. At 3 months, male progeny were left sedentary or were swim trained for 4 weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. -- Highlights: ► Gestational DES changes cardiac SERCA2a and CASQ2 expression. ► Echocardiography identified systolic dysfunction and increased diastolic relaxation. ► DES

  18. Exposure to a northern contaminant mixture (NCM) alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats.

    PubMed

    Mailloux, Ryan J; Florian, Maria; Chen, Qixuan; Yan, Jin; Petrov, Ivan; Coughlan, Melanie C; Laziyan, Mahemuti; Caldwell, Don; Lalande, Michelle; Patry, Dominique; Gagnon, Claude; Sarafin, Kurtis; Truong, Jocelyn; Chan, Hing Man; Ratnayake, Nimal; Li, Nanqin; Willmore, William G; Jin, Xiaolei

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co-exposure

  19. Exposure to a Northern Contaminant Mixture (NCM) Alters Hepatic Energy and Lipid Metabolism Exacerbating Hepatic Steatosis in Obese JCR Rats

    PubMed Central

    Mailloux, Ryan J.; Florian, Maria; Chen, Qixuan; Yan, Jin; Petrov, Ivan; Coughlan, Melanie C.; Laziyan, Mahemuti; Caldwell, Don; Lalande, Michelle; Patry, Dominique; Gagnon, Claude; Sarafin, Kurtis; Truong, Jocelyn; Chan, Hing Man; Ratnayake, Nimal; Li, Nanqin; Willmore, William G.; Jin, Xiaolei

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co-exposure

  20. Prenatal fat-rich diet exposure alters responses of embryonic neurons to the chemokine, CCL2, in the hypothalamus.

    PubMed

    Poon, K; Abramova, D; Ho, H T; Leibowitz, S

    2016-06-01

    Maternal consumption of a high-fat diet (HFD) during pregnancy is found to stimulate the genesis of hypothalamic orexigenic peptide neurons in the offspring, while HFD intake in adult animals produces a systemic low-grade inflammation which increases neuroimmune factors that may affect neurogenesis and neuronal migration. Building on this evidence and our recent study showing that the inflammatory chemokine, CCL2, stimulates the migration of hypothalamic neurons and expression of orexigenic neuropeptides, we tested here the possibility that prenatal exposure to a HFD in rats affects this chemokine system, both CCL2 and its receptors, CCR2 and CCR4, and alters its actions on hypothalamic neurons, specifically those expressing the neuropeptides, enkephalin (ENK) and galanin (GAL). Using primary dissociated hypothalamic neurons extracted from embryos on embryonic day 19, we found that prenatal HFD exposure compared to chow control actually reduces the expression of CCL2 in these hypothalamic neurons, while increasing CCR2 and CCR4 expression, and also reduces the sensitivity of hypothalamic neurons to CCL2. The HFD abolished the dose-dependent, stimulatory effect of CCL2 on the number of migrated neurons and even shifted its normal stimulatory effect on migrational velocity and distance traveled by control neurons to an inhibition of migration. Further, it abolished the dose-dependent, stimulatory effect of CCL2 on neuronal expression of ENK and GAL. These results demonstrate that prenatal HFD exposure greatly disturbs the functioning of the CCL2 chemokine system in embryonic hypothalamic neurons, reducing its endogenous levels and ability to promote the migration of neurons and their expression of orexigenic peptides. PMID:26979053

  1. Altered hematological and immunological parameters in silver catfish (Rhamdia quelen) following short term exposure to sublethal concentration of glyphosate.

    PubMed

    Kreutz, Luiz Carlos; Gil Barcellos, Leonardo José; de Faria Valle, Stella; de Oliveira Silva, Tális; Anziliero, Deniz; Davi dos Santos, Ezequiel; Pivato, Mateus; Zanatta, Rafael

    2011-01-01

    Using agrichemicals to control unwanted species has become a necessary and common worldwide practice to improve crop production. Although most currently used agrichemicals are considered relatively safe, continuous usage contributes for soil and water contamination and collateral toxic effects on aquatic species. Few studies correlated the presence of agrichemicals on fish blood cells and natural immune system. Thus, in this study, silver catfish (Rhamdia quelen) were exposed to sublethal concentrations (10% of the LC(50-96 h)) of a glyphosate based herbicide and hematological and natural immune system parameters were evaluated. Silver catfish fingerlings exposed to glyphosate for 96 h had a significant reduction on blood erythrocytes, thrombocytes, lymphocytes and total leukocytes in contrast to a significant increase in the number of immature circulating cells. The effect of glyphosate on natural immune system was evaluated after 24h or 10 days exposure by measuring the phagocytic index of coelomic cells, and lysozyme, total peroxidase, bacteria agglutination, bactericidal activity and natural complement hemolytic activity in the serum of fingerlings. A significant reduction on phagocytic index, serum bacteria agglutination and total peroxidase was observed only after 24h exposure to glyphosate. In contrast, fingerlings exposed to glyphosate for 10 days had a significant lower serum bacteria agglutination and lysozyme activity. Glyphosate had no effect on serum bactericidal and complement natural hemolytic activity after 24h or 10 days exposure. Nonetheless, the information obtained in this study indicates that glyphosate contaminated water contributes to alter blood cells parameters and to reduce the activity of natural immune components important to mediate fish resistance to infecting microorganisms. PMID:20883798

  2. Selenium exposure results in reduced reproduction in an invasive ant species and altered competitive behavior for a native ant species.

    PubMed

    De La Riva, Deborah G; Trumble, John T

    2016-06-01

    Competitive ability and numerical dominance are important factors contributing to the ability of invasive ant species to establish and expand their ranges in new habitats. However, few studies have investigated the impact of environmental contamination on competitive behavior in ants as a potential factor influencing dynamics between invasive and native ant species. Here we investigated the widespread contaminant selenium to investigate its potential influence on invasion by the exotic Argentine ant, Linepithema humile, through effects on reproduction and competitive behavior. For the fecundity experiment, treatments were provided to Argentine ant colonies via to sugar water solutions containing one of three concentrations of selenium (0, 5 and 10 μg Se mL(-1)) that fall within the range found in soil and plants growing in contaminated areas. Competition experiments included both the Argentine ant and the native Dorymyrmex bicolor to determine the impact of selenium exposure (0 or 15 μg Se mL(-1)) on exploitation- and interference-competition between ant species. The results of the fecundity experiment revealed that selenium negatively impacted queen survival and brood production of Argentine ants. Viability of the developing brood was also affected in that offspring reached adulthood only in colonies that were not given selenium, whereas those in treated colonies died in their larval stages. Selenium exposure did not alter direct competitive behaviors for either species, but selenium exposure contributed to an increased bait discovery time for D. bicolor. Our results suggest that environmental toxins may not only pose problems for native ant species, but may also serve as a potential obstacle for establishment among exotic species. PMID:27038576

  3. Short and long-term exposure to diclofenac alter oxidative stress status in common carp Cyprinus carpio.

    PubMed

    Saucedo-Vence, Karinne; Dublán-García, Octavio; López-Martínez, Leticia Xochitl; Morachis-Valdes, Gabriela; Galar-Martínez, Marcela; Islas-Flores, Hariz; Gómez-Oliván, Leobardo Manuel

    2015-04-01

    Diclofenac (DCF) has been detected in significant amounts in municipal treated wastewater effluent. Diverse studies report that trace concentrations of DCF may induce toxic effects on different aquatic organisms as well as developmental, reproductive and renal damage. This study aimed to determine whether short and long-term exposure to DCF alter the oxidative stress (OS) status in blood, muscle, gills, brain and liver of common carp Cyprinus carpio. The median lethal concentration of DCF at 96 h (96-h LC50) and subsequently the lowest observed adverse effect level were determined. Carp were exposed (short and long-term) to the latter value for different exposure times (4 and 24 days) and the following biomarkers were evaluated in gill, brain, liver and blood: hydroperoxides content (HPC), lipid peroxidation (LPX), protein carbonyl content (PCC) and the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Also, the DCF was determined by LC-MS/MS. Significant increases in HPC, LPX and PCC were observed respect to control (P < 0.05) particularly in blood, muscle, gill, brain and liver. SOD, CAT and GPx activity also increased in these organs, with respect to controls (P < 0.05). DCF concentrations decreased and increased in water system and carp, respectively. Cyprinus carpio exposed to DCF was affected in OS status during the initial days of the study (at 4 days), exhibiting an increased response at 24 days in blood and liver. In contrast, a decrease was observed in muscle, gills and brain at 24 days with respect to 4 days. In conclusion, DCF induces OS on blood, muscle, gills, brain and liver in the carp C. carpio in short and long-term exposure. The biomarkers employed in this study are useful in the assessment of the environmental impact of this agent on aquatic species. PMID:25512029

  4. Exposure to monomethylarsonous acid (MMA{sup III}) leads to altered selenoprotein synthesis in a primary human lung cell model

    SciTech Connect

    Meno, Sarah R.; Nelson, Rebecca; Hintze, Korry J.; Self, William T.

    2009-09-01

    Monomethylarsonous acid (MMA{sup III}), a trivalent metabolite of arsenic, is highly cytotoxic and recent cell culture studies suggest that it might act as a carcinogen. The general consensus of studies indicates that the cytotoxicity of MMA{sup III} is a result of increased levels of reactive oxygen species (ROS). A longstanding relationship between arsenic and selenium metabolism has led to the use of selenium as a supplement in arsenic exposed populations, however the impact of organic arsenicals (methylated metabolites) on selenium metabolism is still poorly understood. In this study we determined the impact of exposure to MMA{sup III} on the regulation of expression of TrxR1 and its activity using a primary lung fibroblast line, WI-38. The promoter region of the gene encoding the selenoprotein thioredoxin reductase 1 (TrxR1) contains an antioxidant responsive element (ARE) that has been shown to be activated in the presence of electrophilic compounds. Results from radiolabeled selenoproteins indicate that exposure to low concentrations of MMA{sup III} resulted in increased synthesis of TrxR1 in WI-38 cells, and lower incorporation of selenium into other selenoproteins. MMA{sup III} treatment led to increased mRNA encoding TrxR1 in WI-38 cells, while lower levels of mRNA coding for cellular glutathione peroxidase (cGpx) were detected in exposed cells. Luciferase activity of TrxR1 promoter fusions increased with addition of MMA{sup III}, as did expression of a rat quinone reductase (QR) promoter fusion construct. However, MMA{sup III} induction of the TRX1 promoter fusion was abrogated when the ARE was mutated, suggesting that this regulation is mediated via the ARE. These results indicate that MMA{sup III} alters the expression of selenoproteins based on a selective induction of TrxR1, and this response to exposure to organic arsenicals that requires the ARE element.

  5. Repeated exposure to the herbicide atrazine alters locomotor activity and the nigrostriatal dopaminergic system of the albino rat.

    PubMed

    Rodríguez, Verónica M; Limón-Pacheco, Jorge H; Mendoza-Trejo, Maria Soledad; González-Gallardo, Adriana; Hernández-Plata, Isela; Giordano, Magda

    2013-01-01

    Atrazine (ATR) is used as a pre- and post-emergent herbicide; although banned in several countries of the European Community, it is still used extensively around the world. A recent study in rats has shown that chronic, daily exposure to 10 mg ATR/kg BW causes hyperactivity, disrupts motor coordination and learning of behavioral tasks, and decreases dopamine levels in the brain. In order to evaluate the short-term effect of ATR exposure on locomotor activity, monoamine markers, and antioxidants, adult male Sprague-Dawley rats received six IP injections of 100 mg ATR/kg BW or vehicle over two weeks. After every ATR injection we found hypoactivity that lasted up to five days, and it was accompanied by reductions in levels of striatal DA, DOPAC, and HVA without any alteration in the striatal expression of the mRNAs for Mn-SOD, Trx-1, DAR-D(1), or DAR-D(2). In contrast, in the nucleus accumbens no changes in monoamine markers were observed, and a down-regulation of Trx-1 expression was detected shortly after the ATR treatment. Moreover, in the ventral midbrain, we found that ATR induced a down-regulation of mRNA for Th and DAT, but it increased VMAT2 mRNA expression. Decreases of monoamine levels and of locomotor activity disappeared three months after ATR treatment; however, an amphetamine challenge (1 mg/kg) given two months after the ATR treatment resulted in a significant stimulation in the exposed group, revealing hidden effects of ATR on dopaminergic systems. These results indicate that ATR exposure differentially modifies the dopaminergic systems, and these modifications may underlie the behavioral changes observed. PMID:23123945

  6. Nocturnal Hypoxia Exposure With Simulated Altitude For 14 Days Does Not Significantly Alter Working Memory or Vigilance in Humans

    PubMed Central

    Thomas, Robert Joseph; Tamisier, Renaud; Boucher, Judith; Kotlar, Yana; Vigneault, Kevin; Weiss, J. Woodrow; Gilmartin, Geoffrey

    2007-01-01

    Study Objectives: To assess the effect of 2 weeks of nocturnal hypoxia exposure using simulated altitude on attention and working memory in healthy adult humans. Design: Prospective experimental physiological assessment. Setting: General Clinical Research Center. Participants: Eleven healthy, nonsmoking, subjects (7 men, 4 women). The subjects had a mean age of 27 ± 1.5 years and body mass index of 23 ± 0.9 kg/m2 Interventions: Subjects were exposed to 9 hours of continuous hypoxia from 2200 to 0700 hours in an altitude tent. Acclimatization was accomplished by graded increases in “altitude” over 3 nights (7700, 10,000 and 13,000 feet), followed by 13,000 feet for 13 consecutive days (FIO2 0.13). Measurements and Results: Polysomnography that included airflow measurements with a nasal cannula were done at baseline and during 3 time points across the protocol (nights 3, 7, and 14). Attention (10-minute Psychomotor Vigilance Task) and working memory (10-minute verbal 2-back) were assessed at baseline and on day 4, 8, 9, and 15. Nocturnal hypoxia was documented using endpoints of minimum oxygen saturation, oxygen desaturation index, and percentage of total sleep time under 90% and 80%. Total sleep time was reduced, stage 1 sleep was increased, and both obstructive and nonobstructive respiratory events were induced by altitude exposure. There was no difference in subjective mood, attention, or working memory. Conclusions: Two weeks of nocturnal continuous hypoxia in an altitude tent did not induce subjective sleepiness or impair objective vigilance and working memory. Caution is recommended in the extrapolation to humans the effects of hypoxia in animal models. Citation: Thomas RJ; Ramisier R; Boucher J; Kotlar Y; Vigneault K; Weiss JW; Gilmartin G. Nocternal hypoxia exposure with simulated altitude for 14 days does not significantly alter working memory or vigilance in humans. SLEEP 2007;30(9):1195-1203. PMID:17910391

  7. Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring.

    PubMed

    Ceccanti, Mauro; Coccurello, Roberto; Carito, Valentina; Ciafrè, Stefania; Ferraguti, Giampiero; Giacovazzo, Giacomo; Mancinelli, Rosanna; Tirassa, Paola; Chaldakov, George N; Pascale, Esterina; Ceccanti, Marco; Codazzo, Claudia; Fiore, Marco

    2016-07-01

    Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offspring. However, the role of paternal alcohol exposure (PAE) on offspring EtOH sensitivity and neurotrophins has not received much attention. The present study examined whether PAE may disrupt nerve growth factor (NGF) and/or brain-derived neurotrophic factor (BDNF) and affect EtOH preference/rewarding properties in the male offspring. CD1 sire mice were chronically addicted for EtOH or administered with sucrose. Their male offsprings when adult were assessed for EtOH preference by a conditioned place preference paradigm. NGF and BDNF, their receptors (p75(NTR) , TrkA and TrkB), dopamine active transporter (DAT), dopamine receptors D1 and D2, pro-NGF and pro-BDNF were also evaluated in brain areas. PAE affected NGF levels in frontal cortex, striatum, olfactory lobes, hippocampus and hypothalamus. BDNF alterations in frontal cortex, striatum and olfactory lobes were found. PAE induced a higher susceptibility to the EtOH rewarding effects mostly evident at the lower concentration (0.5 g/kg) that was ineffective in non-PAE offsprings. Moreover, higher ethanol concentrations (1.5 g/kg) produced an aversive response in PAE animals and a significant preference in non-PAE offspring. PAE affected also TrkA in the hippocampus and p75(NTR) in the frontal cortex. DAT was affected in the olfactory lobes in PAE animals treated with 0.5 g/kg of ethanol while no differences were found on D1/D2 receptors and for pro-NGF or pro-BDNF. In conclusion, this study shows that: PAE affects NGF and BDNF expression in the mouse brain; PAE may induce ethanol intake preference in the male offspring. PMID:25940002

  8. Methamphetamine Self-Administration Causes Persistent Striatal Dopaminergic Alterations and Mitigates the Deficits Caused by a Subsequent Methamphetamine Exposure

    PubMed Central

    McFadden, Lisa M.; Hadlock, Greg C.; Allen, Scott C.; Vieira-Brock, Paula L.; Stout, Kristen A.; Ellis, Jonathan D.; Hoonakker, Amanda J.; Andrenyak, David M.; Nielsen, Shannon M.; Wilkins, Diana G.; Hanson, Glen R.

    2012-01-01

    Preclinical studies have demonstrated that repeated methamphetamine (METH) injections (referred to herein as a “binge” treatment) cause persistent dopaminergic deficits. A few studies have also examined the persistent neurochemical impact of METH self-administration in rats, but with variable results. These latter studies are important because: 1) they have relevance to the study of METH abuse; and 2) the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure. Accordingly, the present study investigated the impact of METH self-administration on dopaminergic neuronal function. Results revealed that self-administration of METH, given according to a regimen that produces brain METH levels comparable with those reported postmortem in human METH abusers (0.06 mg/infusion; 8-h sessions for 7 days), decreased striatal dopamine transporter (DAT) uptake and/or immunoreactivity as assessed 8 or 30 days after the last self-administration session. Increasing the METH dose per infusion did not exacerbate these deficits. These deficits were similar in magnitude to decreases in DAT densities reported in imaging studies of abstinent METH abusers. It is noteworthy that METH self-administration mitigated the persistent deficits in dopaminergic neuronal function, as well as the increases in glial fibrillary acidic protein immunoreactivity, caused by a subsequent binge METH exposure. This protection was independent of alterations in METH pharmacokinetics, but may have been attributable (at least in part) to a pretreatment-induced attenuation of binge-induced hyperthermia. Taken together, these results may provide insight into the neurochemical deficits reported in human METH abusers. PMID:22034657

  9. Alcohol exposure during the first two trimesters-equivalent alters the development of corpus callosum projection neurons in the rat.

    PubMed

    Livy, Daniel J; Elberger, Andrea J

    2008-06-01

    Children exposed prenatally to alcohol can display a variety of neural deficits, including an altered development of the corpus callosum (CC), the largest interhemispheric axon pathway in the brain. Furthermore, these children show functional abnormalities that are related to brain regions with significant numbers of CC connections. Little is known about how alcohol imparts influence on CC development, but one possible mechanism is by affecting the corpus callosum projection neurons (CCpn) directly. The purpose of this study was to quantify the effects of prenatal alcohol exposure on the number, size, and distribution of CCpn within the visual cortex. The visual cortex was selected specifically due to the many vision-related deficits noted in fetal alcohol exposed children and because the critical role of the CC in visual cortex development is well documented. Sprague-Dawley rat pups received one of four alcohol dosages during gestational days (G) 1-20, or reared as nutritional or untreated control animals. Each litter was categorized according to the peak blood alcohol concentration experienced. Pups were removed from each litter on days equivalent to G29, G36, G43, and G50, for histology and measurement. Callosal axons were labeled retrogradely to their CCpn using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and the CCpn were then examined using confocal laser scanning microscopy. Differences between alcohol-exposed and control animals were observed in CCpn cell body size, number, and location with the cortex. This was particularly true of animals exposed to high doses of alcohol. In addition, some trends of CCpn development were found to be unchanged as a result of prenatal alcohol exposure. The results demonstrate clear differences in the development of CCpn in the visual cortex between alcohol-exposed and control animals and suggest that this development is particularly affected in those animals exposed to high doses of alcohol

  10. Altered Gene Expressions and Cytogenetic Repair Efficiency in Cells with Suppressed Expression of XPA after Proton Exposure

    NASA Technical Reports Server (NTRS)

    Zhang, Ye; Rohde, Larry H.; Gridley, Daila S.; Mehta, Satish K.; Pierson, Duane L.; Wu, Honglu

    2009-01-01

    Cellular responses to damages from ionizing radiation (IR) exposure are influenced not only by the genes involved in DNA double strand break (DSB) repair, but also by non- DSB repair genes. We demonstrated previously that suppressed expression of several non-DSB repair genes, such as XPA, elevated IR-induced cytogenetic damages. In the present study, we exposed human fibroblasts that were treated with control or XPA targeting siRNA to 250 MeV protons (0 to 4 Gy), and analyzed chromosome aberrations and expressions of genes involved in DNA repair. As expected, after proton irradiation, cells with suppressed expression of XPA showed a significantly elevated frequency of chromosome aberrations compared with control siRNA treated (CS) cells. Protons caused more severe DNA damages in XPA knock-down cells, as 36% cells contained multiple aberrations compared to 25% in CS cells after 4Gy proton irradiation. Comparison of gene expressions using the real-time PCR array technique revealed that expressions of p53 and its regulated genes in irradiated XPA suppressed cells were altered similarly as in CS cells, suggesting that the impairment of IR induced DNA repair in XPA suppressed cells is p53-independent. Except for XPA, which was more than 2 fold down regulated in XPA suppressed cells, several other DNA damage sensing and repair genes (GTSE1, RBBP8, RAD51, UNG and XRCC2) were shown a more than 1.5 fold difference between XPA knock-down cells and CS cells after proton exposure. The possible involvement of these genes in the impairment of DNA repair in XPA suppressed cells will be further investigated.

  11. Overexpression of cerebral and hepatic cytochrome P450s alters behavioral activity of rat offspring following prenatal exposure to lindane

    SciTech Connect

    Johri, Ashu; Yadav, Sanjay; Dhawan, Alok; Parmar, Devendra

    2007-12-15

    Oral administration of different doses (0.0625, 0.125 or 0.25 mg/kg corresponding to 1/1400th, 1/700th or 1/350th of LD{sub 50}) of lindane to the pregnant Wistar rats from gestation days 5 to 21 were found to produce a dose-dependent increase in the activity of cytochrome P450 (CYP)-dependent 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD) and N-nitrosodimethylamine demethylase (NDMA-d) in brain and liver of offspring postnatally at 3 weeks. The increase in the activity of CYP monooxygenases was found to be associated with the increase in the mRNA and protein expression of xenobiotic metabolizing CYP1A, 2B and 2E1 isoenzymes in the brain and liver of offspring. Dose-dependent alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 3 weeks have suggested that increase in CYP activity may possibly lead to the formation of metabolites to the levels that may be sufficient to alter the behavioral activity of the offspring. Interestingly, the inductive effect on cerebral and hepatic CYPs was found to persist postnatally up to 6 weeks in the offspring at the relatively higher doses (0.125 and 0.25 mg/kg) of lindane and up to 9 weeks at the highest dose (0.25 mg/kg), though the magnitude of induction was less than that observed at 3 weeks. Alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 6 and 9 weeks, though significant only in the offspring at 3 and 6-week of age, have further indicated that due to the reduced activity of the CYPs during the ontogeny, lindane and its metabolites may not be effectively cleared from the brain. The data suggest that low dose prenatal exposure to the pesticide has the potential to produce overexpression of xenobiotic metabolizing CYPs in brain and liver of the offspring which may account for the behavioral changes observed in the offspring.

  12. LACK OF ALTERATIONS IN THYROID HORMONES FOLLOWING EXPOSURE TO POLYBROMINATED DIPHENYL ETHER 47 DURING A PERIOD OF RAPID BRAIN DEVELOPMENT IN MICE

    EPA Science Inventory

    Polybrominated diphenyl ether 47 (PBDE-47) is one of a class of commonly used flame retardants that are accumulating in the environment, including human tissues. There are reports of thyroid alterations following exposure to PBDE mixtures, and it is possible that disruptions in t...

  13. Acute Ozone (O3) Exposure Accelerates Diet-Induced Pulmonary Injury and Metabolic Alterations in a Rat Model of Type II Diabetes

    EPA Science Inventory

    Abstract for Society of Toxicology, March 22-25, 2015, San Diego, CAAcute Ozone (O3) Exposure Accelerates Diet-Induced Pulmonary Injury and Metabolic Alterations in a Rat Model of Type II DiabetesS.J. Snow1,3, D. Miller2, V. Bass2, M. Schladweiler3, A. Ledbetter3, J. Richards3, C...

  14. Hepatic mitochondrial alteration in CD1 mice associated with prenatal exposures to low doses of perfluorooctanoic acid (PFOA)

    PubMed Central

    Quist, Erin M.; Filgo, Adam J.; Cummings, Connie A.; Kissling, Grace E.; Hoenerhoff, Mark J.; Fenton, Suzanne E.

    2014-01-01

    Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3 and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number, but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA. PMID:25326589

  15. Prolonged exposure to (R)-bicalutamide generates a LNCaP subclone with alteration of mitochondrial genome.

    PubMed

    Pignatta, Sara; Arienti, Chiara; Zoli, Wainer; Di Donato, Marzia; Castoria, Gabriella; Gabucci, Elisa; Casadio, Valentina; Falconi, Mirella; De Giorgi, Ugo; Silvestrini, Rosella; Tesei, Anna

    2014-01-25

    Advanced prostate cancers, initially sensitive to androgen deprivation therapy, frequently progress to the castration-resistant prostate cancer phenotype (CRPC) through mechanisms not yet fully understood. In this study we investigated mitochondrial involvement in the establishment of refractoriness to hormone therapy. Two human prostate cancer cell lines were used, the parental LNCaP and the resistant LNCaP-Rbic, the latter generated after continuous exposure to 20 μM of (R)-bicalutamide, the active enantiomer of Casodex®. We observed a significant decrease in mtDNA content and a lower expression of 8 mitochondria-encoded gene transcripts involved in respiratory chain complexes in both cell lines. We also found that (R)-bicalutamide differentially modulated dynamin-related protein (Drp-1) expression in LNCaP and LNCaP-Rbic cells. These data seem to indicate that the androgen-independent phenotype in our experimental model was due, at least in part, to alterations in mitochondrial dynamics and to a breakdown in the Drp-1-mediated mitochondrial network. PMID:24397920

  16. Chronic Nicotine Exposure Systemically Alters MicroRNA Expression Profiles during Post-embryonic Stages in Caenorhabditis elegans

    PubMed Central

    Taki, Faten A; Pan, Xiaoping; Zhang, Baohong

    2014-01-01

    Tobacco smoking is associated with many diseases. Addiction is of the most notorious tobacco-related syndrome and is majorly attributed to nicotine. In this study, we employed C. elegans as a biological model to systemically investigate the effect of chronic nicotine exposure on microRNA (miRNA) expression profile and their regulated biochemical pathways. Nicotine treatment (20μM and 20mM) was limited to the post-embryonic stage from L1–L4 (~31 hours) period after which worms were collected for genome-wide miRNA profiling. Our results show that nicotine significantly altered the expression patterns of 40 miRNAs. The effect was proportional to the nicotine dose and was expected to have an additive, more robust response. Based on pathway enrichment analyses coupled with nicotine-induced miRNA patterns, we inferred that miRNAs as a system mediates “regulatory hormesis”, manifested in biphasic behavioral and physiological phenotypes. We proposed a model where nicotine addiction is mediated by miRNAs’ regulation of fos-1 and is maintained by epigenetic factors. Thus, our study offers new insights for a better understanding of the sensitivity of early developmental stages to nicotine. PMID:23765240

  17. Kidney injury and alterations of inflammatory cytokine expressions in mice following long-term exposure to cerium chloride.

    PubMed

    Sang, Xuezi; Ze, Xiao; Gui, Suxin; Wang, Xiaochun; Hong, Jie; Ze, Yuguan; Zhao, Xiaoyang; Sheng, Lei; Sun, Qingqing; Yu, Xiaohong; Wang, Ling; Hong, Fashui

    2014-12-01

    It has been demonstrated that the organic damages of animals can be caused by exposure to lanthanide oxides or compounds. However, the molecular mechanism of CeCl3 -induced kidney injury remains unclear. In this study, the mechanism of nephric damage in mice induced by an intragastric administration of CeCl3 was investigated. The results showed that Ce(3+) was accumulated in the kidney, which in turn led to oxidative stress, severe nephric inflammation, and dysfunction in mice. Furthermore, CeCl3 activated nucleic factor κB, which in turn increased the expression levels of tumor necrosis factor α, macrophage migration inhibitory factor, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-18, interleukin-1β, cross-reaction protein, transforming growth factor-β, interferon-γ, and CYP1A1, while suppressed heat shock protein 70 expression. These findings implied that Ce(3+) -induced kidney injury of mice might be associated with oxidative stress, alteration of inflammatory cytokine expression, and reduction of detoxification of CeCl3 . PMID:23712967

  18. Genomic and Phenotypic Alterations of the Neuronal-Like Cells Derived from Human Embryonal Carcinoma Stem Cells (NT2) Caused by Exposure to Organophosphorus Compounds Paraoxon and Mipafox

    PubMed Central

    Pamies, David; Sogorb, Miguel A.; Fabbri, Marco; Gribaldo, Laura; Collotta, Angelo; Scelfo, Bibiana; Vilanova, Eugenio; Harris, Georgina; Bal-Price, Anna

    2014-01-01

    Historically, only few chemicals have been identified as neurodevelopmental toxicants, however, concern remains, and has recently increased, based upon the association between chemical exposures and increased developmental disorders. Diminution in motor speed and latency has been reported in preschool children from agricultural communities. Organophosphorus compounds (OPs) are pesticides due to their acute insecticidal effects mediated by the inhibition of acetylcholinesterase, although other esterases as neuropathy target esterase (NTE) can also be inhibited. Other neurological and neurodevelopmental toxic effects with unknown targets have been reported after chronic exposure to OPs in vivo. We studied the initial stages of retinoic acid acid-triggered differentiation of pluripotent cells towards neural progenitors derived from human embryonal carcinoma stem cells to determine if neuropathic OP, mipafox, and non-neuropathic OP, paraoxon, are able to alter differentiation of neural precursor cells in vitro. Exposure to 1 μM paraoxon (non-cytotoxic concentrations) altered the expression of different genes involved in signaling pathways related to chromatin assembly and nucleosome integrity. Conversely, exposure to 5 μM mipafox, a known inhibitor of NTE activity, showed no significant changes on gene expression. We conclude that 1 μM paraoxon could affect the initial stage of in vitro neurodifferentiation possibly due to a teratogenic effect, while the absence of transcriptional alterations by mipafox exposure did not allow us to conclude a possible effect on neurodifferentiation pathways at the tested concentration. PMID:24413757

  19. Exposure to vehicle emissions results in altered blood brain barrier permeability and expression of matrix metalloproteinases and tight junction proteins in mice

    PubMed Central

    2013-01-01

    Background Traffic-generated air pollution-exposure is associated with adverse effects in the central nervous system (CNS) in both human exposures and animal models, including neuroinflammation and neurodegeneration. While alterations in the blood brain barrier (BBB) have been implicated as a potential mechanism of air pollution-induced CNS pathologies, pathways involved have not been elucidated. Objectives To determine whether inhalation exposure to mixed vehicle exhaust (MVE) mediates alterations in BBB permeability, activation of matrix metalloproteinases (MMP) -2 and −9, and altered tight junction (TJ) protein expression. Methods Apolipoprotein (Apo) E−/− and C57Bl6 mice were exposed to either MVE (100 μg/m3 PM) or filtered air (FA) for 6 hr/day for 30 days and resulting BBB permeability, expression of ROS, TJ proteins, markers of neuroinflammation, and MMP activity were assessed. Serum from study mice was applied to an in vitro BBB co-culture model and resulting alterations in transport and permeability were quantified. Results MVE-exposed Apo E−/− mice showed increased BBB permeability, elevated ROS and increased MMP-2 and −9 activity, compared to FA controls. Additionally, cerebral vessels from MVE-exposed mice expressed decreased levels of TJ proteins, occludin and claudin-5, and increased levels of inducible nitric oxide synthase (iNOS) and interleukin (IL)-1β in the parenchyma. Serum from MVE-exposed animals also resulted in increased in vitro BBB permeability and altered P-glycoprotein transport activity. Conclusions These data indicate that inhalation exposure to traffic-generated air pollutants promotes increased MMP activity and degradation of TJ proteins in the cerebral vasculature, resulting in altered BBB permeability and expression of neuroinflammatory markers. PMID:24344990

  20. Exposure to low-dose (56)Fe-ion radiation induces long-term epigenetic alterations in mouse bone marrow hematopoietic progenitor and stem cells.

    PubMed

    Miousse, Isabelle R; Shao, Lijian; Chang, Jianhui; Feng, Wei; Wang, Yingying; Allen, Antiño R; Turner, Jennifer; Stewart, Blair; Raber, Jacob; Zhou, Daohong; Koturbash, Igor

    2014-07-01

    There is an increasing need to better understand the long-term health effects of high-linear energy transfer (LET) radiation due to exposure during space missions, as well as its increasing use in clinical treatments. Previous studies have indicated that exposure to (56)Fe heavy ions increases the incidence of acute myeloid leukemia (AML) in mice but the underlying molecular mechanisms remain elusive. Epigenetic alterations play a role in radiation-induced genomic instability and the initiation and progression of AML. In this study, we assessed the effects of low-dose (56)Fe-ion irradiation on epigenetic alterations in bone marrow mononuclear cells (BM-MNCs) and hematopoietic progenitor and stem cells (HPSCs). Exposure to (56)Fe ions (600 MeV, 0.1, 0.2 and 0.4 Gy) resulted in significant epigenetic alterations involving methylation of DNA, the DNA methylation machinery and expression of repetitive elements. Four weeks after irradiation, these changes were primarily confined to HPSCs and were exhibited as dose-dependent hypermethylation of LINE1 and SINE B1 repetitive elements [4.2-fold increase in LINE1 (P < 0.001) and 7.6-fold increase in SINE B1 (P < 0.01) after exposure to 0.4 Gy; n = 5]. Epigenetic alterations were persistent and detectable for at least 22 weeks after exposure, when significant loss of global DNA hypomethylation (1.9-fold, P < 0.05), decreased expression of Dnmt1 (1.9-fold, P < 0.01), and increased expression of LINE1 and SINE B1 repetitive elements (2.8-fold, P < 0.001 for LINE1 and 1.9-fold, P < 0.05 for SINE B1; n = 5) were observed after exposure to 0.4 Gy. In contrast, exposure to (56)Fe ions did not result in accumulation of increased production of reactive oxygen species (ROS) and DNA damage, exhibited as DNA strand breaks. Furthermore, no significant alterations in cellular senescence and apoptosis were detected in HPSCs after exposure to (56)Fe-ion radiation. These findings suggest that epigenetic reprogramming is possibly involved in

  1. Exposure to Low-Dose 56Fe-Ion Radiation Induces Long-Term Epigenetic Alterations in Mouse Bone Marrow Hematopoietic Progenitor and Stem Cells

    PubMed Central

    Chang, Jianhui; Feng, Wei; Wang, Yingying; Allen, Antiño R.; Turner, Jennifer; Stewart, Blair; Raber, Jacob; Zhou, Daohong

    2014-01-01

    There is an increasing need to better understand the long-term health effects of high-linear energy transfer (LET) radiation due to exposure during space missions, as well as its increasing use in clinical treatments. Previous studies have indicated that exposure to 56Fe heavy ions increases the incidence of acute myeloid leukemia (AML) in mice but the underlying molecular mechanisms remain elusive. Epigenetic alterations play a role in radiation-induced genomic instability and the initiation and progression of AML. In this study, we assessed the effects of low-dose 56Fe-ion irradiation on epigenetic alterations in bone marrow mononuclear cells (BM-MNCs) and hematopoietic progenitor and stem cells (HPSCs). Exposure to 56Fe ions (600 MeV, 0.1, 0.2 and 0.4 Gy) resulted in significant epigenetic alterations involving methylation of DNA, the DNA methylation machinery and expression of repetitive elements. Four weeks after irradiation, these changes were primarily confined to HPSCs and were exhibited as dose-dependent hypermethylation of LINE1 and SINE B1 repetitive elements [4.2-fold increase in LINE1 (P < 0.001) and 7.6-fold increase in SINE B1 (P < 0.01) after exposure to 0.4 Gy; n = 5]. Epigenetic alterations were persistent and detectable for at least 22 weeks after exposure, when significant loss of global DNA hypomethylation (1.9-fold, P < 0.05), decreased expression of Dnmt1 (1.9-fold, P < 0.01), and increased expression of LINE1 and SINE B1 repetitive elements (2.8-fold, P < 0.001 for LINE1 and 1.9-fold, P < 0.05 for SINE B1; n = 5) were observed after exposure to 0.4 Gy. In contrast, exposure to 56Fe ions did not result in accumulation of increased production of reactive oxygen species (ROS) and DNA damage, exhibited as DNA strand breaks. Furthermore, no significant alterations in cellular senescence and apoptosis were detected in HPSCs after exposure to 56Fe-ion radiation. These findings suggest that epigenetic reprogramming is possibly involved in the

  2. Long-term alterations in vulnerability to addiction to drugs of abuse and in brain gene expression after early life ethanol exposure.

    PubMed

    Barbier, Estelle; Pierrefiche, Olivier; Vaudry, David; Vaudry, Hubert; Daoust, Martine; Naassila, Mickaël

    2008-12-01

    Exposure to ethanol early in life can have long-lasting implications on brain function and drug of abuse response later in life. The present study investigated in rats, the long-term consequences of pre- and postnatal (early life) ethanol exposure on drug consumption/reward and the molecular targets potentially associated with these behavioral alterations. Since a relationship has been demonstrated between heightened drugs intake and susceptibility to drugs-induced locomotor activity/sensitization, anxiolysis, we tested these behavioral responses, depending on the drug, in control and early life ethanol-exposed animals. Our results show that progeny exposed to early life ethanol displayed increased consumption of ethanol solutions and increased sensitivity to cocaine rewarding effects assessed in the conditioned place preference test. Offspring exposed to ethanol were more sensitive to the anxiolytic effect of ethanol and the increased sensitivity could, at least in part, explain the alteration in the consumption of ethanol for its anxiolytic effects. In addition, the sensitivity to hypothermic effects of ethanol and ethanol metabolism were not altered by early life ethanol exposure. The sensitization to cocaine (20 mg/kg) and to amphetamine (1.2 mg/kg) was increased after early life ethanol exposure and, could partly explain, an increase in the rewarding properties of psychostimulants. Gene expression analysis revealed that expression of a large number of genes was altered in brain regions involved in the reinforcing effects of drugs of abuse. Dopaminergic receptors and transporter binding sites were also down-regulated in the striatum of ethanol-exposed offspring. Such long-term neurochemical alterations in transmitter systems and in the behavioral responses to ethanol and other drugs of abuse may confer an increased liability for addiction in exposed offspring. PMID:18713641

  3. DNA methylation alterations in response to prenatal exposure of maternal cigarette smoking: A persistent epigenetic impact on health from maternal lifestyle?

    PubMed

    Nielsen, Christina H; Larsen, Agnete; Nielsen, Anders L

    2016-02-01

    Despite increased awareness, maternal cigarette smoking during pregnancy continues to be a common habit causing risk for numerous documented negative health consequences in the exposed children. It has been proposed that epigenetic mechanisms constitute the link between prenatal exposure to maternal cigarette smoking (PEMCS) and the diverse pathologies arising in later life. We here review the current literature, focusing on DNA methylation. Alterations in the global DNA methylation patterns were observed after exposure to maternal smoking during pregnancy in placenta, cord blood and buccal epithelium tissue. Further, a number of specific genes exemplified by CYP1A1, AhRR, FOXP3, TSLP, IGF2, AXL, PTPRO, C11orf52, FRMD4A and BDNF are shown to have altered DNA methylation patterns in at least one of these tissue types due to PEMCS. Investigations showing persistence and indications of trans-generational inheritance of DNA methylation alterations induced by smoking exposure are also described. Further, smoking-induced epigenetic manifestations can be both tissue-dependent and gender-specific which show the importance of addressing the relevant sex, tissue and cell types in the future studies linking specific epigenetic alterations to disease development. Moreover, the effect of paternal cigarette smoking and second-hand smoke exposure is documented and accordingly not to be neglected in future investigations and data evaluations. We also outline possible directions for the future research to address how DNA methylation alterations induced by maternal lifestyle, exemplified by smoking, have direct consequences for fetal development and later in life health and behavior of the child. PMID:25480659

  4. Developmental Nicotine Exposure Alters AMPA Neurotransmission in the Hypoglossal Motor Nucleus and Pre-Bötzinger Complex of Neonatal Rats

    PubMed Central

    Jaiswal, Stuti J.; Pilarski, Jason Q.; Harrison, Caitlyn M.; Fregosi, Ralph F.

    2014-01-01

    Developmental nicotine exposure (DNE) impacts central respiratory control in neonates born to smoking mothers. We previously showed that DNE enhances the respiratory motor response to bath application of AMPA to the brainstem, although it was unclear which brainstem respiratory neurons mediated these effects (Pilarski and Fregosi, 2009). Here we examine how DNE influences AMPA-type glutamatergic neurotransmission in the pre-Bötzinger complex (pre-BötC) and the hypoglossal motor nucleus (XIIMN), which are neuronal populations located in the medulla that are necessary for normal breathing. Using rhythmic brainstem slices from neonatal rats, we microinjected AMPA into the pre-BötC or the XIIMN while recording from XII nerve rootlets (XIIn) as an index of respiratory motor output. DNE increased the duration of tonic activity and reduced rhythmic burst amplitude after AMPA microinjection into the XIIMN. Also, DNE led to an increase in respiratory burst frequency after AMPA injection into the pre-BötC. Whole-cell patch-clamp recordings of XII motoneurons showed that DNE increased motoneuron excitability but did not change inward currents. Immunohistochemical studies indicate that DNE reduced the expression of glutamate receptor subunits 2 and 3 (GluR2/3) in the XIIMN and the pre-BötC. Our data show that DNE alters AMPAergic synaptic transmission in both the XIIMN and pre-BötC, although the mechanism by which this occurs is unclear. We suggest that the DNE-induced reduction in GluR2/3 may represent an attempt to compensate for increased cell excitability, consistent with mechanisms underlying homeostatic plasticity. PMID:23392689

  5. Claudins in a primary cultured puffer fish (Tetraodon nigroviridis) gill epithelium model alter in response to acute seawater exposure.

    PubMed

    Bui, Phuong; Kelly, Scott P

    2015-11-01

    Gill epithelium permeability and qualitative/quantitative aspects of gill claudin (cldn) tight junction (TJ) protein transcriptomics were examined with a primary cultured model gill epithelium developed using euryhaline puffer fish (Tetraodon nigroviridis) gills. The model was prepared using seawater-acclimated fish gills and was cultured on permeable cell culture filter supports. The model is composed of 1-2 confluent layers of gill pavement cells (PVCs), with the outer layer exhibiting prominent apical surface microridges and TJs between adjacent cells. During development of electrophysiological characteristics, the model exhibits a sigmoidal increase in transpithelial resistance (TER) and plateaus around 30 kΩcm(2). At this point paracellular movement of [(3)H]polyethylene glycol (PEG) 4000 was low at ~1.75 cm s(-1)×10(-7). When exposed to apical seawater (SW) epithelia exhibit a marked decrease in TER while PEG flux remained unchanged for at least 6 h. In association with this, transcript encoding cldn TJ proteins cldn3c, -23b, -27a, -27c, -32a and -33b increased during the first 6 h while cldn11a decreased. This suggests that these proteins are involved in maintaining barrier properties between gill PVCs of SW fishes. Gill cldn mRNA abundance also altered 6 and 12 h following abrupt SW exposure of puffer fish, but in a manner that differed qualitatively and quantitatively from the cultured model. This most likely reflects the cellular heterogeneity of whole tissue and/or the contribution of the endocrine system in intact fish. The current study provides insight into the physiological and transcriptomic response of euryhaline fish gill cells to a hyperosmotic environment. PMID:26239219

  6. Critical periods for chlorpyrifos-induced developmental neurotoxicity: alterations in adenylyl cyclase signaling in adult rat brain regions after gestational or neonatal exposure.

    PubMed Central

    Meyer, Armando; Seidler, Frederic J; Aldridge, Justin E; Tate, Charlotte A; Cousins, Mandy M; Slotkin, Theodore A

    2004-01-01

    Developmental exposure to chlorpyrifos (CPF) alters the function of a wide variety of neural systems. In the present study we evaluated the effects in adulthood of CPF exposure of rats during different developmental windows, using the adenylyl cyclase (AC) signaling cascade, which mediates the cellular responses to numerous neurotransmitters. Animals were exposed on gestational days (GD) 9-12 or 17-20 or on postnatal days (PN) 1-4 or 11-14 and assessed at PN60. In addition to basal AC activity, we evaluated the responses to direct AC stimulants (forskolin, Mn2+) and to isoproterenol, which activates signaling through ss-adrenoceptors coupled to stimulatory G-proteins. CPF exposure in any of the four periods elicited significant changes in AC signaling in a wide variety of brain regions in adulthood. In general, GD9-12 was the least sensitive stage, requiring doses above the threshold for impaired maternal weight gain, whereas effects were obtained at subtoxic doses for all other regimens. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus shared by multiple stimulants; superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses, in G-protein function, and in AC expression and subtypes. Exposures conducted at GD17-20 and later all produced sex-selective alterations. These results suggest that developmental exposure to CPF elicits long-lasting alterations in cell-signaling cascades that are shared by multiple neurotransmitter and hormonal inputs; the resultant abnormalities of synaptic communication are thus likely to occur in widespread neural circuits and their corresponding behaviors. PMID:14998743

  7. Acute and long-term exposure to chlorpyrifos induces cell death of basal forebrain cholinergic neurons through AChE variants alteration.

    PubMed

    del Pino, Javier; Moyano, Paula; Anadon, María José; García, José Manuel; Díaz, María Jesús; García, Jimena; Frejo, María Teresa

    2015-10-01

    Chlorpyrifos (CPF) is one of the most widely used organophosphates insecticides that has been reported to induce cognitive disorders both after acute and repeated administration similar to those induced in Alzheimer's disease (AD). However, the mechanisms through which it induces these effects are unknown. On the other hand, the cholinergic system, mainly basal forebrain cholinergic neurons, is involved in learning and memory regulation, and an alteration of cholinergic transmission or/and cholinergic cell loss could induce these effects. In this regard, it has been reported that CPF can affect cholinergic transmission, and alter AChE variants, which have been shown to be related with basal forebrain cholinergic neuronal loss. According to these data, we hypothesized that CPF could induce basal forebrain cholinergic neuronal loss through cholinergic transmission and AChE variants alteration. To prove this hypothesis, we evaluated in septal SN56 basal forebrain cholinergic neurons, the CPF toxic effects after 24h and 14 days exposure on neuronal viability and the cholinergic mechanisms related to it. This study shows that CPF impaired cholinergic transmission, induced AChE inhibition and, only after long-term exposure, increased CHT expression, which suggests that acetylcholine levels alteration could be mediated by these actions. Moreover, CPF induces, after acute and long-term exposure, cell death in cholinergic neurons in the basal forebrain and this effect is independent of AChE inhibition and acetylcholine alteration, but was mediated partially by AChE variants alteration. Our present results provide a new understanding of the mechanisms contributing to the harmful effects of CPF on neuronal function and viability, and the possible relevance of CPF in the pathogenesis of neurodegenerative diseases. PMID:26210949

  8. ASSOCIATIONS BETWEEN PHYSIOLOGICAL ALTERATIONS AND POPULATION CHANGES IN AN ESTUARINE MYSID DURING CHRONIC EXPOSURE TO A PESTICIDE

    EPA Science Inventory

    A number of vital life processes of an estuarine mysid (Mysidopsis bahia) were examined throughout its life cycle during exposure to the thiocarbamate herbicide, thiobencarb. Initial exposure of juvenile mysids to thiobencarb resulted in elevated respiration rates. Concentrations...

  9. Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats.

    PubMed

    Zamberletti, Erica; Beggiato, Sarah; Steardo, Luca; Prini, Pamela; Antonelli, Tiziana; Ferraro, Luca; Rubino, Tiziana; Parolaro, Daniela

    2014-03-01

    Although several findings indicate an association between adolescent cannabis abuse and the risk to develop schizophrenia later in life, the evidence for a causal relationship is still inconclusive. In the present study, we investigated the emergence of psychotic-like behavior in adult female rats chronically exposed to delta-9-tetrahydrocannabinol (THC) during adolescence. To this aim, female Sprague-Dawley rats were treated with THC during adolescence (PND 35-45) and, in adulthood (PND 75), a series of behavioral tests and biochemical assays were performed in order to investigate the long-term effects of adolescent THC exposure. Adolescent THC pretreatment leads to long-term behavioral alterations, characterized by recognition memory deficits, social withdrawal, altered emotional reactivity and sensitization to the locomotor activating effects of acute PCP. Moreover, since cortical disinhibition seems to be a key feature of many different animal models of schizophrenia and GABAergic hypofunction in the prefrontal cortex (PFC) has been observed in postmortem brains from schizophrenic patients, we then investigated the long-lasting consequences of adolescent THC exposure on GABAergic transmission in the adult rat PFC. Biochemical analyses revealed that adolescent THC exposure results in reduced GAD67 and basal GABA levels within the adult PFC. GAD67 expression is reduced both in parvalbumin (PV)- and cholecystokinin (CCK)-containing interneurons; this alteration may be related to the altered emotional reactivity triggered by adolescent THC, as silencing PFC GAD67 expression through a siRNA-mediated approach is sufficient to impact rats' behavior in the forced swim test. Finally, the cellular underpinnings of the observed sensitized response to acute PCP in adult THC-treated rats could be ascribed to the increased cFos immunoreactivity and glutamate levels in the PFC and dorsal striatum. The present findings support the hypothesis that adolescent THC exposure may

  10. Altered mRNA editing and expression of ionotropic glutamate receptors after kainic acid exposure in cyclooxygenase-2 deficient mice.

    PubMed

    Caracciolo, Luca; Barbon, Alessandro; Palumbo, Sara; Mora, Cristina; Toscano, Christopher D; Bosetti, Francesca; Barlati, Sergio

    2011-01-01

    Kainic acid (KA) binds to the AMPA/KA receptors and induces seizures that result in inflammation, oxidative damage and neuronal death. We previously showed that cyclooxygenase-2 deficient (COX-2(-/-)) mice are more vulnerable to KA-induced excitotoxicity. Here, we investigated whether the increased susceptibility of COX-2(-/-) mice to KA is associated with altered mRNA expression and editing of glutamate receptors. The expression of AMPA GluR2, GluR3 and KA GluR6 was increased in vehicle-injected COX-2(-/-) mice compared to wild type (WT) mice in hippocampus and cortex, whereas gene expression of NMDA receptors was decreased. KA treatment decreased the expression of AMPA, KA and NMDA receptors in the hippocampus, with a significant effect in COX-2(-/-) mice. Furthermore, we analyzed RNA editing levels and found that the level of GluR3 R/G editing site was selectively increased in the hippocampus and decreased in the cortex in COX-2(-/-) compared with WT mice. After KA, GluR4 R/G editing site, flip form, was increased in the hippocampus of COX-2(-/-) mice. Treatment of WT mice with the COX-2 inhibitor celecoxib for two weeks decreased the expression of AMPA/KA and NMDAR subunits after KA, as observed in COX-2(-/-) mice. After KA exposure, COX-2(-/-) mice showed increased mRNA expression of markers of inflammation and oxidative stress, such as cytokines (TNF-α, IL-1β and IL-6), inducible nitric oxide synthase (iNOS), microglia (CD11b) and astrocyte (GFAP). Thus, COX-2 gene deletion can exacerbate the inflammatory response to KA. We suggest that COX-2 plays a role in attenuating glutamate excitotoxicity by modulating RNA editing of AMPA/KA and mRNA expression of all ionotropic glutamate receptor subunits and, in turn, neuronal excitability. These changes may contribute to the increased vulnerability of COX-2(-/-) mice to KA. The overstimulation of glutamate receptors as a consequence of COX-2 gene deletion suggests a functional coupling between COX-2 and the

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

    SciTech Connect

    Bardullas, U.; Limon-Pacheco, J.H.; Giordano, M.; Carrizales, L.; Mendoza-Trejo, M.S.; Rodriguez, V.M.

    2009-09-01

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

  12. Bisphenol-A exposure during adolescence leads to enduring alterations in cognition and dendritic spine density in adult male and female rats.

    PubMed

    Bowman, Rachel E; Luine, Victoria; Diaz Weinstein, Samantha; Khandaker, Hameda; DeWolf, Sarah; Frankfurt, Maya

    2015-03-01

    We have previously demonstrated that adolescent exposure of rats to bisphenol-A (BPA), an environmental endocrine disrupter, increases anxiety, impairs spatial memory, and decreases dendritic spine density in the CA1 region of the hippocampus (CA1) and medial prefrontal cortex (mPFC) when measured in adolescents in both sexes. The present study examined whether the behavioral and morphological alterations following BPA exposure during adolescent development are maintained into adulthood. Male and female, adolescent rats received BPA, 40μg/kg/bodyweight, or control treatments for one week. In adulthood, subjects were tested for anxiety and locomotor activity, spatial memory, non-spatial visual memory, and sucrose preference. Additionally, stress-induced serum corticosterone levels and dendritic spine density in the mPFC and CA1 were measured. BPA-treated males, but not females, had decreased arm visits on the elevated plus maze, but there was no effect on anxiety. Non-spatial memory, object recognition, was also decreased in BPA treated males, but not in females. BPA exposure did not alter spatial memory, object placement, but decreased exploration during the tasks in both sexes. No significant group differences in sucrose preference or serum corticosterone levels in response to a stress challenge were found. However, BPA exposure, regardless of sex, significantly decreased spine density of both apical and basal dendrites on pyramidal cells in CA1 but had no effect in the mPFC. Current data are discussed in relation to BPA dependent changes, which were present during adolescence and did, or did not, endure into adulthood. Overall, adolescent BPA exposure, below the current reference safe daily limit set by the U.S.E.P.A., leads to alterations in some behaviors and neuronal morphology that endure into adulthood. PMID:25554518

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

    PubMed

    Bardullas, U; Limón-Pacheco, J H; Giordano, M; Carrizales, L; Mendoza-Trejo, M S; Rodríguez, V M

    2009-09-01

    Arsenic (As) is a toxic metalloid widely present in the environment. Human exposure to As has been associated with the development of skin and internal organ cancers and cardiovascular disorders, among other diseases. A few studies report decreases in intelligence quotient (IQ), and sensory and motor alterations after chronic As exposure in humans. On the other hand, studies of rodents exposed to high doses of As have found alterations in locomotor activity, brain neurochemistry, behavioral tasks, and oxidative stress. In the present study both male and female C57Bl/6J mice were exposed to environmentally relevant doses of As such as 0.05, 0.5, 5.0, or 50 mg As/L of drinking water for 4 months, and locomotor activity was assessed every month. Male mice presented hyperactivity in the group exposed to 0.5 mg As/L and hypoactivity in the group exposed to 50 mg As/L after 4 months of As exposure, whereas female mice exposed to 0.05, 0.5, and 5.0 mg As/L exhibited hyperactivity in every monthly test during As exposure. Furthermore, striatal and hypothalamic dopamine content was decreased only in female mice. Also decreases in tyrosine hydroxylase (TH) and cytosolic thioredoxin (Trx-1) mRNA expression in striatum and nucleus accumbens were observed in male and female mice, respectively. These results indicate that chronic As exposure leads to gender-dependent alterations in dopaminergic markers and spontaneous locomotor activity, and down-regulation of the antioxidant capacity of the brain. PMID:19121333

  14. Multi-generational effects of polybrominated diphenylethers exposure: embryonic exposure of male American kestrels (Falco sparverius) to DE-71 alters reproductive success and behaviors.

    PubMed

    Marteinson, Sarah C; Bird, David M; Shutt, J Laird; Letcher, Robert J; Ritchie, Ian J; Fernie, Kim J

    2010-08-01

    Polybrominated diphenylethers (PBDEs) are additive flame-retardants that are environmentally persistent and bioaccumulative compounds of particular concern to species at high trophic levels, including predatory birds. The developmental effects of in ovo exposure to male birds at environmentally relevant levels of the PBDE technical mixture, DE-71, on reproductive success and behaviors using captive American kestrels (Falco sparverius) were determined. Males were exposed in ovo by direct maternal transfer to DE-71 and unintentionally to low concentrations of hexabromocyclododecane (HBCD) at three mean +/- standard error DE-71 concentrations of 288.60 +/- 33.35 ng/g wet weight (low-exposure), 1130.59 +/- 95.34 ng/g wet weight (high-exposure), or background levels of 3.01 +/- 0.46 ng/g wet weight (control). One year following exposure, males were paired with unexposed females. Reproductive success was lower in the high exposure pairs: 43% failed to lay eggs while all other pairs laid complete clutches; they also laid smaller clutches and produced smaller eggs with reduced fertility, parameters that were negatively correlated with paternal in ovo concentrations of all PBDEs, as well as individual congeners and HBCD. Throughout courtship, there were fewer copulations by all in ovo exposed males, fewer mate-calls made by high-exposure males, and decreasing trends in pair-bonding and nest-box behaviors across treatments that continued during brood rearing. The reductions in clutch size and fertility were associated with the reduced frequencies of male courtship behaviors, and were associated with increasing concentrations of the PBDE congeners BDE-47, -99, -100, -53, -138, and HBCD. The results of the present study confirm effects noted in the F(0) generation and demonstrate that exposure to DE-71 affects multiple generations of this predatory avian species at environmentally relevant levels of exposure. PMID:20821627

  15. Exposure to cypermethrin and mancozeb alters the expression profile of THBS1, SPP1, FEZ1 and GPNMB in human peripheral blood mononuclear cells.

    PubMed

    Mandarapu, Rajesh; Prakhya, Balakrishna Murthy

    2016-07-01

    The complex immune system displays a coordinated transcriptional response to xenobiotic exposure by altering expression of designated transcription factors that, in turn, trigger immune responses. Despite the identification of several transcription factors that contribute to regulatory response, very little is known about the specific role of factors that are triggered due to exposure to obnoxious pesticides. Here, for the first time, alterations in human peripheral blood lymphocyte expression of transcriptional factors - thrombospondin-1 (THBS-1), secretory phospho-protein-1 (SPP-1), glycoprotein non-metastatic-β (GPNMB) and fasciculation and elongation factor ζ-1 (FEZ-1), due to in vitro exposure to the crop protection chemicals cypermethrin and mancozeb are reported. Results revealed significant changes in expression profiles due to mancozeb exposure, supporting its immune dysfunction potential; in contrast, cypermethrin exposure did not cause significant changes. Based on these effects on gene expression across the doses tested, it was likely key components of immune mechanisms such as proliferation, cell adhesion, apoptosis and cell activation in human PBMC were affected. Although these data are from in vitro experiments, the results point out the potential role for changes in these factors in the etiology of defective T-cell immune function seen in humans occupationally exposed to crop protection chemicals like mancozeb. These studies suggest the involvement of transcription factors in regulation of pesticide-induced immune dysfunction; these studies also represent a novel approach for identifying potential immune-related dysfunctions due to exposure to pesticides. Further studies are needed to better understand the functional significance of these in vitro findings. PMID:26796295

  16. Combined Inhaled Diesel Exhaust Particles and Allergen Exposure Alter Methylation of T Helper Genes and IgE Production In Vivo

    PubMed Central

    Liu, Jinming; Ballaney, Manisha; Al-alem, Umaima; Quan, Chunli; Jin, Ximei; Perera, Frederica; Chen, Lung-Chi; Miller, Rachel L.

    2008-01-01

    Changes in methylation of CpG sites at the interleukin (IL)-4 and interferon (IFN)-γ promoters are associated with T helper (Th) 2 polarization in vitro. No previous studies have examined whether air pollution or allergen exposure alters methylation of these two genes in vivo. We hypothesized that diesel exhaust particles (DEP) would induce hypermethylation of the IFN-γ promoter and hypomethylation of IL-4 in CD4+ T cells among mice sensitized to the fungus allergen Aspergillus fumigatus.We also hypothesized that DEP-induced methylation changes would affect immunoglobulin (Ig) E regulation. BALB/c mice were exposed to a 3-week course of inhaled DEP exposure while undergoing intranasal sensitization to A. fumigatus. Purified DNA from splenic CD4+ cells underwent bisulfite treatment, PCR amplification, and pyrosequencing. Sera IgE levels were compared with methylation levels at several CpG sites in the IL-4 and IFN-γ promoter. Total IgE production was increased following intranasal sensitization A. fumigatus. IgE production was augmented further following combined exposure to A. fumigatus and DEP exposure. Inhaled DEP exposure and intranasal A. fumigatus induced hypermethylation at CpG−45, CpG−53, CpG−205 sites of the IFN-γ promoter and hypomethylation at CpG−408 of the IL-4 promoter. Altered methylation of promoters of both genes was correlated significantly with changes in IgE levels. This study is the first to demonstrate that inhaled environmental exposures influence methylation of Th genes in vivo, supporting a new paradigm in asthma pathogenesis. PMID:18042818

  17. Dioxin exposure reduces the steroidogenic capacity of mouse antral follicles mainly at the level of HSD17B1 without altering atresia

    PubMed Central

    Karman, Bethany N.; Basavarajappa, Mallikarjuna S.; Hannon, Patrick; Flaws, Jodi A.

    2013-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent ovarian toxicant. Previously, we demonstrated that in vitro TCDD (1 nM) exposure decreases production/secretion of the sex steroid hormones progesterone (P4), androstenedione (A4), testosterone (T), and 17β-estradiol (E2) in mouse antral follicles. The purpose of this study was to determine the mechanism by which TCDD inhibits steroidogenesis. Specifically, we examined the effects of TCDD on the steroidogenic enzymes, atresia, and the aryl hydrocarbon receptor (AHR) protein. TCDD exposure for 48 h increased levels of A4, without changing HSD3B1 protein, HSD17B1 protein, estrone (E1), T or E2 levels. Further, TCDD did not alter atresia ratings compared to vehicle at 48 h. TCDD, however, did down regulate the AHR protein at 48 h. TCDD exposure for 96 h decreased transcript levels for Cyp11a1, Cyp17a1, Hsd17b1, and Cyp19a1, but increased Hsd3b1 transcript. TCDD exposure particularly lowered both Hsd17b1 transcript and HSD17B1 protein. However, TCDD exposure did not affect levels of E1 in the media nor atresia ratings at 96 h. TCDD, however, decreased levels of the proapoptotic factor Bax. Collectively, these data suggest that TCDD exposure causes a major block in the steroidogenic enzyme conversion of A4 to T and E1 to E2 and that it regulates apoptotic pathways, favoring survival over death in antral follicles. Finally, the down-regulation of the AHR protein in TCDD exposed follicles persisted at 96 h, indicating that the activation and proteasomal degradation of this receptor likely plays a central role in the impaired steroidogenic capacity and altered apoptotic pathway of exposed antral follicles. PMID:22889882

  18. ATRAZINE-INDUCED REPRODUCTIVE TRACT ALTERATIONS AFTER TRANSPLACENTAL AND LACTATIONAL EXPOSURE IN MALE LONG-EVANS RATS.

    EPA Science Inventory

    Studies showed that early postnatal exposure to the herbicide atrazine (ATR) delayed preputial separation (PPS) and increased incidence of prostate inflammation in adult Wistar rats. A cross-fostering paradigm was used in this study to determine if gestational exposure to ATR wou...

  19. ATRAZINE-INDUCED REPRODUCTIVE TRACT ALTERATIONS AFTER TRANSPLACENTAL AND LACTATIONAL EXPOSURE IN LONG-EVANS RAT PUPS

    EPA Science Inventory

    Studies have shown that early postnatal exposure to the common herbicide atrazine (ATR) will delay preputial separation (PPS) in Wistar rats and increase incidence of prostate inflammation in adults. To evaluate ATR exposure parameters required for pubertal delays (PPS), we used...

  20. Novel molecular events associated with altered steroidogenesis induced by exposure to atrazine in the intact and castrate male rat

    EPA Science Inventory

    Toxicology is increasingly focused on molecular events comprising adverse outcome pathways. Atrazine activates the hypothalamic-pituitary adrenal axis, but relationships to gonadal alterations are unknown. We characterized hormone profiles and adrenal (intact and castrate) and te...

  1. Non-invasive assessment of Alterations in Cardiovascular regulation and function and susceptibility to ventricular arrhythmias resulting from microgravity exposure

    NASA Astrophysics Data System (ADS)

    Ramsdell, Craig D.; Sundby, Grete H.; Sherman, Derin; Maa, Ming; Baskin, Jacquelyn L.; Williams, Gordon H.; Cohen, Richard J.

    2000-01-01

    Alterations in cardiovascular regulation and function that occur during and after space flight have been reported. These alterations are manifested, for example, by reduced orthostatic tolerance upon reentry to the earth's gravity from space. However, the precise physiologic mechanisms responsible for these alterations remain to be fully elucidated. Perhaps as a result, fully effective countermeasures have yet to be developed. The National Space Biomedical Research Institute Cardiovascular Alterations Team is currently conducting a head-down tilt bed rest study in Boston. These studies involve the application of two powerful new methodologies developed at the NASA Center for Quantitative Cardiovascular Physiology, Modeling and Data Analysis at the Massachusetts Institute of Technology-cardiovascular system identification and T Wave Alternans analysis-for the study of the effects of simulated microgravity on the cardiovascular system. This study is being used as a basis for developing effective countermeasures against microgravity induced orthostatic hypotension and ventricular arrhythmias. .

  2. Exposure to p,p′-DDE or dieldrin during the reproductive season alters hepatic CYP expression in largemouth bass (Micropterus salmoides)

    PubMed Central

    Barber, David S.; McNally, Alex J.; Garcia-Reyero, Natàlia; Denslow, Nancy D.

    2007-01-01

    Largemouth bass (LMB) in Central Florida living on sites with high levels of organochlorine pesticides (OCPs) have exhibited poor reproductive success and altered steroid profiles. The mechanism underlying these changes is unknown, however changes in the rate of steroid metabolism could alter steroid homeostasis. Members of the CYP2 and CYP3A families play a significant role in the metabolism of many xenobiotics and endogenous compounds, including sex steroids. Therefore, the goal of this study was to identify members of the CYP2 and CYP3A families in LMB and characterize the effects of OCP exposure on their expression. Full-length clones of two CYP3A isoforms were obtained from LMB liver, CYP3A68 and 3A69, which exhibited significant sequence divergence. Full-length clones for CYP2N14 and CYP2P11 were also obtained from LMB liver. Steady-state mRNA levels of each of these CYPs increased in both sexes between early reproductive phase (December) and peak reproductive phase (March). Expression of CYP3A68 and CYP2P11 was sexually dimorphic during peak reproductive phase with 2-fold higher expression in females and males, respectively. Foodborne exposure to 46 ppm p,p′-DDE or 0.8 ppm dieldrin for 30 days did not have a significant effect on expression of CYPs. However, 4 months exposure to p,p′-DDE induced CYP3A68 and 3A69 expression in both sexes, while dieldrin produced weak induction of CYP3A68 and suppressed CYP3A69 expression in females, but had no effect on males. Neither p,p′-DDE nor dieldrin significantly altered the expression of CYP2P11 or CYP2N14. This work demonstrates that there are significant changes in CYP expression that occur during LMB reproduction which can be modified by exposure to OCPs. PMID:17145087

  3. Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio)

    PubMed Central

    Aluru, Neelakanteswar; Kuo, Elaine; Helfrich, Lily W.; Karchner, Sibel I.; Linney, Elwood A.; Pais, June E.; Franks, Diana G.

    2015-01-01

    DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood. Hence, we tested the hypothesis that developmental exposure to TCDD affects dnmt gene expression patterns. Zebrafish embryos were exposed to 5 nM TCDD for one hour from 4 to 5 hours post-fertilization (hpf) and sampled at 12, 24, 48, 72 and 96 hpf to determine dnmt gene expression and DNA methylation patterns. We performed a detailed analysis of zebrafish dnmt gene expression during development and in adult tissues. Our results demonstrate that dnmt3b genes are highly expressed in early stages of development, and dnmt3a genes are more abundant in later stages. TCDD exposure upregulated dnmt1 and dnmt3b2 expression, whereas dnmt3a1, 3b1, and 3b4 are downregulated following exposure. We did not observe any TCDD-induced differences in global methylation or hydroxymethylation levels, but promoter methylation of aryl hydrocarbon receptor (AHR) target genes was altered. In TCDD-exposed embryos, AHR repressor a (ahrra) and c-fos promoters were differentially methylated. To characterize the TCDD effects on DNMTs, we cloned the dnmt promoters with xenobiotic response elements and conducted AHR transactivation assays using a luciferase reporter system. Our results suggest that ahr2 can regulate dnmt3a1, dnmt3a2 and dnmt3b2 expression. Overall, we demonstrate that developmental exposure to TCDD alters dnmt expression and DNA methylation patterns. PMID:25732252

  4. Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: potential role of NMDA receptor-dependent BDNF signaling.

    PubMed

    Neal, April P; Stansfield, Kirstie H; Worley, Paul F; Thompson, Richard E; Guilarte, Tomás R

    2010-07-01

    Lead (Pb(2+)) exposure is known to affect presynaptic neurotransmitter release in both in vivo and cell culture models. However, the precise mechanism by which Pb(2+) impairs neurotransmitter release remains unknown. In the current study, we show that Pb(2+) exposure during synaptogenesis in cultured hippocampal neurons produces the loss of synaptophysin (Syn) and synaptobrevin (Syb), two proteins involved in vesicular release. Pb(2+) exposure also increased the number of presynaptic contact sites. However, many of these putative presynaptic contact sites lack Soluble NSF attachment protein receptor complex proteins involved in vesicular exocytosis. Analysis of vesicular release using FM 1-43 dye confirmed that Pb(2+) exposure impaired vesicular release and reduced the number of fast-releasing sites. Because Pb(2+) is a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, we tested the hypothesis that NMDAR inhibition may be producing the presynaptic effects. We show that NMDAR inhibition by aminophosphonovaleric acid mimics the presynaptic effects of Pb(2+) exposure. NMDAR activity has been linked to the signaling of the transsynaptic neurotrophin brain-derived neurotrophic factor (BDNF), and we observed that both the cellular expression of proBDNF and release of BDNF were decreased during the same period of Pb(2+) exposure. Furthermore, exogenous addition of BDNF rescued the presynaptic effects of Pb(2+). We suggest that the presynaptic deficits resulting from Pb(2+) exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling. PMID:20375082

  5. In Utero and Lactational Exposures to Low Doses of Polybrominated Diphenyl Ether-47 Alter the Reproductive System and Thyroid Gland of Female Rat Offspring

    PubMed Central

    Talsness, Chris E.; Kuriyama, Sergio N.; Sterner-Kock, Anja; Schnitker, Petra; Grande, Simone Wichert; Shakibaei, Mehdi; Andrade, Anderson; Grote, Konstanze; Chahoud, Ibrahim

    2008-01-01

    Background Polybrominated diphenyl ethers (PBDEs) are capable of disrupting thyroid hormone homeostasis. PBDE-47 (2,2′,4,4′-tetrabromodiphenyl ether) is one of the most abundant congeners found in human breast adipose tissue and maternal milk samples. Objectives We evaluated the effects of developmental exposure to low doses of PBDE-47 on the female reproductive system. Methods Pregnant Wistar rats were administered vehicle (peanut oil) or PBDE-47 [140 or 700 μg/kg body weight (bw)] on gestation day (GD) 6, or 5 mg 6-n-propyl-2-thiouracil (PTU)/L in the drinking water from GD7 through postnatal day (PND) 21. Results In female offspring sacrificed on PND38, there was a significant decrease in ovarian weight after exposure to PTU or 140 μg/kg PBDE-47. Alterations in folliculogenesis were apparent: we observed a decrease in tertiary follicles and serum estradiol concentrations in the offspring exposed to either PTU or 700 μg/kg PBDE-47. PTU exposure also resulted in a decrease in primordial follicles. On PND100, persistent effects on the thyroid glands included histologic and morphometric changes after exposure to either PTU or PBDE-47. No relevant changes in reproductive indices were observed after mating the exposed F1 females with nontreated males. Conclusions Administration of PBDE-47 at doses relevant to human exposure led to changes in the rat female reproductive system and thyroid gland. PMID:18335096

  6. Chronic ethanol exposure during adolescence through early adulthood in female rats induces emotional and memory deficits associated with morphological and molecular alterations in hippocampus.

    PubMed

    Oliveira, Ana Ca; Pereira, Maria Cs; Santana, Luana N da Silva; Fernandes, Rafael M; Teixeira, Francisco B; Oliveira, Gedeão B; Fernandes, Luanna Mp; Fontes-Júnior, Enéas A; Prediger, Rui D; Crespo-López, Maria E; Gomes-Leal, Walace; Lima, Rafael R; Maia, Cristiane do Socorro Ferraz

    2015-06-01

    There is increasing evidence that heavy ethanol exposure in early life may produce long-lasting neurobehavioral consequences, since brain structural maturation continues until adolescence. It is well established that females are more susceptible to alcohol-induced neurotoxicity and that ethanol consumption is increasing among women, especially during adolescence. In the present study, we investigated whether chronic ethanol exposure during adolescence through early adulthood in female rats may induce hippocampal histological damage and neurobehavioral impairments. Female rats were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v) by gavage from the 35(th)-90(th) day of life. Ethanol-exposed animals displayed reduced exploration of the central area and increased number of fecal boluses in the open field test indicative of anxiogenic responses. Moreover, chronic high ethanol exposure during adolescence induced marked impairments on short-term memory of female rats addressed on social recognition and step-down inhibitory avoidance tasks. These neurobehavioral deficits induced by ethanol exposure during adolescence through early adulthood were accompanied by the reduction of hippocampal formation volume as well as the loss of neurons, astrocytes and microglia cells in the hippocampus. These results indicate that chronic high ethanol exposure during adolescence through early adulthood in female rats induces long-lasting emotional and memory deficits associated with morphological and molecular alterations in the hippocampus. PMID:25922423

  7. Close-range blast exposure is associated with altered functional connectivity in Veterans independent of concussion symptoms at time of exposure.

    PubMed

    Robinson, Meghan E; Lindemer, Emily R; Fonda, Jennifer R; Milberg, William P; McGlinchey, Regina E; Salat, David H

    2015-03-01

    Although there is emerging data on the effects of blast-related concussion (or mTBI) on cognition, the effects of blast exposure itself on the brain have only recently been explored. Toward this end, we examine functional connectivity to the posterior cingulate cortex, a primary region within the default mode network (DMN), in a cohort of 134 Iraq and Afghanistan Veterans characterized for a range of common military-associated comorbidities. Exposure to a blast at close range (<10 meters) was associated with decreased connectivity of bilateral primary somatosensory and motor cortices, and these changes were not different from those seen in participants with blast-related mTBI. These results remained significant when clinical factors such as sleep quality, chronic pain, or post traumatic stress disorder were included in the statistical model. In contrast, differences in functional connectivity based on concussion history and blast exposures at greater distances were not apparent. Despite the limitations of a study of this nature (e.g., assessments long removed from injury, self-reported blast history), these data demonstrate that blast exposure per se, which is prevalent among those who served in Iraq and Afghanistan, may be an important consideration in Veterans' health. It further offers a clinical guideline for determining which blasts (namely, those within 10 meters) are likely to lead to long-term health concerns and may be more accurate than using concussion symptoms alone. PMID:25366378

  8. Fine Ambient Air Particulate Matter Exposure Induces Molecular Alterations Indicative of Cardiovascular Disease Progression in Atherosclerotic Susceptible Mice -- B

    EPA Science Inventory

    Background: Epidemiology studies have reported associations between increased mortality and morbidity with exposure to particulate air pollution, particularly within individuals with pre-existing cardiovascular disease (CVD). Clinical and toxicological studies have provided evide...

  9. GESTATIONAL PFOA EXPOSURE OF MICE IS ASSOCIATED WITH ALTERED MAMMARY GLAND DEVELOPMENT IN DAMS AND FEMALE OFFSPRING

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA), a ubiquitous and persistent synthetic compound, has been detected in human serum. Previous studies in mice linked prenatal PFOA exposure to increased neonatal mortality and decreased pup weights, in a dose responsive manner. To determine whether dev...

  10. GESTATIONAL PFOA EXPOSURE OF MICE IS ASSOCIATED WITH ALTERED MAMMARY GLAND DEVELOPMENT IN DAMS AND FEMALE OFFSPRING

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA), with diverse and widespread commercial and industrial applications, has been detected in human and wildlife sera. Previous mouse studies linked prenatal PFOA exposure to decreased neonatal body weights (BWs) and survival in a dose-dependent manner. ...

  11. Long-term signal of population disturbance after pulse exposure to an insecticide: rapid recovery of abundance, persistent alteration of structure.

    PubMed

    Liess, Matthias; Pieters, Barry Johan; Duquesne, Sabine

    2006-05-01

    Little is known about the effect of pulse exposure to toxicants on populations when density regulation is present. Yet, for a more realistic risk assessment, it is necessary to include effect and recovery at the population level. Here, we investigate the long-term and delayed effects as well as the subsequent recovery of populations of Daphnia magna. A 24-h pulse of the pyrethroid fenvalerate reduced the abundance at a concentration of 1.0 microg/L and higher. However, abundance recovered and reached control levels after one to two generation times (GTs) following reproduction of surviving individuals (GT = 8 d, from birth until first reproduction). At high concentrations above the acute median lethal concentration (3.2 micorg/L), abundance initially decreased even more strongly but was then elevated compared to control values for an extended period of time. Population structure (size distribution) was affected at lower concentrations than abundance (> 0.8 microg/L). In addition, the alteration of population structure lasted for a long time, so that control levels were approached only after approximately six or seven GTs. Our results show that pulse exposure to toxicants may lead to a long-term alteration of population structure even at sublethal concentrations. Possible mechanisms that sustain the effects of toxicants may be delayed life-history effects on the individual level and elevated competition because of altered population structure on the population level. PMID:16704065

  12. Exposure to the Contraceptive Progestin, Gestodene, Alters Reproductive Behavior, Arrests Egg Deposition, and Masculinizes Development in the Fathead Minnow (Pimephales promelas).

    PubMed

    Frankel, Tyler E; Meyer, Michael T; Kolpin, Dana W; Gillis, Amanda B; Alvarez, David A; Orlando, Edward F

    2016-06-01

    Endogenous progestogens and pharmaceutical progestins enter the environment through wastewater treatment plant effluent and agricultural field runoff. Lab studies demonstrate strong, negative exposure effects of these chemicals on aquatic vertebrate reproduction. Behavior can be a sensitive, early indicator of exposure to environmental contaminants associated with altered reproduction yet is rarely examined in ecotoxicology studies. Gestodene is a human contraceptive progestin and a potent activator of fish androgen receptors. Our objective was to test the effects of gestodene on reproductive behavior and associated egg deposition in the fathead minnow. After only 1 day, males exposed to ng/L of gestodene were more aggressive and less interested in courtship and mating, and exposed females displayed less female courtship behavior. Interestingly, 25% of the gestodene tanks contained a female that drove the male out of the breeding tile and displayed male-typical courtship behaviors toward the other female. Gestodene decreased or arrested egg deposition with no observed gonadal histopathology. Together, these results suggest that effects on egg deposition are primarily due to altered reproductive behavior. The mechanisms by which gestodene disrupts behavior are unknown. Nonetheless, the rapid and profound alterations of the reproductive biology of gestodene-exposed fish suggest that wild populations could be similarly affected. PMID:27129041

  13. Exposure of Human CD4 T Cells to IL-12 Results in Enhanced TCR-Induced Cytokine Production, Altered TCR Signaling, and Increased Oxidative Metabolism

    PubMed Central

    2016-01-01

    Human CD4 T cells are constantly exposed to IL-12 during infections and certain autoimmune disorders. The current paradigm is that IL-12 promotes the differentiation of naïve CD4 T cells into Th1 cells, but recent studies suggest IL-12 may play a more complex role in T cell biology. We examined if exposure to IL-12 alters human CD4 T cell responses to subsequent TCR stimulation. We found that IL-12 pretreatment increased TCR-induced IFN-γ, TNF-α, IL-13, IL-4 and IL-10 production. This suggests that prior exposure to IL-12 potentiates the TCR-induced release of a range of cytokines. We observed that IL-12 mediated its effects through both transcriptional and post-transcriptional mechanisms. IL-12 pretreatment increased the phosphorylation of AKT, p38 and LCK following TCR stimulation without altering other TCR signaling molecules, potentially mediating the increase in transcription of cytokines. In addition, the IL-12-mediated enhancement of cytokines that are not transcriptionally regulated was partially driven by increased oxidative metabolism. Our data uncover a novel function of IL-12 in human CD4 T cells; specifically, it enhances the release of a range of cytokines potentially by altering TCR signaling pathways and by enhancing oxidative metabolism. PMID:27280403

  14. Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP

    PubMed Central

    Nakauchi, Sakura; Malvaez, Melissa; Su, Hailing; Kleeman, Elise; Dang, Richard; Wood, Marcelo A.; Sumikawa, Katumi

    2014-01-01

    Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus-dependent memory, the induction of N-methyl-d-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long-lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic-dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity. PMID:25545599

  15. Prepubertal Di-n-Butyl Phthalate Exposure Alters Sertoli and Leydig Cell Function and Lowers Bone Density in Adult Male Mice.

    PubMed

    Bielanowicz, Amanda; Johnson, Rachelle W; Goh, Hoey; Moody, Sarah C; Poulton, Ingrid J; Croce, Nic; Loveland, Kate L; Hedger, Mark P; Sims, Natalie A; Itman, Catherine

    2016-07-01

    Phthalate exposure impairs testis development and function; however, whether phthalates affect nonreproductive functions is not well understood. To investigate this, C57BL/6J mice were fed 1-500 mg di-n-butyl phthalate (DBP) in corn oil, or vehicle only, daily from 4 to 14 days, after which tissues were collected (prepubertal study). Another group was fed 1-500 mg/kg·d DBP from 4 to 21 days and then maintained untreated until 8 weeks for determination of adult consequences of prepubertal exposure. Bones were assessed by microcomputed tomography and dual-energy X-ray absorptiometry and T by RIA. DBP exposure decreased prepubertal femur length, marrow volume, and mean moment of inertia. Adult animals exposed prepubertally to low DBP doses had lower bone mineral content and bone mineral density and less lean tissue mass than vehicle-treated animals. Altered dynamics of the emerging Leydig population were found in 14-day-old animals fed 100-500 mg/kg·d DBP. Adult mice had variable testicular T and serum T and LH concentrations after prepubertal exposure and a dose-dependent reduction in cytochrome p450, family 11, subfamily A, polypeptide 1. Insulin-like 3 was detected in Sertoli cells of adult mice administered the highest dose of 500 mg/kg·d DBP prepubertally, a finding supported by the induction of insulin-like 3 expression in TM4 cells exposed to 50 μM, but not 5 μM, DBP. We propose that low-dose DBP exposure is detrimental to bone but that normal bone mineral density/bone mineral content after high-dose DBP exposure reflects changes in testicular somatic cells that confer protection to bones. These findings will fuel concerns that low-dose DBP exposure impacts health beyond the reproductive axis. PMID:27058814

  16. Neonatal Phytoestrogen Exposure Alters Oviduct Mucosal Immune Response to Pregnancy and Affects Preimplantation Embryo Development in the Mouse1

    PubMed Central

    Jefferson, Wendy N.; Padilla-Banks, Elizabeth; Phelps, Jazma Y.; Cantor, Amy M.; Williams, Carmen J.

    2012-01-01

    ABSTRACT Treatment of neonatal mice with the phytoestrogen genistein (50 mg/kg/day) results in complete female infertility caused in part by preimplantation embryo loss in the oviduct between Days 2 and 3 of pregnancy. We previously demonstrated that oviducts of genistein-treated mice are “posteriorized” as compared to control mouse oviducts because they express numerous genes normally restricted to posterior regions of the female reproductive tract (FRT), the cervix and vagina. We report here that neonatal genistein treatment resulted in substantial changes in oviduct expression of genes important for the FRT mucosal immune response, including immunoglobulins, antimicrobials, and chemokines. Some of the altered immune response genes were chronically altered beginning at the time of neonatal genistein treatment, indicating that these alterations were a result of the posteriorization phenotype. Other alterations in oviduct gene expression were observed only in early pregnancy, immediately after the FRT was exposed to inflammatory or antigenic stimuli from ovulation and mating. The oviduct changes affected development of the surviving embryos by increasing the rate of cleavage and decreasing the trophectoderm-to-inner cell mass cell ratio at the blastocyst stage. We conclude that both altered immune responses to pregnancy and deficits in oviduct support for preimplantation embryo development in the neonatal genistein model are likely to contribute to infertility phenotype. PMID:22553218

  17. Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates

    SciTech Connect

    Sekizawa, Shin-ichi; Joad, Jesse P.; Pinkerton, Kent E.; Bonham, Ann C.

    2010-01-15

    Exposing children to secondhand tobacco smoke (SHS) is associated with increased risk for asthma, bronchiolitis and SIDS. The role for changes in the developing CNS contributing to these problems has not been fully explored. We used rhesus macaques to test the hypothesis that SHS exposure during development triggers neuroplastic changes in the nucleus tractus solitarius (NTS), where lung sensory information related to changes in airway and lung function is first integrated. Pregnant monkeys were exposed to filtered air (FA) or SHS for 6 h/day, 5 days/week starting at 50-day gestational age. Mother/infant pairs continued the exposures postnatally to age 3 or 13 months, which may be equivalent to approximately 1 or 4 years of human age, respectively. Whole-cell recordings were made of second-order NTS neurons in transverse brainstem slices. To target the consequences of SHS exposure based on neuronal subgroups, we classified NTS neurons into two phenotypes, rapid-onset spiking (RS) and delayed-onset spiking (DS), and then evaluated intrinsic and synaptic excitabilities in FA-exposed animals. RS neurons showed greater cell excitability especially at age of 3 months while DS neurons received greater amplitudes of excitatory postsynaptic currents (EPSCs). Developmental neuroplasticity such as increases in intrinsic and synaptic excitabilities were detected especially in DS neurons. In 3 month olds, SHS exposure effects were limited to excitatory changes in RS neurons, specifically increases in evoked EPSC amplitudes and increased spiking responses accompanied by shortened action potential width. By 13 months, the continued SHS exposure inhibited DS neuronal activity; decreases in evoked EPSC amplitudes and blunted spiking responses accompanied by prolonged action potential width. The influence of SHS exposure on age-related and phenotype specific changes may be associated with age-specific respiratory problems, for which SHS exposure can increase the risk, such as SIDS

  18. Early Life Ozone Exposure Results in Dysregulated Innate Immune Function and Altered microRNA Expression in Airway Epithelium

    PubMed Central

    Gerriets, Joan E.; Wang, Theodore T.; Postlethwait, Edward M.; Evans, Michael J.; Fontaine, Justin H.; Miller, Lisa A.

    2014-01-01

    Exposure to ozone has been associated with increased incidence of respiratory morbidity in humans; however the mechanism(s) behind the enhancement of susceptibility are unclear. We have previously reported that exposure to episodic ozone during postnatal development results in an attenuated peripheral blood cytokine response to lipopolysaccharide (LPS) that persists with maturity. As the lung is closely interfaced with the external environment, we hypothesized that the conducting airway epithelium of neonates may also be a target of immunomodulation by ozone. To test this hypothesis, we evaluated primary airway epithelial cell cultures derived from juvenile rhesus macaque monkeys with a prior history of episodic postnatal ozone exposure. Innate immune function was measured by expression of the proinflammatory cytokines IL-6 and IL-8 in primary cultures established following in vivo LPS challenge or, in response to in vitro LPS treatment. Postnatal ozone exposure resulted in significantly attenuated IL-6 mRNA and protein expression in primary cultures from juvenile animals; IL-8 mRNA was also significantly reduced. The effect of antecedent ozone exposure was modulated by in vivo LPS challenge, as primary cultures exhibited enhanced cytokine expression upon secondary in vitro LPS treatment. Assessment of potential IL-6-targeting microRNAs miR-149, miR-202, and miR-410 showed differential expression in primary cultures based upon animal exposure history. Functional assays revealed that miR-149 is capable of binding to the IL-6 3′ UTR and decreasing IL-6 protein synthesis in airway epithelial cell lines. Cumulatively, our findings suggest that episodic ozone during early life contributes to the molecular programming of airway epithelium, such that memory from prior exposures is retained in the form of a dysregulated IL-6 and IL-8 response to LPS; differentially expressed microRNAs such as miR-149 may play a role in the persistent modulation of the epithelial innate

  19. Cocaine exposure prior to pregnancy alters the psychomotor response to cocaine and transcriptional regulation of the dopamine D1 receptor in adult male offspring.

    PubMed

    Sasaki, Aya; Constantinof, Andrea; Pan, Pauline; Kupferschmidt, Dave A; McGowan, Patrick O; Erb, Suzanne

    2014-05-15

    There is evidence that maternal experience prior to pregnancy can play an important role in behavioral, physiological, and genetic programming of offspring. Likewise, exposure to cocaine in utero can result in marked changes in central nervous system function of offspring. In this study, we examined whether exposure of rat dams to cocaine prior to pregnancy subsequently alters indices of behavior, physiology, and gene expression in offspring. Multiple outcome measures were examined in adult male offspring: (1) behavioral expression of cocaine-induced psychomotor activation; (2) levels of corticosterone in response to immobilization stress; and (3) expression of multiple genes, including dopamine receptor D1 (DRD1) and D2 (DRD2), glucocorticoid receptor (GR), and corticotropin-releasing factor (CRF), in functionally relevant brain regions. Adult Sprague-Dawley females were exposed to cocaine (15-30 mg/kg, i.p.) or saline for 10 days, and were then mated to drug naïve males of the same strain. Separate groups of adult male offspring were tested for their acute psychomotor response to cocaine (0, 15, 30 mg/kg, i.p.), corticosterone responsivity to 20 min of immobilization stress, and expression of multiple genes using quantitative PCR. Offspring of dams exposed to cocaine prior to conception exhibited increased psychomotor sensitivity to cocaine, and upregulated gene expression of DRD1 in the medial prefrontal cortex (mPFC). Neither stress-induced corticosterone levels nor gene expression of GR or CRF genes were altered. These data suggest that cocaine exposure before pregnancy can serve to enhance psychomotor sensitivity to cocaine in offspring, possibly via alterations in dopamine function that include upregulation of the DRD1. PMID:24583058

  20. Exposures involving perturbations of the EM field have non-linear effects on radiation response and can alter the expression of radiation induced bystander effects

    NASA Astrophysics Data System (ADS)

    Mothersill, Carmel; Seymour, Colin

    2012-07-01

    Our recent data suggest there is a physical component to the bystander signal induced by radiation exposure and that alternative medicine techniques such as Reiki and acupuncture or exposures to weak EM fields alter the response of cells to direct irradiation and either altered bystander signal production or altered the response of cells receiving bystander signals. Our proposed mechanism to explain these findings is that perturbation of electromagnetic (EM) fields is central to the induction of low radiation dose responses especially non-targeted bystander effects. In this presentation we review the alternative medicine data and other data sets from our laboratory which test our hypothesis that perturbation of bio-fields will modulate radiation response in the low dose region. The other data sets include exposure to MRI, shielding using lead and or Faraday cages, the use of physical barriers to bystander signal transmission and the use of membrane channel blockers. The data taken together strongly suggest that EM field perturbation can modulate low dose response and that in fact the EM field rather than the targeted deposition of ionizing energy in the DNA may be the key determinant of dose response in a cell or organism The results also lead us to suspect that at least when chemical transmission is blocked, bystander signals can be transmitted by other means. Our recent experiments suggest light signals and volatiles are not likely. We conclude that alternative medicine and other techniques involving electromagnetic perturbations can modify the response of cells to low doses of ionizing radiation and can induce bystander effects similar to those seen in medium transfer experiments. In addition to the obvious implications for mechanistic studies of low dose effects, this could perhaps provide a novel target to exploit in space radiation protection and in optimizing therapeutic gain during radiotherapy.

  1. Alterations along the Hypothalamic-Pituitary-Thyroid Axis of the Zebrafish (Danio rerio) after Exposure to Propylthiouracil

    PubMed Central

    Schmidt, Florian; Braunbeck, Thomas

    2011-01-01

    In the past, various approaches have been developed to detect adverse effects of pollutants on the thyroid of vertebrates, most of these with special emphasis on the South African clawed frog, Xenopus laevis. Although fish are primarily affected by thyroid-disrupting chemicals, studies into alterations of the thyroid of fish are scarce. Therefore, effects of the reference compound propylthiouracil on histopathology of the thyroid axis were analyzed in a modified early life-stage test with zebrafish (Danio rerio) exposed to propylthiouracil. The test substance induced dose-dependent alterations of thyroidal tissue concomitant with increases in the number of surrounding blood vessels. Despite this massive proliferation of the thyroid, zebrafish were not able to maintain thyroxin concentrations. The pituitary was affected displaying significant alterations in thyroid-stimulating hormone cell counts. Quantitative evaluation of pituitary surface areas revealed a dose-dependent increase of adenohypophyseal tissue. Distinct histopathological effects may contribute to a more easy identification and interpretation of alterations induced by thyroid-disrupting chemicals. PMID:21860775

  2. Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio)

    SciTech Connect

    Aluru, Neelakanteswar; Kuo, Elaine; Helfrich, Lily W.; Karchner, Sibel I.; Linney, Elwood A.; Pais, June E.; Franks, Diana G.

    2015-04-15

    DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood. Hence, we tested the hypothesis that developmental exposure to TCDD affects dnmt gene expression patterns. Zebrafish embryos were exposed to 5 nM TCDD for 1 h from 4 to 5 h post-fertilization (hpf) and sampled at 12, 24, 48, 72, and 96 hpf to determine dnmt gene expression and DNA methylation patterns. We performed a detailed analysis of zebrafish dnmt gene expression during development and in adult tissues. Our results demonstrate that dnmt3b genes are highly expressed in early stages of development, and dnmt3a genes are more abundant in later stages. TCDD exposure upregulated dnmt1 and dnmt3b2 expression, whereas dnmt3a1, 3b1, and 3b4 are downregulated following exposure. We did not observe any TCDD-induced differences in global methylation or hydroxymethylation levels, but the promoter methylation of aryl hydrocarbon receptor (AHR) target genes was altered. In TCDD-exposed embryos, AHR repressor a (ahrra) and c-fos promoters were differentially methylated. To characterize the TCDD effects on DNMTs, we cloned the dnmt promoters with xenobiotic response elements and conducted AHR transactivation assays using a luciferase reporter system. Our results suggest that ahr2 can regulate dnmt3a1, dnmt3a2, and dnmt3b2 expression. Overall, we demonstrate that developmental exposure to TCDD alters dnmt expression and DNA methylation patterns. - Highlights: • TCDD altered the dnmt expression in a gene and developmental time-specific manner. • TCDD hypermethylated ahrra and hypomethylated c-fos proximal promoter regions. • Functional analysis suggests that ahr2 can regulate dnmt3a1, 3a2, and 3b2 expression. • Dnmt

  3. Response of Purkinje neurons to hypobaric hypoxic exposure as shown by alteration in expression of glutamate receptors, nitric oxide synthases and calcium binding proteins.

    PubMed

    Kaur, C; Sivakumar, V; Singh, G; Singh, J; Ling, E A

    2005-01-01

    Hypobaric hypoxia is known to impair muscular coordination. It is not known whether hypobaric hypoxia causes any damage to the Purkinje neurons which may be responsible for impairment of muscular coordination. Expression of ionotropic glutamate receptors N-methyl-d-aspartate receptor subunit 1, amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid GluR2/3, calcium binding proteins and nitric oxide synthases in the Purkinje neurons was examined in rats exposed to hypobaric hypoxia. The mRNA expression of N-methyl-d-aspartate receptor subunit 1, GluR2, GluR3 and nitric oxide synthases [neuronal, endothelial and inducible] was upregulated at 3 h peaking at 24 h after the exposure. This was sustained up to 3 days; thereafter, it was comparable to the controls. Immunohistochemical analysis confirmed a marked expression of N-methyl-d-aspartate receptor subunit 1 and GluR2/3 at the above time intervals. Immunoexpression of calbindin-D28k (calbindin) and parvalbumin was intense in the soma of Purkinje neurons in the control rats. It was, however, drastically downregulated up to 3 days after exposure. At 3 days the neuronal dendrites showed intense expression of calbindin which returned to control levels at 7 days. Expression of neuronal nitric oxide synthase and inducible nitric oxide synthase was markedly upregulated from 3 h to 3 days whereas endothelial nitric oxide synthase expression, localized in the blood vessels and Purkinje neurons, remained elevated up to 24 h after the exposure. A progressive darkening of the Purkinje neuron cell bodies was observed at ultrastructural level up to 3 days but degenerating cells were not observed. A salient alteration was the dilation and stacking of smooth endoplasmic reticulum in the dendrites up to 14 days after the exposure. The present results suggest that hypobaric hypoxia leads to overexpression of N-methyl-d-aspartate receptor subunit 1 and GluR2/3 in Purkinje neurons that may be responsive to altered calcium levels as

  4. DNA ALTERATIONS

    EPA Science Inventory

    The exposure of an organism to genotoxic chemicals may induce a cascade of genetic events. nitially, structural alterations to DNA are formed. ext, the DNA damage is processed and subsequently expressed in mutant gene products. inally, diseases result from the genetic damage. he ...

  5. Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice

    PubMed Central

    Deshpande, Krutika T.; Liu, Shinlan; McCracken, Jennifer M.; Jiang, Lu; Gaw, Ta Ehpaw; Kaydo, Lindsey N.; Richard, Zachary C.; O’Neil, Maura F.; Pritchard, Michele T.

    2016-01-01

    Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24–96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure. PMID:26751492

  6. ALTERATIONS IN THE ENERGY METABOLISM OF AN ESTUARINE MYSID (MYSIDOPSIS BAHIA) AS INDICATORS OF STRESS FROM CHRONIC PESTICIDE EXPOSURE

    EPA Science Inventory

    Various aspects of the energy metabolism of an estuarine mysid (Mysidopsis bahia) were examined for different life stages during a life-cycle exposure to the organophosphate pesticide fenthion. Dose-response relationships were developed for several metabolic rate functions (oxyge...

  7. Hardwood smoke alters murine splenic T cell responses to mitogens following a 6-month whole body inhalation exposure

    SciTech Connect

    Burchiel, Scott W. . E-mail: Sburchiel@salud.unm.edu; Lauer, Fredine T.; Dunaway, Sandy L.; Zawadzki, Jerome; McDonald, Jacob D.; Reed, Matthew D.

    2005-02-01

    The purpose of these studies was to assess the effects of hardwood smoke (HWS) inhalation (30-1000 {mu}g/m{sup 3}) on the systemic immune responses of A/J mice evaluated after 6 months of daily exposures. Spleen cells obtained from mice were assessed for changes in cell number, cell surface marker expression [B, T, macrophage, and natural killer (NK) cells], and responses to B cell (LPS, endotoxin) and T cell (Con A) mitogens. Results showed that HWS smoke increased T cell proliferation in the 100 {mu}g/m{sup 3} exposure group and produced a concentration-dependent suppression of T cell proliferation at concentrations >300 {mu}g/m{sup 3}. There were no effects on B cell proliferation or in spleen cell surface marker expression. Analyses of the exposure atmospheres revealed the presence of significant levels of naphthalene and methylated napthalenes, fluorene, phenanthrene, and anthracene in the exposure chambers, as well as low concentrations of several metals (K, Ca, and Fe). Our results demonstrate that environmentally relevant concentrations of HWS may be immunosuppressive to the immune system of mice exposed during a 6-month period.

  8. Acute Exposure to Particulate Matter (PM) Alters Physiologic and Toxicologic Endpoints in a Rat Model of Heart Failure

    EPA Science Inventory

    Human exposure to ambient PM from fossil-fuel emissions is linked to cardiovascular disease and death. This association strengthens in people with preexisting cardiopulmonary diseases—especially heart failure (HF). We previously examined the effects of PM on HF by exposing Sponta...

  9. Modulation of estrogenic exposure effects via alterations in salinity and dissolved oxygen in male fathead minnows, Pimephales promelas

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Laboratory exposure data indicate that estrogens and estrogen mimics can cause endocrine disruption in male fathead minnows (Pimephales promelas). In the wild, conditions are not static as is often the case in the laboratory. Changes in water quality parameters, such as salinity influx due to road s...

  10. Prolonged Oxaliplatin Exposure Alters Intracellular Calcium Signaling: A New Mechanism To Explain Oxaliplatin-Associated Peripheral Neuropathy

    PubMed Central

    Schulze, Christin; McGowan, Margit; Jordt, Sven; Ehrlich, Barbara E

    2012-01-01

    Oxaliplatin is a platinum based cytotoxic agent commonly used to treat colorectal cancers. Despite its effectiveness, oxaliplatin administration is associated with the development of cold-induced peripheral neuropathy. This potentially permanent side effect is provoked by cold exposure and can range from mild and self limited to severe and debilitating. Even with tumor shrinkage, these painful side effects can force dose-reduction or discontinuation of treatment. Neither the mechanism of action of oxaliplatin nor that of cold-induced neuropathy is understood. Paclitaxel, an entirely different chemotherapeutic agent used to treat a variety of malignancies, also is associated with the development of peripheral neuropathy. Unlike oxaliplatin, neurotoxicity arising from paclitaxel treatment is better understood and was found to have profound effects on intracellular calcium signaling (1,2). In this study we examined the effects of oxaliplatin on calcium signaling pathways and found that acute exposure of either a neuroblastoma cell line or primary neurons with therapeutic concentrations of oxaliplatin had no effect on intracellular calcium signaling. We also found that cellular temperature sensors (TRP channels) were also not activated by oxaliplatin. Interestingly, prolonged exposure of oxaliplatin sensitized cells to subsequent stimuli and enhanced the magnitude of intracellular calcium responses. Taken together, our results suggest that acute oxaliplatin exposure will not induce abnormal calcium signaling but oxaliplatin-primed cells do exhibit enhanced sensitivity. These findings provide new insight to the mechanism behind oxaliplatin-induced neuropathy. PMID:21859566

  11. PRENATAL DINOCAP EXPOSURE ALTERS SWIMMING BEHAVIOR IN MICE DUE TO COMPLETE OTOLITH AGENESIS IN THE INNER EAR (JOURNAL VERSION)

    EPA Science Inventory

    Gestational exposure to the fungicide dinocap produces behavioral abnormalities in the house mouse that are not apparent at birth but become obvious at weaning. Torticollis (head-tilting) appears in the treated offspring of CD-1 mice at three weeks of age and, during a test of sw...

  12. Acute developmental exposure to polybrominated diphenyl ether 47 (PBDE 47) alters dopamine concentration within the brains of male mice.

    EPA Science Inventory

    Polybrominated diphenyl ethers (PBDEs) are commonly used as commercial flame retardants in a variety of products including plastics and textiles. Previous studies in our laboratory and in the literature have shown that exposure to a specific PBDE congener, PBDE 47, during a criti...

  13. Alteration of intracellular cysteine and glutathione levels in alveolar macrophages and lymphocytes by diesel exhaust particle exposure.

    PubMed Central

    Al-Humadi, Nabil H; Siegel, Paul D; Lewis, Daniel M; Barger, Mark W; Ma, Jane Y C; Weissman, David N; Ma, Joseph K H

    2002-01-01

    The purpose of this study was to characterize the effects of diesel exhaust particles (DEP) on thiol regulation in alveolar macrophages (AM) and lymphocytes. We obtained AM and lymph node (thymic and tracheal) cells (LNC) (at different time points) from rats exposed intratracheally to DEP (5 mg/kg) or saline, and measured inflammatory markers, thiol levels, and glutathione reductase (GSH-R) activity. DEP exposure produced significant increases in neutrophils, lactate dehydrogenase, total protein, and albumin content in the lavage fluid. AM from DEP-exposed rats showed a time-dependent increase in intracellular cysteine (CYSH) and GSH. In LNC the intracellular GSH reached peak level by 24 hr, declining toward control levels by 72 hr after exposure. LNC-CYSH and AM-CYSH and GSH were increased at both 24 and 72 hr. Both Sprague-Dawley and Brown Norway rats showed similar trends of responses to DEP exposure as per measurement of the inflammatory markers and thiol changes. AM and, to a lesser degree, LNC were both active in cystine uptake. The DEP exposure stimulated GSH-R activity and increased the conversion of cystine to CYSH in both cell types. The intracellular level of GSH in DEP-exposed AM was moderately increased compared with the saline control, and was further augmented when cells were incubated with cystine. In contrast, the intracellular level of GSH in DEP-exposed LNC was significantly reduced despite the increased CYSH level and GSH-R activity when these cells were cultured for 16 hr. DEP absorbed 23-31% of CYSH, cystine, and GSH, and only 8% of glutathione disulfide when incubated in cell free media. These results indicate that DEP exposure caused lung inflammation and affected thiol levels in both AM and LNC. PMID:11940452

  14. Alteration of Fertility Endpoints in Adult Male F-344 Rats by Subchronic Exposure to Inhaled Benzo(a)pyrene

    PubMed Central

    Ramesh, Aramandla; Inyang, Frank; Lunstra, Donald D.; Niaz, Mohammad S.; Kopsombut, Prapaporn M.; Jones, Kea M.; Hood, Daryl B.; Hills, Edward R.; Archibong, Anthony E.

    2012-01-01

    The objective of this study was to evaluate the reproductive risk associated with exposure of adult male Fisher-344 rats to inhaled benzo(a)pyrene (BaP). Rats were assigned randomly to a treatment or control group. Treatment consisted of sub-chronic exposure of rats via inhalation to 75μg BaP/m3, 4 hours daily for 60 days, while control animals were unexposed (UNC). Blood samples were collected immediately after the cessation of exposures (time 0) and subsequently at 24, 48, and 72 hrs, to assess the effect of bioavailable BaP on plasma testosterone and luteinizing hormone (LH) concentrations. Rats were sacrificed after the last blood collection. Testes were harvested, weighed and prepared for histology and morphometric analysis, and cauda epididymides were isolated for the determination of progressive motility and density of stored spermatozoa. BaP exposure reduced testis weight compared with UNC (Mean ± SE; 2.01 ± 0.11 vs. 3.04 ± 0.16 g; P< 0.025), and caused significant reductions in the components of the steroidogenic and spermatogenic compartments of the testis. Progressive motility and mean density of stored spermatozoa were reduced (P< 0.05). Plasma testosterone concentrations were decreased by two-thirds in BaP-exposed rats throughout the time periods studied compared with those of their UNC counterparts (P< 0.05), concomitant with increased concentrations of LH in BaP-exposed rats (P< 0.05). These data suggest that sub-chronic exposure to inhaled BaP contribute to reduced testicular and epididymal function in exposed rats. PMID:18499416

  15. Dioxin exposure reduces the steroidogenic capacity of mouse antral follicles mainly at the level of HSD17B1 without altering atresia

    SciTech Connect

    Karman, Bethany N. Basavarajappa, Mallikarjuna S. Hannon, Patrick Flaws, Jodi A.

    2012-10-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent ovarian toxicant. Previously, we demonstrated that in vitro TCDD (1 nM) exposure decreases production/secretion of the sex steroid hormones progesterone (P4), androstenedione (A4), testosterone (T), and 17β-estradiol (E2) in mouse antral follicles. The purpose of this study was to determine the mechanism by which TCDD inhibits steroidogenesis. Specifically, we examined the effects of TCDD on the steroidogenic enzymes, atresia, and the aryl hydrocarbon receptor (AHR) protein. TCDD exposure for 48 h increased levels of A4, without changing HSD3B1 protein, HSD17B1 protein, estrone (E1), T or E2 levels. Further, TCDD did not alter atresia ratings compared to vehicle at 48 h. TCDD, however, did down regulate the AHR protein at 48 h. TCDD exposure for 96 h decreased transcript levels for Cyp11a1, Cyp17a1, Hsd17b1, and Cyp19a1, but increased Hsd3b1 transcript. TCDD exposure particularly lowered both Hsd17b1 transcript and HSD17B1 protein. However, TCDD exposure did not affect levels of E1 in the media nor atresia ratings at 96 h. TCDD, however, decreased levels of the proapoptotic factor Bax. Collectively, these data suggest that TCDD exposure causes a major block in the steroidogenic enzyme conversion of A4 to T and E1 to E2 and that it regulates apoptotic pathways, favoring survival over death in antral follicles. Finally, the down‐regulation of the AHR protein in TCDD exposed follicles persisted at 96 h, indicating that the activation and proteasomal degradation of this receptor likely plays a central role in the impaired steroidogenic capacity and altered apoptotic pathway of exposed antral follicles. -- Highlights: ► TCDD disrupts steroidogenic enzymes in mouse antral follicles. ► TCDD particularly affects the HSD17B1 enzyme in mouse antral follicles. ► TCDD does not affect atresia ratings in mouse antral follicles. ► TCDD decreases levels of the proapoptitic factor Bax in mouse antral follicles.

  16. Short-term exposure of nontumorigenic human bronchial epithelial cells to carcinogenic chromium(VI) compromises their respiratory capacity and alters their bioenergetic signature.

    PubMed

    Cerveira, Joana F; Sánchez-Aragó, María; Urbano, Ana M; Cuezva, José M

    2014-01-01

    Previous studies on the impact of hexavalent chromium [Cr(VI)] on mammalian cell energetics revealed alterations suggestive of a shift to a more fermentative metabolism. Aiming at a more defined understanding of the metabolic effects of Cr(VI) and of their molecular basis, we assessed the impact of a mild Cr(VI) exposure on critical bioenergetic parameters (lactate production, oxygen consumption and intracellular ATP levels). Cells derived from normal human bronchial epithelium (BEAS-2B cell line), the main in vivo target of Cr(VI) carcinogenicity, were subjected for 48 h to 1 μM Cr(VI). We could confirm a shift to a more fermentative metabolism, resulting from the simultaneous inhibition of respiration and stimulation of glycolysis. This shift was accompanied by a decrease in the protein levels of the catalytic subunit (subunit β) of the mitochondrial H(+)-ATP synthase (β-F1-ATPase) and a concomitant marked increase in those of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The corresponding alteration in the β-F1-ATPase/GAPDH protein ratio (viewed as a bioenergetic signature) upon Cr(VI) exposure was in agreement with the observed attenuation of cellular respiration and enhancement of glycolytic flux. Altogether, these results constitute a novel finding in terms of the molecular mechanisms of Cr(VI) effects. PMID:25161867

  17. Long-term daily vibration exposure alters current perception threshold (CPT) sensitivity and myelinated axons in a rat-tail model of vibration-induced injury.

    PubMed

    Krajnak, Kristine; Raju, Sandya G; Miller, G Roger; Johnson, Claud; Waugh, Stacey; Kashon, Michael L; Riley, Danny A

    2016-01-01

    Repeated exposure to hand-transmitted vibration through the use of powered hand tools may result in pain and progressive reductions in tactile sensitivity. The goal of the present study was to use an established animal model of vibration-induced injury to characterize changes in sensory nerve function and cellular mechanisms associated with these alterations. Sensory nerve function was assessed weekly using the current perception threshold test and tail-flick analgesia test in male Sprague-Dawley rats exposed to 28 d of tail vibration. After 28 d of exposure, Aβ fiber sensitivity was reduced. This reduction in sensitivity was partly attributed to structural disruption of myelin. In addition, the decrease in sensitivity was also associated with a reduction in myelin basic protein and 2',3'- cyclic nucleotide phosphodiasterase (CNPase) staining in tail nerves, and an increase in circulating calcitonin gene-related peptide (CGRP) concentrations. Changes in Aβ fiber sensitivity and CGRP concentrations may serve as early markers of vibration-induced injury in peripheral nerves. It is conceivable that these markers may be utilized to monitor sensorineural alterations in workers exposed to vibration to potentially prevent additional injury. PMID:26852665

  18. Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors.

    PubMed

    Soto, Ana M; Brisken, Cathrin; Schaeberle, Cheryl; Sonnenschein, Carlos

    2013-06-01

    We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to diethylstilbestrol resulted in clear cell carcinoma of the vagina and breast cancer. In this review the effects of the endocrine disruptor bisphenol-A (BPA) on mammary development and tumorigenesis in rodents is used as a paradigmatic example of how altered prenatal mammary development may lead to breast cancer in humans who are also widely exposed to it through plastic goods, food and drink packaging, and thermal paper receipts. Changes in the stroma and its extracellular matrix led to altered ductal morphogenesis. Additionally, gestational and lactational exposure to BPA increased the sensitivity of rats and mice to mammotropic hormones during puberty and beyond, thus suggesting a plausible explanation for the increased incidence of breast cancer. PMID:23702822

  19. Short-term exposure of nontumorigenic human bronchial epithelial cells to carcinogenic chromium(VI) compromises their respiratory capacity and alters their bioenergetic signature

    PubMed Central

    Cerveira, Joana F.; Sánchez-Aragó, María; Urbano, Ana M.; Cuezva, José M.

    2014-01-01

    Previous studies on the impact of hexavalent chromium [Cr(VI)] on mammalian cell energetics revealed alterations suggestive of a shift to a more fermentative metabolism. Aiming at a more defined understanding of the metabolic effects of Cr(VI) and of their molecular basis, we assessed the impact of a mild Cr(VI) exposure on critical bioenergetic parameters (lactate production, oxygen consumption and intracellular ATP levels). Cells derived from normal human bronchial epithelium (BEAS-2B cell line), the main in vivo target of Cr(VI) carcinogenicity, were subjected for 48 h to 1 μM Cr(VI). We could confirm a shift to a more fermentative metabolism, resulting from the simultaneous inhibition of respiration and stimulation of glycolysis. This shift was accompanied by a decrease in the protein levels of the catalytic subunit (subunit β) of the mitochondrial H+-ATP synthase (β-F1-ATPase) and a concomitant marked increase in those of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The corresponding alteration in the β-F1-ATPase/GAPDH protein ratio (viewed as a bioenergetic signature) upon Cr(VI) exposure was in agreement with the observed attenuation of cellular respiration and enhancement of glycolytic flux. Altogether, these results constitute a novel finding in terms of the molecular mechanisms of Cr(VI) effects. PMID:25161867

  20. Perfluorooctanoic acid exposure alters polyunsaturated fatty acid composition, induces oxidative stress and activates the AKT/AMPK pathway in mouse epididymis.

    PubMed

    Lu, Yin; Pan, Yitao; Sheng, Nan; Zhao, Allan Z; Dai, Jiayin

    2016-09-01

    Perfluorooctanoic acid (PFOA) is a degradation-resistant compound with a carbon-fluorine bond. Although PFOA emissions have been reduced since 2000, it remains persistent in the environment. Several studies on laboratory animals indicate that PFOA exposure can impact male fertility. Here, adult male mice received either PFOA (1.25, 5 or 20 mg/kg/d) or an equal volume of water for 28 d consecutively. PFOA accumulated in the epididymis in a dose-dependent manner and resulted in reduced epididymis weight, lower levels of triglycerides (TG), cholesterol (CHO), and free fatty acids (FFA), and activated AKT/AMPK signaling in the epididymis. Altered polyunsaturated fatty acid (PUFA) compositions, such as a higher arachidonic acid:linoleic acid (AA:LA) ratio, concomitant with excessive oxidative stress, as demonstrated by increased malonaldehyde (MDA) and decreased glutathione peroxidase (GSH-Px) in the epididymis, were observed in epididymis tissue following treatment with PFOA. These results indicate that the epididymis is a potential target of PFOA. Oxidative stress and PUFA alteration might help explain the sperm injury and male reproductive dysfunction induced by PFOA exposure. PMID:27262104

  1. Alterations in the infrared spectral signature of avian feathers reflect potential chemical exposure: a pilot study comparing two sites in Pakistan.

    PubMed

    Llabjani, Valon; Malik, Riffat N; Trevisan, Júlio; Hoti, Valmira; Ukpebor, Justina; Shinwari, Zabta K; Moeckel, Claudia; Jones, Kevin C; Shore, Richard F; Martin, Francis L

    2012-11-01

    Chemical contamination of ecosystems is a global issue with evidence that pollutants impact on living organisms in a harmful fashion. Developing sensor approaches that would allow the derivation of biomarkers or signatures of effect in target sentinel organisms and monitor environmental chemical contamination in a high throughput manner is of utmost importance. As biomolecules absorb infrared (IR), signature vibrational spectra related to structure and function can be derived. In light of this, we tested the notion that IR spectra of bird feathers might reflect environmental chemical contaminant exposure patterns. Feathers were collected from monospecific heronries of cattle egret based in two independent locations (Trimu vs. Mailsi) in the Punjab province of Pakistan; these sites were found to differ in their chemical contamination patterns. Feather samples were chemically analyzed for polychlorinated biphenyls, polybrominated diphenyl ethers, organochlorines and heavy metals. Attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy was employed to derive a spectral signature of individual feathers. Resultant IR spectra were then subjected to canonical correspondence analysis (CAA) to determine whether feather spectral signatures correlate to chemical exposure. Additionally, we explored if principal component analysis (PCA) and linear discriminant analysis (LDA) could be applied to distinguish site-specific differences; linear discriminant function (LDF) was also applied to classify sites. The sampled feathers varied in their chemical exposure patterns depending on whether they were sourced from one site associated with heavy metal exposure or the other which suggested high organic pollutant exposures. CCA of chemical and spectral data showed a correlation between spectral signatures and chemical exposure. PCA-LDA readily distinguished feathers from the two different sites. Discriminating alterations were identified and these were associated with

  2. Long-term exposure to triphenylphosphate alters hormone balance and HPG, HPI, and HPT gene expression in zebrafish (Danio rerio).

    PubMed

    Liu, Xiaoshan; Jung, Dawoon; Jo, Areum; Ji, Kyunghee; Moon, Hyo-Bang; Choi, Kyungho

    2016-09-01

    With the global decline in the use of polybrominated diphenyl ethers, the demand for alternative flame retardants, such as triphenylphosphate (TPP), has increased substantially. Triphenylphosphate is now detected in various environments including aquatic ecosystems worldwide. However, studies on the toxicological consequences of chronic TPP exposure on aquatic organisms are scarce. The zebrafish model was used to investigate the effects of long-term TPP exposure on the endocrine system. Zebrafish embryos were exposed to 5 µg/L, 50 µg/L, or 500 µg/L TPP for 120 d, and hormonal and transcriptional responses were measured along the hypothalamic-pituitary-gonad (HPG) axis, the hypothalamic-pituitary-interrenal (HPI) axis, and the hypothalamic-pituitary-thyroid (HPT) axis. Exposure to TPP significantly increased plasma 17β-estradiol, but decreased 11-ketotestosterone in both sexes. Gene expression data support these changes. In the HPI axis, plasma cortisol and proopiomelanocortin (pomc) and mineralocorticoid receptor transcripts increased in females, but in males cortisol decreased whereas pomc increased (p < 0.05). Thyroxine and triiodothyronine increased, and thyrotrophin-releasing hormone receptor 2 (trhr2) and trh expression were affected only in females (p < 0.05). In summary, long-term exposure to TPP enhanced estrogenicity in both males and females, potentially through influencing the HPG axis, but modulated the HPI, and HPT axes differently by sex, suggesting that both genomic and nongenomic responses might be involved. Environ Toxicol Chem 2016;35:2288-2296. © 2016 SETAC. PMID:26865342

  3. Oral exposure of pubertal male mice to endocrine-disrupting chemicals alters fat metabolism in adult livers.

    PubMed

    Jin, Yuanxiang; Lin, Xiaojian; Miao, Wenyu; Wang, Linggang; Wu, Yan; Fu, Zhengwei

    2015-12-01

    The potential for the exposure of humans and wildlife to environmental endocrine-disrupting chemicals (EDCs) has been increasing. Risk assessment for such EDCs is primarily based on detecting the main endpoints related to the endocrine and reproductive systems, while the effects on glucose and fat metabolism have only received limited attention. In this study, pubertal male C57BL/6J mice were orally administered 10 mg/kg body weight cypermethrin (CYP), 100 mg/kg body weight atrazine (ATZ), and 0.1 mg/kg body weight 17α-ethynyestradiol (EE2) for 4 weeks and then switched to a high-energy diet (HD) for 8 weeks. The body weight gain in the EDC-treated groups was lower than that in the control group during exposure and then tended to show values similar to the HD group. The epididymal fat weight, cell size and serum triacylglycerol (TG) and total cholesterol (TCH) levels in the EDC-HD groups were lower than those in the HD group. The transcription of genes related to glycolytic and gluconeogenic processes in the liver was affected by EDC exposure. Furthermore, the expression levels of transcriptional factors including PPARα, PPARγ, and SREBP1C and their target genes related to fatty acid synthesis and oxidation in the liver were also influenced by early life EDC administration. The results showed that early-life-stage exposure to high doses of various environmental EDCs affected the homeostasis of glucose and fatty acid metabolism in the livers of adult male mice. PMID:24916741

  4. Alterations in nitric oxide synthase-expressing neurons in the forebrain regions of rats after developmental exposure to organophosphates.

    PubMed

    Naseh, Maryam; Vatanparast, Jafar; Baniasadi, Mansoureh; Hamidi, Gholam Ali

    2013-01-01

    Several mechanisms have been addressed as contributors to the long lasting behavioral deficits after developmental exposure to organophosphate (OP) compounds. Here, the effects of developmental exposure to two common OP insecticides, chlorpyrifos (CPF) and diazinon (DZN), on nitric oxide synthase (NOS)-expressing neurons in the rat forebrain are reported. A daily dose of 1mg/kg of either CPF or DZN was administered to rats during gestational days 15-18 or postnatal days (PND) 1-4. We then assessed NADPH-diaphorase and neuronal NOS (nNOS) immunohistochemistry in forebrain sections on different postnatal days. Prenatal exposure to CPF and DZN induced a transient reduction of NADPH-d(+)/nNOS-immunoreactive (IR) neurons in most cortical regions on PND 4 but exceptionally increased them in the entorhinal/piriform cortex. On PND 15, NADPH-d(+)/nNOS-IR neurons showed morphological abnormalities within entorhinal/piriform cortex of the rats that gestationally exposed to CPF. Postnatal exposure to CPF and DZN did not induce widespread effects on the number of NADPH-d(+)/nNOS-IR neurons on PNDs 7 and 15 but significantly reduced them in most cortical regions and hippocampal subfields on PND 60. The OPs affected NADPH-d(+)/nNOS-IR neurons in a sex independent manner and apparently spared them in the striatum. While the NADPH-d reactivity of microvessels was normally diminished by age, OP treated rats evidently preserved the NADPH-d reactivity of microvessels in the cerebral cortex and hippocampus. The effects of OPs on NADPH-d(+)/nNOS-IR neurons may contribute to the long-lasting behavioral outcomes and expand the neurotransmitter system that need to be considered in OP neurotoxicity evaluations. PMID:23416429

  5. Neurological effects of inorganic arsenic exposure: altered cysteine/glutamate transport, NMDA expression and spatial memory impairment

    PubMed Central

    Ramos-Chávez, Lucio A.; Rendón-López, Christian R. R.; Zepeda, Angélica; Silva-Adaya, Daniela; Del Razo, Luz M.; Gonsebatt, María E.

    2015-01-01

    Inorganic arsenic (iAs) is an important natural pollutant. Millions of individuals worldwide drink water with high levels of iAs. Chronic exposure to iAs has been associated with lower IQ and learning disabilities as well as memory impairment. iAs is methylated in tissues such as the brain generating mono and dimethylated species. iAs methylation requires cellular glutathione (GSH), which is the main antioxidant in the central nervous system (CNS). In humans, As species cross the placenta and are found in cord blood. A CD1 mouse model was used to investigate effects of gestational iAs exposure which can lead to oxidative damage, disrupted cysteine/glutamate transport and its putative impact in learning and memory. On postnatal days (PNDs) 1, 15 and 90, the expression of membrane transporters related to GSH synthesis and glutamate transport and toxicity, such as xCT, EAAC1, GLAST and GLT1, as well as LAT1, were analyzed. Also, the expression of the glutamate receptor N-methyl-D-aspartate (NMDAR) subunits NR2A and B as well as the presence of As species in cortex and hippocampus were investigated. On PND 90, an object location task was performed to associate exposure with memory impairment. Gestational exposure to iAs affected the expression of cysteine/glutamate transporters in cortex and hippocampus and induced a negative modulation of NMDAR NR2B subunit in the hippocampus. Behavioral tasks showed significant spatial memory impairment in males while the effect was marginal in females. PMID:25709567

  6. Long-term, low-dose lead exposure alters the gonadotropin-releasing hormone system in the male rat.

    PubMed Central

    Sokol, Rebecca Z; Wang, Saixi; Wan, Yu-Jui Y; Stanczyk, Frank Z; Gentzschein, Elisabet; Chapin, Robert E

    2002-01-01

    Lead is a male reproductive toxicant. Data suggest that rats dosed with relatively high levels of lead acetate for short periods of time induced changes in the hypothalamic gonadotropin-releasing hormone (GnRH) at the molecular level, but these changes were attenuated with increased concentration of exposure. The current study evaluated whether exposure to low levels of lead acetate over longer periods of time would produce a similar pattern of adaptation to toxicity at the molecular and biologic levels. Adult 100-day-old Sprague-Dawley male rats were dosed with 0, 0.025, 0.05, 0.1, and 0.3% lead acetate in water. Animals were killed after 1, 4, 8, and 16 weeks of treatment. Luteinzing hormone (LH) and GnRH levels were measured in serum, and lead levels were quantified in whole blood. Hypothalamic GnRH mRNA levels were also quantified. We found no significant differences in serum LH and GnRH among the groups of animals treated within each time period. A significant dose-related increase of GnRH mRNA concentrations with lead dosing occurred in animals treated for 1 week. Animals treated for more than 1 week also exhibited a significant increase in GnRH mRNA, but with an attenuation of the increase at the higher concentrations of lead with increased duration of exposure. We conclude that the signals within and between the hypothalamus and pituitary gland appear to be disrupted by long-term, low-dose lead exposure. PMID:12204820

  7. Persistent Cognitive Alterations in Rats after Early Postnatal Exposure to Low Doses of the Organophosphate Pesticide, Diazinon

    PubMed Central

    Timofeeva, Olga A.; Roegge, Cindy S.; Seidler, Frederic J.; Slotkin, Theodore A.; Levin, Edward D.

    2008-01-01

    Background Developmental neurotoxicity of organophosphorous insecticides (OPs) involves multiple mechanisms in addition to cholinesterase inhibition. We have found persisting effects of developmental chlorpyrifos (CPF) and diazinon (DZN) on cholinergic and serotonergic neurotransmitter systems and gene expression as well as behavioral function. Both molecular/neurochemical and behavioral effects of developmental OP exposure have been seen at doses below those which cause appreciable cholinesterase inhibition. Objectives We sought to determine if developmental DZN exposure at doses which do not produce significant acetylcholinesterase inhibition cause cognitive deficits. Methods Rats were exposed to DZN on postnatal days 1-4 at doses (0.5 and 2 mg/kg/d) that span the threshold for cholinesterase inhibition. They were later examined with a cognitive battery tests similar to that used with CPF. Results In the T-maze DZN caused significant hyperactivity in the initial trials of the session, but not later. In a longer assessment of locomotor activity no DZN-induced changes were seen over a 1-hour session. Prepulse inhibition was reduced by DZN exposure selectively in males vs. females; DZN eliminated the sex difference present in controls. In the radial maze, the lower but not higher DZN dose significantly impaired spatial learning. This has previously been seen with CPF as well. The lower dose DZN group also showed significantly greater sensitivity to the memory-impairing effects of the anticholinergic drug scopolamine. Conclusions Neonatal DZN exposure below the threshold for appreciable cholinesterase inhibition caused neurocognitive deficits in adulthood. The addition of some inhibition of AChE with a higher dose reversed the cognitive impairment. This non-monotonic dose-effect function has also been seen with neurochemical effects. Some of the DZN effects on cognition resemble those seen earlier for CPF, some differ. Our data suggest that DZN and CPF affect

  8. Short-term exposure to a treated sewage effluent alters reproductive behaviour in the three-spined stickleback (Gasterosteus aculeatus).

    PubMed

    Sebire, Marion; Katsiadaki, Ioanna; Taylor, Nick G H; Maack, Gerd; Tyler, Charles R

    2011-09-01

    Some UK sewage treatment work (STW) effluents have been found to contain high levels of anti-androgenic activity, but the biological significance of this activity to fish has not been determined. The aim of this study was to investigate the effects of exposure to a STW effluent with anti-androgenic activity on the reproductive physiology and behaviour of three-spined sticklebacks (Gasterosteus aculeatus). Fish were exposed to a STW effluent (50 and 100%, v/v) with a strong anti-androgenic activity (328.56±36.83 μgl(-1) flutamide equivalent, as quantified in a recombinant yeast assay containing the human androgen receptor) and a low level of oestrogenic activity (3.32±0.66 ngl(-1) oestradiol equivalent, quantified in a recombinant yeast assay containing the human oestrogen receptor) for a period of 21 days in a flow-through system in the laboratory. Levels of spiggin, an androgen-regulated protein, were not affected by the STW effluent exposure, nor were levels of vitellogenin (a biomarker of oestrogen exposure), but the reproductive behaviour of the males was impacted. Males exposed to full strength STW effluent built fewer nests and there was a significant reduction in male courtship behaviour for exposures to both the 50 and 100% STW effluent treatments compared with controls. The effect seen on the reproduction of male sticklebacks may not necessarily have been as a consequence of the endocrine active chemicals present in the STW effluent alone, but could relate to other features of the effluent, such as turbidity that can impair visual signalling important for courtship interactions. Regardless the specific causation, the data presented show that effluents from STW have an impact on reproductive behaviour in male sticklebacks which in turn affects reproductive performance/outcome. The study further highlights the use of fish behaviour as a sensitive endpoint for assessing potential effects of contaminated water bodies on fish reproduction. PMID:21684244

  9. Structural alterations in the cornea from exposure to infrared radiation. Final report, 1 April 1986-14 April 1988

    SciTech Connect

    Farrall, R.A.; McCally, R.L.; Bargeron, C.B.; Green, W.R.

    1989-08-01

    This report summarizes our research on the interaction of infrared radiation, especially from high-intensity CO{sub 2} TEA lasers, with the cornea. The research reported here was performed between April 1, 1986 and April 14 1988. The report discusses threshold epithelial damage from single- and multiple-pulse exposures, material ejection from the anterior corneal surface, lesion histology, and possible damage mechanisms.

  10. Alterations in the oxidative metabolism of Rhipicephalus (Boophilus) microplus ticks in response to exposure to the insect growth regulator fluazuron.

    PubMed

    Gaudêncio, Fabrício Nascimento; Tunholi-Alves, Vinícius Menezes; Lima, Mariana Gomes; Gôlo, Patrícia Silva; Angelo, Isabele da Costa; Castro, Rosane Nora; Fonseca, Adivaldo Henrique da; Scott, Fabio Barbour; Pinheiro, Jairo

    2016-01-01

    Aiming to characterize the potential off-target effects of fluazuron on ticks, biochemical analyses were conducted to evaluate changes in the carbohydrate metabolism of Rhipicephalus (Boophilus) microplus ticks after exposure to fluazuron. Hemolymph and fat body were collected from female ticks before and after (4, 8 and 15 days) exposure to fluazuron. Spectrophotometric analyses were done to quantify glucose concentration and lactate dehydrogenase (LDH) activity in the hemolymph and the concentration of glycogen in the tick's fat body. High Performance Liquid Chromatography (HPLC) was employed to determine the concentration of carboxylic acids in the hemolymph and to evaluate changes in intermediary metabolic processes requiring oxygen consumption. Increases in the levels of LDH activity and lactic acid concentration indicated that fluazuron enhanced fermentative metabolism in ticks. Exposure to fluazuron was also found to increase glucose concentrations in the hemolymph over time, although no significant differences were noted daily. In addition to expanding the body of knowledge about the mode of action of fluazuron, investigations into these mechanisms may also be useful in discovering new and as yet unexplored secondary effects. PMID:26982563

  11. Prenatal Exposure to Sodium Arsenite Alters Placental Glucose 1, 3, and 4 Transporters in Balb/c Mice

    PubMed Central

    Gutiérrez-Torres, Daniela Sarahí; González-Horta, Carmen; Del Razo, Luz María; Infante-Ramírez, Rocío; Ramos-Martínez, Ernesto; Levario-Carrillo, Margarita; Sánchez-Ramírez, Blanca

    2015-01-01

    Inorganic arsenic (iAs) exposure induces a decrease in glucose type 4 transporter (GLUT4) expression on the adipocyte membrane, which may be related to premature births and low birth weight infants in women exposed to iAs at reproductive age. The aim of this study was to analyze the effect of sodium arsenite (NaAsO2) exposure on GLUT1, GLUT3, and GLUT4 protein expression and on placental morphology. Female Balb/c mice (n = 15) were exposed to 0, 12, and 20 ppm of NaAsO2 in drinking water from 8th to 18th day of gestation. Morphological changes and GLUT1, GLUT3, and GLUT4 expression were evaluated in placentas by immunohistochemical and image analysis and correlated with iAs and arsenical species concentration, which were quantified by atomic absorption spectroscopy. NaAsO2 exposure induced a significant decrease in fetal and placental weight (P < 0.01) and increases in infarctions and vascular congestion. Whereas GLUT1 expression was unchanged in placentas from exposed group, GLUT3 expression was found increased. In contrast, GLUT4 expression was significantly lower (P < 0.05) in placentas from females exposed to 12 ppm. The decrease in placental GLUT4 expression might affect the provision of adequate fetal nutrition and explain the low fetal weight observed in the exposed groups. PMID:26339590

  12. Funduscopic alterations in the rhesus monkey induced by exposure to heavy ions /0+8/ 250 MeV/nucleon

    NASA Technical Reports Server (NTRS)

    Beckman, F. N.; Bonney, C. H.; Hunter, D. M.

    1974-01-01

    A heavy-ion, high-energy beam has been extracted from the Lawrence Radiation Laboratory Bevatron, making controlled exposure of biological systems feasible, and a series of experiments have been undertaken to determine the possible deleterious effects of such irradiation upon the primate retina. The left eyes of 54 rhesus monkeys have been exposed to accelerated 0+8 (250 MeV/nucleon). Beam flux ranged from 1.3 x 10 to the 7th particles/ sq cm (171 rads) to