title: Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, College of Medicine, Arkansas Children's Hospital Research Institute, 13 Children's Way, Little Rock, AR 72202, United States. Electronic address: blossomsarah@uams.edu.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Blossom
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, College of Medicine, Arkansas Children's Hospital Research Institute, 13 Children's Way, Little Rock, AR 72202, United States.
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.affiliation: Department of Research and Development, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, United States.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Cooney
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, College of Medicine, Arkansas Children's Hospital Research Institute, 13 Children's Way, Little Rock, AR 72202, United States.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gilbert
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, College of Medicine, Arkansas Children's Hospital Research Institute, 13 Children's Way, Little Rock, AR 72202, United States.
authors.forename: S Jill
authors.initials: SJ
authors.lastname: James
mesh_terms: D000367:Age Factors; D000818:Animals; D015415:Biomarkers / Q000097:blood; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D008745:Methylation; D051379:Mice; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D014241:Trichloroethylene / Q000633:toxicity*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D004785:Environmental Pollutants; D009414:Nerve Growth Factors; C518911:neurotropin 3, mouse; D014241:Trichloroethylene; C002744:3-nitrotyrosine; D014443:Tyrosine; D020932:Nerve Growth Factor; D005978:Glutathione