title: Chronic exposure to trichloroethylene increases DNA methylation of the Ifng promoter in CD4+T cells.
abstract: CD4+T cells in female MRL+/+ mice exposed to solvent and water pollutant trichloroethylene (TCE) skew toward effector/memory CD4+T cells, and demonstrate seemingly non-monotonic alterations in IFN-γ production. In the current study we examined the mechanism for this immunotoxicity using effector/memory and naïve CD4+T cells isolated every 6 weeks during a 40 week exposure to TCE (0.5mg/ml in drinking water). A time-dependent effect of TCE exposure on both Ifng gene expression and IFN-γ protein production was observed in effector/memory CD4+T cells, with an increase after 22 weeks of exposure and a decrease after 40 weeks of exposure. No such effect of TCE was observed in naïve CD4+T cells. A cumulative increase in DNA methylation in the CpG sites of the promoter of the Ifng gene was observed in effector/memory, but not naïve, CD4+T cells over time. Also unique to the Ifng promoter was an increase in methylation variance in effector/memory compared to naïve CD4+T cells. Taken together, the CpG sites of the Ifng promoter in effector/memory CD4+T cells were especially sensitive to the effects of TCE exposure, which may help explain the regulatory effect of the chemical on this gene.
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States. Electronic address: gilbertkathleenm@uams.edu.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gilbert
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States. Electronic address: blossomsarah@uams.edu.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Blossom
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States. Electronic address: serickson@rti.org.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Erickson
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States. Electronic address: bbroadfoot@uams.edu.
authors.forename: Brannon
authors.initials: B
authors.lastname: Broadfoot
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States. Electronic address: kwest@uams.edu.
authors.forename: Kirk
authors.initials: K
authors.lastname: West
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States. Electronic address: sbai@uams.edu.
authors.forename: Shasha
authors.initials: S
authors.lastname: Bai
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States. Electronic address: JLi@uams.edu.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Li
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, United States. Electronic address: cooneycraiga@gmail.com.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Cooney
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018899:CpG Islands / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005091:Exons / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D059165:Hormesis; D007156:Immunologic Memory / Q000187:drug effects; D007371:Interferon-gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007438:Introns / Q000187:drug effects; D019463:Mice, Inbred MRL lpr; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D015203:Reproducibility of Results; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014241:Trichloroethylene / Q000008:administration & dosage / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: C000611649:IFNG protein, mouse; D012997:Solvents; D014874:Water Pollutants, Chemical; D014241:Trichloroethylene; D007371:Interferon-gamma
keywords: CD4(+) T cells; Epigenetics; Immunotoxicity; Next-generation sequencing; Trichloroethylene