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Prior studies showed that exposure to TCE in the drinking water of autoimmune-prone mice expanded effector\/memory CD4+ T cells with an interferon-\u03b3 (IFN-\u03b3)-secreting Th1-like phenotype. However, very little is known how TCE exposure skews CD4+ T cells towards this pro-inflammatory Th1 subset. As observed previously, TCE exposure was associated with hypermethylation of regions of the genome related to transcriptional repression in purified effector\/memory CD4 T cells. We hypothesized that TCE modulates transcriptional and\/or epigenetic programming of CD4+ T cells as they differentiate from a naive to effector phenotype. In the current study, purified naive CD4 T cells from both male and female autoimmune-prone MRL\/MpJ mice were activated ex vivo and polarized towards a Th1 subset for 4\u2009days in the presence or absence of the oxidative metabolite of TCE, trichloroacetaldehyde hydrate (TCAH) in vitro. An RNA-seq assessment and reduced representation bisulfite sequencing for DNA methylation were conducted on Th1 cells or activated, non-polarized cells. The results demonstrated TCAH\u2019s ability to regulate key genes involved in the immune response and autoimmunity, including Ifng, by altering the level of DNA methylation at the gene promoter. Intriguing sex differences were observed and for the most part, the effects were more robust in females compared to males. In conclusion, TCE via TCAH epigenetically regulates gene expression in CD4+ T cells. These results may have implications for mechanistic understanding or future therapeutics for autoimmunity.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae032","type":"journal-article","created":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T18:57:10Z","timestamp":1711133830000},"page":"289-300","source":"Crossref","is-referenced-by-count":1,"title":["Trichloroethylene metabolite modulates DNA methylation-dependent gene expression in Th1-polarized CD4+ T cells from autoimmune-prone mice"],"prefix":"10.1093","volume":"199","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6555-3031","authenticated-orcid":false,"given":"Samrat Roy","family":"Choudhury","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pediatrics, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72202, USA"},{"name":"Arkansas Children\u2019s Research Institute, Department of Pediatrics , Little Rock, Arkansas 72202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie D","family":"Byrum","sequence":"additional","affiliation":[{"name":"Arkansas Children\u2019s Research Institute, Department of Pediatrics , Little Rock, Arkansas 72202, USA"},{"name":"Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3110-4577","authenticated-orcid":false,"given":"Sarah J","family":"Blossom","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of New Mexico , Albuquerque, New Mexico 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,3,22]]},"reference":[{"key":"2024052809252560000_kfae032-B1","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1093\/toxsci\/kfad090","article-title":"Low-dose inhalation exposure to trichloroethylene induces dopaminergic neurodegeneration in rodents","volume":"196","author":"Adamson","year":"2023","journal-title":"Toxicol. 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