Chronic exposure to trichloroethylene increases DNA methylation of the Ifng promoter in CD4+ T cells

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-gamma production. In the current study we examined the mechanism for this immunotoxicity using effector/memory and naive CD4(+) T cells isolated every 6 weeks during a 40 week exposure to TCE (0.5 mg/ml in drinking water). A time-dependent effect of TCE exposure on both Ifng gene expression and IFN-g 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 naive 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 naive, CD4(+) T cells over time. Also unique to the Ifng promoter was an increase in methylation variance in effector/memory compared to naive 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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.