Epigenetic Alterations May Regulate Temporary Reversal of CD4⁺ T Cell Activation Caused by Trichloroethylene Exposure

Abstract

Previous studies have shown that short-term (4 weeks) or chronic (32 weeks) exposure to trichloroethylene (TCE) in drinking water of female MRL+/+ mice generated CD4⁺ T cells that secreted increased levels of interferon (IFN)-γ and expressed an activated (CD44^hiCD62L^lo) phenotype. In contrast, the current study of subchronic TCE exposure showed that midway in the disease process both of these parameters of CD4⁺ T cell activation were reversed. This phase of the disease process may represent an attempt by the body to counteract the inflammatory effects of TCE. The decrease in CD4⁺ T cell production of IFN-γ following subchronic TCE exposure could not be attributed to skewing toward a Th2 or Th17 phenotype or to an increase in Treg cells. Instead, the suppression corresponded to alterations in markers used to assess DNA methylation, namely increased expression of retrotransposons Iap (intracisternal A particle) and Muerv (murine endogenous retrovirus). Also observed was an increase in the expression of Dnmt1 (DNA methyltransferase-1) and decreased expression of several genes known to be downregulated by DNA methylation, namely Ifng, Il2, and Cdkn1a. CD4⁺ T cells from a second study in which MRL+/+ mice were treated for 17 weeks with TCE showed a similar increase in Iap and decrease in Cdkn1a. In addition, DNA collected from the CD4⁺ T cells in the second study showed TCE-decreased global DNA methylation. Thus, these results described the biphasic nature of TCE-induced alterations in CD4⁺ T cell function and suggested that these changes represented potentially reversible alterations in epigenetic processes.

trichloroethylene, epigenetics, CD4⁺ T cells, immunotoxicity