Andreas Vesalius (1514-64).

Abstract

Trichloroethylene (TCE) is an industrial solvent and drinking water pollutant associated with autoimmunity in human populations. Previous studies in autoimmune-prone MRL+/+ mice revealed autoimmune pathology and CD4 + T cell autoreactivity were more robust when exposure occurred during development rather than adulthood. To determine whether these effects were linked to epigenetic changes, mice were exposed to vehicle control or TCE in the drinking water beginning at gestation until 37 weeks of age. In some mice, TCE was removed from drinking water at 22 weeks of age. Whole genome reduced representation bisulfite sequencing (RRBS) was used to compare methylation of CpG sites in autosomal chromosomes in effector/memory CD4+ T cells. Few significant changes occurred in mice when TCE was removed from drinking water. In contrast, continuous developmental TCE exposure revealed differential methylation of 252 CpG sites relative to controls. When CpG sites were overlapped with the Open Regulatory Annotation database (ORegAnno), continuous TCE treatment resulted in 130 differentially methylated regions (DMRs) that included 12 unique transcription factors. Interestingly, 80% of DMRs occurred in areas known to bind Polycomb group (PcG) proteins that form the polycomb-repressive complex 2 (PRC2) in mammalian cells, namely, SUZ12, EZH2, JARID2, and MTF2. Pathway analysis of the DMRs indicated that TCE primarily altered the methylation of genes asociated with regulation of cellular metabolism and cell signaling pathways. In summary, TCE differentially methylated binding sites of PcG proteins in effector/memory CD4+ cells, and point toward a novel mechanism by which TCE could modulate CD4 + T cell function and promote autoimmunity.