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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02016

Continuous developmental and early life trichloroethylene exposure promoted DNA methylation alterations in polycomb protein binding sites in effector/memory CD4+ T cells

Stephanie D. Byrum1, 2,  Charity L. Washam1, 2, John D. Patterson1, Kanan K. Vyas1, 2, Kathleen M. Gilbert1, 2 and  Sarah J. Blossom1, 2*
  • 1University of Arkansas for Medical Sciences, United States
  • 2Arkansas Children's Research Institute (ACRI), United States

Trichloroethylene (TCE) is an industrial solvent and drinking water pollutant associated with CD4+ T cell-mediated autoimmunity. In our mouse model, discontinuation of TCE exposure during adulthood after developmental exposure did not prevent immunotoxicity. To determine whether persistent effects were linked to epigenetic changes we conducted whole genome reduced representation bisulfite sequencing (RRBS) to evaluate methylation of CpG sites in autosomal chromosomes in activated effector/memory CD4+ T cells. Female MRL+/+ mice were exposed to vehicle control or TCE in the drinking water from gestation until ~37 weeks of age [postnatal day (PND) 259]. In a subset of mice, TCE exposure was discontinued at ~22 weeks of age (PND 154). At PND 259, RRBS assessment revealed more global methylation changes in the continuous exposure group vs. the discontinuous exposure group. A majority of the differentially methylated CpG regions (DMRs) across promoters, islands, and regulatory elements were hypermethylated (~90%). However, continuous developmental TCE exposure altered the methylation of 274 CpG sites in promoters and CpG islands. In contrast, only 4 CpG island regions were differentially methylated (hypermethylated) in the discontinuous group. Interestingly, 2 of these 4 sites were also hypermethylated in the continuous exposure group, and both of these island regions are associated with lysine 27 on histone H3 (H3K27) involved in polycomb complex-dependent transcriptional repression via H3K27 tri-methylation. CpG sites were overlapped with the Open Regulatory Annotation database. Unlike the discontinuous group, continuous TCE treatment resulted in 129 DMRs including 12 unique transcription factors and regulatory elements; 80% of which were enriched for one or more polycomb group (PcG) protein binding regions (i.e., SUZ12, EZH2, JARID2, and MTF2). Pathway analysis of the DMRs indicated that TCE primarily altered the methylation of genes associated with regulation of cellular metabolism and cell signaling. The results demonstrated that continuous developmental exposure to TCE differentially methylated binding sites of PcG proteins in effector/memory CD4+ cells. There were minimal yet potentially biologically significant effects that occurred when exposure was discontinued. These results point toward a novel mechanism by which chronic developmental TCE exposure may alter terminally differentiated CD4+ T cell function in adulthood.

Keywords: polycomb, Trichloroethylene, CD4 T cell, DNA Methylation, Developmental exposure

Received: 24 Jan 2019; Accepted: 08 Aug 2019.

Copyright: © 2019 Byrum, Washam, Patterson, Vyas, Gilbert and Blossom. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Sarah J. Blossom, University of Arkansas for Medical Sciences, Little Rock, 72205, Arkansas, United States, blossomsarah@uams.edu