Dataset Information

Continuous Developmental and Early Life Trichloroethylene Exposure Promoted DNA Methylation Alterations in Polycomb Protein Binding Sites in Effector/Memory CD4+ T Cells.

ABSTRACT: 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.

SUBMITTER: Byrum SD

PROVIDER: S-EPMC6724578 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Continuous Developmental and Early Life Trichloroethylene Exposure Promoted DNA Methylation Alterations in Polycomb Protein Binding Sites in Effector/Memory CD4<sup>+</sup> T Cells.

Byrum Stephanie D SD Washam Charity L CL Patterson John D JD Vyas Kanan K KK Gilbert Kathleen M KM Blossom Sarah J SJ

Frontiers in immunology 20190828

Trichloroethylene (TCE) is an industrial solvent and drinking water pollutant associated with CD4<sup>+</sup> 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 effe ...[more]

PMID: 31555266

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Project description:Trichloroethylene (TCE) is a common environmental toxicant linked with hypersensitivity and autoimmune responses in humans and animal models. While autoimmune diseases are more common in females, mechanisms behind this disparity are not clear. Recent evidence suggests that autoimmunity may be increasing in males, and occupational studies have shown that TCE-mediated hypersensitivity responses occur just as often in males. Previous experimental studies in autoimmune-prone MRL+/+ mice have focused on responses in females. However, it is important to include both males and females in order to better understand sex-disparity in autoimmune disease. In addition, because of an alarming increase in autoimmunity in adolescents, developmental and/or early life exposures to immune-enhancing environmental pollutants should also be considered. Using MRL+/+ mice, we hypothesized that TCE would alter markers related to autoimmunity to a greater degree in female mice relative to male mice, and that TCE would enhance these effects. Mice were continuously exposed to either TCE or vehicle beginning at gestation, continuing during lactation, and directly in the drinking water. Both male and female offspring were evaluated at 7 weeks of age. Sex-specific effects were evident. Female mice were more likely than males to show enhanced CD4+ T cell cytokine responses (e.g., IL-4 and IFN-γ). Although none of the animals developed pathological or serological signs of autoimmune hepatitis-like disease, TCE-exposed female mice were more likely than males in either group to express higher levels of biomarkers in the liver related to regeneration/repair and proliferation. Levels of bacterial populations in the intestinal ileum were also altered by TCE exposure and were more prominent in females as compared to males. Thus, our expectations were correct in that young adult female mice developmentally exposed to TCE were more likely to exhibit alterations in immunological and gut/liver endpoints compared to male mice.

Project description:Protection at the peak of Plasmodium chabaudi blood-stage malaria infection is provided by CD4 T cells. We have shown that an increase in Th1 cells also correlates with protection during the persistent phase of malaria; however, it is unclear how these T cells are maintained. Persistent malaria infection promotes protection and generates both effector T cells (Teff), and effector memory T cells (Tem). We have previously defined new CD4 Teff (IL-7R?-) subsets from Early (TeffEarly, CD62LhiCD27+) to Late (TeffLate, CD62LloCD27-) activation states. Here, we tested these effector and memory T cell subsets for their ability to survive and protect in vivo. We found that both polyclonal and P. chabaudi Merozoite Surface Protein-1 (MSP-1)-specific B5 TCR transgenic Tem survive better than Teff. Surprisingly, as Tem are associated with antigen persistence, Tem survive well even after clearance of infection. As previously shown during T cell contraction, TeffEarly, which can generate Tem, also survive better than other Teff subsets in uninfected recipients. Two other Tem survival mechanisms identified here are that low-level chronic infection promotes Tem both by driving their proliferation, and by programming production of Tem from Tcm. Protective CD4 T cell phenotypes have not been precisely determined in malaria, or other persistent infections. Therefore, we tested purified memory (Tmem) and Teff subsets in protection from peak pathology and parasitemia in immunocompromised recipient mice. Strikingly, among Tmem (IL-7R?hi) subsets, only TemLate (CD62LloCD27-) reduced peak parasitemia (19%), though the dominant memory subset is TemEarly, which is not protective. In contrast, all Teff subsets reduced peak parasitemia by more than half, and mature Teff can generate Tem, though less. In summary, we have elucidated four mechanisms of Tem maintenance, and identified two long-lived T cell subsets (TemLate, TeffEarly) that may represent correlates of protection or a target for longer-lived vaccine-induced protection against malaria blood-stages.

Dataset Information

Continuous Developmental and Early Life Trichloroethylene Exposure Promoted DNA Methylation Alterations in Polycomb Protein Binding Sites in Effector/Memory CD4+ T Cells.

Publications

Continuous Developmental and Early Life Trichloroethylene Exposure Promoted DNA Methylation Alterations in Polycomb Protein Binding Sites in Effector/Memory CD4<sup>+</sup> T Cells.

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