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

Gilbert, Kathleen M.; Blossom, Sarah J.; Erickson, Stephen W.; Broadfoot, Brannon; West, Kirk; Bai, Shasha; Li, Jingyun; Cooney, Craig A.

doi:10.1016/j.toxlet.2016.08.017

Cited by 22 publications

(10 citation statements)

References 35 publications

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“…TRIM68 (Tripartite Motif Containing 68) is involved in immunity and cancer and has been shown to negatively regulate an antagonist of interferon gamma, interferon beta [19]. A time-dependent effect of TCE on interferon gamma gene expression and protein expression was observed in mice [9]. Also, an increase in interferon gamma has previously been reported as an effect of occupational exposure to TCE [20].…”

Section: Discussionmentioning

confidence: 96%

“…The most significant and biologically relevant DVPs were found in genes CTNND2 (Catenin Delta 2), EFNB2 (Ephrin B2), CAP2 (Cyclase Associated Actin Cytoskeleton Regulatory Protein 2), and ZNF259 (Zinc Finger Protein ZPR1/259), which have all been related to cancer and autoimmune disease [15][16][17][18]. Also, almost all of the 25 genomewide significant DVPs were hypermethylated (Supplementary Table S1(J-M)) and, interestingly, this pattern was hypothesized in [9]. Perhaps increased variability of DNA CpG methylation may be precursor to changes in mean DNA CpG methylation?…”

Section: Discussionmentioning

confidence: 99%

“…For example, TCE exposure led to dissociation of DNA methyltransferase 3a from heterochromatin in a dose-dependent manner in HeLa and HEK293 cells, which resulted in global DNA hypomethylation [7]. In mouse effector/memory CD4 + T cells, TCE exposure led to DNA methylation alterations that were enriched in polycomb protein binding sites [8], along with hypermethylation and increased variance of DNA methylation of the interferongamma promoter [9]. Also, cardiac myoblast cells and rat embryonic cardiac tissue exposed to TCE exhibited Serca2 promoter region hypermethylation [10].…”

Section: Introductionmentioning

confidence: 99%

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Human exposure to trichloroethylene is associated with increased variability of blood DNA methylation that is enriched in genes and pathways related to autoimmune disease and cancer

et al. 2019

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Human exposure to trichloroethylene (TCE) is linked to kidney cancer, autoimmune diseases, and probably non-Hodgkin lymphoma. Additionally, TCE exposed mice and cell cultures show altered DNA methylation. To evaluate associations between TCE exposure and DNA methylation in humans, we conducted an epigenome-wide association study (EWAS) in TCE exposed workers using the HumanMethylation450 BeadChip. Across individual CpG probes, genomic regions, and globally (i.e., the 450K methylome), we investigated differences in mean DNA methylation and differences in variability of DNA methylation between 73 control (< 0.005 ppm TCE), 30 lower exposed (< 10 ppm TCE), and 37 higher exposed (10 ppm TCE) subjects' white blood cells. We found that TCE exposure increased methylation variation globally (Kruskal-Wallis p-value = 3.75e-3) and in 25 CpG sites at a genome-wide significance level (Bonferroni p-value < 0.05). We identified a 609 basepair region in the TRIM68 gene promoter that exhibited hypomethylation with increased exposure to TCE (FWER = 1.20e-2). Also, genes that matched to differentially variable CpGs were enriched in the 'focal adhesion' biological pathway (p-value = 2.80e-2). All in all, human exposure to TCE was associated with epigenetic alterations in genes involved in cell-matrix adhesions and interferon subtype expression, which are important in the development of autoimmune diseases; and in genes related to cancer development. These results suggest that DNA methylation may play a role in the pathogenesis of TCE exposure-related diseases and that TCE exposure may contribute to epigenetic drift.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human exposure to trichloroethylene is associated with increased variability of blood DNA methylation that is enriched in genes and pathways related to autoimmune disease and cancer

et al. 2019

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“…Because the effects persisted after TCE was removed from the drinking water suggested that programming events played a role in disease pathology. Indeed TCE altered the DNA methylation profile of the IFN-γ promoter in mouse CD4 + T cells [63]. In a genome-wide DNA methylation and gene expression study, TCE exposure in vivo differentially methylated CpGs in regions that bind polycomb group proteins [64] whose function is to regulate T effector cell expansion and differentiation [65].…”

Section: Trichloroethylenementioning

confidence: 99%

Epigenetic underpinnings of developmental immunotoxicity and autoimmune disease

Blossom

Gilbert

2018

Current Opinion in Toxicology

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The concordance rate for developing autoimmune disease in identical twins is around 50% demonstrating that gene and environmental interactions contribute to disease etiology. The environmental contribution to autoimmune disease is a wide-ranging concept including exposure to immunotoxic environmental chemicals. Because the immune system is immature during development suggests that adult-onset autoimmunity may originate when the immune system is particularly sensitive. Among the pollutants most closely associated with inflammation and/or autoimmunity include Bisphenol-A, mercury, TCDD, and trichloroethylene. These toxicants have been shown to impart epigenetic changes (e.g., DNA methylation) that may alter immune function and promote autoreactivity. Here we review these autoimmune-promoting toxicants and their relation to immune cell epigenetics both in terms of adult and developmental exposure.

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“…A subsequent study, using targeted bisulfite next generation sequencing of amplicons generated on a Fluidigm Access Array, examined TCE- and time-dependent changes in DNA methylation associated with 16 functionally important genes in CD4 + T cells. TCE was found to increase gene-specific methylation variance in effector/memory CD4 + cells [ 6 ], and to induce a time-dependent cumulative increase in DNA methylation in the CpG sites of the promoter of the Ifng gene [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

Trichloroethylene-induced alterations in DNA methylation were enriched in polycomb protein binding sites in effector/memory CD4+ T cells

Gilbert

Blossom

Reisfeld

et al. 2017

Environmental Epigenetics

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Exposure to industrial solvent and water pollutant trichloroethylene (TCE) can promote autoimmunity, and expand effector/memory (CD62L) CD4+ T cells. In order to better understand etiology reduced representation bisulfite sequencing was used to study how a 40-week exposure to TCE in drinking water altered methylation of ∼337 770 CpG sites across the entire genome of effector/memory CD4+ T cells from MRL+/+ mice. Regardless of TCE exposure, 62% of CpG sites in autosomal chromosomes were hypomethylated (0–15% methylation), and 25% were hypermethylated (85–100% methylation). In contrast, only 6% of the CpGs on the X chromosome were hypomethylated, and 51% had mid-range methylation levels. In terms of TCE impact, TCE altered (≥ 10%) the methylation of 233 CpG sites in effector/memory CD4+ T cells. Approximately 31.7% of these differentially methylated sites occurred in regions known to bind one or more Polycomb group (PcG) proteins, namely Ezh2, Suz12, Mtf2 or Jarid2. In comparison, only 23.3% of CpG sites not differentially methylated by TCE were found in PcG protein binding regions. Transcriptomics revealed that TCE altered the expression of ∼560 genes in the same effector/memory CD4+ T cells. At least 80% of the immune genes altered by TCE had binding sites for PcG proteins flanking their transcription start site, or were regulated by other transcription factors that were in turn ordered by PcG proteins at their own transcription start site. Thus, PcG proteins, and the differential methylation of their binding sites, may represent a new mechanism by which TCE could alter the function of effector/memory CD4+ T cells.

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

Cited by 22 publications

References 35 publications

Human exposure to trichloroethylene is associated with increased variability of blood DNA methylation that is enriched in genes and pathways related to autoimmune disease and cancer

Human exposure to trichloroethylene is associated with increased variability of blood DNA methylation that is enriched in genes and pathways related to autoimmune disease and cancer

Epigenetic underpinnings of developmental immunotoxicity and autoimmune disease

Trichloroethylene-induced alterations in DNA methylation were enriched in polycomb protein binding sites in effector/memory CD4+ T cells

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