Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women

Abstract

Arsenic, a carcinogen with immunotoxic effects, is a common contaminant of drinking water and certain food worldwide. We hypothesized that chronic arsenic exposure alters gene expression, potentially by altering DNA methylation of genes encoding central components of the immune system. We therefore analyzed the transcriptomes (by RNA sequencing) and methylomes (by target-enrichment next-generation sequencing) of primary CD4-positive T cells from matched groups of four women each in the Argentinean Andes, with fivefold differences in urinary arsenic concentrations (median concentrations of urinary arsenic in the lower- and high-arsenic groups: 65 and 276 μg/l, respectively). Arsenic exposure was associated with genome-wide alterations of gene expression; principal component analysis indicated that the exposure explained 53% of the variance in gene expression among the top variable genes and 19% of 28,351 genes were differentially expressed (false discovery rate <0.05) between the exposure groups. Key genes regulating the immune system, such as tumor necrosis factor alpha and interferon gamma, as well as genes related to the NF-kappa-beta complex, were significantly downregulated in the high-arsenic group. Arsenic exposure was associated with genome-wide DNA methylation; the high-arsenic group had 3% points higher genome-wide full methylation (>80% methylation) than the lower-arsenic group. Differentially methylated regions that were hyper-methylated in the high-arsenic group showed enrichment for immune-related gene ontologies that constitute the basic functions of CD4-positive T cells, such as isotype switching and lymphocyte activation and differentiation. In conclusion, chronic arsenic exposure from drinking water was related to changes in the transcriptome and methylome of CD4-positive T cells, both genome wide and in specific genes, supporting the hypothesis that arsenic causes immunotoxicity by interfering with gene expression and regulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1879-4) contains supplementary material, which is available to authorized users.

Current status of development of methylation biomarkers for in vitro diagnostic IVD applications

“…For example, inorganic arsenic (iAs) is a relatively well-studded environmental pollutant present in water and certain food in specific geological regions and exposure to arsenic is a risk factor for different types of cancers as well as cardiovascular and lung diseases [27]. We have shown that exposure to this pollutant induced methylation changes in CD4 + cells that can potentially affect the immune system [28]. Others showed significant associations between genespecific methylation changes in the DNA from blood cells and arsenic exposure [29].…”

Prenatal arsenic exposure is associated with increased plasma IGFBP3 concentrations in 9-year-old children partly via changes in DNA methylation

“…DNA methylation has a high plasticity in utero, making embryogenesis a particularly susceptible window for epigenetic alterations that can alter disease susceptibility later in life (Hochberg et al 2011). In general, the correlation between DNA methylation and gene expression of nearby genes in studies focused on As was reported to be low (Boellmann et al 2010; Engstrom et al 2017; Rojas et al 2015). However, changes in DNA methylation could have a permissive role in regulating gene expression by, e.g.…”

Arsenic exposure impels CD4 commitment in thymus and suppress T cell cytokine secretion by increasing regulatory T cells

“…However, low CD4 + population in splenic lymphocytes was reported following 30 days exposure of 1 ppm arsenic to male CD57BL6N mice 21 . Therefore, the differential response of CD4 + cells may be due to either dose difference or species specificity 21 , 35 , 36 .…”