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Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
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Number of Authors: 10
2017 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, no 5, 2067-2078 p.Article in journal (Refereed) Published
Abstract [en]

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 mu g/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.

Place, publisher, year, edition, pages
2017. Vol. 91, no 5, 2067-2078 p.
Keyword [en]
Arsenic, Transcriptomics, Methylomics, CD4 cells, Immune system, Immunotoxic
National Category
Pharmacology and Toxicology Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-143389DOI: 10.1007/s00204-016-1879-4ISI: 000399875300003PubMedID: 27838757OAI: oai:DiVA.org:su-143389DiVA: diva2:1104659
Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2017-06-01Bibliographically approved

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Ewels, PhilipVezzi, Francesco
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