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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Karin Engström
  • Tomasz K. Wojdacz
  • Francesco Marabita
  • Philip Ewels
  • Max Käller
  • Francesco Vezzi
  • Nicola Prezza
  • Joel Gruselius
  • Marie Vahter
  • Karin Broberg
Organisations
External organisations
  • Karolinska Institutet
  • Aarhus University
  • KTH Royal Institute of Technology
  • Stockholm University
  • Karolinska University Hospital
  • University of Udine
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology

Keywords

  • Arsenic, CD4 cells, Immune system, Immunotoxic, Methylomics, Transcriptomics
Original languageEnglish
Pages (from-to)2067-2078
JournalArchives of Toxicology
Volume91
Issue number5
Early online date2016 Nov 12
Publication statusPublished - 2017
Publication categoryResearch
Peer-reviewedYes