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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Karin Engström
  • Tomasz K. Wojdacz
  • Francesco Marabita
  • Philip Ewels
  • Max Käller
  • Francesco Vezzi
  • Nicola Prezza
  • Joel Gruselius
  • Marie Vahter
  • Karin Broberg
Enheter & grupper
Externa organisationer
  • Karolinska Institute
  • Aarhus University
  • KTH Royal Institute of Technology
  • Stockholms universitet
  • Karolinska University Hospital
  • University of Udine
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Farmakologi och toxikologi

Nyckelord

Originalspråkengelska
Sidor (från-till)2067-2078
TidskriftArchives of Toxicology
Volym91
Utgivningsnummer5
Tidigt onlinedatum2016 nov 12
StatusPublished - 2017
PublikationskategoriForskning
Peer review utfördJa