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

Engström, Karin LU ; Wojdacz, Tomasz K. LU ; Marabita, Francesco; Ewels, Philip; Käller, Max; Vezzi, Francesco; Prezza, Nicola; Gruselius, Joel; Vahter, Marie and Broberg, Karin LU (2017) In Archives of Toxicology 91(5). p.2067-2078
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Arsenic, CD4 cells, Immune system, Immunotoxic, Methylomics, Transcriptomics
in
Archives of Toxicology
volume
91
issue
5
pages
2067 - 2078
publisher
Springer
external identifiers
  • scopus:84994742990
  • wos:000399875300003
ISSN
0340-5761
DOI
10.1007/s00204-016-1879-4
language
English
LU publication?
yes
id
4e909f07-1fd0-4ba4-bb2a-770dbc916cd6
date added to LUP
2016-11-28 12:32:30
date last changed
2018-01-07 11:37:20
@article{4e909f07-1fd0-4ba4-bb2a-770dbc916cd6,
  abstract     = {<p>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 &lt;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 (&gt;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.</p>},
  author       = {Engström, Karin and Wojdacz, Tomasz K. and Marabita, Francesco and Ewels, Philip and Käller, Max and Vezzi, Francesco and Prezza, Nicola and Gruselius, Joel and Vahter, Marie and Broberg, Karin},
  issn         = {0340-5761},
  keyword      = {Arsenic,CD4 cells,Immune system,Immunotoxic,Methylomics,Transcriptomics},
  language     = {eng},
  number       = {5},
  pages        = {2067--2078},
  publisher    = {Springer},
  series       = {Archives of Toxicology},
  title        = {Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women},
  url          = {http://dx.doi.org/10.1007/s00204-016-1879-4},
  volume       = {91},
  year         = {2017},
}