title: 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.
authors.affiliation: Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, 221 85, Lund, Sweden.|Unit of Metals and Health, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Engström
authors.affiliation: Unit of Metals and Health, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77, Stockholm, Sweden. wojdacz@biomed.au.dk.|Aarhus Institute of Advanced Studies, Aarhus University, 8000, Aarhus C, Denmark. wojdacz@biomed.au.dk.
authors.forename: Tomasz K
authors.initials: TK
authors.lastname: Wojdacz
authors.affiliation: Unit of Computational Medicine, Center for Molecular Medicine, Karolinska University Hospital, L805, 171 76, Stockholm, Sweden.|Bioinformatics Infrastructure for Life Sciences, Karolinska Institutet, 171 65, Solna, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marabita
authors.affiliation: Science for Life Laboratory (SciLifeLab), Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden.
authors.forename: Philip
authors.initials: P
authors.lastname: Ewels
authors.affiliation: Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, 171 65, Solna, Sweden.
authors.forename: Max
authors.initials: M
authors.lastname: Käller
authors.affiliation: Science for Life Laboratory (SciLifeLab), Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vezzi
authors.affiliation: Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, 171 65, Solna, Sweden.
authors.forename: Nicola
authors.initials: N
authors.lastname: Prezza
authors.affiliation: Department of Mathematical and Computer Science, University of Udine, 331 00, Udine, Italy.
authors.forename: Joel
authors.initials: J
authors.lastname: Gruselius
authors.affiliation: Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, 221 85, Lund, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Vahter
authors.affiliation: Unit of Metals and Health, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77, Stockholm, Sweden. karin.broberg@ki.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
mesh_terms: D000328:Adult; D001118:Argentina; D001151:Arsenic / Q000633:toxicity*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: D001151:Arsenic
keywords: Arsenic; CD4 cells; Immune system; Immunotoxic; Methylomics; Transcriptomics