title: Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood.
abstract: Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation.
  
  
  
  To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism.
  
  
  
  The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N=80 women) and DNA methylation (N=93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively.
  
  
  
  U-As concentrations, ranging 10-1251μg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes.
  
  
  
  Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap.
authors.affiliation: Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden.
authors.forename: Syeda Shegufta
authors.initials: SS
authors.lastname: Ameer
authors.affiliation: Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden; Institute of Environmental Medicine, Unit of Metals & Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Engström
authors.affiliation: Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden.
authors.forename: Mohammad Bakhtiar
authors.initials: MB
authors.lastname: Hossain
authors.affiliation: Science Department, Risk Benefit Assessment Unit, National Food Agency, Uppsala, Sweden.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Concha
authors.affiliation: Institute of Environmental Medicine, Unit of Metals & Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Vahter
authors.affiliation: Institute of Environmental Medicine, Unit of Metals & Health, Karolinska Institutet, Stockholm, Sweden. Electronic address: Karin.broberg@ki.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
mesh_terms: D000293:Adolescent; D000328:Adult; D001118:Argentina / Q000453:epidemiology; D001151:Arsenic / Q000008:administration & dosage / Q000633:toxicity; D020261:Arsenic Poisoning / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D060766:Drinking Water / Q000009:adverse effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D055815:Young Adult
chemical_list: D060766:Drinking Water; D001151:Arsenic
keywords: Arsenic metabolism efficiency; Cancer; Epigenetic; Genome-wide; Pathway analyses