There
is strong epidemiologic evidence linking chronic exposure
to inorganic arsenic (iAs) to myriad adverse health effects, including
cancer of the bladder. We set out to identify DNA methylation patterns
associated with arsenic and its metabolites in exfoliated urothelial
cells (EUCs) that originate primarily from the urinary bladder, one
of the targets of arsenic-induced carcinogenesis. Genome-wide, gene-specific
promoter DNA methylation levels were assessed in EUCs from 46 residents
of Chihuahua, Mexico, and the relationship was examined between promoter
methylation profiles and the intracellular concentrations of total
arsenic and arsenic species. A set of 49 differentially methylated
genes was identified with increased promoter methylation associated
with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their
roles in metabolic disease and cancer. Notably, no genes had differential
methylation associated with EUC dimethylated As (DMAs), suggesting
that DMAs may influence DNA methylation-mediated urothelial cell responses
to a lesser extent than iAs or MMAs. Further analysis showed that
22 of the 49 arsenic-associated genes (45%) are also differentially
methylated in bladder cancer tissue identified using The Cancer Genome
Atlas repository. Both the arsenic- and cancer-associated genes are
enriched for the binding sites of common transcription factors known
to play roles in carcinogenesis, demonstrating a novel potential mechanistic
link between iAs exposure and bladder cancer