Locus -Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low -to -Moderate Arsenic Exposure

B ACKGROUND : Chronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes. O BJECTIVES : We investigated the association between total urinary As and locus -speci fi c DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low -to -moderate As exposure [total urinary As, mean ? ?SD ? lg / g creatinine: 11.7 (10.6)]. M ETHODS : DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test di ff erentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular fi ltration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species. R ESULTS : In adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (FDR < 0 . 05). After Bonferroni correction, 5 CpGs remained associated with total urinary As ( p Bonferroni < 0 . 05), located in SLC7A11 , ANKS3 , LINGO3 , CSNK1D , ADAMTSL4 . We identi fi ed one DMR on chromosome 11 (chr11:2,322,050-2,323,247), annotated to C11orf2 ; TSPAN32 genes. D ISCUSSION : This is one of the fi rst epigenome-wide association studies to investigate As exposure and locus -speci fi c DNA methylation using the Illumina MethylationEPIC array and the largest epigenome-wide study of As exposure. The top DMP was located in SLC7A11A , a gene involved in cystine/glutamate transport and the biosynthesis of glutathione, an antioxidant that may protect against As -induced oxidative stress. Additional DMPs were located in genes associated with tumor development and glucose metabolism. Further research is needed, including research in more diverse populations, to investigate whether As -related DNA methylation signatures are associated with gene expression or may serve as biomarkers of disease development. https://doi.org/10.1289/EHP6263