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

• Authors: Anne K. Bozack, Columbia University; Arce Domingo-Relloso, Columbia University; Karin Haack, Texas Biomedical Research Institute; Mary V. Gamble, Columbia University; Maria Tellez-Plaza, Carlos III Health Institute; Jason G. Umans, MedStar Health Research Institute; Lyle G. Best, MedStar Health Research Institute; Joseph Yracheta, MedStar Health Research Institute; Matthew Gribble, Emory University; Andres Cardenas, University of California Berkeley; Kevin A. Francesconi, University of Graz; Walter Goessler, University of Graz; Wan-Yee Tang, Johns Hopkins University; M. Daniele Fallin, Johns Hopkins University; Shelley A. Cole, Texas Biomedical Research Institute; Ana Navas-Acien, Columbia University
• Journal Title: ENVIRONMENTAL HEALTH PERSPECTIVES
• Volume: Volume 128, Number 6
• Publisher: US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE | 2020-06-01, Pages 1-12
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1289/EHP6263
• Subjects: Health Sciences, Toxicology; Health Sciences, Obstetrics and Gynecology; Health Sciences, Public Health
• Keywords: Science & Technology; Life Sciences & Biomedicine; Environmental Sciences; Public, Environmental & Occupational Health; Toxicology; Environmental Sciences & Ecology; UMBILICAL-CORD BLOOD; CARDIOVASCULAR-DISEASE; AMERICAN-INDIANS; DOSE-RESPONSE; EARLY-LIFE; GLUTATHIONE; PACKAGE; POPULATION; EXPRESSION; PLACENTA

Abstract

BACKGROUND: 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. OBJECTIVES: We investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, mean ð±SDÞ lg=g creatinine: 11.7 (10.6)]. METHODS: DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially 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 filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species. RESULTS: 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 (pBonferroni <0:05), located in SLC7A11, ANKS3, LINGO3, CSNK1D, ADAMTSL4. We identified one DMR on chromosome 11 (chr11:2,322,050-2,323,247), annotated to C11orf2; TSPAN32 genes. DISCUSSION: This is one of the first epigenome-wide association studies to investigate As exposure and locus-specific 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.