Extracellular vesicle microRNAs as an epigenetic biosignature of arsenic-associated diabetes in the Strong Heart Study.

The burden of type 2 diabetes mellitus (T2D) is disproportionately higher among American Indian (AI) communities. Arsenic, a ubiquitous water contaminant, is linked to T2D and is common in water sources across AI tribal lands in the Southwest and Great Plains. Extracellular vesicles (EVs) and their microRNA cargo (EV-miRNAs) facilitate intercellular communication and may play a role in arsenic-related T2D pathogenesis through immune dysregulation. This study leveraged data from the Strong Heart Study (SHS) to investigate associations between arsenic exposure and metabolism, EV-miRNA abundance, and T2D-related phenotypes. A total of 719 participants with complete biomarker, demographic, clinical, and urinary arsenic data were included. Generalized estimating equations, accounting for study site-specific differences in arsenic exposure, were used to identify associations with EV-miRNA abundance, adjusting for age, sex, body mass index, smoking status, estimated glomerular filtration rate, education, alcohol consumption, and the first five genetic principal components that capture major genetic variation. Multiple comparisons were corrected using the Bonferroni method. Of the 182 highly abundant EV-miRNAs (≥70 % detection), 38 were significantly associated with total urinary arsenic concentrations (sum of inorganic and methylated arsenic species) (pBonf<0.05), many overlapping with arsenic metabolism species. Forty EV-miRNAs were associated with at least two T2D-related phenotypes (pBonf<0.05), including 18 overlapping with arsenic exposure and metabolism. Analysis of the EV-miRNA cargo associated with arsenic exposure and T2D risk revealed a profound convergence of targets on pathways encompassing cancer, tissue proliferation, and the immune-metabolic axis, providing a novel hypothesis that arsenic may drive T2D progression via a systemic, shared chronic disease mechanism. These findings suggest EV-miRNAs may influence arsenic exposure and metabolism effects on metabolic dysfunction, offering insight into pathways by which environmental inequities contribute to T2D disparities.