Causal Molecular Mechanisms Linking Drinking Water Metal Exposures to Cardiometabolic Disease

Project 4 Summary Chronic exposure to metals and metalloids (hereafter metals) is detrimental to human cardiovascular and metabolic health. Native Americans living in the Northern Plains consume well water with elevated levels of arsenic (As) and uranium (U), common Superfund site contaminants. Metal exposures in these populations are epidemiologically linked to high rates of cardiovascular disease and diabetes. However, strategies to prevent or treat the disease burdens related to groundwater metal exposures have been limited by poor understanding of the molecular mechanisms of individual and combined metal exposures. To fill this gap, Project 4 of the Columbia University Northern Plains Superfund Research Program (CUNP-SRP) will establish human-relevant mouse models of chronic metal exposures and cardiometabolic disease to comprehensively evaluate such mechanisms. We will leverage genetically engineered mouse models to investigate developmental vulnerability, tissue and cellular level effects, and specific molecular mediators of exposure–outcome relationships. We will expose mice to environmentally relevant concentrations of As and/or U in addition to well water samples containing a naturally elevated As/U mixture that people in the Northern Plains consume (collected in Project 1). We will then determine the cardiometabolic effects of these exposures, compare early-life to lifelong exposures, and determine how dietary folate mitigates As toxicity. Aim 1 will define health impacts and developmental vulnerability of early-life or lifelong exposure to As/U in drinking water in genetically engineered mice. Mouse cardiometabolic health will be evaluated longitudinally with a battery of clinical, histological, behavioral, and functional tests with a focus on atherosclerosis, hypertension, adiposity and diabetes, in the context of a hyperlipidemic model. Moreover, this aim will generate a biobank of As and/or U exposed animal tissues for future studies, creating an expansive resource for collaborative research projects with other SRP centers. Aim 2 will profile mouse multi-omics biomarkers altered by early-life or lifelong exposure to As/U in drinking water. DNA methylation, gene expression, and the metabolome will be profiled in mouse blood, liver, and pancreas samples collected in Aim 1 to reveal molecular markers of metal exposure and cardiometabolic disease. Molecular signatures in mice will be compared to Project 3 human molecular signatures to identify conserved pathogenic mechanisms as well as the utility of blood biospecimen markers to represent target organ pathologies not typically available in human observational research. Aim 3 will evaluate the human-relevant potential for and mechanisms of dietary folate supplementation to reduce As toxicity. Since laboratory mice rapidly eliminate consumed As via methylation, we will use mice that instead metabolize As similarly to humans. Through these three aims, we will establish a valid animal model system for causal discovery science and to test therapeutic interventions to tackle the extensive and disproportionate disease burden attributable to groundwater metal exposures affecting tribal populations in the Northern Plains.