SUMMARY The metabolic syndrome affects a quarter of the global adult population and a third of US adults. Efforts are needed to identify and intervene on preventable risk factors for the metabolic syndrome. Firm evidence supports that metals and metalloids (metals for simplicity) play a role in atherosclerosis and increased risk of CV disease. Evidence also suggests that exposure to metals may contribute to the development and accelerated progression of metabolic syndrome. Studying whether metabolic outcomes are potential mediators of metal-related CV disease during young adulthood is critical as it is a time when prevention interventions can be implemented before overt cardiovascular risk factors such as hypertension, hyperlipidemia and diabetes have fully developed. In this supplement, we will leverage data from the VapeScan Study (parent R01) in young adults 18 to 50 years of age from New York City to examine associations of metal exposure with metabolic profiles and the role of metabolic outcomes in metal-related atherosclerosis. We hypothesize that metal exposures (e.g., cadmium, manganese), including metal mixtures, are associated with higher levels of metabolic markers measured at fasting (aim 1). Subsequently we will evaluate if these metabolic outcomes are associated with coronary artery calcification in young adults (aim 2). In aim 3, we will evaluate if metabolic outcomes influence the association of metals with coronary artery calcification, through mediation or moderation. We will utilize metals measured in urine and blood and metabolic outcomes measured under fasting conditions (glucose, lipids, blood pressure) in adults 18 to 50 years of age who have been recruited as part of the VapeScan Study. We will evaluate metals individually and as a mixture. Priority metals include cadmium (Cd), manganese (Mn), lead (Pb), Selenium (Se) and zinc (Zn) in blood, and the same metals as well as 10 other metals in urine. Metabolic factors are obtained at the baseline visit and two follow-visits over a 1.5 year period. Coronary artery calcification is obtained by cardiac CT at the baseline visit. As the participants are healthy young adults, the metabolic outcomes (glucose, lipids, blood pressure) will be primarily included as continuous. Metals and coronary artery calcification will be log-transformed as they are right-skewed. Models will be adjusted for age, sex, race/ethnicity, vaping status and other relevant variables. This project will provide novel evidence on the role of metals and metal mixtures on metabolic outcomes and the role of metabolic outcomes to influence metal-related atherosclerosis. These data can support early interventions that target modifiable disease factors to prevent metal-related CV risk. By providing advanced skills, training, and research opportunities to an MPH student with focus in Environmental and Molecular Epidemiology, this project will enhance diversity in our research team at Columbia University and down the ...