Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and evidence has suggested that exposure to environmental toxicants can increase CVD risk. Recently, high levels of arsenic (As), a leading environmental contaminant of concern have been associated with increases in CVD incidence, mortality, blood pressure, and systemic inflammation. Arsenic's effects at lower exposure levels are uncertain and studies are limited, but exposure at these low levels may be more widespread than previously thought, as data suggest that both water and dietary sources may contribute to overall As exposure in adults and children. In this study, the candidate proposes to take a life course approach to examining the effects of a wider range of As exposure levels on CVD risk in both adults and children and identify preclinical indicators and biomarkers of susceptibility for CVD. In the K99 mentored phase, using existing data from two adult populations ranging in levels of As exposure, the candidate will explore the relationship between As exposure and biomarkers of CVD risk, while gaining expertise in molecular epidemiology. The candidate will test archived blood and urine samples from a U.S. population to examine the relationship between low level As exposure and markers of systemic inflammation, oxidative stress and endothelial function, which have been related to high levels of As exposure among adults. In a more highly exposed Bangladeshi population, the candidate will analyze a set of potential genetic susceptibility loci in relation to As exposure and their impact on blood pressure measurements over time. She will also advance her knowledge of molecular and cardiovascular disease epidemiology through formal coursework, workshops and guidance from a diverse advisory committee of respected researchers. In the R00 independent phase, she will apply her findings to initiate a new line of investigation testing whether in utero and/or early life As exposure influences early indicators of CVD risk in two populations of children, as pregnancy and early childhood are particularly vulnerable periods when environmental insults may impact development and thus later risk of disease. In conjunction with the Health Effects of Arsenic Longitudinal Study in Bangladesh and the New Hampshire Birth Cohort Study, the candidate will implement two parallel investigations of early indicators of CVD risk among five-year-old children exposed to As. She will test whether non-invasive measures of endothelial function are associated with varying levels of in utero and/or early childhood As exposure in these two populations, as subclinical effects of As on CVD risk may occur far in advance of clinical presentation. Developing insight into the mechanisms underlying As-related CVD and identifying biomarkers of CVD risk across life stages as they relate to As exposure, will help to define the contribution of environmental As exposure to different phases of disease, from initiation to clinical presentation. With this proposed study, the candidate is positioned to take advantage of existing resources to in order to develop independent, yet complementary projects, designed to help to fill critical gaps in our understanding of the lifelong cardiovascular health impacts of a range of As exposures levels. ExpandCollapse Abstract