PROJECT SUMMARY/ABSTRACT Chronic exposure of the general population to low-doses of toxic metals, including lead, cadmium, and manganese, from contaminated food and drinking water is widespread in the United States, with African Americans being more exposed than their white counterparts. This racial disparity in exposure may contribute to the unequal burden of disease experienced by African Americans, including the development of uterine fibroids. These smooth muscle uterine tumors develop in more than 80% of African American women by age 50 and are associated with substantial morbidity. Few risk factors for this disease have been identified that are amenable to intervention, motivating the need to investigate the role of environmental factors. In addition, given the difficulty in avoiding exposure to toxic metals that are ubiquitous in the environment, understanding behavioral and biologic factors, including diet and iron stores, involved in the body's uptake of these chemicals is critical for prevention. However, few human studies have been conducted on these factors that may influence the uptake and absorption of toxic metals, particularly among reproductive-age women, the majority of whom have inadequate dietary intakes of iron, zinc, and calcium, and for whom menstrual blood loss is a major contributor to iron deficiency. In addition, prior human studies of metals and uterine fibroids have yielded contradictory results, likely due to the limitations of the study designs employed. The central hypotheses in this proposal are that 1) common deficiencies in the dietary intake of iron, calcium, and zinc as well as the depletion of iron stores from heavy menstrual bleeding, increase the body's uptake of lead, cadmium and manganese in women, and 2) these toxic metals increase uterine fibroid risk given the mutagenic and hormonal actions exhibited in vivo and in vitro. To test these hypotheses, the proposed research will build on an established cohort of nearly 1,700 young, African American women using data and archived biosamples from the Study of Environment, Lifestyle & Fibroids (SELF), a 5-year prospective study of fibroids funded by the National Institute of Environmental Health Sciences (ZIAES049013, D. Baird, Principal Investigator). Archived whole blood samples from enrollment will be analyzed for lead, cadmium, and manganese and stored serum samples will be measured for biomarkers of body iron stores, ferritin and transferrin receptor. These biomarker data will be linked to questionnaire data on dietary intake and heavy menstrual bleeding as well as to ultrasound data on fibroids collected every 20 months over 5 years to accomplish the following aims: 1) to determine the extent to which deficiencies in dietary intake of essential nutrients iron, calcium, and zinc are associated with altered blood concentrations of lead, cadmium, and manganese; 2) to determine the associations between low body iron stores, heavy menstrual bleeding, and lead,...