Gump, B. B. (PI) A number of studies have found that increasing lead (Pb) exposure is associated with increases in cardiovascular disease (CVD;e.g., hypertension) in humans. A mechanism to explain this association remains unclear. A number of studies have considered increased cardiovascular reactivity (CVR) to acute stress as a potential mechanism for the development of atherosclerosis. Heightened CVR has been shown to prospectively predict higher baseline blood pressure and increased left ventricular mass in children as well as predict future hypertension and carotid atherosclerosis in adults. We have considered whether lead might affect blood pressure and CVD through changes in CVR. For example, studies with animals have shown lead-induced increases in vascular resistance. We recently demonstrated that 9 1/2 year old children with higher early childhood lead levels were associated with greater total peripheral (vascular) resistance (TPR) responses to acute stress (Gump et al., 2005). These effects were significant for lead levels considered low, notably, below the 10 [unreadable]g/dL threshold currently adopted by the CDC for deleterious effects. We replicated this effect in a small pilot study (N = 40) and at blood lead levels below 3.76 [unreadable]g/dL. The mechanism explaining the association between lead and vascular reactivity is not clear, however, it is presumed to involve a number of systems that regulate vasoconstriction and vasodilation, including the kallikrein-kinin system (KKS), oxidative stress, the renin-angiotensin system (RAS), the sympathoadrenal-medullary (SAM) system, and the hypothalamic-pituitary-adrenal (HPA) system. These potential mediators have not been studied in the context of the association in children between blood lead levels and heightened vascular responses to acute stress. In addition to this question of mechanism, some effect modifiers for the association between lead and vascular reactivity may operate. For example, we recently observed a significant interaction between socioeconomic status and blood lead in the prediction of vascular reactivity in children [19]. We observed that blood lead levels were most strongly associated with blood pressure and vascular reactivity for those children with relatively high SES. The goals in the current research application are therefore to: (a) confirm the lead-TPR reactivity association in children, (b) consider potential mechanisms for this important association, using both a targeted assay approach and a more exploratory proteomics approach, and (c) consider SES as an effect modifier for this association. - Gump, B. B. (PI) Cardiovascular disease (CVD) remains the leading cause of death in the United States and disables 10 million Americans each year. Blood lead (Pb) may increase cardiovascular risk factors in children and thereby contribute to the development CVD. These effects of lead on cardiovascular risk factors may occur at very low levels, levels well below the thresholds currently adopted by the CDC for deleterious effects of lead.