Lead and Vascular Reactivity to Acute Stress in Children

描述(申请人提供)：Gump，B.B.(Pi)许多研究发现，铅暴露的增加与人类心血管疾病(CVD；例如高血压)的增加有关。解释这种联系的机制仍不清楚。许多研究认为，心血管对急性应激的反应性(CVR)增加是动脉粥样硬化发生的潜在机制。研究表明，CVR升高可预测儿童基础血压升高和左心室重量增加，也可预测成人未来高血压和颈动脉粥样硬化。我们考虑了铅是否可能通过CVR的变化影响血压和心血管疾病。例如，对动物的研究表明，铅导致血管阻力增加。我们最近证明，儿童早期铅水平较高的9岁半儿童与对急性应激的总外周(血管)阻力(TPR)反应较大相关(Gump等人，2005年)。这些影响对于被认为较低的铅水平是显著的，尤其是低于疾控中心目前采用的有害影响的10？g/dL门槛。我们在一项小型先导性研究(N=40)中复制了这种效应，并在血铅水平低于3.76g/dL的情况下进行了研究。铅和血管反应性之间的联系机制尚不清楚，然而，它被认为涉及许多调节血管收缩和血管扩张的系统，包括激肽释放酶-激动素系统(KKS)、氧化应激、肾素-血管紧张素系统(RAS)、交感肾上腺-髓质(SAM)系统和下丘脑-垂体-肾上腺(HPA)系统。这些潜在的介质还没有在儿童血铅水平和对急性应激的血管反应增强之间的关联的背景下进行研究。除了这个机制问题，铅和血管反应性之间的关联的一些效应修饰剂可能起作用。例如，我们最近观察到，在预测儿童的血管反应性方面，社会经济地位和血铅之间存在显著的交互作用[19]。我们观察到，对于SES相对较高的儿童，血铅水平与血压和血管反应性的相关性最强。因此，当前研究应用的目标是：(A)确认儿童中铅-TPR的反应性关联，(B)使用靶向分析方法和更具探索性的蛋白质组学方法，考虑这一重要关联的潜在机制，以及(C)将SES视为这种关联的效果修饰物。心血管疾病(CVD)仍然是美国主要的死亡原因，每年使1000万美国人致残。血铅可增加儿童心血管危险因素，从而促进心脑血管疾病的发生。铅对心血管危险因素的这些影响可能发生在非常低的水平，远远低于疾控中心目前采用的铅有害影响的阈值。

DESCRIPTION (provided by applicant): 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 ¿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 ¿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.