Lead and Vascular Reactivity to Acute Stress in Children

描述（由申请人提供）：Gump, b.b. （PI）许多研究发现，铅（Pb）暴露的增加与人类心血管疾病（CVD，如高血压）的增加有关。解释这种关联的机制尚不清楚。许多研究认为心血管反应性（CVR）对急性应激的增加是动脉粥样硬化发展的潜在机制。CVR升高可以预测儿童基线血压升高和左心室体积增大，也可以预测成人未来的高血压和颈动脉粥样硬化。我们考虑了铅是否可能通过改变CVR影响血压和CVD。例如，对动物的研究表明，铅会导致血管阻力增加。我们最近证明，儿童早期铅含量较高的9岁半儿童对急性应激的总外周（血管）阻力（TPR）反应更大（Gump等，2005）。当铅含量被认为较低时，特别是低于美国疾病控制与预防中心目前采用的有害影响阈值10克/分升时，这些影响是显著的。我们在一个小规模的试点研究（N = 40）中重复了这一效果，并且血铅水平低于3.76 g/dL。铅与血管反应性之间的关联机制尚不清楚，但据推测可能涉及一些调节血管收缩和舒张的系统，包括钾化钾素-激肽系统（KKS）、氧化应激、肾素-血管紧张素系统（RAS）、交感神经肾上腺-髓质（SAM）系统和下丘脑-垂体-肾上腺（HPA）系统。这些潜在的介质尚未在儿童血铅水平与血管对急性应激反应增强之间的关联的背景下进行研究。除了这个机制问题之外，铅与血管反应性之间的关系可能还存在一些效应调节剂。例如，我们最近观察到社会经济地位和血铅在预测儿童血管反应性方面有显著的相互作用。我们观察到，对于那些相对较高社会经济地位的儿童，血铅水平与血压和血管反应性的关系最为密切。因此，当前研究应用的目标是：(a)确认儿童铅- tpr反应性关联，(b)考虑这种重要关联的潜在机制，使用靶向分析方法和更具探索性的蛋白质组学方法，以及(c)考虑SES作为这种关联的效果调节剂。心血管疾病（CVD）仍然是美国死亡的主要原因，每年有1000万美国人因此致残。血铅（Pb）可能增加儿童心血管危险因素，从而促进心血管疾病的发展。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，远低于疾病预防控制中心目前采用的铅有害影响阈值。

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.