PB-Environmental Stress Interactions: Re-evaluating Risk

描述（由申请人提供）：美国社会经济地位较低 (SES) 的儿童现在是铅 (Pb) 暴露升高的主要目标。低SES已经是疾病和行为功能障碍（包括儿童学习障碍）的危险因素，这种影响被认为是由于低SES人群面临更大的环境压力以及相关的皮质醇长期升高所致。社会经济地位较高的人群也经历着长期的生活压力。铅和压力都会影响大脑中皮质边缘（MES）系统并产生类似的行为缺陷。一个明显的问题是铅和压力是否相互作用，如果是，它如何改变我们对铅神经毒性机制和相关人类健康风险的理解？我们目前的研究表明，断奶前或断奶后铅与铅/应激相互作用，以及母体单独使用铅后后代皮质酮水平永久升高。该应用检验了铅和压力通过改变皮质酮相互作用的假设，皮质酮随后调节 MES 功能以及铅的相关行为和神经化学效应。使用断奶前或连续铅与母体压力或母体加子代压力，拟议的实验将检查铅暴露水平、压力和性别如何影响行为功能的铅-压力相互作用的表达和性质，使用2个已证明铅敏感性的基线并由MES系统介导（固定间隔，重复学习）。神经化学功能、皮质酮结合和血浆皮质酮的相关变化的时间过程曲线将与行为相关。皮质类固醇拮抗剂和母亲肾上腺切除术将用于提供对皮质酮在铅或铅应激效应中的作用的机制理解。脑铅的改变作为一种潜在机制也将被评估。铅应激相互作用对我们目前对铅神经毒性机制的理解和当前风险评估的充分性提出了疑问。如果铅改变皮质酮和应激反应，它还可以调节对疾病和功能障碍的易感性。

DESCRIPTION (provided by applicant): Lower socioeconomic status (SES) children in the U.S. are now the primary target of elevated lead (Pb) exposure. Low SES is already a risk factor for disease and behavioral dysfunctions, including learning disorders in children, an effect believed due to greater environmental stress in low SES populations and associated prolonged cortisol elevation. Even higher SES populations experience chronic life stress. Pb and stress both affect brain mesocorticolimbic (MES) systems and produce similar behavioral deficits. An obvious question is whether Pb and stress interact, and, if so, how does it change our understanding of mechanisms of Pb neurotoxicity and associated human health risks? Our current studies demonstrate Pb/ stress interactions from preweaning or postweaning Pb and permanently elevated corticosterone levels in offspring after maternal Pb alone. This application examines the hypothesis that Pb and stress interact by altering corticosterone which then modulates MES function and associated behavioral and neurochemical effects of Pb. Using preweaning or continuous Pb with maternal stress or maternal plus offspring stress, the proposed experiments will examine how Pb exposure level, stress and gender influence the expression and nature of Pb-stress interactions for behavioral function using 2 baselines with demonstrated Pb sensitivity and mediated by MES systems (Fixed Interval, repeated learning). Time course profiles of associated changes in neurochemical function, corticosterone binding and plasma corticosterone will be related to behavior. Corticosteroid antagonists and maternal adrenalectomy wjll be used to provide a mechanistic understanding of corticosterone's role in Pb or Pb+stress effects. Brain Pb alterations as a potential mechanism will also be evaluated. Pb+stress interactions pose questions about our current understanding of mechanisms of Pb neurotoxicity and of the adequacy of current risk assessment. If Pb alters corticosterone and stress responsiveness, it could also modulate susceptibility to disease and dysfunction.