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。低社会经济地位已经是疾病和行为功能障碍的危险因素，包括儿童的学习障碍，这种影响被认为是由于低社会经济地位人群的环境压力更大以及相关的长期皮质醇升高。即使是社会经济地位较高的人群也会经历慢性生活压力。铅和压力都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，如果是这样，它如何改变我们对铅神经毒性机制和相关的人类健康风险的理解？我们目前的研究表明，从断奶前或断奶后的铅和永久升高的皮质酮水平后，母体铅的后代铅/压力的相互作用。这个应用程序检查的假设，铅和压力相互作用，改变皮质酮，然后调节MES功能和相关的行为和神经化学的铅的影响。使用断奶前或连续铅与母亲的压力或母亲加后代的压力，拟议的实验将研究铅暴露水平，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个基线与表现出铅的敏感性和介导的MES系统（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相关变化的时程曲线与行为相关。皮质类固醇拮抗剂和母体肾上腺切除术将用于提供皮质酮在铅或铅+应激效应中的作用的机制理解。还将评价脑铅变化作为潜在机制。铅+压力的相互作用提出的问题，我们目前的理解铅神经毒性的机制和目前的风险评估的充分性。如果铅改变皮质酮和应激反应，它也可以调节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.