PB-Environmental Stress Interactions: Re-evaluating Risk

描述(申请人提供)：低社会经济地位(SES)的美国儿童现在是铅暴露升高的主要目标。低SES已经是疾病和行为功能障碍的风险因素，包括儿童学习障碍，这种影响被认为是由于低SES人群中更大的环境压力和相关的皮质醇升高延长所致。即使是较高的社会经济地位人群也会经历长期的生活压力。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和相关的人类健康风险机制的理解？我们目前的研究表明，断奶前或断奶后铅与应激之间存在交互作用，母猪单独断奶后，子代皮质酮水平会永久升高。这项应用检验了铅和压力通过改变皮质酮而相互作用的假说，皮质酮随后调节MES功能以及相关的铅的行为和神经化学效应。在断奶前或持续铅加母体应激或母体+子代应激的情况下，本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应激交互作用的表达和性质，使用两个已证明对铅敏感的基线，并通过MES系统(固定间隔、重复学习)进行调节。神经化学功能、皮质酮结合和血浆皮质酮相关变化的时间进程将与行为相关。皮质类固醇拮抗剂和母体肾上腺切除术将用于从机制上了解皮质酮在铅或铅应激效应中的作用。脑铅的改变作为一种潜在的机制也将被评估。铅应激相互作用对我们目前对铅神经毒性机制的理解以及当前风险评估的充分性提出了疑问。如果铅改变了皮质酮和应激反应，它也可能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.