PB-Environmental Stress Interactions: Re-evaluating Risk

描述（由申请人提供）：在美国，低社会经济地位（SES）的儿童现在是高铅（Pb）暴露的主要目标。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，以及相关的皮质醇升高时间更长。即使社会地位较高的人群也会经历长期的生活压力。铅和应激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，铅和应激是否相互作用，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，断奶前或断奶后的铅与应激相互作用，以及母亲单独使用铅后后代皮质酮水平的永久性升高。本应用检验了铅和应激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。本实验采用断奶前或连续受铅的母鼠应激或母鼠加子鼠应激，利用已证实的铅敏感性和MES系统（固定间隔、重复学习）介导的2条基线，研究铅暴露水平、应激和性别如何影响铅-应激相互作用对行为功能的表达和性质。神经化学功能、皮质酮结合和血浆皮质酮相关变化的时间过程将与行为相关。皮质类固醇拮抗剂和母亲肾上腺切除术将用于提供皮质酮在铅或铅+应激效应中的作用的机制理解。脑铅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和当前风险评估的充分性提出了问题。如果铅改变皮质酮和应激反应，它也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.