Environmentally Induced Alterations In Neuron And Glia Development and Aging

发育中的神经系统对环境因素的易感性一直是儿童健康问题的一个主要关切。大脑中各种细胞类型的形成和相互作用是关键的定时事件。这种脆弱性窗口被认为是发育中的生物体对环境侮辱的不同易感性的主要组成部分。该项目研究了神经系统发育过程中化学诱导的扰动，这是由发育中的大脑形态和分子谱的各种改变以及青少年和衰老动物相关的神经行为结果所表明的。我们已经报道了在出生后发育期间低水平的铅暴露会改变细胞凋亡和修剪的正常发育过程。在研究非人类灵长类动物早期发育铅暴露的长期影响时，我们已经证明了铅暴露与海马中淀粉样斑块形成增加与衰老之间的联系。另外的研究还检查了发育期间接触汞的影响。这些研究是基于自闭症患者免疫功能改变和大脑免疫细胞（小胶质细胞）变化的报告。为了研究作为免疫系统改变的功能，发育中的大脑可能增加的脆弱性，我们进行了一项广泛的研究，以重复和扩展先前的工作，表明乙基汞（作为硫柳汞作为儿童疫苗接种模型）在自身免疫性易感性SJL小鼠中具有不同的作用。使用定向的特定行为任务来模拟自闭症，如除了运动表现之外的社会行为、免疫组织化学、无偏体视学和汞的靶器官化学分析，我们没有发现发育暴露于乙基汞或儿童疫苗的不良影响。我们与毒理学行动处合作，制定了一项测试方案，以检查环境化学品的神经发育毒性，该方案可用于评估与发育神经毒性有关的化合物。除了在发育过程中发生的变化外，该项目还将开发一种方法来评估早期接触环境化学物质对老年大脑的潜在影响或影响。在这些研究中，我们继续使用多种方法来检查暴露于环境因子后发育中的神经系统的变化，包括免疫组织化学，检测mRNA水平的分子技术，以及评估神经行为功能。

The susceptibility of the developing nervous system to environmental agents has been a major concern with regard to children's health issues. The formation and interactions between the various cell types in the brain are critically timed events. Such windows of vulnerability is assummed to be a major component in the differential susceptibility of the developing organism to environmental insult. This project examines chemical induced perturbations during development of the nervous system as indicated by various alterations in the morphology and molecular profile in the developing brain and assoicated neurobehavioral outcome in adolescent and aging animals. We have reported that low-level lead exposure during post-natal development alters the normal developmental process of apoptosis and pruning. In examining the long term effect of early developmental lead exposure in the non-human primate, we have demonstrated an association between lead exposure and the increase in amyloid plaque formation in the hippocampus with aging. Additional studies have examined the effects of mercury exposure during development. These studies were based upon reports of altered immune functioning and changes in the brain immune cell, the microglia, in autistic patients. In examining a possible increased vulnerability of the developing brain as a function of an altered immune system, we have conducted an extensive study to replicate and expand previous work suggesting a differential effect of ethyl mercury (administered as thimerosal as a model of childhood vaccination) in the autoimmune prone SJL mice. Using targeted specific behavioral tasks modeling autism such as social behavior in addition to motor performance, immunohistochemistry, unbiased stereology, and target organ chemical analysis for mercury, we did not identify adverse effects of developmental exposure to ethyl mercury or childhood vaccines. Working with the Toxicology Operations Branch, we have establishing a testing protocol to examine the neurodevelopmental toxicities of environmental chemicals that can be employed in an applied manner to evaluate compounds of concern for developmental neurotoxicity. In addition to changes occurring during development, this project will also develop an approach to evaluate latent effects or effects on the aged brain as the result of early developmental exposure to environmental chemicals. For these studies we continue to use a number of methods to examine alterations in the developing nervous system following exposure to environmental agents including immunohistochemistry, molecular techniques to examine mRNA levels, as well as assessment of neurobehavioral functioning.