Environmentally Induced Alterations In Neuron And Glia D

发育中的神经系统对环境因子的敏感性一直是儿童健康问题的主要关注点。虽然目前暴露于环境因子的水平并不代表急性损伤，但神经系统的破坏可能与神经网络形成和/或神经系统功能的结构改变有关。该项目的目标是开发和验证测试方法，使我们能够评估发育过程中各种类型的化学诱导的大脑扰动。大脑中各种细胞类型的形成和相互作用是关键的时间事件。这种脆弱性窗口被认为是发育中的生物体对环境伤害的不同敏感性的主要组成部分。该项目研究了神经发育过程中化学诱导的扰动，如与发育不同过程相关的各种发育调节蛋白质的mRNA时空表达的改变，化合物向神经系统的分布，以及这种暴露的神经行为结果。正在研究的具体项目包括：1）肌肉注射各种汞制剂后，汞在幼龄动物大脑中的分布。2)早期暴露于促炎细胞因子IL-6后神经行为功能的改变作为母体感染和早产的模型。3)妊娠期和出生后发育期间暴露于干扰甲状腺激素稳态维持的化合物后脑中神经元过程的改变。关于肌肉注射甲基汞、乙基汞、硫柳汞后汞向大脑的释放，与口服甲基汞相比，两种接触途径的分布模式截然不同，表明金属在肌肉中被隔离，导致大脑中的汞水平最低。通过将超IL 6直接递送至皮质层而产生的幼年小鼠脑中的神经炎症导致神经行为功能的细微改变，其特征在于对环境刺激的高反应性以及在成年动物中持续的学习和表现的相对稳定性。无论是六氯苯或多氯联苯引起的妊娠和哺乳期间的甲状腺激素水平的变化产生不同的模式中断小脑神经元的高尔基染色的神经元过程所证明的。对于多氯联苯，这种破坏模式是短暂的，可能与活跃的发展时期有关。已知早期发育暴露于无机铅会改变大脑发育。基于我们以前的研究，检查特定的神经元和神经胶质细胞标记物低水平铅暴露后，我们开始了一项研究，以更广泛的方式检查多个神经系统特异性基因的发育个体发生使用DNA阵列技术。这些研究的一个具体的发现是一个特定的氯丛基因的发育模式的转变，表明氯丛的早期成熟作为一种保护机制，对重金属暴露，然而，这种早期成熟的后果还有待研究。在这些研究中，我们使用了许多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，以及神经行为功能的评估。

The susceptibility of the developing nervous system to environmental agents has been a major concern with regard to children's health issues. While current exposure levels to environmental agents does not represent an acute injury, disruption to the nervous system may be associated with either a structural alteration in the formation of the neural network and/or in nervous system functioning. It is the goal of this project to develop and validate test methods that will allow us to assess various types of chemical-induced perturbations of the brain during development. 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 nevous as indicated by alterations in the spatio-temporal expression of mRNA for various developmentally regulated proteins associated with distinct processes of development, distribution of compounds to the nervous system, and the neurobehavioral outcome of such exposure. The specific projects under study include 1) distribution of mercury to the brain of young animals following the intramuscular injection of various mercuricals. 2) alterations in the neurobehavioral functioning following early exposure to the pro-inflammatory cytokine IL-6 as a model of maternal infection and premature delivery. 3) Alterations in neuronal processes in the brain following exposure to compounds that perturb homeostatic maintenance of thyroid hormone during gestational and postnatal development. With regard to delivery of mercury to the brain following an intramuscular injection of either methyl mercury, ethyl mercury, thimerosal, as compared to an oral administration of methyl mercury demonstrated a distribution pattern distinct between the two routes of exposure suggesting a sequestration of the metal within the muscle resulting a minimal level within the brain. Neuroinflammation in the young mouse brain as generated by a direct delivery of hyper-IL6 to the cortical layer resulted in subtle alterations in neurobehavioral functioning characterized by a hyper-reactivity to environmental stimuli and a relatively inflexibility in learning and performance that continued in the adult animal. Alterations in thyroid hormone levels during gestation and lactation induced by either hexachlorobenzene or PCBs produced distinct patterns of disruption in cerebellar neurons as demonstrated by Golgi staining of neuronal processes. For PCBs this pattern of disruption was transient and may be linked to the period of active development. Early developmental exposure to inorganic lead is known to alter brain development. Based upon our previous studies examining specific neuronal and glia markers following low level lead exposure we initiated a study to examine in a more broad manner the developmental ontogeny of multiple nervous system specific genes using DNA array techniques. One specific finding of these studies was the shift in the developmental pattern for a specific chlorid plexus gene suggesting an early maturation of the chlorid plexus as a protective mechanism against a heavy metal exposure however, the consequences to such an early maturation is yet to be studied. For these studies we have used 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.