DEVELOPMENTAL NEUROTOXICOLOGY OF PERINATAL EXPOSURE TO HALOGENATED AROMATICS

接触环境毒物几乎总是接触复杂的混合物。 为了确定风险和这些代理人通过什么机制 要改变人类健康，有必要了解 毒药。我们建议确定围产期暴露的影响 对多氯联苯、二苯并呋喃和二恶英的影响及其相互作用 大鼠的神经化学发育。所有这些毒物都存在 在纽约州马塞纳的土壤和野生动物中存在高浓度的 暴露在阿克韦萨塞纳的妇女的母乳中。围产期暴露对大鼠的影响 邻位取代的多氯联苯同系物或非邻位取代的二恶英类化合物 同系物对大脑多巴胺功能产生不同的影响。我们 假设这些制剂改变的生物化学机制 发育中的神经系统不同，同时暴露在这些环境中 卤代芳烃会改变神经反应 在接触到单独的毒剂后被看到。我们会揭露怀孕的人 老鼠：(1)发现的单个多氯联苯同系物和同系物的混合物 阿克韦森母乳；(2)2，3，7，8-二苯并呋喃和二恶英；(3) 邻位取代和非邻位取代的多氯联苯同系物和二恶英以及 二苯并呋喃，并确定这些手法对大脑的影响 多巴胺浓度。我们将用高效液相色谱法测定脑儿茶酚胺 电化学检测，脑内多氯联苯和二苯并呋喃和二恶英的气体- 层析和高分辨率质谱学，脑和肝脏 紫外光谱分析AHH活性。使用体内微透析程序 将决定这些制剂通过何种生化机制影响 神经递质多巴胺的合成、分解代谢、释放和摄取 受卤代芳香烃影响最大。 这些实验的数据将确定 在Akwesasne Superfund现场发现的卤代芳香烃， 在同时接触到这些物质后发生的相互作用 药物，导致大脑变化的生化机制 多巴胺含量及神经化学变化与AHH的关系 归纳法。这些信息将允许对风险进行更现实的估计 暴露在卤代芳烃的复杂环境混合物中 碳氢化合物，并提供了对生物化学机制的见解 对于暴露于多氯联苯的婴儿的神经功能障碍，通过 雅各布森和罗根，我们认为这可能发生在马塞纳超级基金 地点。

Exposure to environmental toxicants is almost always to complex mixtures. In order to determine the risks and the mechanisms by which these agents alter human health it is necessary to understand the interactions between the toxicants. We propose to determine the effects of perinatal exposure to PCBs, dibenzofurans and dioxins and the interactions of these agents on neurochemical development of the rat. All of these toxicants are present in high concentrations in soil and wildlife at Massena, NY and are present in breast milk from exposed Akwesasne women. Perinatal exposure of the rat to ortho-substituted PCB congeners or to non-ortho-substituted dioxin-like congeners yield differential effects on brain dopamine function. We hypothesize that the biochemical mechanisms by which these agents alter the developing nervous system differ and that simultaneous exposure to these halogenated aromatic hydrocarbons will modify the neurological responses seen following exposure to the individual agents. We will expose pregnant rats to: (1) individual PCB congeners and mixtures of congeners found in Akwesasne breast milk; (2) 2,3,7,8-dibenzofuran and dioxin; (3) mixtures of ortho-substituted and non-ortho-substituted PCB congeners and dioxins and dibenzofurans and determine the effects of these manipulations on brain dopamine concentrations. We will measure brain catecholamines by HPLC with electrochemical detection, brain PCBs and dibenzofurans and dioxins by gas- chromatography and high-resolution mass spectrometry, and brain and liver AHH activity by UV spectrometry. Using in-vivo microdialysis procedures we will determine the biochemical mechanisms by which these agents affect the synthesis, catabolism, release and uptake of dopamine, the neurotransmitter shown to be most affected by exposure to halogenated aromatic hydrocarbons. Data from these experiments will determine the neurotoxicity of the halogenated aromatic hydrocarbons found at the Akwesasne Superfund site, the interactions that occur following simultaneous exposure to these agents, the biochemical mechanisms responsible for the alterations in brain dopamine content and the relationship between neurochemical change and AHH induction. This information will allow a more realistic estimate of risk of exposure to complex environmental mixtures of halogenated aromatic hydrocarbons and provide insights to the biochemical mechanisms responsible for the neurological dysfunctions observed in PCB-exposed infants by Jacobson and Rogan and that we suggest may occur at the Massena Superfund site.