DEVELOPMENTAL NEUROTOXICOLOGY OF PERINATAL EXPOSURE TO HALOGENATED AROMATICS

围产期接触卤代芳烃的发育神经毒理学

• 批准号: 3840814
• 负责人: RICHARD F SEEGAL
• 金额: --
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3840814
• 关键词: chemical structure function; developmental neurobiology; dioxins; dopamine; embryo /fetus toxicology; environmental contamination; environmental toxicology; enzyme induction /repression; gas chromatography; halobiphenyl /halotriphenyl compound; high performance liquid chromatography; human milk; human tissue; industrial waste; laboratory rat; mass spectrometry; microdialysis; neurochemistry; neurotransmitter metabolism; perinatal; polychlorodibenzofuran; toxicant interaction; ultraviolet spectrometry; urinalysis; waste disposal

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.

暴露于环境毒物几乎总是复杂的混合物。 为了确定这些药物的风险和作用机制， 改变人类健康，有必要了解 有毒物质。 我们建议确定围产期暴露的影响 多氯联苯、二苯并呋喃和二恶英以及这些物质对 大鼠的神经化学发育。 所有这些有毒物质 在纽约州马塞纳的土壤和野生动物中浓度较高， 母乳中的微量元素 大鼠围产期暴露 邻位取代的多氯联苯同系物或非邻位取代的二恶英类 同系物对脑多巴胺功能产生不同的影响。 我们 假设这些药物改变细胞的生化机制， 发育中的神经系统各不相同， 卤代芳烃会改变神经反应 暴露于单独的药剂后观察到的。 我们将揭露怀孕 （1）在大鼠体内发现的个别多氯联苯同系物和同系物混合物 （2）2，3，7，8-二苯并呋喃和二恶英; 邻位取代和非邻位取代的多氯联苯同系物和二恶英， 并确定这些操作对大脑的影响 多巴胺浓度 我们将通过HPLC测量脑儿茶酚胺， 电化学检测，脑多氯联苯和二苯并呋喃和二恶英的气体- 色谱和高分辨率质谱，以及大脑和肝脏 AHH活性（UV光谱法）。 使用体内微透析程序， 将确定这些药物影响机体的生化机制， 神经递质多巴胺的合成、催化、释放和摄取 受卤代芳烃影响最大。 来自这些实验的数据将确定神经毒性。 在Akwesasne超级基金现场发现的卤代芳烃， 同时暴露于这些物质后发生的相互作用 代理商，负责改变大脑的生化机制， 多巴胺含量及神经化学变化与AHH的关系 诱导 这一信息将有助于对风险作出更现实的估计 卤代芳香化合物的复杂环境混合物 碳氢化合物，并提供见解的生化机制负责 在接触多氯联苯的婴儿中观察到的神经功能障碍， 雅各布森和罗根，我们建议可能发生在马塞纳超级基金 绝佳的价钱