NEUROBEHAVIORAL EFFECTS OF EXPOSURE TO A SUPERFUND SITE

位于纽约马塞纳的超级基金场地含有高浓度的 多氯联苯（PCBs），已知会导致严重的 动物和人类的神经行为缺陷。 的机制 多氯联苯的神经行为影响尚不清楚，但以前的工作已经导致 邻位取代的多氯联苯具有选择性作用的假设， 大脑，导致神经递质多巴胺的耗尽。 我们 建议1）确定：（a）神经系统中多氯联苯的同系物分布情况 从超级基金网站收集的几类动物的系统; (b)确定大脑中的多巴胺水平是否降低;以及（c） 确定暴露对几个简单反射的影响。 2)继续 使用海洋软体动物，Aaplasia，以实验验证假设 只有邻位取代的多氯联苯会导致大脑多巴胺的丢失 （3）评价脑萎缩的相对贡献 多巴胺相比，非特异性相互作用的多氯联苯与膜 脂质作为神经行为变化的基础， 在这种无脊椎动物以及高等哺乳动物和人类中观察到。 在很多方面都非常适合这项研究。 将厌食症暴露于广泛的 68种PCBs的光谱混合物导致翻正反射延迟（RRR）， 多巴胺水平降低（DLR），优先生物富集6 神经系统中的邻位取代同系物。 暴露于单一 亲神经同系物，2，4，4 '三氯联苯，模仿神经行为 混合物的影响。 关键神经元和神经回路介导 RRR和多巴胺神经元可在失智症中识别。 他们会暴露的 不同剂量的单个或多组亲神经性邻位多氯联苯， neurophilic ortho-PCBs，non-ortho coplanar PCBs，and extracts from 超级基金网站，以确定：1）相对贡献 每种同系物类型或组对RRR和DLR的影响; 2）剂量/效应， 产生RRR和DLR的同系物的结构/活性关系;以及3） 暴露于超级基金提取物的神经行为影响 绝佳的价钱 非平面和平面PCB的影响也将在 神经元水平。 膜生物物理性质的变化，离子 电导，电流-电压关系，轴突传导速度， 对神经递质的反应和突触传递将被确定 在体内暴露的可识别的同源反射和多巴胺神经元中， 在体外对非平面和平面PCB的影响。 综合起来，这些结果将 阐明多氯联苯对基本过程的作用机制， 神经系统的信号和整合能力， 验证这些机制对其他动物的适用性，包括 与超级基金网站有关的人

The superfund site at Massena, New York, contains high concentrations of polychlorinated biphenyls (PCBs) which are known to cause serious neurobehavioral deficits in animals and humans. The mechanisms of neurobehavioral effects of PCBs are not known, but previous work has led to the hypothesis that ortho-substituted PCBs have selective action on the brain, resulting in a depletion of the neurotransmitter, dopamine. We propose 1) to determine: (a) the congener profile of PCBs in the nervous systems of several classes of animals collected from the superfund site; (b) determine if dopamine levels are reduced in the brain; and (c) determine the effects of exposure on several simple reflexes. 2) continue use of the marine mollusc, Aplysia, to experimentally test the hypothesis that only ortho-substituted PCBs contribute to the loss of brain dopamine and 3) evaluate the relative contribution of the reduction of brain dopamine as compared to non-specific interactions of PCBs with membrane lipids as the basis for the neurobehavioral changes which have been observed in this invertebrate as well as higher mammals and man. Aplysia is ideal for this study in many regards. Exposure of Aplysia to a broad spectrum mixture of 68 PCBs results in righting reflex retardation (RRR), dopamine level reduction (DLR), and preferential bioconcentration of 6 ortho-substituted congeners in the nervous system. Exposure to a single neurophilic congener, 2,4,4' trichlorobiphenyl, mimics the neurobehavioral effects of the mixture. The critical neurons and neural circuits mediating RRR and dopamine neurons are identifiable in Aplysia. They will be exposed to graded doses of individual or groups of neurophilic ortho PCBs, non- neurophilic ortho-PCBs, non-ortho coplanar PCBs, and extracts from the superfund site in order to determine: 1) the relative contributions of each congener type or group to RRR and DLR; 2) the dose/effect and structure/activity relationships of congeners producing RRR and DLR; and 3) the neurobehavioral effects of exposure to extracts from the superfund site. Effects of non-planar and planar PCBs will also be compared at the neuronal level. Changes in membrane biophysical properties, ionic conductances, current-voltage relationships, axonal conduction velocity, response to neurotransmitters, and synaptic transmission will be determined in identifiable homologous reflex and dopamine neurons exposed in vivo and in vitro to non-planar and planar PCBs. Taken together, these results will elucidate the mechanism of PCB action on fundamental processes underlying signalling and integrative capacities of the nervous system in Aplysia and validate the applicability of these mechanisms to other animals, including those associated with the superfund site.