NEUROBEHAVIORAL EFFECTS OF EXPOSURE TO A SUPERFUND SITE

位于纽约马塞纳的超级基金网站包含高度集中的 已知会对人体造成严重危害的多氯联苯 动物和人类的神经行为缺陷。它的作用机制 多氯联苯对神经行为的影响尚不清楚，但之前的研究已经导致 邻位取代多氯联苯对苯系物具有选择性作用的假设 大脑，导致神经递质多巴胺的枯竭。我们 建议1)确定：(A)神经中多氯联苯的同系物分布 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；及。(C) 确定暴露对几种简单反射的影响。2)继续 利用海洋软体动物海兔对这一假说进行实验验证 只有邻位取代的多氯联苯才会导致脑多巴胺的损失 3)评估脑萎缩的相对贡献 多巴胺与多氯联苯与膜的非特异性相互作用的比较 作为神经行为改变的基础的血脂，已经被 在这种无脊椎动物以及高等哺乳动物和人类身上观察到的。海兔属 在许多方面都是这项研究的理想选择。海兔暴露在广泛的环境中 68种多氯联苯的光谱混合物导致翻正反射延迟(RRR)， 降低多巴胺水平(DLR)，优先生物浓缩6 神经系统中的邻位取代的同系物。暴露于单一的 亲神经的同系物，2，4，4‘三氯联苯，模拟神经行为 混合物的影响。关键神经元和神经回路 在海兔中可以识别RRR和多巴胺神经元。他们将会被曝光 对于个人或组的亲神经邻位多氯联苯的分级剂量，非 亲神经性邻位多氯联苯，非邻位共面多氯联苯，以及 超级基金网站，以确定：1)相对贡献的 RRR和DLR的每个同类类型或组；2)剂量/效应和 产生RRR和DLR的同系物的结构/活性关系； 暴露在超级基金提取物中的神经行为影响 地点。非平面和平面印刷电路板的影响也将在 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 体外转化为非平面和平面多氯联苯。总而言之，这些结果将 阐明多氯联苯对基本过程的作用机制 海兔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 那些与超级基金网站相关的信息。

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.