NEUROCHEMICAL/BEHAVIORAL/ENDOCRINE EFFECTS OF DEVELOPMENTAL EXPOSURE TO PBCS

人类在子宫内和哺乳期接触多氯联苯 （多氯联苯）与认知功能障碍有关， 实验动物暴露于多氯联苯会引起神经递质的变化 和认知功能。 因为大多数实验室和流行病学 研究已经调查了发育暴露于 多氯联苯的混合物或复杂的环境样品，有必要， 为了了解多氯联苯改变发展的机制， 中枢神经系统的功能，以研究发育影响 暴露于个别同源物。 我们建议确定 神经化学、神经行为和内分泌影响， 实验大鼠哺乳期暴露于单个共面、双 邻位取代和单邻位取代的多氯联苯同系物， 假设将改变神经化学和第二信使系统， 大脑正常发育所需的关键内分泌系统的发展。 我们将确定：（i）生物胺神经递质浓度， 体外接触这些同系物后的纹状体脑切片;（二） 局部脑生物胺浓度，循环浓度 暴露期间子代体内T3、T4、TSH和循环促性腺激素的变化 妊娠期和哺乳期对这些同系物的反应;（三）神经化学物质， 暴露期间后代的神经行为和内分泌反应 开发药物和体内产生的代谢物 （α-甲基对酪氨酸、NSD-1015、丙基硫氧嘧啶、儿茶酚雌激素 和羟基联苯）和（iv）动物认知功能的变化 接触多氯联苯同系物和上述制剂。 这些实验，使用 一些典型的PCB同系物，将使我们能够确定 同系物直接影响重要神经递质的发育; 哪些同源物通过改变关键基因来间接影响大脑发育 内分泌系统在发展和行为后果 在发育过程中接触这些同系物。 反过来，这些数据将允许 更全面地了解复杂混合物的作用， 同源物，对发育中的人类的风险，并建议药理学和 行为策略，可能会改善一些认知 在发育期暴露的人类婴儿中观察到的功能障碍。

In -utero and lactational exposure of humans to polychlorinated biphenyls (PCBs) is associated with cognitive dysfunctions while developmental exposure of laboratory animals to PCBs induces changes in neurotransmitter and cognitive function. Because most laboratory-based and epidemiological studies have investigated the effects of developmental exposure to either mixtures of PCBs or complex environmental samples, it is necessary, in order to understand the mechanisms by which PCBs alter the development and function of the central nervous system, to study the developmental effects of exposure to individual congeners. We propose to determine the neurochemical, neurobehavioral and endocrine effects of in-utero and lactational exposure of the laboratory rat to individual coplanar, di- ortho-substituted and mono-ortho-substituted PCB congeners that we hypothesize will alter neurochemical and second messenger systems and the development of key endocrine systems needed for normal brain development. We will determine; (i) biogenic amine neurotransmitter concentrations in striatal brain slices following in-vitro exposure to these congeners; (ii) regional brain biogenic amine concentrations, circulating concentrations of T3, T4, TSH and circulating gonadotropins in offspring exposed during gestation and lactation to these congeners; (iii) neurochemical, neurobehavioral and endocrine responses in offspring exposed during development to pharmacologic agents and in-vivo generated metabolites (alpha-methyl paratyrosine, NSD-1015, propylthiouracil, catecholestrogens and hydroxybiphenyls) and (iv) changes in cognitive function in animals exposed to PCB congeners and the above agents. These experiments, using a number of prototypical PCB congeners, will allow us to determine which congeners directly affect the development of important neurotransmitters; which congeners indirectly affect brain development by altering key endocrine systems during development and the behavioral consequences of developmental exposure to these congeners. In turn, these data will allow a more complete understanding of the action of complex mixtures of congeners, the risk to the developing human and suggest pharmacologic and behavioral strategies that may ameliorate some of the cognitive dysfunctions observed in developmentally-exposed human infants.