MECHANISMS OF REPRODUCTIVE NEUROENDOCRINE TOXICITY

两个阶级代表的行为或生殖 有毒物质、重金属(铅)和多氯联苯 Aroclor 1254合剂对5-羟色胺-促性腺激素的影响 促性腺激素释放激素-促性腺激素神经内分泌途径 将对控制GTH分泌进行广泛的研究 生殖内分泌功能和内分泌的硬骨鱼模型 毒理学，大西洋大黄鱼(Micropogonias Undulatus) 目前，异源干扰的部位和机制 生殖神经内分泌途径知之甚少。 因此，将检验以下总体假设： 和Aroclor 1254通过干扰不同的基因来改变GTH的分泌 5-羟色胺-促性腺激素释放激素-生长激素刺激性神经内分泌途径的组成 控制繁殖。大黄鱼和其他鱼类的初步结果 脊椎动物物种表明Aroclor 1254主要作用于5- 羟色胺成分，而铅可能作用于GnRH和GTH(脑下垂体) 神经内分泌系统的组成部分。因此，这三个人 系统的组成部分将使用多个指数进行调查 暴露在模型化合物中后神经内分泌功能的变化。 将对几种神经药理学进行平行研究。 模拟外源生物诱导的干扰或 把它们倒过来。GTH分泌的平行紊乱将是 解释为模型化合物具有相同的主要成分的证据 作为神经药剂的作用部位。 具体目标是： 1.比较Aroclor 1254的神经药理作用 5-羟色胺-促性腺激素释放激素-促性腺激素途径和促性腺激素释放激素途径分离成分的药物 分泌物；多氯联苯的积累与 神经内分泌紊乱。 2.比较铅和神经药理药物对小鼠的影响。 5-羟色胺-GnRH-GTH途径和GTH分泌的分离成分； 铅蓄积与神经内分泌程度的相关性 颠覆。 对模型化合物影响的拟议研究 控制生殖的主要神经内分泌系统的组成部分， 5-羟色胺-促性腺激素释放激素-生长激素途径，应提供有价值的新信息 生殖神经内分泌干扰的机制和靶点 脊椎动物体内的外源生物。对这一非 哺乳动物生殖神经内分泌毒理学模型将 促进比较内分泌干扰的机制，通过 更广泛的脊椎动物中的化学物质，因此提供了 更准确地预测它们对生殖的长期危害 人类。此外，这种硬骨鱼模型应该是有价值的 污染对水生态系统的危害及其潜在的哨兵 环境污染对人类的生殖危害 人口。

The actions of representatives of two classes or reproductive toxicants, a heavy metal (lead), and a polychlorinated biphenyl mixture (Aroclor 1254), on the serotonin (5-HT)-gonadotropin releasing hormone (GnRH)-gonadotropin (GtH) neuroendocrine pathway controlling GtH secretion will be investigated in an extensive teleost model of reproductive endocrine function and endocrine toxicology, the Atlantic croaker (Micropogonias undulatus). Currently, the sites and mechanisms of xenobiotic interference with the reproductive neuroendocrine pathway are poorly understood. Therefore, the following overall hypothesis will be tested: that lead and Aroclor 1254 alter GtH secretion by disrupting different components of the 5-HT-GnRH-GtH stimulatory neuroendocrine pathway controlling reproduction. Preliminary results in croaker and other vertebrate species suggest that Aroclor 1254 acts primarily on the 5- HT component, whereas lead may act on the GnRH and GtH (pituitary) components of the neuroendocrine system. Therefore all three components of the system will be investigated using multiple indices of neuroendocrine function after exposure to the model compounds. Parallel studies will be conducted with several neuropharmacological agents which either mimic the xenobiotic-induced disturbances or reverse them. Parallel disturbances of GtH secretion will be interpreted as evidence that the model compound has the same primary site of action as the neuropharmacological agent. Specific objectives are to: 1. Compare the actions of Aroclor 1254 and the neuropharmacological agents on separate components of the 5-HT-GnRH-GtH pathway and GtH secretion; correlate PCB accumulation with the degree of neuroendocrine disruption. 2. Compare the actions of lead and the neuropharmacological agents on separate components of the 5-HT-GnRH-GtH pathway and GtH secretion; correlate lead accumulation with the degree of neuroendocrine disruption. The proposed research on the effects of the model compounds on components of a major neuroendocrine system controlling reproduction, the 5-HT-GnRH-GtH pathway, should provide valuable new information on the mechanisms and targets of reproductive neuroendocrine disruption by xenobiotics in vertebrates. The further evaluation of this non- mammalian model of reproductive neuroendocrine toxicology will facilitate comparisons of the mechanisms of endocrine disruption by chemicals among a broader range of vertebrates and thus provide a more accurate prediction of their long term reproductive hazards to humans. In addition this teleost model should be valuable as a sentinel of pollution damage to aquatic ecosystems and the potential reproductive hazards of environmental contamination to human populations.