MECHANISMS OF REPRODUCTIVE NEUROENDOCRINE TOXICITY

两个阶级的代表的行动或生殖 有毒物质，重金属（铅）和多氯联苯 混合物（Aroclor 1254），对血清素（5-HT）-促性腺激素 促性腺激素释放激素（GnRH）-促性腺激素（GtH）神经内分泌通路 控制GtH分泌将进行广泛的研究， 硬骨鱼生殖内分泌功能和内分泌模型 毒理学，大西洋黄鱼（Micropogonias undulatus）。 目前，外源性干扰的部位和机制， 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通过破坏不同的 5-HT-GnRH-GtH刺激性神经内分泌通路的组分 控制繁殖。 在黄花鱼和其他鱼类中的初步结果 脊椎动物物种表明，Aroclor 1254主要作用于5- HT成分，而铅可能作用于GnRH和GtH（垂体） 神经内分泌系统的组成部分。 因此，所有三个 系统的组成部分将使用多个指标进行研究 的神经内分泌功能。 将使用几种神经药理学方法进行平行研究。 模拟外源性物质诱导的干扰的试剂， 扭转他们。 GtH分泌的平行紊乱将是 解释为证明模型化合物具有相同的主要 作为神经药理学试剂的作用部位。 具体目标是： 1. Aroclor 1254与神经药理作用的比较 药物对5-HT-GnRH-GtH途径和GtH的不同组分的作用 分泌;相关PCB积累的程度， 神经内分泌紊乱 2.比较铅和神经药理学药物对 5-HT-GnRH-GtH途径和GtH分泌的单独组分; 铅蓄积与神经内分泌功能障碍程度相关 破坏 关于模型化合物对 控制生殖的主要神经内分泌系统的组成部分， 5-HT-GnRH-GtH通路，应该提供有价值的新信息， 生殖神经内分泌干扰的机制和靶点 被脊椎动物中的异生物质所污染。 进一步评估这一非- 生殖神经内分泌毒理学的哺乳动物模型将 促进内分泌干扰机制的比较， 化学物质在更广泛的脊椎动物中，从而提供了一个 更准确地预测其长期生殖危害， 人类 此外，这种硬骨鱼模型应该是有价值的， 监测污染对水生生态系统的损害以及 环境污染对人类生殖危害 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.