Neuroendocrine outcomes of prenatal PCB exposures

描述（由申请人提供）：暴露于环境毒物会深刻影响神经和生殖发育、功能和行为，特别是当暴露发生在易感的产前时期。本研究计划的总体目标是研究环境毒物在成年期破坏生殖神经内分泌功能的分子靶点。我们的工作假设是，子宫内暴露于内分泌干扰化学物质（EDCs）对生殖结果有长期影响，表现为生殖行为和功能的改变，生育能力和生殖力的降低，以及生殖衰老的加速。这些变化至少部分是由EDCs对大脑中负责生殖调节的神经内分泌区域（即下丘脑和视前区）的影响所介导的。我们的目标是建立一个模型来研究一类EDCs，多氯联苯（pcb）是如何引起这些长期后果的，并以雌性Sprague-Dawley大鼠为模型，确定EDCs的分子和细胞靶点。在具体目标1中，我们将建立剂量-反应模型来测试产前多氯联苯对成年期生殖神经内分泌功能（生育能力、生殖力、行为、生殖早衰）的影响。在具体目标2中，我们将使用新的基因技术（差异显示PCR和微阵列）确定下丘脑中产前多氯联苯作用的靶基因。最后，在Specific Aim 3中，我们将研究多氯联苯在神经内分泌脑区作用的靶分子的神经解剖学表达和调控。这些研究应该为产前暴露于多氯联苯干扰成年雌性哺乳动物生殖神经内分泌功能的可能机制提供新的信息。研究结果对于理解野生动物和人类暴露于多氯联苯等EDCs的后果和开发治疗方法具有重要意义。

DESCRIPTION (provided by applicant): Exposure to environmental toxicants can profoundly affect neurological and reproductive development, function and behavior, particularly when the exposure occurs during the susceptible prenatal period. The overall goal of this research proposal is to study the molecular targets at which environmental toxicants act to disrupt reproductive neuroendocrine function in adulthood. It is our working hypothesis that in utero exposure to endocrine disrupting chemicals (EDCs) has long-term consequences on reproductive outcomes, manifested as alterations in reproductive behavior and function, diminished fertility and fecundity, and a hastening of reproductive aging. These changes are mediated at least in part by effects of EDCs on neuroendocrine regions of the brain responsible for the regulation of reproduction, namely the hypothalamus and preoptic area. Our goal is to establish a model for investigating how one class of EDCs, polychlorinated biphenyls (PCBs) causes these long-term consequences, and to identify the molecular and cellular targets of the EDCs, using female Sprague-Dawley rats as a model. In Specific Aim 1, we will establish dose-response models to test effects of prenatal PCBs on reproductive neuroendocrine function in adulthood (fertility, fecundity, behavior, premature reproductive aging). In Specific Aim 2, we will identify target genes acted upon by prenatal PCBs in the hypothalamus using novel gene technologies (differential display PCR and microarrays). Finally, in Specific Aim 3, we will examine the neuroanatomical expression and regulation of the target molecules on which PCBs act in neuroendocrine brain regions. These studies should provide novel information on the possible mechanisms by which prenatal exposure to PCBs interferes with reproductive neuroendocrine function of adult female mammals. The results should have important implications for understanding consequences of, and developing therapies for, exposures of wildlife and humans to EDCs such as PCBs.