Fetal Basis of Sexual Dysfunction: Brain Differentiation

描述（由申请人提供）：生殖健康恶化是一个主要的公共卫生问题。在胎儿发育的关键时期暴露于内分泌干扰物质会改变生殖器官、神经内分泌系统的组织或分化，以及随后的性功能和行为。例如，研究表明，环境和遗传因素对促性腺激素释放激素（GnRH）系统的破坏可导致下丘脑性腺功能减退和不孕。Vinclozolin是一种广泛使用的农业杀菌剂，是一种已知的环境抗雄激素，可能参与GnRH系统的破坏，从而深刻影响生殖功能的各个方面。我们的数据显示，兔在发育过程中暴露于vinclozolin会导致男性性行为的严重破坏，并导致阳痿。视前/下丘脑前部区（POA/AH）是脊椎动物大脑中最具性别二态性的区域之一，因其对男性性行为的影响而闻名。我们最近发现的兔POA/AH的两性二态方面为vinclozolin的作用提供了可能的神经学基础。拟议中的实验将确定是否正是在发育过程中暴露于vinclozolin的抗雄激素作用下，改变了成年男性性功能所必需的大脑机制。我们的初步数据表明，围产期暴露于vinclozolin选择性地影响GnRH神经元系统的部分和POA/AH细胞组织的多个方面。前人的研究表明，多巴胺和神经元一氧化氮合酶（nNOS）是通过POA/AH介导男性性行为的关键参与者。在两个特定的目标中，我们将评估兔的大脑，在子宫内暴露于vinclozolin后，是否有任何：1)通过绘制出生后（PND）的整个喙端-尾端分布范围来改变GnRH神经元的发育，以及24周龄时行为缺陷动物的细胞和纤维的位置；2) POA/AH细胞结构的改变，通过绘制PND 1以及24周龄行为缺陷动物的两性二型细胞（含有免疫反应性钙结合蛋白）和可能对雄性性行为重要的细胞（含有免疫反应性nNOS）的分布来实现。vinclozolin治疗的动物将与用雄激素受体拮抗剂氟他胺治疗的动物进行比较，以检验GnRH神经元系统的改变和影响雄性性行为的POA/AH化学结构的改变是由vinclozolin的抗雄激素作用引起的假设。通过使用相关且实用的动物模型，拟议的研究将推进污染物引起的性/勃起功能障碍的知识基础，这是人类生殖健康/成功的关键领域。

DESCRIPTION (provided by applicant): Deteriorating reproductive health is a major public health concern. Exposure to endocrine disrupting chemicals during critical periods in fetal development can alter the organization or differentiation of reproductive organs, the neuroendocrine system, and subsequent sexual function and behavior. For example, it has been shown that disruption of the gonadotropin-releasing hormone (GnRH) system by environmental and genetic influences can produce hypothalamic hypogonadism and infertility. Vinclozolin, a widely used agricultural fungicide, is a known environmental anti-androgen and may be involved in disruption of the GnRH system that can profoundly affect all aspects of reproductive function. Our data show that developmental exposure of rabbits to vinclozolin results in significant disruption of masculine sexual behavior and causes impotence. The preoptic/anterior hypothalamic area (POA/AH) is one of the most sexually dimorphic regions of vertebrate brain and well known for its influence on masculine sexual behaviors. Our recent discovery of sexually dimorphic aspects of the rabbit POA/AH provides likely neurological substrates for vinclozolin action. The proposed experiments will determine whether it is developmental anti-androgenic exposure to vinclozolin that alters brain mechanisms necessary for adult male sexual function. Our preliminary data suggest that perinatal exposure to vinclozolin selectively influences portions of the GnRH neuronal system and multiple aspects of POA/AH cellular organization. Previous work by others shows that dopamine and neuronal nitric oxide synthase (nNOS) are key players in mediating male sexual behavior by acting in the POA/AH. In two specific aims, we will assess rabbit brains, following in utero exposure to vinclozolin, for any: 1) alterations in GnRH neuron development by mapping the entire rostral-caudal extent of the distribution at postnatal day (PND) 1, and the positions of cells and fibers in animals with behavioral deficits at 24 wk of age; and 2) alterations in POA/AH cytoarchitecture by mapping the distribution of cells that are sexually dimorphic (containing immunoreactive calbindin) and cells that may be important for male sexual behavior (containing immunoreactive nNOS) at PND 1 as well as in animals with behavioral deficits at 24 wk of age. Vinclozolin-treated animals will be compared with animals treated with the well characterized androgen receptor antagonist flutamide to test the hypotheses that alterations in the GnRH neuronal system and alterations in the chemoarchitecture of the POA/AH that influences male sex behavior are due to anti-androgenic actions of vinclozolin. By using a relevant and yet practical animal model the proposed studies will advance the knowledge base in pollutant-induced sexual/erectile dysfunction, an area pivotal to reproductive health/success in humans.