Fetal Basis of Sexual Dysfunction: Brain Differentiation

描述(申请人提供)：日益恶化的生殖健康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会改变生殖器官的组织或分化、神经内分泌系统以及随之而来的性功能和行为。例如，已有研究表明，环境和遗传影响扰乱促性腺激素释放激素(GnRH)系统可导致下丘脑性腺功能低下和不孕症。长春花灵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方方面面。我们的数据显示，兔在发育过程中暴露于长春新灵会导致男性性行为的显著中断，并导致阳萎。视前/下丘脑前区(POA/AH)是脊椎动物大脑中性别差异最大的区域之一，以其对男性性行为的影响而闻名。我们最近发现的兔POA/AH的性二型性特征为长春花碱的作用提供了可能的神经学底物。拟议中的实验将确定是否是发育中的抗雄激素暴露于长春花碱改变了成年男性性功能所需的大脑机制。我们的初步数据表明，围产期接触长春新灵选择性地影响部分GnRH神经元系统和POA/AH细胞组织的多个方面。前人的工作表明，多巴胺和神经元型一氧化氮合酶(NNOS)是通过作用于POA/AH来调节男性性行为的关键角色。在两个特定的目标中，我们将评估宫内暴露于长春新灵的兔脑是否有任何变化：1)通过绘制出生后第1天(PND)1的整个嘴-尾部分布的变化，以及24周龄有行为缺陷的动物的细胞和纤维的位置；2)通过绘制PND 1的性二型性细胞(包含免疫活性钙结合蛋白)和可能对男性性行为(包含免疫活性nNOS)重要的细胞的分布，以及在24周龄有行为缺陷的动物的POA/AH细胞结构的变化。长春花碱治疗的动物将与特征明确的雄激素受体拮抗剂氟他胺治疗的动物进行比较，以检验GnRH神经元系统的变化和影响男性性行为的POA/AH化学结构改变是由于长春花碱的抗雄激素作用的假说。通过使用相关但实用的动物模型，拟议的研究将推进污染物诱导性/勃起功能障碍的知识库，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.