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化学品可改变生殖器官的组织或分化、神经内分泌系统以及随后的性功能和行为。例如，已经表明，促性腺激素释放激素（GnRH）系统受环境和遗传影响的破坏可导致下丘脑性腺功能减退和不育。阿米洛唑林是一种广泛使用的农业杀真菌剂，是一种已知的环境抗雄激素，可能参与破坏GnRH系统，从而深刻影响生殖功能的各个方面。我们的数据表明，发育暴露的兔子乙烯菌核利的结果在显着的破坏男性性行为，并导致阳痿。视前区/下丘脑前区（POA/AH）是脊椎动物脑内最具性二态性的区域之一，对雄性动物的性行为有重要影响。我们最近发现的兔POA/AH的性二态性方面提供了可能的乙烯菌核利行动的神经基板。拟议的实验将确定是否是发育中的抗雄激素暴露于乙烯氯唑啉，改变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。其他人以前的工作表明，多巴胺和神经元型一氧化氮合酶（nNOS）是通过在POA/AH中起作用来介导男性性行为的关键参与者。在两个特定的目标中，我们将评估子宫内暴露于乙烯氯唑啉后的兔脑的任何：1）通过绘制出生后第1天（PND）GnRH神经元分布的整个头-尾范围以及24周龄时行为缺陷动物的细胞和纤维位置，来改变GnRH神经元发育;和2）通过绘制性二型细胞分布图改变POA/AH细胞结构（含有免疫反应性钙结合蛋白）和可能对男性性行为很重要的细胞（含有免疫反应性nNOS），以及在24周龄的行为缺陷的动物。将阿伐洛唑林给药动物与充分表征的雄激素受体拮抗剂氟氯噻嗪给药动物进行比较，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于乙烯氯唑林的抗雄激素作用所致的假设。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.