Fetal Basis of Sexual Dysfunction: Brain Differentiation

胎儿性功能障碍的基础：大脑分化

• 批准号: 7030102
• 负责人: D. N. RAO VEERAMACHANENI
• 金额: $ 21.9万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030102
• 关键词: androgen inhibitor; antifungal agents; brain mapping; brain morphology; calbindin; cell parasexuality; developmental neurobiology; embryo /fetus toxicology; endocrine disrupting compound; gender difference; gonadotropin releasing factor; hypothalamus; laboratory rabbit; neuroendocrine system; pesticide biological effect; preoptic areas; sex behavior disorder; sex development disorder

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.

描述（由申请人提供）：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，暴露于内分泌的化学物质会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，通过环境和遗传影响，促性腺激素释放激素（GNRH）系统的破坏可以产生下丘脑的性下降性和不育。 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，可能与GNRH系统的破坏有关，可以深刻影响生殖功能的各个方面。我们的数据表明，兔子对vinclozolin的发育暴露会导致男性性行为的严重破坏，并引起阳ot。下丘脑前/前丘脑前区域（POA/AH）是脊椎动物大脑中最大的二态性区域之一，以其对男性性行为的影响而闻名。我们最近发现的兔POA/AH性二态方面的发现可能为Vinclozolin作用提供了神经系统底物。拟议的实验将确定是否是对成年男性性功能所必需的大脑机制的发育性抗雄激素暴露。我们的初步数据表明，围产期暴露于Vinclozolin，有选择地影响GNRH神经元系统的一部分和POA/AH细胞组织的多个方面。其他人的先前工作表明，多巴胺和神经元一氧化氮合酶（NNOS）是通过在POA/AH中作用来介导男性性行为的关键参与者。在两个具体目标中，我们将在子宫暴露于vinclozolin之后评估兔子大脑，以进行任何：1）通过绘制出产后分布的整个rostral-caudal范围（PND）1的改变，以及位置1，以及这些位置的改变。在24周龄的行为缺陷的动物中的细胞和纤维； 2）通过绘制POA/AH细胞结​​构的改变，通过映射性二态性的细胞分布（含有免疫反应性的钙蛋白）和细胞，对于在PND 1和具有行为不足的动物的男性性行为（包含免疫反应性NNOS）可能很重要的细胞以及可能很重要的细胞在24周龄。将将经芬克洛唑素治疗的动物与用良好的雄激素受体拮抗剂氟丁酰胺处理的动物进行比较，以测试gnRH神经元系统改变的假设以及POA/AH化学结构的改变，其影响男性性行为是由于抗雄激素性行为引起的。 Vinclozolin的作用。通过使用相关但实用的动物模型，提出的研究将推进污染物诱导的性/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。