Fetal Basis of Sexual Dysfunction: Brain Differentiation

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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.