AhR- and ER-Regulated Genes in Brain Development

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DESCRIPTION (provided by applicant): Our long-term objective is to determine the mechanisms by which developmental exposure to dioxins and other ubiquitous arylhydrocarbon receptor (AhR) ligands alters reproductive functions in adulthood. We recently showed that a single developmental exposure to the potent AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), interferes with estrogen-dependent sexual differentiation of the male anteroventral periventricular nucleus (AVPV). The AVPV controls the female pattern of luteinizing hormone (LH) release; therefore, TCDD-exposed males have a female-like AVPV structure and they show the female, cyclic pattern of LH release in adulthood. Considering that estradiol (E2) derived from fetal production of testosterone is responsible for the sexual differentiation process, we hypothesize that TCDD interferes with E2 regulation of a set of genes during development. To test this hypothesis, we will use Affymetrix microarrays and cluster analysis to identify sex-specific genes that are regulated by E2 and TCDD. We will use a "redundancy model", testing different animal treatments predicted by our hypothesis to target the same set of genes. We will validate our microarray findings using RT-QPCR, in situ hybridization histochemistry, developmental ontogeny studies, dose response studies and promoter analysis. Our findings will be important for identifying genes underlying effects of dioxins and other ubiquitous AhR ligands on reproductive toxicity, as well as on other neural functions disrupted by perinatal TCDD exposure in a sex-specific manner. Such findings will be important for mechanism-based risk assessment, as well as for development of pharmaceutical interventions to prevent neurotoxicity.