ABSTRACT IBN 97-31599 PI = PETERSEN, Sandra L. The objective of this research is to understand the role of the arylhydrocarbon receptor (AhR) in the regulation of estrogen actions in the hypothalamus, the part of the brain that plays a central role in reproduction. The AhR is generally considered as the receptor that binds dioxin and dioxin-like environmental contaminants. However, this receptors has apparently been conserved throughout evolution and, therefore, is likely to have ligands other than the dioxins that have been produced only within the past 50 years. Although the AhR has been studied in non-neural tissue, virtually no studies have been conducted in the brain. In other estrogen-sensitive tissues, such as breast tissue, activation of the AhR is anti-estrogenic. Dr. Petersen recently discovered that the genes for AhR and estrogen receptor (ER) are co-localized in regions of the hypothalamus that control ovulation. Other recent work has shown that a single dose of dioxin (which activates the AhR) blocks the ability of estrogen to induce the preovulatory surge of luetinizing hormone (LH) required for ovulation. Based on this finding, Dr. Petersen hypothesized that activation of the AhR may interfere with specific ER functions in hypothalamus. To test this hypothesis, it will be determined whether: (1) activation of the AhR alters estrogen expression or receptor protein expression, (2) activation of the AhR induces the gene expression of specific hydroxylases that metabolize estrogen, thereby decreasing hormone availability and creating neurotoxic substances, and (3) known estrogen actions in the hypothalamus, such as progesterone receptor induction and changes in proopiomelanocortin, tyrosine hydroxylase and NPA gene expression, are blocked by activation of the AhR. Taken together, these studies will provide important new insights into the mechanisms by which ligands for the AhR might affect ER-mediated events required for ovulation. In addition, the proposed experiments will provide important clues to help identify the endogenous ligand(s) for the receptor.
