Mechanisms of Arylhydrocarbon Receptor-Mediated Interactions with Estrogen Receptor in Hypothalamus

摘要 IBN 97-31599 PI = PETERSEN，Sandra L. 本研究的目的是了解芳香烃受体（AhR）在调节下丘脑雌激素作用中的作用，下丘脑是大脑中在生殖中起核心作用的部分。 AhR通常被认为是结合二恶英和二恶英类环境污染物的受体。 然而，这种受体显然在整个进化过程中是保守的，因此，很可能有配体，而不是在过去50年中才产生的二恶英。 虽然AhR已经在非神经组织中进行了研究，但几乎没有在大脑中进行过研究。 在其他雌激素敏感组织中，如乳腺组织，AhR的激活是抗雌激素的。 彼得森博士最近发现，AhR和雌激素受体（ER）的基因共同定位于控制排卵的下丘脑区域。 其他最近的研究表明，单剂量的二恶英（激活AhR）阻断了雌激素诱导排卵所需的促黄体生成素（LH）的排卵前激增的能力。 基于这一发现，Petersen博士假设AhR的激活可能会干扰下丘脑中特定的ER功能。 为了检验这一假设，将确定：（1）AhR的激活改变雌激素表达或受体蛋白表达，（2）AhR的激活诱导代谢雌激素的特异性羟化酶的基因表达，从而降低激素的可用性并产生神经毒性物质，和（3）已知的下丘脑中的雌激素作用，例如孕酮受体诱导和阿黑皮素原、酪氨酸羟化酶和NPA基因表达的变化，都被AhR的激活所阻断。 总之，这些研究将提供重要的新的见解的机制，AhR的配体可能会影响ER介导的事件所需的排卵。 此外，拟议的实验将提供重要的线索，以帮助确定受体的内源性配体。

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.