The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity of many environmental chemicals. In addition to mediating the toxicity of environmental chemicals, the AhR plays a key role in regulating fertility. Female AhR deficient (AhRKO) mice have reduced fertility compared to their wild-type (WT) littermates. The reduced fertility in AhRKO females is due to slow growth of follicles to the antral stage in AhRKO ovaries compared to WT ovaries. Although the reasons for the slow follicular growth in AhRKO ovaries compared to WT ovaries are unknown, our preliminary data indicate that AhR deletion reduces the ability of ovarian follicles to synthesize and respond to estradiol, and that it results in a reduced ability of follicles to respond to gonadotropins, a scenario that indirectly leads to a reduced ability of follicles to synthesize and respond to estradiol. Thus, the studies in this proposal are designed to test the hypothesis that AhR deficiency causes slow follicular growth from the preantral to late antral stage by reducing the ability of follicles to synthesize and respond to estradiol. The proposed work will further determine whether the reduced ability of AhR deficient follicles to synthesize and respond to estradiol is due to direct effects of AhR deletion on estrogen receptors and key steroidogenic enzymes and/or if it is due to effects of AhR deletion on gonadotropin responsiveness, which indirectly lead to reduced estradiol synthesis and thus, slow follicular growth. To test this hypothesis, we will determine whether: 1) AhR deficiency alters the expression/activity of key enzymes and levels of hormone intermediates required for estradiol synthesis, 2) estradiol replacement restores follicular growth in AhRKO ovaries, 3) AhR replacement restores estradiol synthesis and follicular growth in AhRKO mice and 4) the AhR interacts with the promoters of FSHR, LHR, ERa, ER? and selected steroidogenic enzymes. The proposed work will greatly improve our understanding of the role of the AhR in the ovary and the mechanisms by which it regulates follicular growth. In turn, this improved understanding may lead to the development of novel targets for the treatment and/or prevention of infertility.
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