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The Aryl Hydrocarbon Receptor Affects Mouse Ovarian Follicle Growth via Mechanisms Involving Estradiol Regulation and Responsiveness¹

Department of Epidemiology and Preventive Medicine,³ University of Maryland School of Medicine, Baltimore, Maryland 21201 Department of Veterinary Biosciences,⁴ University of Illinois Urbana-Champaign, Illinois 61802

ABSTRACT

The aryl hydrocarbon receptor (AHR) is a known transcription factor. Although studies indicate that Ahr-deficient (AhRKO) mice have defects in female reproduction, only a few studies have examined the role of AHR in the ovary. Previous studies have suggested, without directly testing, that AhRKO mice have slower follicular growth than wild-type (WT) mice. Therefore, the first objective of the present study was to examine whether AhRKO follicles grow slower than WT follicles and if so, to determine whether the mechanism by which Ahr affects follicular growth is through effects on antrum size, granulosa cell proliferation, and regulators of cell cycle progression. Since estradiol (E₂) is critical for the normal growth of ovarian follicles, the second objective of the present study was to determine the role of Ahr in regulating E₂ production and responsiveness. The third objective of the present study was to determine whether E₂ replacement restores follicular growth of AhRKO follicles to WT levels in vitro. We found that AhRKO follicles grew slower than WT follicles in vitro. While AhRKO and WT follicles had similar antrum sizes, AhRKO follicles showed decreased granulosa cell proliferation and reduced mRNA and protein levels of cell cycle regulators, as compared to WT follicles. Furthermore, the AhRKO mice had lower serum and follicle-produced E₂ levels and showed decreased Esr1 and Esr2 mRNA levels compared to WT mice. Finally, E₂ treatment of AhRKO follicles restored follicular growth to WT levels in vitro. Collectively, these findings suggest that the AHR affects follicular growth via mechanisms that involve E₂ regulation and responsiveness.

estrdiol, estradiol receptor, follicle, ovary, toxicology

¹Supported by NIH HD 047275 and NIH MARC Predoctoral Fellowship F31 GM072195-01.

Correspondence: ²Jodi Anne Flaws, University of Illinois, Department of Veterinary Biosciences, 3223 VMBS Building, 2001 S. Lincoln Ave, Urbana, IL 61802. FAX: 217 244 1652; e-mail: jflaws{at}uiuc.edu

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