Aryl Hydrocarbon Receptor Regulates Growth, But Not Atresia, of Mouse Preantral and Antral Follicles1

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that binds various environmental contaminants. Despite our knowledge regarding the role of the AhR in mediating toxicity, little is known about the physiological role of the AhR. Previous studies indicate that the AhR may regulate folliculogenesis, because AhR-deficient (AhRKO) mice have fewer preantral and antral follicles than wild-type (WT) mice during postnatal life. Thus, the first objective of the present study was to test the hypothesis that AhR deficiency reduces the numbers of preantral and antral follicles by slowing growth and/or increasing atresia of follicles. Because alterations in follicular growth or atresia can affect the ability to ovulate, the second objective was to test whether AhR deficiency reduces the number of ovulated eggs. To test these hypotheses, follicular growth was compared in WT and AhRKO ovaries using morphometric techniques and by measuring the ability of the ovary and follicles to grow in response to eCG. Atresia was compared in WT and AhRKO ovaries using morphometric techniques, TUNEL assays, and 3'-end labeling of fragmented DNA. Ovulation was compared in WT and AhRKO mice by assessing the number of corpora lutea per ovary. The results indicate that follicular growth and ovulation were reduced in AhRKO ovaries compared to WT ovaries. The WT ovaries had a 1.5-fold increase in the number of preantral and antral follicles between Postnatal Days 32 and 45, were more responsive to eCG, and contained more corpora lutea than AhRKO ovaries. In contrast, no significant difference was observed in the incidence of atresia in WT and AhRKO ovaries. Taken together, these results suggest that the AhR may regulate growth, but not atresia, of preantral and antral follicles in the mouse ovary.

Intrinsic Function of the Aryl Hydrocarbon (Dioxin) Receptor as a Key Factor in Female Reproduction

“…Abbott et al described that AhR Ϫ/Ϫ females exhibited difficulties in maintaining conceptuses during pregnancy (1), while Benedict et al reported that AhR deficiency affected follicular maturation and ovulation under normal growth conditions (3,4). Our studies indicated that follicles present in the ovaries of AhR Ϫ/Ϫ mice developed to an antral/preovulatory stage, while the corpus luteum was barely detectable.…”

Effects of reduction of the number of primordial follicles on follicular development to achieve puberty in female rats

“…Various xenobiotics, such as Congo red, VCH and its active metabolite, cyclophosphamide, and several aromatic hydrocarbons, benzo[a]pyrene, 3-methyl-cholanthrene and 7,12-dimethyl-benz [a]antrathene, are known to target primordial, primary and preantral follicles (for review, see Hoyer and Sipes, 1996;Gray, 1997). In addition, aryl hydrocarbon receptor, the receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin and coplanar polychlorinated biphenyls, contributes to the slowing of the initial and early recruitment of follicles (Benedict et al, 2000). In evaluating the ability of various xenobiotics to affect the number of primordial follicles, the concentration of circulating inhibin during the neonatal and infantile periods may be a useful indicator in the rodent model.…”

The Aryl Hydrocarbon Receptor sans Xenobiotics: Endogenous Function in Genetic Model Systems

“…During normal estrous, hormonal signals induce maturation of the granulosa cell layer surrounding the oocyte and trigger release of the follicle into the fallopian tube (Gilbert, 2000). Although the number and morphology of immature, preovulatory follicles is unchanged between wildtype and Ahr knockout females, several reports have noted a marked reduction in the number of mature follicles (Benedict et al, 2000(Benedict et al, , 2003Baba et al, 2005). Evidence indicates that these defects are not due to upstream changes in the endocrine regulation of ovulatory-stimulating hormones (Baba et al, 2005;Trewin et al, 2007).…”

“…In addition to being refractory to most, if not all, aspects of TCDD toxicity, "Ahr-knockouts" exhibit multiple physiological abnormalities that are independent of xenobiotic exposure (Fernandez-Salguero et al, 1995;Schmidt et al, 1996;Mimura et al, 1997). Studies of the mutant mouse models have reproducibly demonstrated that the AHR has an intrinsic role in diverse aspects of mammalian biology that extend beyond (or are entirely independent from) xenobiotic metabolism (Andreola et al, 1997;Fernandez-Salguero et al, 1997;Zaher et al, 1998;Abbott et al, 1999;Benedict et al, 2000Benedict et al, , 2003Lahvis et al, 2000;Thackaberry et al, 2002;Lund et al, 2003Lund et al, , 2005Vasquez et al, 2003;Corchero et al, 2004;Guo et al, 2004;Baba et al, 2005;Lahvis et al, 2005). Moreover, these studies of null models have led to speculation that aspects of TCDD toxicity may be the result of sus-tained interference in these endogenous, physiological pathways mediated by the AHR.…”