Involvement of Estrogen Receptor β in the Induction of Polyovular Follicles in Mouse Ovaries Exposed Neonatally to Diethylstilbestrol

Abstract

Natural and synthetic estrogens, Including diethylstilbestrol (DES), given during the critical period of newborn life Induce abnormalities in ovaries of mice. Induction of polyovular follicles (PFs) containing two or more oocytes in a follicle is one example. In this study, the involvement of estrogen receptor subtypes ERalpha and ERbeta in induction of PFs by neonatal treatment with DES was analyzed by using ERalpha knockout (alphaERKO) and ERbeta knockout (betaERKO) mice. Ovaries of mice injected with 3 microg DES for 5 days from the day of birth were examined histologically from 10 to 60 days of age, and the expression of genes involved in folliculogenesis was analyzed by real-time quantitative PCR. The PF Incidence (percent of PFs per 100 follicles greater than 50 microm in diameter) in the ovary of alphaERKO mice treated with DES was not different from that in the DES-treated wild-type mice. However, neonatal DES treatment did not increase the PF incidence in betaERKO mice, suggesting that PFs were induced by DES through ERbeta but not ERalpha. The expression of bone morphogenetic protein 15, growth differentiation factor 9, inhibin-alpha, Müllerian inhibiting substance, and other genes in the ovaries of DES-treated betaERKO mice was not different from that in the ovaries of DES-treated wild-type mice. These results indicate that ERbeta but not ERalpha is essential for DES to Induce PFs in mice.

Endocrine-disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling

“…Interestingly, further studies on ESR deficient mice (aERKO and bERKO) have shown that DES (3 mg) induces ovarian abnormalities through different ESRs. Specifically, DES inhibits follicle formation and development through ESR1 (Kim et al 2009b), whereas it induces polyovular follicles through ESR2 (Kirigaya et al 2009). In mice, in utero exposure to DES (100 mg/kg) was shown to change ovarian morphology and alter ex vivo ovarian steroidogenesis in the offspring of the dosed dams (Haney et al 1984).…”

Effects of Endocrine-disrupting Chemicals on Female Reproductive Health

“…MOFs were also observed in ovaries that were treated in vitro at PND 1-5, following their transplantation to untreated mice, suggesting a direct effect of DES in the ovary [122]. Recent studies showed that neonatal exposure to 3 μg/kg DES induced MOFs, a process mediated by ESR2 and not ESR1 [97]. DES exposure was shown to reduce oocyte apoptosis (potentially suppressing oocyte nest breakdown) via ESR2 signaling mechanisms.…”

Effects of 2,3-Bis(4-hydroxyphenyl)-propionitrile on Induction of Polyovular Follicles in the Mouse Ovary

“…These facts indicate that PF induction can be accompanied with changes in expression of those genes. Ηowever, no significant changes in the expression of Gdf9 and Bmp15 are found in the ovary of mice neonatally exposed to DES at 5, 20 and 30 days, but only Inha is increased (4,9). Since DES can bind and transactivate both ERα and ERβ (10,6), it is possible that changes in gene expression include all of the genes downstream of ERα and ERβ.…”

“…Surprisingly, neonatal exposure to 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl) triphenol (PPT), a specific ERα agonist, also induces PFs in the mouse ovary at 30 days, although not having significant estrogenic activity on mouse ERβ in in vitro transactivation assay (6). These results suggest that both ERα and ERβ are involved in PF induction, however, ERβ is essential for PF induction because a lack of ERβ results in no PF induction in the ovary even after neonatal exposure to DES (4).…”

“…However, the role of ERβ in the neonatal ovary is still unclear. It is reported that neonatal treatment with genistein or diethylstilbestrol (DES) induces polyovular follicles (PFs), which contain more than two oocytes in a follicle, through ERβ, not ERα (1,4). These findings indicate that ERβ in the neonatal mouse ovary can be physiologically activated by ERβ ligand.…”