Bisphenol A Exposure In Utero Disrupts Early Oogenesis in the Mouse

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Abstract
Estrogen plays an essential role in the growth and maturation of the mammalian oocyte, and recent studies suggest that it also influences follicle formation in the neonatal ovary. In the course of studies designed to assess the effect of the estrogenic chemical bisphenol A (BPA) on mammalian oogenesis, we uncovered an estrogenic effect at an even earlier stage of oocyte development—at the onset of meiosis in the fetal ovary. Pregnant mice were treated with low, environmentally relevant doses of BPA during mid-gestation to assess the effect of BPA on the developing ovary. Oocytes from exposed female fetuses displayed gross aberrations in meiotic prophase, including synaptic defects and increased levels of recombination. In the mature female, these aberrations were translated into an increase in aneuploid eggs and embryos. Surprisingly, we observed the same constellation of meiotic defects in fetal ovaries of mice homozygous for a targeted disruption of ERβ, one of the two known estrogen receptors. This, coupled with the finding that BPA exposure elicited no additional effects in ERβ null females, suggests that BPA exerts its effect on the early oocyte by interfering with the actions of ERβ. Together, our results show that BPA can influence early meiotic events and, importantly, indicate that the oocyte itself may be directly responsive to estrogen during early oogenesis. This raises concern that brief exposures during fetal development to substances that mimic or antagonize the effects of estrogen may adversely influence oocyte development in the exposed female fetus. The potential effects on reproduction of chemicals with hormone-like activity is a growing concern. One estrogenic chemical, bisphenol A (BPA), has received considerable attention because low-dose exposures have been reported to induce a variety of reproductive effects in rodents. In the course of studies to assess the effects of BPA on the mouse oocyte, we have uncovered a novel “grandmaternal” effect: exposure to BPA during pregnancy disturbs oocyte development in unborn female fetuses. When these fetuses reach adulthood, the perturbations are translated into an increase in chromosomally abnormal eggs and embryos. Thus, low-dose BPA exposure during pregnancy has multigenerational consequences; it increases the likelihood of chromosomally abnormal grandchildren. Our studies also provide mechanistic insight, and, surprisingly, suggest that BPA acts in the fetal ovary not by mimicking the actions of estrogen but by interfering with the function of one of the known estrogen receptors. Thus, our data suggest that estrogen plays a far earlier role in oocyte development than previously suspected and, importantly, raise the possibility that a variety of substances—both synthetic and naturally occurring—that mimic the actions of estrogen or act as estrogen antagonists may affect early oocyte development.