Low-dose bisphenol exposure affecting follicle development in next generation in mice

Abstract

Bisphenols (BPA, BPS and BPF) are group of endocrine disruptive chemicals (EDC) because of their weak estrogenic effect. However, whether these bisphenols exert similar estrogenic effect to mammalian reproductive functions remains largely unknown. Recently, an in vivo study in female mice (F0) showed that exposure of chronic low-dose BPA before and during gestation impaired fertility of their offspring (F1). Their ovaries became vulnerable to challenges of environmental pollutants. We hypothesized that exposure to low-dose bisphenols during embryonic development altered ovarian development and functions, leading to impaired fertility in adulthood. In this study, female mice were treated with bisphenol A, S, F and A+F at 500 mg/Kg/day for 30 days before pregnancy and throughout gestation. The ovaries of their female offspring were collected at 6-8 weeks of age and serial sectioning were performed. The number of developing follicles at different developmental stages were counted. Apoptosis and cell proliferation of the developing follicles were quantitated by TUNEL and Ki67 staining, respectively. We found that the number of activated follicles (i.e. secondary, pre-antral and antral) were significantly increased in BPA (p<0.01) and BPF (p<0.05) group when compared to controls while activated follicle number in BPA+BPF group is comparable to control. Apoptosis in granulosa cells were significantly higher in BPA (p<0.05), BPF (p<0.05) and BPA+F (p<0.01) groups than that in the control. No significant difference was found in granulosa cells proliferation among all groups. Although more primordial follicles were activated in adult F1 mice, the apoptosis level of the activated follicle was also increased, indicating more developing follicles underwent atresia before ovulation. Therefore, low-dose bisphenols may lead to early primordial follicle pool exhaustion in adulthood resulting in impaired fertility in the F1 generation. [This project is supported in part by GRF 17120415 to KFL]