Bisphenol A (BPA), one of the most frequently detected emerging pollutants in the environment, has been implicated in adverse effects in male and female reproduction at extremely low concentrations. This study aimed to investigate the effects and potential mechanism of BPA on mouse ovarian follicular development and female germline stem cells (FGSCs). Female CD-1 adult mice were administered gradient concentrations of BPA (12.5, 25, and 50 mg/kg/day) by intraperitoneal injection. We found that the number of atretic ovarian follicles was significantly increased at high BPA concentrations. Additionally, the numbers of primordial follicles, primary follicles, and corpus luteum (CL) were significantly reduced at high BPA concentrations. Interestingly, the number of FGSCs was remarkably reduced in BPA-treated ovaries. Furthermore, the increased apoptotic rate of FGSCs in vitro was triggered by BPA accompanied by increased BPA concentrations. To investigate the mechanism of BPA in ovarian follicular development, 193 differentially expressed proteins were identified in BPA-treated ovaries by the isobaric tags for relative and absolute quantification-coupled 2D liquid chromatography-mass spectrometry technique. A total of 106 proteins were downregulated and 85 proteins were upregulated. Among these proteins, the apoptosis-related protein SAFB-like transcriptional modulator (SLTM) was remarkably upregulated, and this result was consistent with western blotting. Taken together, our results suggest that an ovarian follicular development, especially, the development of primordial follicles, primary follicles, and the CL, is inhibited by high BPA concentrations, and the ovarian follicle atresia is initiated by BPA through upregulated expression of SLTM. Furthermore, BPA induces apoptosis of cultured FGSCs. The effect of BPA on ovarian follicular development and FGSCs, especially the effect on FGSCs, suggests a novel mechanism of how BPA causes female infertility.
Bisphenol A (BPA) Ovarian follicle development Female germline stem cells (FGSCs) Apoptosis SAFB-like transcriptional modulator (SLTM) Proteomics
Female germline stem cells
Bovine serum albumin
Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
Liquid chromatography–mass spectrometry
Differentially expressed proteins
Kyoto Encyclopedia of Genes and Genomes
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This work was supported by National Natural Science Foundation of China (81720108017), National Basic Research Program of China (2017YFA0504201), and Shanghai Jiao Tong University Medicine-Engineering Fund (YG2017ZD11).
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1.Renji Hospital, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
2.Key Laboratory of Fertility Preservation and Maintenance of Ministry of EducationNingxia Medical UniversityYinchuanChina