Transgenerational inheritance of diminished ovarian reserve triggered by prenatal propylparaben exposure in mice

  • Nat Commun. 2025 Sep 16;16(1):8289. doi: 10.1038/s41467-025-63440-z.
Milu Li  1  2  3 ,  Yaling Wu  1  2  3 ,  Siting Wei  4  5  6  7 ,  Tianyu Zhang  1  2  3 ,  Wei Yan  1  2  3 ,  Yueyue Gao  1  2  3 ,  Yingying Chen  1  2  3 ,  Dianxing Hu  1  2  3 ,  Tong Wu  1  2  3 ,  Mo Li  1  2  3 ,  Wenwen Wang  1  2  3 ,  Yan Li  1  2  3 ,  Su Zhou  8  9  10 ,  Ximiao He  11  12  13  14 ,  Shixuan Wang  15  16  17 ,  Jinjin Zhang  18  19  20
Affiliations
  • 1. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, China.
  • 3. Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, China.
  • 4. Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5. Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6. Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7. Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China.
  • 8. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 9. National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, China. [email protected].
  • 10. Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, China. [email protected].
  • 11. Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 12. Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 13. Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 14. Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 15. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 16. National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, China. [email protected].
  • 17. Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, China. [email protected].
  • 18. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 19. National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, China. [email protected].
  • 20. Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, China. [email protected].
PMID: 40957879 DOI: 10.1038/s41467-025-63440-z
Abstract

Diminished ovarian reserve (DOR) is associated with heightened risk of infertility, premature menopause, and various long-term health issues. Our previous research demonstrated a correlation between prenatal propylparaben exposure and DOR in F1 mice. Here, we further reveal that the DOR phenotypes can be transgenerationally inherited in F1-F3 mice, manifested through increased follicular atresia and decreased anti-Müllerian hormone levels. Excessive Apoptosis of granulosa cells is found to underlie these pathological processes. By combining diverse Sequencing techniques, we identify persistent Rhobtb1 hypomethylation across multiple generations. Further exploration reveals that RhoBTB1 regulates FGF18 via ubiquitination, triggering MAPK pathway activation and subsequent granulosa cell Apoptosis. Notably, similar Rhobtb1 hypomethylation patterns are observed in blood samples from DOR patients. Furthermore, intervention with a methyl-donor diet effectively ameliorates DOR phenotypes in F1-F3 offspring. These findings highlight the transgenerational effects of DOR, elucidate its underlying causes and pathogenic mechanisms, and propose potential epigenetic therapy strategies.

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