2. Academic Validation
  3. Transgenerational inheritance of diminished ovarian reserve triggered by prenatal propylparaben exposure in mice

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

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. suzhou@tjh.tjmu.edu.cn.
  • 9 National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, China. suzhou@tjh.tjmu.edu.cn.
  • 10 Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, China. suzhou@tjh.tjmu.edu.cn.
  • 11 Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. XimiaoHe@hust.edu.cn.
  • 12 Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. XimiaoHe@hust.edu.cn.
  • 13 Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. XimiaoHe@hust.edu.cn.
  • 14 Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China. XimiaoHe@hust.edu.cn.
  • 15 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. shixuanwang@tjh.tjmu.edu.cn.
  • 16 National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, China. shixuanwang@tjh.tjmu.edu.cn.
  • 17 Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, China. shixuanwang@tjh.tjmu.edu.cn.
  • 18 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. jinjinzhang@tjh.tjmu.edu.cn.
  • 19 National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, China. jinjinzhang@tjh.tjmu.edu.cn.
  • 20 Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, China. jinjinzhang@tjh.tjmu.edu.cn.
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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