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

Milu Li, Yaling Wu, Siting Wei, Tianyu Zhang, Wei Yan, Yueyue Gao, Yingying Chen, Dianxing Hu, Tong Wu, Mo Li, Wenwen Wang, Yan Li, Su Zhou (), Ximiao He (), Shixuan Wang () and Jinjin Zhang ()
Additional contact information
Milu Li: Huazhong University of Science and Technology
Yaling Wu: Huazhong University of Science and Technology
Siting Wei: Huazhong University of Science and Technology
Tianyu Zhang: Huazhong University of Science and Technology
Wei Yan: Huazhong University of Science and Technology
Yueyue Gao: Huazhong University of Science and Technology
Yingying Chen: Huazhong University of Science and Technology
Dianxing Hu: Huazhong University of Science and Technology
Tong Wu: Huazhong University of Science and Technology
Mo Li: Huazhong University of Science and Technology
Wenwen Wang: Huazhong University of Science and Technology
Yan Li: Huazhong University of Science and Technology
Su Zhou: Huazhong University of Science and Technology
Ximiao He: Huazhong University of Science and Technology
Shixuan Wang: Huazhong University of Science and Technology
Jinjin Zhang: Huazhong University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63440-z

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