Li Milu, Wu Yaling, Wei Siting, Zhang Tianyu, Yan Wei, Gao Yueyue, Chen Yingying, Hu Dianxing, Wu Tong, Li Mo, Wang Wenwen, Li Yan, Zhou Su, He Ximiao, Wang Shixuan, Zhang Jinjin
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, China.
Nat Commun. 2025 Sep 16;16(1):8289. doi: 10.1038/s41467-025-63440-z.
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.
卵巢储备功能减退（DOR）与不孕、过早绝经及各种长期健康问题的风险增加有关。我们之前的研究表明，F1代小鼠产前暴露于对羟基苯甲酸丙酯与DOR之间存在关联。在此，我们进一步揭示，DOR表型可在F1 - F3代小鼠中跨代遗传，表现为卵泡闭锁增加和抗苗勒管激素水平降低。发现颗粒细胞过度凋亡是这些病理过程的基础。通过结合多种测序技术，我们确定了多代小鼠中持续存在的Rhobtb1低甲基化。进一步研究发现，RhoBTB1通过泛素化调节FGF18，触发MAPK途径激活及随后的颗粒细胞凋亡。值得注意的是，在DOR患者的血液样本中观察到类似 的Rhobtb1低甲基化模式。此外，采用甲基供体饮食进行干预可有效改善F1 - F3代后代的DOR表型。这些发现突出了DOR的跨代效应，阐明了其潜在原因和致病机制，并提出了潜在的表观遗传治疗策略。
