{"title":"Intrauterine hyperglycemia impairs mouse primordial germ cell development and fertility by sex-specific epigenetic reprogramming interference.","authors":"Jiangshan Cong, Qing Li, Yangyang Li, Minghao Li, Yan Shi, Peiran Hu, Xidi Yin, Qianyun Zhang, Jianzhong Sheng, Jinsong Li, Guolian Ding, Yu Zhang, Hefeng Huang","doi":"10.1038/s41421-025-00821-0","DOIUrl":null,"url":null,"abstract":"<p><p>Adverse intrauterine environments, such as hyperglycemia, impair sexual reproduction and species continuity, yet the underlying mechanisms remain poorly understood. In this study, we demonstrated that intrauterine hyperglycemia significantly disrupted primordial germ cell (PGC) development, especially in female offspring, thus reducing fertility. Using Oct4-EGFP transgenic mice with intrauterine hyperglycemia exposure, we revealed that hyperglycemia compromised sexually specific chromatin accessibility and DNA methylation reprogramming during PGC development. Particularly, in female PGCs, hyperglycemia leads to the aberrant retention of chromatin accessibility at pluripotency gene promoters such as Nanog and Tfap2c, inhibiting proper gene silencing and blocking the initiation of meiosis, which ultimately hinders oocyte maturation. Conversely, male PGCs exhibit less severe changes in chromatin accessibility and gene transcription. Intriguingly, the global DNA methylation reconstruction is impaired in male PGCs, particularly in key imprinted gene regions, suggesting potential developmental ramifications for later stages and even subsequent generations. Particularly, our findings indicate that intrauterine hyperglycemia adversely affects sex differentiation in PGCs by disrupting the expression of critical sex-determining transcription factors. Collectively, these findings highlight how intrauterine hyperglycemia interferes with sex-specific epigenetic reprogramming during PGC development, leading to abnormal germ cell development, reduced fertility, and adverse intergenerational effects.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"74"},"PeriodicalIF":12.5000,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417548/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Discovery","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41421-025-00821-0","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Adverse intrauterine environments, such as hyperglycemia, impair sexual reproduction and species continuity, yet the underlying mechanisms remain poorly understood. In this study, we demonstrated that intrauterine hyperglycemia significantly disrupted primordial germ cell (PGC) development, especially in female offspring, thus reducing fertility. Using Oct4-EGFP transgenic mice with intrauterine hyperglycemia exposure, we revealed that hyperglycemia compromised sexually specific chromatin accessibility and DNA methylation reprogramming during PGC development. Particularly, in female PGCs, hyperglycemia leads to the aberrant retention of chromatin accessibility at pluripotency gene promoters such as Nanog and Tfap2c, inhibiting proper gene silencing and blocking the initiation of meiosis, which ultimately hinders oocyte maturation. Conversely, male PGCs exhibit less severe changes in chromatin accessibility and gene transcription. Intriguingly, the global DNA methylation reconstruction is impaired in male PGCs, particularly in key imprinted gene regions, suggesting potential developmental ramifications for later stages and even subsequent generations. Particularly, our findings indicate that intrauterine hyperglycemia adversely affects sex differentiation in PGCs by disrupting the expression of critical sex-determining transcription factors. Collectively, these findings highlight how intrauterine hyperglycemia interferes with sex-specific epigenetic reprogramming during PGC development, leading to abnormal germ cell development, reduced fertility, and adverse intergenerational effects.
Cell DiscoveryBiochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍:
Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research.
Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals.
In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.