Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure
Abstract Androgen exposure (AE) poses a profound health threat to women, yet its transgenerational impacts on male descendants remain unclear. Here, employing a large-scale mother-child cohort, we show that maternal hyperandrogenism predisposes sons to β-cell dysfunction. Male offspring mice with pr...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-025-00769-1 |
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| author | Yuqing Zhang Shourui Hu Shan Han Congcong Liu Xiaofan Liang Yuxuan Li Zongxuan Lin Yiming Qin Chunxuan Geng Yue Liu Linlin Cui Jingmei Hu Changming Zhang Zhao Wang Xin Liu Jinlong Ma Zi-Jiang Chen Han Zhao |
| author_facet | Yuqing Zhang Shourui Hu Shan Han Congcong Liu Xiaofan Liang Yuxuan Li Zongxuan Lin Yiming Qin Chunxuan Geng Yue Liu Linlin Cui Jingmei Hu Changming Zhang Zhao Wang Xin Liu Jinlong Ma Zi-Jiang Chen Han Zhao |
| author_sort | Yuqing Zhang |
| collection | DOAJ |
| description | Abstract Androgen exposure (AE) poses a profound health threat to women, yet its transgenerational impacts on male descendants remain unclear. Here, employing a large-scale mother-child cohort, we show that maternal hyperandrogenism predisposes sons to β-cell dysfunction. Male offspring mice with prenatal AE exhibited hyperglycemia and glucose intolerance across three generations, which were further exacerbated by aging and a high-fat diet. Mechanistically, compromised insulin secretion underlies this transgenerational susceptibility to diabetes. Integrated analyses of methylome and transcriptome revealed differential DNA methylation of β-cell functional genes in AE-F1 sperm, which was transmitted to AE-F2 islets and further retained in AE-F2 sperm, leading to reduced expression of genes related to insulin secretion, including Pdx1, Irs1, Ptprn2, and Cacna1c. The methylation signatures in AE-F1 sperm were corroborated in diabetic humans and the blood of sons with maternal hyperandrogenism. Moreover, caloric restriction and metformin treatments normalized hyperglycemia in AE-F1 males and blocked their inheritance to offspring by restoring the aberrant sperm DNA methylations. Our findings highlight the transgenerational inheritance of impaired glucose homeostasis in male offspring from maternal AE via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations’ metabolic health. |
| format | Article |
| id | doaj-art-2f1965c818774e00a63d668d5485af2f |
| institution | OA Journals |
| issn | 2056-5968 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj-art-2f1965c818774e00a63d668d5485af2f2025-08-20T02:13:14ZengNature Publishing GroupCell Discovery2056-59682025-02-0111111710.1038/s41421-025-00769-1Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposureYuqing Zhang0Shourui Hu1Shan Han2Congcong Liu3Xiaofan Liang4Yuxuan Li5Zongxuan Lin6Yiming Qin7Chunxuan Geng8Yue Liu9Linlin Cui10Jingmei Hu11Changming Zhang12Zhao Wang13Xin Liu14Jinlong Ma15Zi-Jiang Chen16Han Zhao17State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, the Second Hospital, Shandong UniversityAbstract Androgen exposure (AE) poses a profound health threat to women, yet its transgenerational impacts on male descendants remain unclear. Here, employing a large-scale mother-child cohort, we show that maternal hyperandrogenism predisposes sons to β-cell dysfunction. Male offspring mice with prenatal AE exhibited hyperglycemia and glucose intolerance across three generations, which were further exacerbated by aging and a high-fat diet. Mechanistically, compromised insulin secretion underlies this transgenerational susceptibility to diabetes. Integrated analyses of methylome and transcriptome revealed differential DNA methylation of β-cell functional genes in AE-F1 sperm, which was transmitted to AE-F2 islets and further retained in AE-F2 sperm, leading to reduced expression of genes related to insulin secretion, including Pdx1, Irs1, Ptprn2, and Cacna1c. The methylation signatures in AE-F1 sperm were corroborated in diabetic humans and the blood of sons with maternal hyperandrogenism. Moreover, caloric restriction and metformin treatments normalized hyperglycemia in AE-F1 males and blocked their inheritance to offspring by restoring the aberrant sperm DNA methylations. Our findings highlight the transgenerational inheritance of impaired glucose homeostasis in male offspring from maternal AE via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations’ metabolic health.https://doi.org/10.1038/s41421-025-00769-1 |
| spellingShingle | Yuqing Zhang Shourui Hu Shan Han Congcong Liu Xiaofan Liang Yuxuan Li Zongxuan Lin Yiming Qin Chunxuan Geng Yue Liu Linlin Cui Jingmei Hu Changming Zhang Zhao Wang Xin Liu Jinlong Ma Zi-Jiang Chen Han Zhao Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure Cell Discovery |
| title | Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure |
| title_full | Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure |
| title_fullStr | Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure |
| title_full_unstemmed | Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure |
| title_short | Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure |
| title_sort | transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure |
| url | https://doi.org/10.1038/s41421-025-00769-1 |
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