Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure

被引:1
作者
Zhang, Yuqing [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
Hu, Shourui [1 ,2 ,3 ]
Han, Shan [1 ,2 ,3 ]
Liu, Congcong [1 ,2 ,3 ]
Liang, Xiaofan [1 ,2 ,3 ]
Li, Yuxuan [1 ,2 ,3 ]
Lin, Zongxuan [1 ,2 ,3 ]
Qin, Yiming [1 ,2 ,3 ]
Geng, Chunxuan [1 ,2 ,3 ]
Liu, Yue [1 ,2 ,3 ]
Cui, Linlin [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
Hu, Jingmei [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
Zhang, Changming [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
Wang, Zhao [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
Liu, Xin [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
Ma, Jinlong [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
Chen, Zi-Jiang [1 ,2 ,3 ,4 ,5 ,6 ,7 ,8 ,9 ]
Zhao, Han [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
机构
[1] Shandong Univ, Inst Women Children & Reprod Hlth, Ctr Reprod Med,Hosp 2, State Key Lab Reprod Med & Offspring Hlth, Jinan, Shandong, Peoples R China
[2] Shandong Univ, Natl Res Ctr Assisted Reprod Technol & Reprod Gene, Jinan, Shandong, Peoples R China
[3] Shandong Univ, Key Lab Reprod Endocrinol, Minist Educ, Jinan, Shandong, Peoples R China
[4] Shandong Technol Innovat Ctr Reprod Hlth, Jinan, Shandong, Peoples R China
[5] Shandong Prov Clin Res Ctr Reprod Hlth, Jinan, Shandong, Peoples R China
[6] Shandong Key Lab Reprod Res & Birth Defect Prevent, Jinan, Shandong, Peoples R China
[7] Chinese Acad Med Sci 2021RU001, Res Unit Gametogenesis & Hlth ART Offspring, Jinan, Shandong, Peoples R China
[8] Shanghai Key Lab Assisted Reprod & Reprod Genet, Shanghai, Peoples R China
[9] Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med, Dept Reprod Med, Shanghai, Peoples R China
基金
中国国家自然科学基金; 国家重点研发计划;
关键词
PRENATAL EXPOSURE; UNITED-STATES; INSULIN; SECRETION; PREVALENCE; GENE;
D O I
10.1038/s41421-025-00769-1
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 beta-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 beta-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.
引用
收藏
页数:17
相关论文
共 50 条
[41]   Estimated Maternal Pesticide Exposure from DrinkingWater and Heart Defects in Offspring [J].
Kim, Jihye ;
Swartz, Michael D. ;
Langlois, Peter H. ;
Romitti, Paul A. ;
Weyer, Peter ;
Mitchell, Laura E. ;
Luben, Thomas J. ;
Ramakrishnan, Anushuya ;
Malik, Sadia ;
Lupo, Philip J. ;
Feldkamp, Marcia L. ;
Meyer, Robert E. ;
Winston, Jennifer J. ;
Reefhuis, Jennita ;
Blossom, Sarah J. ;
Bell, Erin ;
Agopian, A. J. .
INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH, 2017, 14 (08)
[42]   Maternal Chronic Ethanol Exposure Decreases Stress Responses in Zebrafish Offspring [J].
Kitson, Juliet E. ;
Ord, James ;
Watt, Penelope J. .
BIOMOLECULES, 2022, 12 (08)
[43]   The Maternal Environment Programs Postnatal Weight Gain and Glucose Tolerance of Male Offspring, but Placental and Fetal Growth Are Determined by Fetal Genotype in the Leprdb/ plus Model of Gestational Diabetes [J].
Nadif, Raja ;
Dilworth, Mark R. ;
Sibley, Colin P. ;
Baker, Philip N. ;
Davidge, Sandra T. ;
Gibson, J. Martin ;
Aplin, John D. ;
Westwood, Melissa .
ENDOCRINOLOGY, 2015, 156 (01) :360-366
[44]   Maternal electronic cigarette exposure in relation to offspring development: a comprehensive review [J].
Zhang, Yijia ;
Angley, Meghan ;
Qi, Xinran ;
Lu, Liping ;
D'Alton, Mary E. ;
Kahe, Ka .
AMERICAN JOURNAL OF OBSTETRICS & GYNECOLOGY MFM, 2022, 4 (05)
[45]   Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome [J].
Canouil, Mickael ;
Khamis, Amna ;
Keikkala, Elina ;
Hummel, Sandra ;
Lobbens, Stephane ;
Bonnefond, Amelie ;
Delahaye, Fabien ;
Tzala, Evangelia ;
Mustaniemi, Sanna ;
Vaarasmaki, Marja ;
Jarvelin, Marjo-Riitta ;
Sebert, Sylvain ;
Kajantie, Eero ;
Froguel, Philippe ;
Andrew, Toby .
DIABETES CARE, 2021, 44 (09) :1992-1999
[46]   Maternal nicotine exposure impairs brown adipose tissue via AMPK-SIRT1-PGC-1α signals in male offspring [J].
Li, Gai-ling ;
Ping, Jie ;
Chen, Hui-jian ;
Zhang, Wan-xia ;
Fan, Jie ;
Peng, Dang-sheng ;
Zhang, Li ;
Yan, You-e .
LIFE SCIENCES, 2021, 264
[47]   Incretin and Glucagon Levels in Adult Offspring Exposed to Maternal Diabetes in Pregnancy [J].
Kelstrup, Louise ;
Clausen, Tine D. ;
Mathiesen, Elisabeth R. ;
Hansen, Torben ;
Holst, Jens J. ;
Damm, Peter .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2015, 100 (05) :1967-1975
[48]   Maternal and Offspring Genetic Risk of Type 2 Diabetes and Offspring Birthweight Among African Ancestry Populations [J].
Rahman, Mohammad L. ;
Shrestha, Deepika ;
Workalemahu, Tsegaselassie ;
Wu, Jing ;
Zhu, Chunming ;
Zhang, Cuilin ;
Tekola-Ayele, Fasil .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2019, 104 (11) :5032-5042
[49]   Maternal Pregnancy Levels of Polychlorinated Biphenyls and Risk of Hypospadias and Cryptorchidism in Male Offspring [J].
McGlynn, Katherine A. ;
Guo, Xuguang ;
Graubard, Barry I. ;
Brock, John W. ;
Klebanoff, Mark A. ;
Longnecker, Matthew P. .
ENVIRONMENTAL HEALTH PERSPECTIVES, 2009, 117 (09) :1472-1476
[50]   Prenatal Exposure to Bisphenol A, E, and S Induces Transgenerational Effects on Male Reproductive Functions in Mice [J].
Shi, Mingxin ;
Whorton, Allison E. ;
Sekulovski, Nikola ;
MacLean, James A., II ;
Hayashi, Kanako .
TOXICOLOGICAL SCIENCES, 2019, 172 (02) :303-315