PMID- 37642904 OWN - NLM STAT- MEDLINE DCOM- 20240304 LR - 20240304 IS - 1720-8386 (Electronic) IS - 0391-4097 (Print) IS - 0391-4097 (Linking) VI - 47 IP - 3 DP - 2024 Mar TI - Maternal androgen excess inhibits fetal cardiomyocytes proliferation through RB-mediated cell cycle arrest and induces cardiac hypertrophy in adulthood. PG - 603-617 LID - 10.1007/s40618-023-02178-1 [doi] AB - PURPOSE: Maternal hyperandrogenism during pregnancy is associated with adverse gestational outcomes and chronic non-communicable diseases in offspring. However, few studies are reported to demonstrate the association between maternal androgen excess and cardiac health in offspring. This study aimed to explore the relation between androgen exposure in utero and cardiac health of offspring in fetal and adult period. Its underlying mechanism is also illustrated in this research. METHODS: Pregnant mice were injected with dihydrotestosterone (DHT) from gestational day (GD) 16.5 to GD18.5. On GD18.5, fetal heart tissue was collected for metabolite and morphological analysis. The hearts from adult offspring were also collected for morphological and qPCR analysis. H9c2 cells were treated with 75 muM androsterone. Immunofluorescence, flow cytometry, qPCR, and western blot were performed to observe cell proliferation and explore the underlying mechanism. RESULTS: Intrauterine exposure to excessive androgen led to thinner ventricular wall, decreased number of cardiomyocytes in fetal offspring and caused cardiac hypertrophy, compromised cardiac function in adult offspring. The analysis of steroid hormone metabolites in fetal heart tissue by ultra performance liquid chromatography and tandem mass spectrometry showed that the content of androgen metabolite androsterone was significantly increased. Mechanistically, H9c2 cells treated with androsterone led to a significant decrease in phosphorylated retinoblastoma protein (pRB) and cell cycle-related protein including cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin D1 (CCND1) in cardiomyocytes. This resulted in cell cycle arrest at G1-S phase, which in turn inhibited cardiomyocyte proliferation. CONCLUSION: Taken together, our results indicate that in utero exposure to DHT, its metabolite androsterone could directly decrease cardiomyocytes proliferation through cell cycle arrest, which has a life-long-lasting effect on cardiac health. Our study highlights the importance of monitoring sex hormones in women during pregnancy and the follow-up of cardiac function in offspring with high risk of intrauterine androgen exposure. CI - (c) 2023. The Author(s). FAU - Huo, Y AU - Huo Y AD - National Children's Medical Center, Children's Hospital of Fudan University, Fudan University, Shanghai, 201102, China. AD - National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, 399 Wanyuan Road, Minhang, Shanghai, 201102, China. FAU - Wang, W AU - Wang W AD - Guangzhou Center for Disease Control and Prevention, Guangzhou, 510080, China. FAU - Zhang, J AU - Zhang J AD - National Children's Medical Center, Children's Hospital of Fudan University, Fudan University, Shanghai, 201102, China. AD - National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, 399 Wanyuan Road, Minhang, Shanghai, 201102, China. AD - Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, 201102, China. FAU - Xu, D AU - Xu D AD - National Children's Medical Center, Children's Hospital of Fudan University, Fudan University, Shanghai, 201102, China. AD - National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, 399 Wanyuan Road, Minhang, Shanghai, 201102, China. FAU - Bai, F AU - Bai F AD - National Children's Medical Center, Children's Hospital of Fudan University, Fudan University, Shanghai, 201102, China. AD - National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, 399 Wanyuan Road, Minhang, Shanghai, 201102, China. FAU - Gui, Y AU - Gui Y AD - National Children's Medical Center, Children's Hospital of Fudan University, Fudan University, Shanghai, 201102, China. yhgui_sh@163.com. AD - National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, 399 Wanyuan Road, Minhang, Shanghai, 201102, China. yhgui_sh@163.com. AD - Cardiovascular Center, Children's Hospital of Fudan University, Shanghai, 201102, China. yhgui_sh@163.com. LA - eng GR - XM06221237/construction of Innovation Platform for Early Childhood Health and Maintenance/ PT - Journal Article DEP - 20230829 PL - Italy TA - J Endocrinol Invest JT - Journal of endocrinological investigation JID - 7806594 RN - 0 (Androgens) RN - C24W7J5D5R (Androsterone) RN - 0 (Cell Cycle Proteins) RN - 08J2K08A3Y (Dihydrotestosterone) SB - IM MH - Humans MH - Adult MH - Pregnancy MH - Female MH - Animals MH - Mice MH - *Androgens/adverse effects MH - *Myocytes, Cardiac MH - Androsterone MH - Cell Cycle Checkpoints MH - Cell Proliferation MH - Cell Cycle Proteins MH - Dihydrotestosterone MH - Cardiomegaly/chemically induced PMC - PMC10904501 OTO - NOTNLM OT - Androgen excess OT - Cardiac function OT - Cardiomyocytes' proliferation OT - DOHaD COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/08/29 12:42 MHDA- 2024/03/04 06:48 PMCR- 2023/08/29 CRDT- 2023/08/29 11:17 PHST- 2023/05/18 00:00 [received] PHST- 2023/08/16 00:00 [accepted] PHST- 2024/03/04 06:48 [medline] PHST- 2023/08/29 12:42 [pubmed] PHST- 2023/08/29 11:17 [entrez] PHST- 2023/08/29 00:00 [pmc-release] AID - 10.1007/s40618-023-02178-1 [pii] AID - 2178 [pii] AID - 10.1007/s40618-023-02178-1 [doi] PST - ppublish SO - J Endocrinol Invest. 2024 Mar;47(3):603-617. doi: 10.1007/s40618-023-02178-1. Epub 2023 Aug 29.