Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome

The transgenerational maternal effects of polycystic ovary syndrome (PCOS) in female progeny are being revealed. As there is evidence that a male equivalent of PCOS may exists, we ask whether sons born to mothers with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a register-based cohort and a clinical case-control study, we find that PCOS-sons are more often obese and dyslipidemic. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in first-generation (F1) male offspring are passed down to F3. Sequencing of F1–F3 sperm reveals distinct differentially expressed (DE) small non-coding RNAs (sncRNAs) across generations in each lineage. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism, strengthening the translational relevance and highlighting a previously underappreciated risk of transmission of reproductive and metabolic dysfunction via the male germline. CC BY 4.0© 2023 The Author(s)Correspondence: qiaolin.deng@ki.se (Q.D.), elisabet.stener-victorin@ki.se (E.S.-V.)We thank Zhiyi Zhao, Jacob Victorin, Sonja Edström, and Sara Pilström for technical assistance during animal work and molecular analysis; TSE Systems and the Metabolic Phenotyping Center at the Strategic Research program in Diabetes at the Karolinska Institutet; and the electron microscopy unit Emil at Huddinge University Hospital at the Karolinska Institutet. This work is supported by the Swedish Medical Research Council: project nos. 2018-02435 and 2022-00550 (E.S.-V.) and 2018-02557 and 2020-00253 (Q.D.); the Knut and Alice Wallenberg Foundation: 2019.0211 (Q.D.); Distinguished Investigator Grant – Endocrinology and Metabolism, Novo Nordisk Foundation: NNF22OC0072904 (E.S.-V.); the Diabetes Foundation:DIA2021-633 (E.S.-V.); the Novo Nordisk Foundation: NNF18OC0033992 and NNF19OC0056647 (E.S.-V.); the Strategic Research Program in Diabetes at the Karolinska Institutet (E.S.-V.); the Adlerbertska Research Foundation: GU 2019/86 (E.S.-V.); Karolinska Institutet KID funding: 2020-00990 (E.S.-V.); a Karolinska Instiutet faculty funded position (Q.D.); the Regional Agreement on Medical Training and Clinical Research between the Stockholm County Council and the Karolinska Institutet: 20190079 (E.S.-V.); O.E. och Edla Johanssons Stiftelse 2021 (S.R.); the Karolinska Institutet China scholarship council program (Q.L.); Magnus Bergvalls Stiftelse: 2020-03808 and 2021-04329 (S.R.); the Karolinska Institutet: 2020-02026 (S.R.); the National Fund for Scientific and Technological Development (FONDECYT): project no. 1151531 (T.S.P.); the FONDECYT: project no. 1201483 (B.E.); the National Commission for Scientific and Technological Research (CONICYT) (R.F.); HKH Kronprinsessan Lovisas förening för barnasjukvård (R.F.); and Stiftelsen Axel Tielmans minnesfond (R.F.)