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Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden ; Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden ; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
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2023 (English)In: Cell Reports Medicine, E-ISSN 2666-3791 , Vol. 4, no 5, article id 101035Article in journal (Refereed) Published
Abstract [en]

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. 

Place, publisher, year, edition, pages
Cell Press , 2023. Vol. 4, no 5, article id 101035
Keywords [en]
adipose tissue, male offspring, male offspring to male germline, maternal hyperandrogenism, maternal obesity, polycystic ovary syndrome, small non-coding RNAs, sperm, transgenerational transmission, Animals, Case-Control Studies, Female, Humans, Male, Mice, Obesity, Pregnancy, Reproduction, Semen, small untranslated RNA, animal experiment, animal model, animal tissue, Article, case control study, childhood obesity, cohort analysis, controlled study, differential gene expression, dyslipidemia, fetus outcome, fetus risk, gene locus, genetic risk, genital system disease, germ line, high risk infant, high risk patient, human, hyperandrogenism, maternal fetal transmission, metabolic disorder, mouse, nonhuman, ovary polycystic disease, prenatal exposure, progeny, risk assessment, RNA analysis, vertical transmission, animal, genetics
National Category
Obstetrics, Gynecology and Reproductive Medicine Physiology
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-22630DOI: 10.1016/j.xcrm.2023.101035ISI: 001001951100001PubMedID: 37148878Scopus ID: 2-s2.0-85159450311OAI: oai:DiVA.org:his-22630DiVA, id: diva2:1761313
Funder
Knut and Alice Wallenberg Foundation, 2019.0211Novo Nordisk Foundation, NNF18OC0033992, NNF19OC0056647Adlerbertska Research Foundation, GU 2019/86O.E. och Edla Johanssons vetenskapliga stiftelse, 2021Magnus Bergvall Foundation, 2020-03808, 2021-04329H.R.H. Crown Princess Lovisa's Association for Child CareAxel Tielmans minnesfond
Note

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.)

Available from: 2023-06-01 Created: 2023-06-01 Last updated: 2023-07-14Bibliographically approved

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