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

Description

The transgenerational maternal effects of PCOS in female progeny have been revealed. As there are evidence that a male equivalent of PCOS may exist, we asked whether sons born to mother with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a Swedish nationwide register-based cohort and a clinical case-control study from Chile we found that PCOS-sons are more often obese and dyslipidemic. Their serum miRNAs are found to potentially regulate PCOS-risk genes. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in F1 male offspring are passed down to F3. Small non-coding RNAs (sncRNAs) sequencing of F1-F3 sperm revealed distinct differentially expressed (DE) sncRNAs across generations in the androgenized, obese, and obese and androgenized lineages, respectively. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism. These findings strengthen the translational relevance highlighting a previously under-appreciated risk of reproductive and metabolic dysfunction via the male germline transmission and potential molecular markers to study in future generations.

Institutions

• Karolinska Institutet

Categories

Funders

• Swedish Research Council

  Sweden

  Grant ID: 2018-02435, 2022-00550 (ESV); 2018-02557 and 2020-00253 (QD)
• Knut and Alice Wallenberg Foundation

  Sweden

  Grant ID: 2019.0211 (QD)
• Novo Nordisk Foundation

  Denmark

  Grant ID: NNF18OC0033992, NNF19OC0056647 and NNF22OC0072904 (ESV)
• Diabetesfonden

  Sweden

  Grant ID: DIA2021-633 (ESV)
• Strategic Research Program in Diabetes at the Karolinska Institutet
• Adlerbertska Foundations

  Sweden

  Grant ID: GU 2019/86 (ESV)
• Karolinska Institutet

  Sweden

  Grant ID: KID funding: 2020-00990 (ESV)
• Regional Agreement on Medical Training and Clinical Research between the Stockholm County Council and the Karolinska Institutet

  Grant ID: 20190079 (ESV)
• O. E. och Edla Johanssons Vetenskapliga Stiftelse

  Sweden

  Grant ID: 2021 (SR)
• Magnus Bergvalls Stiftelse

  Sweden

  Grant ID: 2020-03808 and 2021-04329 (SR)
• Karolinska Institutet

  Sweden

  Grant ID: 2020-02026 (SR)
• National Fund for Scientific and Technological Development (FONDECYT)

  Grant ID: 1151531 (TSP)
• National Fund for Scientific and Technological Development (FONDECYT)

  Grant ID: 1201483 (BE)
• National Commission for Scientific and Technological Research (CONICYT)

  Grant ID: RF
• Stiftelsen Axel Tielmans minnesfond

  Grant ID: RF
• HKH Kronprinsessan Lovisas förening för barnasjukvård

  Grant ID: RF

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