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.
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Funding
Vetenskapsrådet
2018-02435, 2022-00550 (ESV); 2018-02557 and 2020-00253 (QD)
Knut och Alice Wallenbergs Stiftelse
2019.0211 (QD)
Novo Nordisk Fonden
NNF18OC0033992, NNF19OC0056647 and NNF22OC0072904 (ESV)
Diabetesfonden
DIA2021-633 (ESV)
Strategic Research Program in Diabetes at the Karolinska Institutet
Adlerbertska Research Foundation
GU 2019/86 (ESV)
Karolinska Institutet
KID funding: 2020-00990 (ESV)
Regional Agreement on Medical Training and Clinical Research between the Stockholm County Council and the Karolinska Institutet
20190079 (ESV)
O. E. och Edla Johanssons Vetenskapliga Stiftelse
2021 (SR)
Magnus Bergvalls Stiftelse
2020-03808 and 2021-04329 (SR)
Karolinska Institutet
2020-02026 (SR)
National Fund for Scientific and Technological Development (FONDECYT)
1151531 (TSP)
National Fund for Scientific and Technological Development (FONDECYT)
1201483 (BE)
National Commission for Scientific and Technological Research (CONICYT)
RF
Stiftelsen Axel Tielmans minnesfond
RF
HKH Kronprinsessan Lovisas förening för barnasjukvård
RF