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

Summary

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 (F ₁) male offspring are passed down to F ₃. Sequencing of F ₁–F ₃ 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.

Graphical abstract

Highlights

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  PCOS-sons are often obese and have dyslipidemia

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  miRNAs altered in the serum of PCOS-sons and women with PCOS targets PCOS-risk genes

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  Small RNAs present in sperm imply transgenerational transmission of phenotype in mice

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  Shared miRNAs between mouse sperm of F ₁–F ₃ generations and human serum are revealed

Abstract

Risal et al. found that the sons of women affected by polycystic ovary syndrome (PCOS) are frequently obese and dyslipidemic. Male descendants of obese or androgen-exposed mothers also exhibit reproductive and metabolic problems across generations, mediated by sperm small RNAs dysregulation. Common predicted small RNA targets are suggested in PCOS-affected mice and PCOS-sons’ serum.