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

Polycystic ovary syndrome (PCOS), affecting ~15% of women at reproductive age worldwide, is a highly heritable disorder and linked to comorbidities such as infertility, type-2 diabetes, psychiatric disorders, and cancer. The transgenerational maternal effects of polycystic ovary syndrome (PCOS) in female progeny have been revealed. As there are evidences that a male equivalent of PCOS may exist, one unexplored question is 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. Moreover, serum miRNAs from PCOS-sons are found to potentially regulate PCOS-risk genes. Our PCOS-like mouse model induced by late gestation injection of dihydrotestosterone with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in first-generation male offspring are passed down to the third generation. Small non-coding RNAs (sncRNAs) sequencing of 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 DEsncRNAs in serum from PCOS-sons provide evidence of similar effects of maternal hyperandrogenism. These findings strengthen the translational relevance and shed light on a previously underappreciated risk of reproductive and metabolic dysfunction transmission via the male germline and identify possible molecular markers for prediction of transmission of disease in future generations.