Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome

How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F₀) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F₁-F₃ offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F₁-F₃ offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.