Mus musculus strain:C57Bl/6J Raw sequence reads
Hyperandrogenism during pregnancy in women with polycystic ovary syndrome (PCOS) can negatively impact embryo development and offspring health. Moreover, pregnancies in PCOS condition are associated with miscarriage, preterm delivery, and perinatal mortality. Yet, the mechanisms of these pregnancy complications and the impact of hyperandrogenic in utero environment on the offspring is unknown. In a dihydrotestosterone-induced peripubertal PCOS-like mice model with anovulation, aberrant ovarian morphology, and obesity we found a marked reduced pregnancy rate and impaired placenta and embryonic development at embryonic (E) day 10.5 and 13.5, which was normal when treated with the androgen receptor blocker, flutamide. Moreover, whole genome bisulphite and RNA sequencing of primordial germ cells (PGCs) and placenta revealed molecular mechanisms causing the aberrant placenta and embryo development. The proportion of placenta trophoblast precursor cells was severely reduced, which led to impaired formation of syncytiotrophoblast layers and trophoblast giant cells contributing to impaired implantation and maintenance of pregnancy. Similar disruptions were observed in human trophoblast organoids when treated with androgens suggesting that these effects are the underlying causes of pregnancy complications in women with PCOS.