Dissecting the Impact of Maternal Androgen Exposure on Developmental Programming through Targeting the Androgen Receptor

Abstract Women with polycystic ovary syndrome (PCOS) exhibit sustained elevation in circulating androgens during pregnancy, an independent risk factor linked to pregnancy complications and adverse outcomes in offspring. Yet, further studies are required to understand the effects of elevated androgens on cell type‐specific placental dysfunction and fetal development. Therefore, a PCOS‐like mouse model induced by continuous androgen exposure is examined. The PCOS‐mice exhibited impaired placental and embryonic development, resulting in mid‐gestation lethality. Co‐treatment with the androgen receptor blocker, flutamide, prevents these phenotypes including germ cell specification. Comprehensive profiling of the placenta by whole‐genome bisulfite and RNA sequencing shows a reduced proportion of trophoblast precursors, possibly due to the downregulation of Cdx2 expression. Reduced expression of Gcm1 , Synb , and Prl3b1 is associated with reduced syncytiotrophoblasts and sinusoidal trophoblast giant cells, impairs placental labyrinth formation. Importantly, human trophoblast organoids exposed to androgens exhibit analogous changes, showing impaired trophoblast differentiation as a key feature in PCOS‐related pregnancy complications. These findings provide new insights into the potential cellular targets for future treatments.