Placentation Disruption by Perfluorooctanoic Acid and Perfluorooctanesulfonate in Human Trophoblast Organoids

Prenatal exposure to perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) is associated with low birth weight, a condition often resulting from placental dysfunction. However, whether and how PFOA and PFOS affect human placentation and placental-specific functions remains unclear. In this study, we reconstructed a human trophoblast organoid model, incorporating a near-physiological proportion of extravillous trophoblast (EVT). The organoids were exposed to PFOA or PFOS for 7 days. Exposure to PFOA at 10 nM significantly increased the proportion of villous cytotrophoblast (CTB) cells, while reducing the proportion of EVT and syncytiotrophoblast (STB) cells at 10 and 100 nM, respectively. A similar pattern was observed with PFOS, albeit at concentrations 10 times higher than those of PFOA. Mechanistically, both PFOA and PFOS inhibited trophoblast differentiation by antagonizing the transcriptional activity of cAMP response element-binding protein (CREB). This disruption in placentation impaired placental function, as evidenced by significantly decreasing hormone secretion and invasion potential. Our investigation may provide mechanistic insight into the association of PFOA and PFOS with low birth weight observed in epidemiological studies, with PFOA demonstrating a stronger effect than PFOS. These findings may aid in evaluating the toxicity of emerging PFAS and support the development or selection of safer chemical alternatives.