Impairment of placental function and maternal-fetal immunity cross-talk by per- and polyfluoroalkyl substances during early pregnancy

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants that have been associated with adverse pregnancy outcomes and immune dysfunction. However, the impact of PFAS on trophoblast-mediated immune interactions at the maternal-fetal interface remains unclear. In this study, we evaluated the effects of human-relevant PFAS on trophoblast function and immune crosstalk using a three-dimensional (3D) trophoblast spheroid model and a co-culture system with CD4+ T cells. JEG-3 spheroids were exposed to multiple PFAS, including perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), individually and as a mixture at real-life concentrations to assess viability, invasion and trophoblast-derived β-hCG secretion. Using a placental–immune cell co-culture model, we examined bidirectional interactions and their respective effects on functional endpoints in both cellular compartments and further investigated how exposure to PFAS may interfere in the bidirectional communication. We report a significant decrease in trophoblast viability, after exposure to individual PFOS, PFOA and the PFAS mixture. PFAS mixture, PFOS, PFHxS, PFNA and PFDA exposure significantly increased invasiveness in JEG-3 spheroids, while PFOA decreased JEG-3 invasion significantly. Additionally, β-hCG production declined after 48 hours of PFOS and PFAS mixture exposure in JEG-3 spheroids. Moreover, following PFAS mixture exposure, we observed a downregulation of CD69 and IFNγ production in CD4+ T cells, particularly within Th2 cells, while CD154 expression was also reduced. Overall, these findings suggest that PFAS exposure may influence trophoblast-mediated immune signaling, with potential implications for pregnancy-related processes.