F-53B-induced placental vascular endothelial dysfunction leads to intrauterine growth retardation of fetal mice

Chlorinated polyfluoroalkyl ether sulfonic acid (Cl-PFESAs, trade name F-53B) is a perfluorinated compound substitute whose concentration in the placenta is negatively correlated with neonatal weight, yet its toxic mechanism remains unclear. In this study, pregnant C57BL/6 mice were orally administered with 5, 50, and 500 μg/kg of F-53B from gestational days 0.5 to 17.5. By integrating in vivo imaging and laser scattering imaging, we found that F-53B exposure resulted in increased placental barrier permeability and reduced maternal-fetal blood perfusion, which may underline the observed fetal growth retardation. Pathological and immunofluorescence examination revealed that F-53B may trigger the endothelial-to-mesenchymal transition (EndMT) in the placental labyrinth vasculature. Combining RNA sequencing and trophoblast-endothelial cell co-culture experiments, we identified EndMT induced placental vascular injury as a key mechanism in F-53B induced fetal growth retardation, potentially initiated by interfered pro-angiogenic function of trophoblasts. Our results indicate that EndMT driven placental vascular injury is a key event in F-53B-induced fetal growth restriction, providing a new perspective on the developmental toxicity mechanism of F-53B. • Maternal exposure to F-53B caused retarded fetal development in mice. • Endothelial to mesenchymal transition in labyrinth may be the primary cause of placental vascular dysfunction. • F-53B interferes with the pro-angiogenesis function of trophoblast may contribute to the endothelial dysfunction.