PFOS暴露通过损伤滋养层线粒体诱导先兆子痫样综合征

Abstract

Preeclampsia, defined as a hypertensive disorder during pregnancy, is a major cause of maternal and fetal mortality. Observational studies have shown that the exposure of per- and polyfluoroalkyl substances, such as perfluorooctane sulfonate (PFOS), is emerging as a significant environmental factor associated with preeclampsia risk. However, epidemiologic evidence is of correlative in nature, and unable to establish a causal relationship. Here, we established an animal model of PFOS-induced preeclampsia to explore the molecular mechanism of PFOS in placental trophoblast. In the mouse model, PFOS exposure by gavage at a dose of 10 mg/kg/d from embryonic day 7.5–16.5 was sufficient to induce preeclampsia-like symptoms such as hypertension, proteinuria, and renal glomerular endotheliosis, accompanied with placental abnormal stromal collagen deposition. In-vitro experiments of JEG-3 cells, PFOS exposure impaired trophoblast motility including the compromised abilities of migration, invasion and vascularization. Mechanistically, these pathological effects on cells resulted from SLC25A5-mediated mitochondrial damages, characterized by excessive ROS generation, decreased ATP production and mitochondrial membrane potential loss, and accompanied by the activation of p38 MAPK and JNK signaling pathways. This pioneering study provided biological plausibility to the causality verified by the animal model and the in vitro experiments, which indicates that PFOS exposure may cause preeclampsia during pregnancy via impairing trophoblast mitochondria.