Triphenyl phosphate inhibit migration and invasion of EVT cells through PPARγ-mediated autophagy

Triphenyl phosphate (TPhP) is a commonly used organophosphorus flame retardant, and its potential health risks to mothers and infants are considerable. Our previous research revealed that gestational TPhP exposure significantly reduces the depth of placental implantation and impairs uterine spiral arteries remodelling, leading to preeclampsia (PE)-like symptoms, but the underlying mechanism remains unclear. In this study, we further demonstrate that TPhP activated the transcription of Phosphatase and tensin homolog (PTEN) by activating peroxisome proliferator activated receptor gamma (PPARγ). This activation subsequently inhibits the PI3K-AKT-mTOR signaling pathway, modulates autophagy homeostasis, and inhibits the migration and invasion of extravillous trophoblast (EVT) cells. Notably, knockdown of PTEN or PPARγ with shRNA, or inhibition of autophagy with chloroquine (CQ) alleviates the TPhP-induced inhibition of EVT cells migration or invasion. Furthermore, using an established murine intrauterine exposure model, we confirmed that TPhP activates PPARγ, increases PTEN expression in placental trophoblast, inhibits the PI3K-AKT-mTOR signaling pathway and disturbs autophagy homeostasis. Collectively, these findings elucidate that TPhP inhibits EVT cells migration and invasion via the PPARγ-PTEN-PI3K-AKT-mTOR mediated autophagy pathway, providing a new toxicity pathway in placental toxicology. Additionally, this study provides new insights into the etiological research of PE.