Bisphenol A induces placental ferroptosis and fetal growth restriction via the YAP/TAZ-ferritinophagy axis

Abstract

Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR patients showed higher levels of BPA in the urine, serum, and placenta; meanwhile, trophoblast ferroptosis was observed in FGR placentas, as indicated by accumulated intracellular iron, impaired antioxidant molecules, and increased lipid peroxidation products. To investigate the role of ferroptosis in placental and fetal growth, BPA stimulation was performed both in vivo and in vitro. BPA exposure during gestation was associated with FGR in mice; also, it induces ferroptosis in mouse placentas and human placental trophoblast. Pretreatment with ferroptosis inhibitor ferritin-1 (Fer-1) alleviated BPA-induced oxidative damage and cell death. Notably, BPA reduced the trophoblastic expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which regulated tissue growth and organ size. YAP or TAZ siRNA enhanced BPA-induced ferroptosis, suggesting that trophoblast ferroptosis is dependent on YAP/TAZ downregulation after BPA stimulation. Consistently, the protein levels of YAP/TAZ were also reduced in FGR placentas. Further results revealed that silencing YAP/TAZ promoted BPA-induced ferroptosis through autophagy. Pretreatment with autophagy inhibitor chloroquine (CQ) attenuated BPA-induced trophoblast ferroptosis. Ferritinophagy, an autophagic degradation of ferritin (FTH1), was observed in FGR placentas. Similarly, BPA reduced the protein level of FTH1 in placental trophoblast. Pretreatment with iron chelator desferrioxamine (DFO) and NCOA4 (an autophagy cargo receptor) siRNA weakened the ferroptosis of trophoblast after exposure to BPA, indicating that autophagy mediates ferroptosis in BPA-stimulated trophoblast by degrading ferritin. In summary, ferroptosis was featured in BPA-associated FGR and trophoblast injury; the regulation of ferroptosis involved the YAP/TAZ-autophagy-ferritin axis.