TBBPA-BDBPE induces ferroptosis in trophoblasts through chaperone-mediated autophagy of GPX4

Tetrabromobisphenol A-bis (2,3-dibromopropyl ether) (TBBPA-BDBPE), a novel brominated flame retardant, is increasingly utilized across various industries due to its effective flame-retardant properties. However, its potential gestational toxicity has not been thoroughly investigated, raising concerns about its impact on maternal and fetal health. In this study, we explored the effects of TBBPA-BDBPE on fetal growth restriction (FGR) and placental trophoblast ferroptosis through a comprehensive approach that included both in vivo and in vitro experiments. We employed techniques such as transmission electron microscopy, immunofluorescence, co-immunoprecipitation (co-IP), and flow cytometry to elucidate the underlying mechanisms. Our results demonstrated that gestational exposure to TBBPA-BDBPE significantly induced FGR in mice, highlighting its detrimental effects on fetal development. Furthermore, we found that TBBPA-BDBPE impaired the biological functions of placental trophoblasts by instigating ferroptosis, a form of regulated cell death. Notably, we revealed for the first time that TBBPA-BDBPE enhances the expression of HSC70 and LAMP-2a, which facilitates their interaction with GPX4. This interaction triggers chaperone-mediated autophagy (CMA) of GPX4, ultimately leading to ferroptosis in trophoblasts. Importantly, our study showed that inhibiting ferroptosis effectively rescues trophoblast function, with cordycepin emerging as a promising therapeutic agent to mitigate TBBPA-BDBPE-induced trophoblast damage. These findings unveil a novel molecular mechanism underlying the toxic effects of TBBPA-BDBPE on placental health and fetal development, underscoring the urgent need for further research into the reproductive toxicity of brominated flame retardants and their implications for maternal and fetal health.