Epidemiological studies have demonstrated that fine particulate matter (PM2.5) is associated with adverse obstetric and postnatal metabolic health outcomes, but the mechanism remains unclear. This study aimed to investigate the toxicological pathways by which PM2.5 damaged placental trophoblasts in vivo and in vitro. We confirmed that PM2.5 induced adverse gestational outcomes such as increased fetal mortality rates, decreased fetal numbers and weight, damaged placental structure, and increased apoptosis of trophoblasts. Additionally, PM2.5 induced dysfunction of the trophoblast cell line HTR8/SVneo, including in its proliferation, apoptosis, invasion, migration and angiogenesis. Moreover, we comprehensively analyzed the transcriptional landscape of HTR8/SVneo cells exposed to PM2.5 through RNA-Seq and observed that PM2.5 triggered overexpression of pathways involved in oxidative stress and mitochondrial apoptosis to damage HTR8/SVneo cell biological functions through CYP1A1. Mechanistically, PM2.5 stimulated KLF9, a transcription factor identified as binding to CYP1A1 promoter region, which further modulated the CYP1A1-driven downstream phenotypes. Together, this study demonstrated that the KLF9/CYP1A1 axis played a crucial role in the toxic progression of PM2.5 induced adverse pregnancy outcomes, suggesting adverse effects of environmental pollution on pregnant females and putative targeted therapeutic strategies.

• Gestational GenX exposure causes fetal growth restriction and placental damage. • GenX induces offspring vascular maldevelopment and endothelial dysfunction. • GenX triggers endothelial ferroptosis via GSH/SOD depletion & MDA/Fe²⁺/ROS rise. • GenX binds GPX4, promoting its ubiquitination-mediated degradation. • GPX4 overexpression rescues GenX-induced ferroptosis & endothelial damage.

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.