1-nitropyrene triggers trophoblast dysfunction via EMPs-mediated ferroptosis through Glutathione peroxidase 4

Abstract

1-Nitropyrene (1-NP), a prevalent environmental pollutant, poses significant risks to vascular and placental health. This study demonstrates that 1-NP induces vascular endothelial dysfunction by dose-dependently reducing human umbilical vein endothelial cell (HUVEC) viability, inhibiting proliferation, promoting apoptosis, and impairing tube formation. Notably, endothelial microparticles (EMPs) isolated from 1-NP-treated HUVECs (N-EMPs) exhibited distinct biological effects compared to control EMPs (C-EMPs). N-EMPs suppressed trophoblast viability, proliferation, invasion, and migration, correlating with N-cadherin downregulation and E-cadherin upregulation. Mechanistically, ferroptosis emerged as the primary driver of N-EMPs-induced trophoblast dysfunction, evidenced by reactive oxygen species (ROS) accumulation, glutathione depletion, elevated malondialdehyde and Fe²⁺ levels, and mitochondrial oxidative stress. Crucially, glutathione peroxidase 4 (GPX4) was identified as a central regulator, with its expression significantly downregulated by N-EMPs. Overexpression of GPX4 reversed ferroptosis markers (restoring GSH/SOD, reducing MDA/Fe²⁺) and rescued trophoblast viability, migration, and invasiveness. These findings establish a previously unrecognized pathogenic cascade wherein 1-NP triggers endothelial injury, releasing cytotoxic EMPs that propagate ferroptosis-dependent trophoblast dysfunction via GPX4 suppression. The central role of EMPs as mediators of environmental pollutant toxicity highlights their potential as biomarkers and therapeutic targets for mitigating placental developmental disorders caused by 1-NP exposure.