Endoplasmic reticulum stress mediates oxidative stress-driven endothelial impairment and atherogenesis induced by sodium perfluorononenoxybenzene sulfonate exposure

Sodium perfluorononenoxybenzene sulfonate (OBS), a substitute for perfluorooctane sulfonate (PFOS), has been frequently detected in the environment and human blood. Although OBS exposure has been identified as a novel risk factor for atherosclerosis associated with endothelial dysfunction, the underlying molecular mechanisms remain unclear. In this study, in vitro experiments using human umbilical vein endothelial cells (HUVECs) demonstrated that OBS exposure induced oxidative stress, activated the PERK-eIF2α-ATF4 axis of endoplasmic reticulum stress (ERS) and triggered NF-κB signaling. Pharmacological inhibition with N-acetylcysteine (NAC, an antioxidant), 4-phenylbutyric acid (4-PBA, an ERS inhibitor), and BAY 11-7082 (an inhibitor for NF-κB signaling pathway) revealed a sequential pathogenic cascade, in which oxidative stress acts upstream to initiate ERS and compromise endothelial barrier function, leading to NF-κB activation, which drives inflammatory responses, monocyte adhesion, and impaired endothelial migration. Consistent with these findings, in vivo experiments in apoE^-/- mice showed that OBS exposure caused endothelial impairment, Collagen deposition, and oxidative stress in aortic tissues, accompanied by upregulating the expression of ERS and inflammation-related markers. These findings suggest that ERS serves as a key mediator linking oxidative stress to inflammation in OBS-induced endothelial dysfunction, highlighting the potential cardiovascular hazards of OBS as an emerging PFOS alternative.

Endoplasmic reticulum stress; Endothelial impairment; NF-κB signaling pathway; Oxidative stress; Sodium perfluorononenoxybenzene sulfonate (OBS).