PFAS exposure is associated with retinal neurotoxicity in Chinese adolescents: Mechanistic insights from integrated toxicogenomic and in vitro analyses.

Per- and polyfluoroalkyl substances (PFAS) have raised increasing concerns due to their potential neurotoxicity; however, their effects on retina, a highly specialized neural tissue, remain unclear. This study aimed to investigate the retinal toxicity of PFAS in adolescents and to elucidate underlying molecular mechanisms and therapeutic targets. A cross-sectional study involving 1686 Chinese adolescents was conducted to evaluate associations between serum PFAS concentrations and retinal structural characteristics. In parallel, toxicogenomic analyses were performed to identify key genes associated with PFAS exposure and retinal diseases. Correspondingly, in vitro experiments were conducted to reveal the potential molecular mechanisms underlying the cytotoxic effects of PFAS on retinal ganglion cells (RGCs). Higher serum levels of PFOA (β = -0.05, P = 0.01), PFOS (β = -0.06, P = 0.04) and PFHxS (β = -0.11, P = 0.03), were negatively associated with global retinal nerve fiber layer (RNFL) thickness. Applying toxicogenomic screening, nine hub genes related to PFAS (e.g., CCL2, TNF-α, and TLR4) were identified to be enriched in inflammatory pathways. Mechanistically, apoptotic cell death in R28 and RGCs were promoted by PFAS exposure, characterized by elevated cleaved PARP and cleaved Caspase-3. This study provides evidence that PFAS exposures are correlated with retinal neurotoxicity in adolescents through inflammatory activation and apoptosis. The identified gene signatures highlight potential targets for prevention and therapeutic intervention.