Perfluorooctanoic acid exposure induces visual impairment via microglia-mediated neuroinflammation and retinal ganglion cell apoptosis.

Perfluoroalkyl and polyfluoroalkyl substances are closely associated with visual impairment; however, the pathogenic mechanisms through which they cause optic nerve damage and their relationships with the onset of ocular diseases remain poorly defined. In this study, a mouse model of perfluorooctanoic acid (PFOA) exposure was established by oral administration of PFOA (1 mg/kg/day) for 60 consecutive days to investigate the effects of PFOA on retinal ganglion cells (RGCs), the primary constituents of the optic nerve, and retinal microglia, the immune sentinels of the optic nerve. Retinal ischemia‒reperfusion (IR) is a key common pathological process of multiple vision-threatening ocular diseases. Comparisons of changes in visual function, retinal structure and key cellular biological processes between PFOA-exposed mice and IR-injured mice revealed that PFOA contributed to visual impairment by inducing microglia-mediated neuroinflammation and RGC apoptosis. Experiments using an in vitro coculture system further demonstrated that PFOA directly impaired RGCs by affecting mitochondrial function and indirectly caused RGC damage by triggering microglial activation and subsequent inflammatory cascades. Moreover, we observed that PFOA exposure increased retinal susceptibility and exacerbated neuroinflammation and RGC injury under pathological conditions, thereby accelerating disease progression and vision loss. This study reveals the mechanisms underlying PFOA-induced optic nerve damage and its potential role in promoting retinal disease progression, suggesting that PFOA may represent an environmental risk factor for visual impairment.