Promoted Translocation of Perfluorooctanoic Acid across the Blood–Retinal Barrier due to its Inhibition of Tight Junction Assembly by Antagonizing LPAR1

Eye health is becoming a significant public health concern, and a recent epidemiological investigation suggested that perfluorooctanoic acid (PFOA), a so-called forever chemical, was correlated with decreased human visual acuity; however, it remains unknown whether PFOA can pass through the blood–retinal barrier (BRB) to cause visual toxicity. In this study, the mice received a 28-day subchronic oral exposure to PFOA. The results of spatial mass spectrometry imaging indicated that the eye-enriched PFOA dispersed into the subretina primarily through the outer BRB (oBRB), which subsequently resulted in significantly increased apoptosis and decreased thickness of multiple oBRB-associated layers. BRB integrity and function were compromised due to decreased expression of the tight junction (TJ). Mechanistically, PFOA outcompeted lysophosphatidic acid to bind strongly with lysophosphatidic acid receptor 1 (LPAR1) in its antagonism, abolishing its ability to stimulate the TJ assembly-related signaling pathway. This subsequently attenuated phosphorylation of the myosin light chain, rendering insufficient contraction of the actomyosin cytoskeleton, leading to decreased TJ assembly and BRB leakage. This, in turn, facilitated PFOA translocation across the BRB and accumulation within the subretinal space. Our findings suggest that oBRB is particularly vulnerable to PFOA, which targets directly LPAR1 to disable its function of maintaining TJ assembly cascades, leading to adverse visual effects.