Abstract
Perfluorooctane sulfonate (PFOS) is a widespread environmental pollutant and may cause a variety of adverse health effects. The hepatotoxicity of PFOS has attracted particular attention, given the fact that the liver has one of the highest PFOS accumulations among human tissues. In this study, we revealed that subchronic PFOS exposure may exacerbate carbon tetrachloride (CCl4 )-induced liver fibrosis in animal models. Administration with 1 mg/kg PFOS every other day for 56 days dramatically enhanced CCl4 -mediated liver injury and hepatic stellate cell (HSC) activation. Furthermore, PFOS exposure may promote the activation of high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) signaling pathway through inducing the secretion of HMGB1 from hepatocytes. PFOS exposure induced the translocation of HMGB1 from the nucleus into the cytoplasm of hepatocytes and cultured BRL-3A cells at a starting concentration of 50 μM. This process is accompanied with concurrent flux of calcium, suggesting a link between calcium signaling and HMGB1 release following PFOS exposure. Finally, we showed that PFOS-exposed conditional medium (PFOS-CM) of hepatocytes may induce the translocation of Smad2/3 in HSCs in a TLR4-dependent manner. Taken together, subchronic PFOS exposure might play a pro-fibrotic role via a HMGB1/TLR4-dependent Smad signaling in HSCs. Our findings for the first time uncovered an involvement of PFOS exposure in liver fibrosis via HMGB1/TLR4/Smad signaling.