Dose-Dependent PFESA-BP2 Exposure Increases Risk of Liver Toxicity and Hepatocellular Carcinoma

Per- and polyfluoroalkyl substances (PFASs) are persistent and highly bioaccumulative emerging environmental contaminants of concern that display significant toxic and carcinogenic effects. An emerging PFAS is PFESA-BP2, a polyfluoroalkyl ether sulfonic acid found in drinking water and the serum of humans and animals. While PFESA-BP2-induced liver and intestinal toxicity has been demonstrated, the toxicological mechanisms and carcinogenic potential of PFESA-BP2 have remained relatively understudied. Here, we studied how different doses of PFESA-BP2 affect gene activity related to liver toxicity and the risk of liver cancer such as hepatocellular carcinoma (HCC) in mice exposed to PFESA-BP2 once daily through oral gavage for seven days. An analysis of key hepatic pathways suggested increased risk of hepatotoxicity as a result of PFESA-BP2 exposure. Increased oxidative stress response was associated with all concentrations of exposure. Liver toxicity pathways, including PXR/RXR activation and hepatic fibrosis, showed dose-dependent alteration with activation primarily at low doses, suggesting an increased risk of hepatic inflammation and injury. Additionally, an analysis of carcinogenic and HCC-specific pathways suggested PFESA-BP2-induced risk of liver cancer, particularly at low doses. Low-dose PFESA-BP2 exposure (0.03 and 0.3 mg/kg-day) was associated with an increased risk of HCC carcinogenesis, as indicated by the activation of tumor-related and HCC-associated pathways. In contrast, these pathways were inhibited at high doses (3.0 and 6.0 mg/kg-day), accompanied by the activation of HCC-suppressive pathways. The increased risk of HCC development at low doses was mechanistically linked to the activation of signaling pathways such as HIF, EGF, NOTCH4, HGF, and VEGF. Biomarkers linked to liver cancer risk, prognoses, and diagnoses were also identified as a result of exposure. Overall, our findings on liver carcinogenic and hepatotoxic pathway activation patterns suggest that PFESA-BP2 increases the risk of liver toxicity and HCC development, particularly at low doses.