Perfluorohexanesulfonic Acid (PFHxS) Induces Hepatotoxicity through the PPAR Signaling Pathway in Larval Zebrafish (Danio rerio)

In recent years, the industrial substitution of long-chain per- and polyfluoroalkyl substances (PFAS) with short-chain alternatives has become increasingly prevalent, resulting in the widespread environmental detection of perfluorohexanesulfonic acid (PFHxS), a short-chain PFAS. However, there remains limited information about the potential adverse effects of PFHxS at environmental concentrations to wildlife. Here, early life stage zebrafish ( Danio rerio ) were exposed to environmentally relevant concentrations of PFHxS to better characterize the adverse effects of PFHxS on aquatic organisms. Nontargeted, transcriptomic analysis revealed potential hepatotoxic effects in exposed larvae, including macrovesicular and microvesicular hepatic steatosis, as well as focal liver necrosis. Morphological, histological, biochemical, and targeted transcript expression profiles further confirmed significant alterations in hepatocellular lesion numbers, liver pathological structures, relative liver size, liver biochemical parameters, and liver function genes. To validate the PPAR-mediated toxicological mechanism identified as an enriched pathway through in silico bioinformatics analysis, we tested the coexposure to an antagonist and PPAR morpholino knockdown. This intervention alleviated PFHxS-induced hepatic effects, including reductions in the levels of aspartate aminotransferase, alanine aminotransferase, total cholesterol, and total triglycerides. Our results demonstrate that environmentally relevant concentrations of PFHxS can impair liver development and function in fish, which could have potential risks to aquatic organisms.