A comparative review of the toxicity mechanisms of perfluorohexanoic acid (PFHxA) and perfluorohexanesulphonic acid (PFHxS) in fish

Industrial and consumer goods contain diverse perfluoroalkyl substances (PFAS). These substances, like perfluorohexanoic acid (PFHxA) and perfluorohexanesulphonic acid (PFHxS), are under increased scrutiny due to their potential toxicity to aquatic organisms. However, our understanding of their biological impacts and mechanisms of action remains limited. The objectives of this review were to compare data for levels of PFHxA and PFHxS in aquatic environments and fish tissues, as well as toxicity mechanisms related to morphological, endocrine, metabolic, and behavioral endpoints. A computational assessment was also performed to identify putative mechanisms of toxicity and to characterize exposure biomarkers. Studies have shown that both PFHxA and PFHxS residues are present in diverse marine and freshwater fish tissues, suggesting the importance of monitoring these PFAS in aquatic organisms. In fish tissues, these chemicals have been reported to be as high as 37.5 ng/g for PFHxA and 1290 ng/g for PFHxS, but their persistence in aquatic environments and degradation in tissues requires further study. In terms of mechanisms of toxicity, both oxidative stress and endocrine disruption have been reported. Based on evidence for endocrine disruption, we modeled interactions of estrogen and androgen receptors of several fish species with PFHxA and PFHxS. Molecular docking revealed that PFHxS has a stronger affinity for interacting with the estrogen and androgen receptors of fish compared to PFHxA and that estrogen and androgen receptors of fathead minnow, zebrafish, Atlantic salmon, and largemouth bass show comparable binding affinities for each chemical except for salmon Esr2b, which was predicted to have lower affinity for PFHxA relative to Esr2a. While mechanistic data are lacking in fish in general for these chemicals, a computational approach revealed that PFHxA can perturb the endocrine system, nervous system, and is linked to changes in kidney and liver weight. Proteins associated with PFHxA and PFHxS exposures in fish include those related to lipid and glucose regulation, reproductive proteins like KISS metastasis suppressor, and proteins associated with the immune system (specifically RAG1, RAG2), all of which are potential biomarkers of exposure. Taken together, we synthesize current knowledge regarding the environmental fate and ecotoxicology of PFHxA/PFHxS in fish species.