Occurrence and toxicity mechanisms of hexafluoropropylene oxide dimer acid (HPFO-DA, GenX) in aquatic species.

Hexafluoropropylene oxide dimer acid (HPFO-DA) is marketed under the trade name "GenX" and is used as a replacement for other per- and polyfluoroalkyl substance (PFAS) like perfluorooctanoic acid (PFOA). However, there are growing concerns about its regulation due to environmental and health impacts in organisms. Here, we review literature regarding the prevalence and toxicity of GenX in aquatic species and performed molecular docking and computational analysis to identify mechanisms of GenX-induced toxicity. Studies report measurable body burden levels of GenX in fish and other aquatic species, indicating that exposure and uptake do occur, which can lead to sub-lethal biological effects (e.g., developmental toxicity, oxidative stress, metabolic disruption, immune modulation, endocrine activity, neurobehavioral alterations). Effects on hormone receptor - mediated signaling (i.e., estrogenic and thyroid pathways) were noted based on computational analysis. In silico molecular docking of GenX to several fish receptors (e.g., estrogen, androgen, and thyroid hormone receptors) supported the potential for GenX to interact with key nuclear receptors, suggesting plausible mechanisms of endocrine disruption in fish. Molecular and omics-based analyses also revealed that GenX interferes with several pathways related to lipid and energy metabolism, as well as redox balance. Notably, several transcripts altered in abundance by GenX are related to the AGE-RAGE signaling pathway (Advanced Glycation End products (AGEs) bind to the Receptor for Advanced Glycation End products (RAGE)), which is related to oxidative stress and inflammation, and glucagon receptor (GCGR) signaling that activates transcription factors like CREB/CRTC2 and FOXO1 to promote gluconeogenesis. This review underscores useful toxicological endpoints for GenX in aquatic animals to guide future risk assessments.