HFPO-TA, a PFOA replacement, causes greater gut-liver toxicity in hook snout carp (Opsariichthys bidens) than PFOA, and is mitigated by curcumin.

The ecological safety of replacement per- and polyfluoroalkyl substances (PFASs), such as hexafluoropropylene oxide trimer acid (HFPO-TA), remains controversial and insufficiently assessed. In this study, we systematically compared the toxicological profiles of HFPO-TA and the legacy contaminant perfluorooctanoic acid (PFOA) at environmentally relevant concentrations, aiming to assess the potential risk of "regrettable substitution". Opsariichthys bidens were exposed to 5, 50, and 500 μg L concentrations of HFPO-TA and PFOA for 60 days. Compared with PFOA, HFPO-TA induced more severe hepatic injury in O. bidens, characterized by pronounced hepatocellular vacuolation, elevated malondialdehyde (MDA) levels, reduced glutathione (GSH) content, and enhanced apoptosis through activation of caspase3 and caspase9. Concurrently, intestinal barrier integrity was compromised, as evidenced by decreased expression of barrier proteins (ZO-1 and occludin) and marked gut microbiota dysbiosis, including depletion of beneficial Firmicutes and enrichment of potentially pathogenic Proteobacteria. Mechanistically, HFPO-TA exhibited greater mitochondrial disruption than PFOA, promoting excessive mitochondrial fission via upregulation of dynamin-related protein 1 (drp1) and downregulation of mitofusin 1/2 (mfn1/2), along with a sharp decline in ATP production. Co-treatment with the natural polyphenol curcumin markedly mitigated this multi-organ toxicity. Curcumin attenuated hepatic oxidative injury, restored intestinal barrier integrity, normalized mitochondrial fusion-fission dynamics via increased mfn1 expression, and enhanced mitochondrial biogenesis by upregulating peroxisome proliferator-activated receptor gamma coactivator-1α (pgc-1α). Collectively, our findings demonstrate that HFPO-TA is not a safe substitute for PFOA and highlight the urgent need to re-evaluate its ecological risk.