HFPO-TA Mimics PFOA-induced neurotoxic potential in the brain of hook snout carp: Evidence from oxidative stress, mitochondrial dysfunction, and apoptosis

Per- and polyfluoroalkyl substances (PFASs) hexafluoropropylene oxide trimer acid (HFPO-TA), now frequently applied as a replacement for perfluorooctanoic acid (PFOA), has been consistently found in aquatic ecosystems worldwide. Despite its increasing prevalence, the specific neurotoxic pathways of HFPO-TA in commercially valuable fish species remain poorly characterized. To fill this knowledge gap, we conducted controlled exposures of hook snout carp ( Opsariichthys bidens ) to equal doses of PFOA and HFPO-TA and systematically compared their impacts on brain physiology. The analyses revealed that both compounds triggered severe neuropathological alterations, including neuronal degeneration and capillary congestion, accompanied by oxidative stress, endocrine disruption, mitochondrial impairment, neural biomarker disturbances, and dysregulation of apoptosis. Although HFPO-TA and PFOA elicited broadly similar patterns of neurophysiological disruption in the brain, PFOA produced a more extensive and severe spectrum of cerebral injury, as evidenced by a higher integrated biomarker response (IBR) index. In contrast, HFPO-TA provoked more pronounced perturbations in several discrete neurobiological endpoints, suggesting a distinct toxicity profile at the level of specific functional indicators. Collectively, these findings demonstrated that both HFPO-TA and PFOA possessed marked neurotoxic potential in O. bidens , thereby highlighting their non-negligible ecological and neurobiological risks in aquatic systems. Furthermore, the toxicological resemblance between HFPO-TA and PFOA challenged the prevailing assumption that restrictions on legacy PFASs are sufficient to alleviate ecological hazards. Consequently, HFPO-TA could not be regarded as a benign substitute for PFOA with respect to neurotoxic potential. Rather than constituting a safer alternative, HFPO-TA might impose a unique spectrum of ecological and toxicological burdens, underscoring the imperative for rigorous, systematic safety assessments prior to its large-scale industrial deployment.