Mitochondrial and inflammatory dysfunctions underlie perfluorooctane sulfonic acid (PFOS)-induced neurotoxicity in adult zebrafish

Abstract

Perfluorooctane sulfonic acid (PFOS) is a persistent environmental contaminant widely detected in aquatic ecosystems and associated with neurotoxicity. However, the mechanisms underlying its neurological effects remain unclear. This study investigated acute and chronic neurotoxic effects of PFOS in adult zebrafish (Danio rerio), focusing on behavioral alterations, mitochondrial dysfunction, neuroinflammation, and histological abnormalities in different brain regions. Adult zebrafish were exposed to PFOS at 0.1, 1, and 10 μM for 30 min (acute) and 14 days (chronic). Behavioral assays evaluated exploration, social preference, and aggression. High-resolution respirometry assessed brain mitochondrial functionality, while gene expression and histological analyses examined markers of neuroinflammation, neural plasticity, and cell death after chronic exposure. Acute exposure showed no significant behavioral changes but trends of reduced exploration and aggression. Chronic exposure at 10 μM significantly reduced aggression. Mitochondrial respirometry revealed contrasting effects between acute and chronic exposures: acute PFOS resulted in increased oxidative phosphorylation capacity and bioenergetic efficiency, while chronic exposure impaired oxidative phosphorylation, bioenergetic efficiency, and electron transport chain activity. Gene expression supported dysregulation in mitochondrial dynamics, with mffa and mfn1a downregulated. Additionally, inflammation-related genes (il6, il10) and apoptosis/neural activation-related genes (casp3a, cyc1, fosaa, egr1) were altered. Histopathological evaluation showed neuronal vacuolation, architectural disorganization, cell damage, and increased inflammation in telencephalon, optic tectum, and cerebellum reinforcing neurotoxicity. Our findings indicate mitochondrial dysfunction and inflammatory dysregulation are key events underlying PFOS-induced neurotoxicity in adult zebrafish. Given the environmental persistence and bioaccumulative nature of PFOS, further research is needed to assess long-term neurotoxic risks and develop mitigation strategies.

Keywords: Brain; Environmental toxicology; Immune dysregulation; Mitochondrial dynamics; PFOS; Zebrafish.