Prothioconazole stereoselectively drives neuroimmune disruption via systemic inflammation and blood-brain barrier failure

Prothioconazole (PTCZ) is a widely used chiral fungicide whose environmental residues pose potential risks to aquatic ecosystems. However, the stereoselective neuro-immunotoxicity of its enantiomers at environmentally relevant concentrations remains poorly understood. This study investigated these effects in zebrafish larvae by assessing systemic inflammation, blood-brain barrier (BBB) integrity, central nervous system (CNS) oxidative stress, glial activation, and neuronal function. Exposure to the S-(+)-enantiomer, but not the R-(-)-enantiomer, induced a potent systemic inflammatory response mediated by the NF-κB pathway. Peripheral inflammation resulted in a stereoselective disruption of the blood-brain barrier (BBB), subsequently inducing a severe neuroinflammatory condition within the central nervous system (CNS). This condition was characterized by significant glial activation and increased oxidative stress. This pathological cascade culminated in significant neurological dysfunction, marked by the depletion of monoamine neurotransmitters and impaired synaptic protein expression. Collectively, these findings reveal a complete toxicological pathway where the neurotoxicity of S-(+)-PTCZ is driven by its initial immunotoxic effects. This work highlights the critical need to incorporate enantiomer-specific, mechanistic endpoints into the ecological risk assessment of chiral pesticides to better protect aquatic ecosystem health.