Developmental neurotoxicity of anesthetic etomidate in zebrafish larvae: Alterations in motor function, neurotransmitter signaling, and lipid metabolism.

Etomidate (ETO), a widely used anesthetic, has emerged as a concerning environmental contaminant due to its increasing misuse and demonstrated neurotoxicity in aquatic organisms. This study employed an integrated multi-omics strategy to investigate the developmental neurotoxic effects of ETO in zebrafish (Danio rerio). ETO exposure induced dose-dependent toxicity in zebrafish embryos, characterized by decreased hatching rates (10-20 %), elevated mortality (up to 30 %), and morphological abnormalities such as scoliosis and pericardial edema. Behavioral assays revealed marked locomotor suppression (40-65 % reduction) and disrupted circadian rhythmicity. Neurochemical profiling indicated a 2.1-fold increase in dopamine levels, accompanied by significant reductions in GABAergic (38 %) and serotonergic (42 %) signaling, consistent with transcriptomic downregulation of related pathway genes. Metabolomic analysis revealed dysregulated lipid metabolism, including a 3.2-fold increase in eicosapentaenoic acid (EPA), and perturbations in phenylalanine metabolism. Transgenic zebrafish models (Tg(hb9:eGFP), Tg(coro1a:DsRed), Tg(elavl3:GCaMP6f)) further demonstrated motor neuron damage, inflammatory cell infiltration in the brain, and disrupted Ca dynamics, indicating blood-brain barrier disruption and neuroinflammation responses. Molecular docking analysis confirmed ETO's binding affinity for GABA-A receptors, aligning with observed neurotransmitter imbalances. These findings elucidate ETO's neurotoxic mechanisms, involving neurotransmitter imbalance, metabolic disruption, and neuroinflammatory. The results underscore the dual threat of ETO as both an emerging aquatic pollutant and a developmental neurotoxicant, highlighting the urgent need for stricter environmental monitoring and a reevaluation of its safety profile, particularly during critical developmental windows.