Mechanistic insights into developmental neurotoxicity in zebrafish induced by environmental-level risperidone exposure: An integrated transcriptomic and metabolomic study

Risperidone (RIS), a first-line antipsychotic for bipolar disorder, is frequently detected in aquatic systems due to its environmental persistence. Although several studies have reported the neurotoxic effects of RIS on fishes, the underlying toxicological mechanisms remain largely unclear. To fill this gap, zebrafish embryos were exposed to environmentally relevant concentrations of RIS (0.05, 0.5, and 5 μg/L), with astaxanthin (Asta) used as an inhibitor, to investigate the neurodevelopmental toxicity of RIS. Our findings demonstrated that RIS induced morphological abnormalities and neurobehavioral deficits in larvae. This toxicity was primarily driven by the disruption of the antioxidant defense system, leading to significant oxidative stress and subsequent neural apoptosis. Crucially, RIS exposure dysregulated key neurodevelopmental genes (including neurogenin-1 , mbp , manf , gfap , and c-fo s) and reduced levels of critical neurotransmitters (5-HT, DA, and ACh) by 18 %-54 %, thereby impairing neuronal development and synaptic transmission. Transcriptomic profiling revealed that RIS disrupted neural cell homeostasis by modulating critical pathways such as the TNF signaling pathway, aldosterone-regulated sodium reabsorption, and tyrosine metabolism. Non-targeted metabolomic analysis further showed that RIS disrupted amino acid, purine, and pyrimidine metabolism, impairing energy supply and signal transduction in neuronal cells. Integrated multi-omics analysis established that RIS exposure disrupted lipid metabolism, promotes cell death, and impairs the metabolic homeostasis of fundamental biomolecules such as amino acids. These collective disturbances ultimately compromised energy provision, signal transduction, and neuro-metabolic homeostasis within the developing nervous system. This study delineates the mechanistic basis for RIS-induced developmental neurotoxicity, providing critical insights for its environmental risk assessment.