多组学和计算机模拟揭示哌罗匹隆通过AKT/FOXO3a介导的凋亡诱导斑马鱼发育神经毒性

Abstract

Perospirone, an atypical antipsychotic increasingly detected in aquatic environments, raises concerns regarding potential developmental hazards in early vertebrates. As an emerging personal care product (PPCP) contaminant, its developmental neurotoxicity remains poorly characterized. To evaluate its biological effects, zebrafish embryos were exposed to perospirone (nominal 0.1, 1, 10 mg/L) from 5-120 hpf. At 5 dpf, larvae exposed to 1 mg/L displayed increased locomotion with anxiety-like features, whereas exposure to 10 mg/L was associated with reduced body length and hyperactivity suppression, together with elevated Caspase 9 and Pro- Caspase 3 expression consistent with apoptosis activation. Neurotransmitter profiling revealed an increase in 5-HIAA and decreases in dopamine and glutamine, accompanied by transcriptomic enrichment of pathways related to serotonergic signaling, oxidative stress, and FOXO/AKT regulation. Besides, molecular docking revealed high-affinity perospirone-AKT1 binding (-7.88 kcal/mol). These multi-omics findings establish that perospirone-induced developmental neurotoxicity stems from AKT/FOXO3a-mediated apoptosis, providing critical insights into its neurotoxicological profile and environmental risks as an emerging pharmaceutical contaminant.