Ecotoxicological risk assessment of the novel psychoactive substance Esketamine: Emphasis on fish skeletal, behavioral, and vascular development.

Novel psychoactive substances (NPS), such as Esketamine (Esket), often contaminate the aquatic ecosystems following human consumption, raising concerns about the residues and potential ecological hazards to non-target organisms. The study used zebrafish as a model organism to investigate the developmental toxicity and ecotoxicological effects of acute Esket exposure. Our findings demonstrate that exposure to Esket significantly affected the early development and angiogenesis of zebrafish embryos/larvae. The mandible length was significantly decreased, and the angles between the pharyngeal arch cartilages were narrowed compared to the control group (all P < 0.05). Additionally, Esket resulted in a decrease of 47.6-89.8 % in the number of neural crest cells (NCC). Transcriptome analysis indicated altered expression of genes associated with cartilage and osteoblast growth. Moreover, Esket significantly inhibited swimming ability in zebrafish larvae and was accompanied by behavioral abnormalities and molecular alterations in the brain. Potential mechanisms underlying Esket-induced behavioral disorders involve neurotransmitter system impairment, abnormal cartilage development and function, aberrant vascular development, as well as perturbations in oxidative stress and apoptosis signaling pathways. Notably, the dysregulation of skeleton development through the bone morphogenetic protein (BMP) signaling pathway is identified as the primary mechanistic behind Esket-induced behavioral disorder. This study enhances our understanding of Esket's ecotoxicology profile and provides a comprehensive assessment of the environmental risks associated with NPS.