Toxicological effects of ADB-FUBINACA on early zebrafish development: An analysis utilizing metabolomics

ADB-FUBINACA, which is a type-1 indazole cannabinoid receptor (CB1) agonist, is a prevalent synthetic cannabinoid due to its widespread abuse and confiscation. Numerous clinical reports have indicated the potential for ADB-FUBINACA to induce multisystemic bodily harm when smoked, but a comprehensive understanding of its potential toxicity to aquatic life remains largely unexplored. Our study used zebrafish as a model organism to assess the toxic effects of exposure to different doses of ADB-FUBINACA on embryonic development. By integrating a nontargeted metabolomics strategy, we aimed to explore the metabolic pathways that are implicated in the toxic effects of ADB-FUBINACA on the early development of zebrafish. Our findings revealed that exposure to ADB-FUBINACA reduced the heart rate, survival rate, hatching rate, and body length of zebrafish embryos/larvae in a dose-dependent manner. Additionally, we observed lipid disorders and reduced motor behaviour. Moreover, ADB-FUBINACA affected the mechanism of oxidative stress in zebrafish larvae. Compared with the control, high-dose treatment resulted in a 2.19-fold increase in reactive oxygen species (ROS) levels and a 42.56 % decrease in reduced glutathione (GSH) levels. The embryos were subsequently analysed using ultrahigh-performance liquid chromatography-quadrupole-orbitrap-high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS); the results identified 45 differentially abundant metabolites and showed that the arachidonic acid metabolic pathway was significantly activated, the latter of which was suggested by bioinformatics analysis. RTqPCR revealed that lpcat3 gene expression was upregulated by 2.51-fold in zebrafish in the ADB-FUBINACA treatment group, whereas gclc gene expression was reduced by 70.94 %. Additionally, the expression of genes related to inflammatory factors and heart development showed varying degrees of change. In summary, our study revealed that ADB-FUBINACA can exert toxic effects on the early development of zebrafish, and its mechanism may involve activating the arachidonic acid metabolic pathway, triggering lipid metabolism disorders, and inducing inflammatory responses and oxidative damage.