New Psychoactive Substance Esketamine Causes Endocrine-Disrupting Effects and Developmental Toxicity

Esketamine (ESK), a new psychoactive substance known for its strong hallucinogenic effect, has been detected in surface water worldwide. The toxicity of ESK to fish at a certain environmental concentration remains unclear. In this study, zebrafish embryos and ZF4 cells were exposed to ESK (0, 0.12, 1.02, and 10.6 μg L^-1, marked by SC, LC, MC, and HC, respectively) for 14 days post fertilization (dpf) and 24 h, respectively. Biphasic dose responses induced by ESK were observed after 24 h of exposure. ESK-LC and ESK-MC obviously increased embryo area and length, height, and volume of yolk sac, whereas ESK-HC had the opposite effect. ESK-LC and ESK-MC appreciably upregulated the transcription and expression levels of <i>vtg</i>, disrupting the cell cycle after 24 h of exposure. After 14 dpf exposure, KEGG analysis indicated that circadian rhythm, nucleotide excision repair, and estrogen signaling pathways were the top three impacted pathways, with ESK significantly enhancing gene transcription in these three pathways, except for <i>cyp7a1</i> and <i>bh1he41</i>. Correspondingly, ESK notably increased the VTG level, aligning with the relatively high affinity of estrogen receptors, as analyzed through molecular docking. Our research demonstrated that ESK exhibits developmental toxicity and endocrine-disrupting effects in zebrafish, highlighting the need to address its ecological toxicity in fish.