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

Area of Science:

• Environmental toxicology
• Aquatic ecotoxicology
• Endocrinology

Background:

• Esketamine (ESK), a psychoactive substance, is increasingly detected in global surface waters.
• Its potential toxicity and endocrine-disrupting effects on aquatic organisms, particularly fish, are not well understood.

Purpose of the Study:

• To investigate the developmental toxicity and endocrine-disrupting potential of esketamine (ESK) in zebrafish.
• To assess the impact of environmentally relevant ESK concentrations on zebrafish embryos and cells.

Main Methods:

• Zebrafish embryos and ZF4 cells were exposed to varying concentrations of ESK (0, 0.12, 1.02, 10.6 μg L⁻¹) for 24 hours and 14 days post-fertilization.
• Gene expression, cell cycle, yolk sac parameters, and Vitellogenin (VTG) levels were analyzed.
• KEGG pathway analysis and molecular docking were employed to understand molecular mechanisms.

Main Results:

• ESK exhibited biphasic dose-dependent effects on zebrafish embryo development, with low/medium concentrations promoting growth and high concentrations inhibiting it.
• ESK exposure upregulated *vtg* expression and disrupted the cell cycle.
• KEGG analysis revealed significant impacts on circadian rhythm, nucleotide excision repair, and estrogen signaling pathways.
• Elevated VTG levels and molecular docking confirmed interaction with estrogen receptors, indicating endocrine disruption.

Conclusions:

• Esketamine (ESK) demonstrates significant developmental toxicity and endocrine-disrupting effects in zebrafish.
• The findings underscore the ecological risks posed by ESK contamination in aquatic environments and necessitate further investigation into its impact on fish health.