Toxicological Implications of Fluoxetine Exposure on Zebrafish: Developmental Stage-Specific Metabolic Perturbations Revealed by High-Resolution Magic Angle Spinning NMR
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Fluoxetine, a common antidepressant and an environmental contaminant, was investigated for its effects on zebrafish larvae and adults using NMR-based metabolomics. Adult zebrafish were exposed to fluoxetine concentrations of 70 and 700 µg/L for 72 hours, while larvae were exposed to 7 and 70 µg/L from 1 to 72 hours post-fertilization. Our analysis revealed alterations in 77 metabolites in adults and 58 in larvae, with both groups showing changes in citrate, serine, and glutathione levels, and decrease in succinate and fumarate, highlighting some conserved metabolic responses to fluoxetine. Pathway analysis indicated significant effects on the TCA cycle, as well as glycine, serine, and threonine metabolism across both developmental stages. Notably, larvae exhibited distinct shifts with increased glutamine and decrease in glutamate and glycine, suggesting heightened sensitivity during early development. In adults, specific changes included increases in ATP, N,N-dimethylglycine, and alanine, with decreases in phenylalanine, tyrosine, betaine, NADP⁺ and 3-hydroxyisovalerate, pointing to possible metabolic disruptions. These alterations affected key pathways, notably the glycerolipid pathway in larvae and tyrosine and β-alanine metabolism in adults, indicating stage-specific susceptibility to fluoxetine. Furthermore, the application of HR-MAS NMR has proven instrumental in elucidating the complex metabolic responses to fluoxetine exposure, underscoring its utility in biotoxicity assessments.
Abstract
Fluoxetine, a common antidepressant and an environmental contaminant, was investigated for its effects on zebrafish larvae and adults using NMR-based metabolomics. Adult zebrafish were exposed to fluoxetine concentrations of 70 and 700 µg/L for 72 hours, while larvae were exposed to 7 and 70 µg/L from 1 to 72 hours post-fertilization. Our analysis revealed alterations in 77 metabolites in adults and 58 in larvae, with both groups showing changes in citrate, serine, and glutathione levels, and decrease in succinate and fumarate, highlighting some conserved metabolic responses to fluoxetine. Pathway analysis indicated significant effects on the TCA cycle, as well as glycine, serine, and threonine metabolism across both developmental stages. Notably, larvae exhibited distinct shifts with increased glutamine and decrease in glutamate and glycine, suggesting heightened sensitivity during early development. In adults, specific changes included increases in ATP, N,N-dimethylglycine, and alanine, with decreases in phenylalanine, tyrosine, betaine, NADP⁺ and 3-hydroxyisovalerate, pointing to possible metabolic disruptions. These alterations affected key pathways, notably the glycerolipid pathway in larvae and tyrosine and β-alanine metabolism in adults, indicating stage-specific susceptibility to fluoxetine. Furthermore, the application of HR-MAS NMR has proven instrumental in elucidating the complex metabolic responses to fluoxetine exposure, underscoring its utility in biotoxicity assessments.