Enantioselective toxicity of (S)-amlodipine towards zebrafish embryos: Abnormal ocular development, cardiac dysfunction, and malformed intersegmental vessels

초록

Amlodipine (AM), widely used for the treatment of hypertension and angina, consists of two enantiomers: (S)-AM and (R)-AM. The extensive use of this medication has raised concerns regarding environmental contamination, but the enantioselective toxicity of AM in aquatic organisms has not been adequately investigated. This study aimed to examine the enantioselective toxicity of AM using zebrafish (Danio rerio) embryos, focusing on acute toxicity and developmental toxicity. Neither enantiomer exhibited acute toxicity at the tested concentrations (0.25-20 mg/L). With respect to ocular development, (R)-AM reduced eye volume at the highest tested concentration. The lens-to-eye volume ratio showed a significant increase in embryos treated with both enantiomers compared to the control. Enantioselective toxicity was evident in cardiac function, as (S)-AM-induced heart dysfunction, despite both enantiomers displaying similar patterns of heart development-related gene expression. Severe defects in ISV formation were observed in both (S)-AM and (R)-AM treatments, indicating that AM exposure may result in abnormal blood vessel formation in other fish. Metabolomic analysis indicated that exposure to either enantiomer led to the upregulation of most metabolic pathways, except for starch and sucrose metabolism. Further research needs to confirm enantioselective toxicity under chronic conditions at environmentally relevant concentrations of AM.

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