Tachycardia induced by chiral citalopram in adult zebrafish: Mechanistic insights into exacerbation by its demethylated metabolites.

Ecological risks of the widely detected antidepressant citalopram may be amplified through environmental transformation, yet the enantioselective cardiotoxicity of its bioactive demethylated metabolites remains unquantified. After enantiomer-specific exposure, our electrocardiographic analysis in adult zebrafish revealed that the primary demethylated metabolite at 1 μg/L, S-didesmethyl-citalopram, induced exacerbated tachycardia relative to the parent citalopram. Bioaccumulation analysis confirmed stepwise demethylation to desmethyl- and didesmethyl-citalopram, with preferential enrichment of S-enantiomers. Mechanistic investigations integrating high-resolution proteomic, histopathological and biochemical analyses, revealed that the observed tachycardia was driven by interlinked pathological mechanisms, initiating with myocardial fibrosis evidenced by cardiomyocyte damage and elevated serum biomarkers of cardiac injury. Myocardial fibrosis was further exacerbated by mitochondrial dysfunction characterized by ultrastructural damage, impaired respiratory activity, and a critically blocked mitophagy flux, as demonstrated by the dysregulated LC3-II/LC3-I ratio and accumulated P62. Our findings indicate that enantioselective metabolism amplifies the cardiotoxic risk of citalopram, and then underscore the imperative for enantiomer-specific assessment in environmental toxicology.