Mechanism of aggravated cardiotoxicity induced by demethylated metabolites of chiral citalopram in zebrafish (Danio rerio)

Citalopram is a widely prescribed selective serotonin reuptake inhibitor used in the treatment of depression and anxiety disorders. Citalopram and its demethylated metabolites have been frequently detected with enantiomer-specific in aquatic environments. The characteristics of chirality and demethylation make citalopram-induced cardiotoxicity more complex. In this study, we carried out an 11-day exposure experiment at an environmentally relevant concentration (500 ng/L), using racemic and individual enantiomers of citalopram, desmethyl-citalopram, and didemethyl-citalopram to assess the differential cardiotoxicity in zebrafish embryo-larvae. Racemic exposure experiments showed that S-enantiomers of citalopram, desmethyl-citalopram, and didemethyl-citalopram were preferentially accumulated over R-enantiomers. S-enantiomer exposure demonstrated that the demethylation behavior occurred, and its demethylated metabolites accumulated. This biotransformation could result from an abnormality of cytochrome P450 gene expression. The demethylated citalopram induced cardiac malformations more severe than those induced by the parent compound in developmental zebrafish, especially induced by S-enantiomers. Dissection of cardiac tissues revealed that S-didemethyl-citalopram exposure induced the worst increase in heartbeats and impaired ejection fraction in developmental zebrafish, which might be mediated by calcium dysregulation and dysfunction of myocardial contractility. Our findings could offer a comprehensive perspective on citalopram-induced cardiotoxicity in non-target aquatic organisms and highlight the importance of metabolic transformation and chirality of environmental pollutants in ecosystem risk assessments. • Citalopram was demethylated stepwise into desmethyl- and didemethyl- citalopram. • S-enantiomers were preferentially accumulated over R-enantiomers. • S-didemethyl-citalopram exerts more severe heart malformation than parent compounds. • Cardiac dysfunction linked to abnormal calcium and contraction in dissected hearts.