Work

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

Year: 2025

Type: article

Abstract: 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.

Source: Environmental Technology & Innovation

DOI: 10.1016/j.eti.2025.104680

Authors: Laiyun Zhang, Liyan Teng, Liudong Xu, Feng Cui, Tingting Chai

Institution: Zhejiang A & F University

Language: English

Topic: Environmental Toxicology and Ecotoxicology

Subfield: Health, Toxicology and Mutagenesis

Field: Environmental Science

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,930