Differential Metabolic Changes in Zebrafish Embryos Are Induced by Discontinued Citalopram Exposure

Background/Objectives: Citalopram is a selective serotonin reuptake inhibitor that is prescribed to relieve anxiety and depression. Widespread use has led to the contamination of freshwater systems downstream of wastewater treatment facilitates. Few studies have investigated the impact of citalopram on early embryonic development in humans or other species, despite the prevalence of intentional or unintentional exposure. Danio rerio (zebrafish) is a model organism for investigating effects of environmental exposure to xenobiotics on developmental outcomes in vertebrates. Methods: In this study, we examined the metabolome of developing zebrafish embryos exposed to citalopram hydrobromide concentrations (0.03-250 ng/mL) spanning environmental to therapeutic doses during the first 24 h post-fertilization. Exposure was followed by 24 h exposure-free development before harvest at 48 h. Results: Gross morphology of the embryos was normal, although changes were observed in the heart rates of citalopram-exposed embryos. Untargeted metabolomic and multivariate analyses revealed significant, nonlinear changes in the metabolome in response to citalopram exposure. Arginine and proline metabolism was significantly altered, potentially reflecting changes in serotonin signaling, nitric oxide metabolism, and polyamine synthesis. Conclusions: Together, these data demonstrate that transient exposure to citalopram can induce long-lasting metabolomic changes during development, including dose-dependent changes that include aberrant metabolic processes in the developing metabolome. As a result, this work reveals potential biomarkers for early developmental exposure.