Study on the developmental, behavioral toxicity, and toxicological mechanism of the antidepressant drug venlafaxine and its active metabolites in zebrafish

Abstract As a representative agent of bicyclic antidepressants, venlafaxine (VEN) has become widely used worldwide and is frequently detected in surface waters with concentrations ranging from ng/L to µg/L. To evaluate the toxicological effects of such medications on aquatic species, studies on environmentally relevant concentrations are essential. Zebrafish were used as a model organism to assess growth and development in larvae and examine tissue accumulation, oxidative stress, and DNA methylation in adults. The results showed adverse effects, including an 18.5% decrease in embryo hatching rate and an increase in mortality by 18.5%. There was also a reduction in body length (4.5%) and eye area (12.2%) in the larvae, along with abnormal developmental issues, such as pericardial edema, yolk sac edema, and spinal curvature. Venlafaxine and its metabolites induced oxidative stress, leading to observable toxic effects. In adult zebrafish, VEN and O-desmethylvenlafaxine (ODV) accumulated primarily in the liver, followed by the brain and intestines, and caused a reduction in DNA methyltransferase activity, leading to DNA hypomethylation. VEN had the most significant impact on DNA methyltransferase 1 and altered its conformation more than ODV. Overall, venlafaxine was found to be more toxic than its metabolites, providing a scientific basis for evaluating the toxic effects and ecological risks of antidepressant residues on aquatic organisms.