Carbamazepine, venlafaxine, tramadol, and their main metabolites: Toxicological effects on zebrafish embryos and larvae

Pharmaceutical compounds and their metabolites are found in natural and wastewater. However, investigation of their toxic effects on aquatic animals has been neglected, especially for metabolites. This work investigated the effects of the main metabolites of carbamazepine, venlafaxine and tramadol. Zebrafish embryos were exposed (0.1-100 mu g/L) for 168hpf exposures to each metabolite (carbamazepine-10,11-epoxide, 10,11-dihydrocarbama-zepine, O-desmethylvenlafaxine, N-desmethylvenlafaxine, O-desmethyltramadol, N-desmethyltramadol) or the parental compound. A concentration-response relationship was found for the effects of some embryonic mal-formations. Carbamazepine-10,11-epoxide, O-desmethylvenlafaxine and tramadol elicited the highest malfor-mation rates. All compounds significantly decreased larvae responses on a sensorimotor assay compared to controls. Altered expression was found for most of the 32 tested genes. In particular, abcc1, abcc2, abcg2a, nrf2, pparg and raraa were found to be affected by all three drug groups. For each group, the modelled expression patterns showed differences in expression between parental compounds and metabolites. Potential biomarkers of exposure were identified for the venlafaxine and carbamazepine groups. These results are worrying, indicating that such contamination in aquatic systems may put natural populations at significant risk. Furthermore, me-tabolites represent a real risk that needs more scrutinising by the scientific community.

Automated summary

Pharmaceutical compounds and their metabolites in natural and wastewater have been neglected in terms of their toxic effects on aquatic animals, especially the metabolites. This study investigated the effects of the main metabolites of carbamazepine, venlafaxine, and tramadol on zebrafish embryos. The results showed that some metabolites elicited higher rates of embryonic malformations and significantly decreased larvae responses compared to controls. The expression of several tested genes was found to be affected, and potential biomarkers of exposure for venlafaxine and carbamazepine groups were identified. This study highlights the risk of contamination in aquatic systems and the importance of scrutinizing metabolites by the scientific community.