Interdisciplinary Centre of Marine and Environmental Research - CIIMAR, University of Porto, Terminal de Cruzeiros do Porto de Leixões Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal; Faculty of Sciences - Biology Department, Rua do Campo Alegre s/n, University of Porto, 4169-007 Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Interdisciplinary Centre of Marine and Environmental Research - CIIMAR, University of Porto, Terminal de Cruzeiros do Porto de Leixões Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal; Faculty of Sciences - Biology Department, Rua do Campo Alegre s/n, University of Porto, 4169-007 Porto, Portugal.
J Hazard Mater. 2023 Apr 15;448:130909. doi: 10.1016/j.jhazmat.2023.130909. Epub 2023 Jan 31.
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 µg/L) for 168hpf exposures to each metabolite (carbamazepine-10,11-epoxide, 10,11-dihydrocarbamazepine, O-desmethylvenlafaxine, N-desmethylvenlafaxine, O-desmethyltramadol, N-desmethyltramadol) or the parental compound. A concentration-response relationship was found for the effects of some embryonic malformations. Carbamazepine-10,11-epoxide, O-desmethylvenlafaxine and tramadol elicited the highest malformation 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, metabolites represent a real risk that needs more scrutinising by the scientific community.
药物化合物及其代谢物存在于天然水和废水中。然而，对其对水生动物的毒性影响的研究一直被忽视，尤其是对代谢物。本工作研究了卡马西平、文拉法辛和曲马多的主要代谢物的影响。斑马鱼胚胎在 168hpf 暴露于每个代谢物（卡马西平-10,11-环氧化物、10,11-二氢卡马西平、O-去甲文拉法辛、N-去甲文拉法辛、O-去甲曲马多、N-去甲曲马多）或母体化合物（0.1-100μg/L）中。发现一些胚胎畸形的效应存在浓度-反应关系。卡马西平-10,11-环氧化物、O-去甲文拉法辛和曲马多引起的畸形率最高。与对照组相比，所有化合物在感觉运动测定中显著降低了幼虫的反应。在测试的 32 个基因中，大多数基因的表达都发生了改变。特别是，abcc1、abcc2、abcg2a、nrf2、pparg 和 raraa 被发现受三种药物的影响。对于每个组，模拟的表达模式显示母体化合物和代谢物之间的表达差异。文拉法辛和卡马西平组鉴定出了潜在的暴露生物标志物。这些结果令人担忧，表明水生系统中的这种污染可能使自然种群面临重大风险。此外，代谢物是一个真正的风险，需要科学界更仔细地研究。
