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自然界和废水中。然而，对其对水生动物的毒性作用的研究一直被忽视，特别是对于代谢物。这项工作调查了卡马西平、文拉法辛和曲马多的主要代谢物的影响。斑马鱼胚胎暴露 (0.1–100 µg/L) 168hpf 暴露于每种代谢物（卡马西平-10,11-环氧化物、10,11-二氢卡马西平、O-去甲基文拉法辛、N-去甲基文拉法辛、O-去甲基曲马多、N-去甲基曲马多）或亲本化合物。对于某些胚胎畸形的影响，发现了浓度-反应关系。Carbamazepine-10,11-epoxide、O-desmethylvenlafaxine 和 tramadol 引起的畸形率最高。与对照相比，所有化合物都显着降低了幼虫对感觉运动试验的反应。32 个测试基因中的大多数都发现了表达改变。特别是，一个bcc1、abcc2、abcg2a、nrf2、pparg和raraa被发现受所有三个药物组的影响。对于每组，建模的表达模式显示母体化合物和代谢物之间的表达差异。确定了文拉法辛和卡马西平组的潜在暴露生物标志物。这些结果令人担忧，表明水生系统中的此类污染可能会使自然种群面临重大风险。此外，代谢物代表了一种真正的风险，需要科学界进行更多的审查。