Yan Zhenhua, Chen Yufang, Zhang Xiadong, Lu Guanghua
Key Laboratory of Integrated Regulation and Resource Development on Shallow Lakes of Ministry of Education, Hohai University, Nanjing 210098, China; College of Environment, Hohai University, Nanjing 210098, China.
Key Laboratory of Integrated Regulation and Resource Development on Shallow Lakes of Ministry of Education, Hohai University, Nanjing 210098, China; College of Environment, Hohai University, Nanjing 210098, China.
Aquat Toxicol. 2023 Apr;257:106467. doi: 10.1016/j.aquatox.2023.106467. Epub 2023 Mar 1.
The ubiquitous pharmaceuticals in aquatic environments have attracted huge attention due to their significant risks to humans and ecosystems. However, even though the knowledge of the negative effects induced by the parent pharmaceuticals is quite extensive, little is known about their metabolites for a long time. This study provides systematical knowledge about the potential toxicity of metabolite norfluoxetine and its parent fluoxetine on zebrafish (Danio rerio) at the early life stage. The results showed that the metabolite norfluoxetine had similar acute toxicity in fish with the parent fluoxetine. For the altered fish development, there was no significant difference in most cases between the two pharmaceuticals. Compared to the control, the metabolite markedly inhibited the locomotor behavior under light-to-dark transitions, which was comparable to the parent. Norfluoxetine could easily accumulate but hardly eliminate from fish, relative to fluoxetine. In addition, the accumulated fluoxetine in zebrafish may rapidly metabolize to norfluoxetine and then be eliminated through different metabolic pathways. The functional genes related to serotonergic process (5-ht1aa, 5-ht2c, slc6a4b, and vmat), early growth (egr4), and circadian rhythm (per2) were downregulated by both the norfluoxetine and fluoxetine, indicative of the same mode-of-action of norfluoxetine with its parent in these functions. Meanwhile, the alterations caused by norfluoxetine were more pronounced than that of fluoxetine in the genes of 5-ht2c, slc6a4b, vmat, and per2. The molecular docking also confirmed that norfluoxetine could bind with serotonin transporter protein in the same as fluoxetine with a lower binding free energy. Overall, the metabolite norfluoxetine could induce similar and even more toxic effects on zebrafish with the same mode of action. The different and binding energy of the metabolite norfluoxetine and its parent fluoxetine on zebrafish may be responsible for the differentiated effects. It highlights the risks of the metabolite norfluoxetine in the aquatic environment could not be ignored.
水生环境中普遍存在的药物因其对人类和生态系统的重大风险而备受关注。然而，尽管关于母体药物所产生的负面影响的知识相当广泛，但长期以来对其代谢物却知之甚少。本研究提供了关于代谢物去甲氟西汀及其母体氟西汀对斑马鱼（Danio rerio）幼鱼潜在毒性的系统知识。结果表明，代谢物去甲氟西汀在鱼类中的急性毒性与母体氟西汀相似。对于鱼类发育的改变，两种药物在大多数情况下没有显著差异。与对照组相比，代谢物在明-暗转换条件下显著抑制运动行为，这与母体相当。相对于氟西汀，去甲氟西汀在鱼类中易于积累但难以消除。此外，斑马鱼体内积累的氟西汀可能迅速代谢为去甲氟西汀，然后通过不同的代谢途径被消除。与血清素能过程（5-ht1aa、5-ht2c、slc6a4b和vmat）、早期生长（egr4）和昼夜节律（per2）相关的功能基因在去甲氟西汀和氟西汀作用下均下调，表明去甲氟西汀与其母体在这些功能上具有相同的作用模式。同时，在5-ht2c、slc6a4b、vmat和per2基因中，去甲氟西汀引起的变化比氟西汀更明显。分子对接也证实，去甲氟西汀能与血清素转运蛋白结合，其方式与氟西汀相同，但结合自由能较低。总体而言，代谢物去甲氟西汀可通过相同的作用模式对斑马鱼产生相似甚至更强的毒性作用。代谢物去甲氟西汀及其母体氟西汀在斑马鱼上的不同作用和结合能可能导致了不同的效应。这突出了水生环境中代谢物去甲氟西汀的风险不容忽视。
