Key Laboratory of Reservoir Aquatic Environment, Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Key Laboratory of Reservoir Aquatic Environment, Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China.
Aquat Toxicol. 2018 Aug;201:151-161. doi: 10.1016/j.aquatox.2018.06.008. Epub 2018 Jun 9.
Tetracycline hydrochloride (TH), indomethacin (IM), and bezafibrate (BF) belong to the three different important classes of pharmaceuticals, which are well known for their toxicity and environmental concerns. However, studies are still elusive to highlight the mechanistic toxicity of these pharmaceuticals and rank them using both, the toxicity prediction and confirmation approaches. Therefore, we employed the next generation toxicity testing in 21st century (TOX21) tools and estimated the in vitro/vivo toxic endpoints of mentioned pharmaceuticals, and then confirmed them using in vitro/vivo assays. We found significant resemblance in the results obtained via both approaches, especially in terms of in vivo LC50 s and developmental toxicity that ranked IM as most toxic among the studied pharmaceuticals. However, TH appeared most toxic with the lowest estimated AC50s, the highest experimental IC50s, and DNA damages in vitro. Contrarily, IM was found as congener with priority concern to activate the Pi3k-Akt-mTOR pathway in vitro at concentrations substantially lower than that of TH and BF. Further, IM exposure at lower doses (2.79-13.97 μM) depressed the pharmaceuticals detoxification phase I (CYP450 s), phase II (UGTs, SULTs), and phase III (TPs) pathways in zebrafish, whereas, at relatively higher doses, TH (2.08-33.27 μM) and BF (55.28-884.41 μM) partially activated these pathways, which ultimately caused the developmental toxicity in the following order: IM > TH > BF. In addition, we also ranked these pharmaceuticals in terms of their particular toxicity to myogenesis, hematopoiesis, and hepatogenesis in zebrafish embryos. Our results revealed that IM significantly affected myogenesis, hematopoiesis, and hepatogenesis, while TH and BF induced prominent effects on hematopoiesis via significant downregulation of associated genetic markers, such as drl, mpx, and gata2a. Overall, our findings confirmed that IM has higher toxicity than that of TH and BF, therefore, the consumption of these pharmaceuticals should be regulated in the same manner to ensure human and environmental safety.
盐酸四环素（TH）、吲哚美辛（IM）和苯扎贝特（BF）属于三种不同的重要类别的药物，它们因毒性和对环境的关注而广为人知。然而，目前仍缺乏研究来强调这些药物的机制毒性，并使用毒性预测和确认方法对它们进行排序。因此，我们采用了 21 世纪下一代毒性测试（TOX21）工具，估计了所研究药物的体外/体内毒性终点，然后使用体外/体内测定法对其进行了确认。我们发现两种方法的结果非常相似，特别是在体内 LC50 和发育毒性方面，IM 被评为研究药物中最毒的一种。然而，TH 的最低估计 AC50、最高实验 IC50 和体外 DNA 损伤使其表现出最强的毒性。相反，IM 被发现与优先关注的同类物一样，能够在比 TH 和 BF 低得多的浓度下激活 Pi3k-Akt-mTOR 途径。此外，IM 暴露在较低剂量（2.79-13.97 μM）下会抑制鱼类的药物解毒第一阶段（CYP450）、第二阶段（UGTs、SULTs）和第三阶段（TPs）途径，而在相对较高的剂量下，TH（2.08-33.27 μM）和 BF（55.28-884.41 μM）部分激活了这些途径，最终按以下顺序导致发育毒性：IM>TH>BF。此外，我们还根据这些药物对斑马鱼胚胎的肌生成、造血和肝生成的特定毒性对它们进行了排序。我们的结果表明，IM 显著影响肌生成、造血和肝生成，而 TH 和 BF 通过下调相关基因标志物（如 drl、mpx 和 gata2a）对造血产生显著影响。总的来说，我们的研究结果证实 IM 的毒性高于 TH 和 BF，因此应同样管制这些药物的使用，以确保人类和环境的安全。
