Xu Jiaqi, Qian Qiuhui, Xia Min, Wang Xuedong, Wang Huili
National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou, 215009, China.
National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou, 215009, China.
Environ Pollut. 2021 Jan 10;273:116479. doi: 10.1016/j.envpol.2021.116479.
Trichlorocarban (TCC) is ubiquitously detected in environmental matrices, while there is a paucity of information regarding its systemic toxicity. In the present study, we observed that TCC exposure led to high embryo mortality, delayed hatching and yolk absorption, as well as increased malformations, such as closure of swim sac and yolk sac edema. Meanwhile, TCC affected the formation and branch of subintestinal veins (SIVs), intersegmental vessels and posterior cardinal veins. Especially, the SIVs were shrunk, and their branches were reduced or even broken along with reduced coverage area. TCC-induced oxidative stress and excessive apoptosis resulted from abnormal expression of the anti/pro-apoptotic genes. Significant reduction in the number and aggregation function of immune cells proved that TCC had prominent immunotoxicity to zebrafish. TCC-targeted TLR4 signaling pathway was demonstrated by abnormal expression of the marker genes (tlr4, MyD88 and nf-κb) and release of the downstream inflammatory factors (TNF-α, IL-6, etc.). Inhibition of TLR4/MyD88/NF-κB pathway by an inhibitor (CA-4948) rescued the decreasing trend of the immune cells induced by TCC. Molecular docking results demonstrated that TCC could stably bind to TLR4 receptor to form hydrogen bonds and hydrophobic interactions with amino acids. Overall, these findings reveal the underlying molecular mechanisms on TCC-induced developmental and immune toxicity to zebrafish.
三氯卡班（TCC）在环境基质中普遍存在，然而关于其全身毒性的信息却很匮乏。在本研究中，我们观察到TCC暴露导致高胚胎死亡率、孵化延迟和卵黄吸收延迟，以及畸形增加，如鳔闭合和卵黄囊水肿。同时，TCC影响了肠下静脉（SIVs）、节间血管和后主静脉的形成与分支。特别是，SIVs收缩，其分支减少甚至断裂，覆盖面积也随之减小。TCC诱导的氧化应激和过度凋亡是由抗凋亡/促凋亡基因的异常表达引起的。免疫细胞数量和聚集功能的显著降低证明TCC对斑马鱼具有显著的免疫毒性。通过标记基因（tlr4、MyD88和nf-κb）的异常表达以及下游炎症因子（TNF-α、IL-6等）的释放，证实了TCC靶向TLR4信号通路。用抑制剂（CA-4948）抑制TLR4/MyD88/NF-κB通路可挽救TCC诱导的免疫细胞减少趋势。分子对接结果表明，TCC可以与TLR4受体稳定结合，与氨基酸形成氢键和疏水相互作用。总体而言，这些发现揭示了TCC对斑马鱼诱导发育和免疫毒性的潜在分子机制。
