College of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China; School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.
College of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China.
J Hazard Mater. 2023 Feb 5;443(Pt B):130297. doi: 10.1016/j.jhazmat.2022.130297. Epub 2022 Nov 4.
Although triclosan (TCS) is ubiquitously detected in environmental media and organisms, little information is available on its cardiotoxicity and underlying mechanisms. Herein, acute TCS exposure (0.69-1.73 μM) to zebrafish from embryos (6 hpf) to larvae (72 hpf) resulted in cardiac development defects, including increased angle between atrium and ventricle, prolonged SV-BA distance, linearized heart and pericardial cyst in 72-hpf larvae. These malformations resulted from interfered oxidative-stress pathways, reflecting in accumulated ROS and MDA and inhibited SOD and CAT activities. By RT-qPCR, the transcription levels of four cardiac development-related marker genes were significantly up-regulated except for gata4. Besides, miR-144 was identified as a regulatory molecule of TCS-induced cardiac defects by integrating analyses of artificial intervene expression and RNA-Seq data. Interestingly, the target genes of miR-144 were found and interacted with the above marker genes through constructing protein-protein interaction networks. After intervening the expression of miR-144 by microinjecting and activating Wnt pathway by an agonist BML-284, we confirmed that up-regulated miR-144 suppressed the expression of angiogenesis-related genes and negatively regulated Wnt pathway, further triggering angiogenesis disorders and cardiac phenotypic malformation. These findings unravel the underlying molecular mechanisms regarding TCS-induced cardiac development toxicity, and contribute to early warning and risk management of TCS.
尽管三氯生（TCS）广泛存在于环境介质和生物体内，但关于其心脏毒性及其潜在机制的信息却很少。本研究中，急性 TCS 暴露（0.69-1.73μM）于胚胎期（6 hpf）至幼鱼期（72 hpf）斑马鱼，导致心脏发育缺陷，包括心房和心室之间角度增加、SV-BA 距离延长、心脏和心包囊肿线性化。这些畸形是由于氧化应激途径受到干扰所致，反映在 ROS 和 MDA 积累以及 SOD 和 CAT 活性抑制上。通过 RT-qPCR，四个心脏发育相关标记基因的转录水平显著上调，除了 gata4。此外，通过整合人工干预表达和 RNA-Seq 数据分析，miR-144 被鉴定为 TCS 诱导心脏缺陷的调节分子。有趣的是，miR-144 的靶基因通过构建蛋白质-蛋白质相互作用网络与上述标记基因相互作用。通过微注射干预 miR-144 的表达并通过激动剂 BML-284 激活 Wnt 通路，我们证实上调的 miR-144 抑制了血管生成相关基因的表达，并负调控了 Wnt 通路，进而引发血管生成障碍和心脏表型畸形。这些发现揭示了 TCS 诱导心脏发育毒性的潜在分子机制，并有助于 TCS 的早期预警和风险管理。
