Huang Cheng-Chen, Chen Peng-Chi, Huang Chin-Wei, Yu John
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Toxicol Sci. 2007 Dec;100(2):486-94. doi: 10.1093/toxsci/kfm235. Epub 2007 Sep 6.
Aristolochic Acid (AA) is a component of Chinese herbs that has been found to be toxic to multiple organs in adults. Its toxicity to developing embryos has not been reported. Here, we describe that AA specifically causes heart defects in developing zebrafish embryos in a dosage-dependent manner. The treated embryos are able to develop their hearts normally up to 24 h postfertilization, when cardiac contraction initiates, but begin to show deformation and reduction of the hearts followed by gradual contractility loss and eventually lethality, suggesting that AA is primarily affecting cardiac physiology rather than cardiogenesis. Histological analyses reveal that the AA-treated hearts develop hypertrophy and disorganization of cardiomyocytes and loss of endocardium. By transmission electron microscopy, we observed broken and disorganized cardiac fibers in the AA-treated hearts. AA induces the expression of proinflammation genes, including cox-2, IL-1beta, and others. The AA-induced cardiac defects can be attenuated by the cox-2 antagonist NS398 via reducing the expression of the inflammatory genes. This attenuation could be further enhanced by known heart failure drugs, such as angiotensin-converting enzyme inhibitor and beta-adrenergic receptor antagonist. In contrast, the heart defects are enhanced by a beta-adrenergic receptor agonist. In summary, AA causes profound toxicity to zebrafish embryos that exhibit pathophysiological and pharmacological features resembling those of heart failure in humans and other model organisms, and thus, zebrafish could be a new model for studies on heart failure.
马兜铃酸（AA）是中草药的一种成分，已发现其对成年人的多个器官具有毒性。尚未有其对发育中胚胎毒性的报道。在此，我们描述了AA以剂量依赖的方式特异性地导致斑马鱼发育胚胎出现心脏缺陷。经处理的胚胎在受精后24小时心脏开始收缩时仍能正常发育心脏，但随后心脏开始出现变形和缩小，接着逐渐失去收缩能力并最终死亡，这表明AA主要影响心脏生理功能而非心脏发生。组织学分析显示，经AA处理的心脏出现心肌肥大、心肌细胞排列紊乱以及心内膜缺失。通过透射电子显微镜，我们观察到经AA处理的心脏中存在断裂且紊乱的心肌纤维。AA诱导促炎基因的表达，包括环氧化酶-2（cox-2）、白细胞介素-1β（IL-1β）等。cox-2拮抗剂NS398可通过降低炎症基因的表达减轻AA诱导的心脏缺陷。已知的心力衰竭药物，如血管紧张素转换酶抑制剂和β-肾上腺素能受体拮抗剂可进一步增强这种减轻作用。相反，β-肾上腺素能受体激动剂会加重心脏缺陷。总之，AA对斑马鱼胚胎具有严重毒性，这些胚胎表现出类似于人类和其他模式生物心力衰竭的病理生理和药理特征，因此，斑马鱼可能成为研究心力衰竭的新模型。
