Flurbiprofen axetil (FA) is a nonsteroidal targeted analgesic and widely used for postoperative analgesia and cancer analgesia. Extensive works have been done in the evaluation of FA's clinical analgesic effect on adults. Along with the increase of FA usage, the potential toxicity and molecular mechanism in embryo development need to be better understood. In this article, multiple embryonic development indexes of zebrafish were introduced to evaluate the FA toxicity to provide clinical guidance for gravidas medicine. We performed a zebrafish embryo toxicity (ZFET) test by exposing embryos to a series of concentration gradients of FA medium starting from 24 hours postfertilization (hpf). The mortality rate, hatching rate, and malformation rate of drug-treated zebrafish were assessed at 72, 96, and 120 hpf. Effects of ≤10% lethal concentration (LC₁₀) of FA on embryogenesis were evaluated by eye area, body length, and yolk sac area. A 0.5 μg/mL or fewer FA treatment did not show any adverse effects, but the LC₁₀ FA significantly caused zebrafish malformation. Organ disorders, including slow heart rate, enlarged pericardium, and liver atrophy, were found in the dysplasia individuals when compared with control. TUNEL assay suggested that apoptotic cells in malformation embryos were produced by FA and the increasing dosage exacerbated apoptosis. Quantitative real-time polymerase chain reaction revealed that expressions of cardiac development-associated transcription factors, liver development-related genes, and apoptosis regulating genes were aberrant. These results indicate that the ZFET can be applied in the FA toxicity test, and a low lethal dose of FA is harmful to zebrafish embryogenesis, especially in embryo carcinogenesis and hepatogenesis.

中文翻译：

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氟比洛芬酯对斑马鱼胚胎的发育心脏毒性和肝毒性

氟比洛芬酯（FA）是一种非甾体靶向镇痛药，广泛用于术后镇痛和癌症镇痛。在评估 FA 对成人的临床镇痛作用方面进行了广泛的工作。随着 FA 使用量的增加，需要更好地了解胚胎发育中的潜在毒性和分子机制。本文介绍了斑马鱼的多种胚胎发育指标来评价FA毒性，为妊娠用药提供临床指导。我们通过从受精后 24 小时 (hpf) 开始将胚胎暴露于一系列浓度梯度的 FA 培养基进行了斑马鱼胚胎毒性 (ZFET) 测试。经药物处理的斑马鱼的死亡率、孵化率和畸形率分别为 72、96 和 120 hpf。₁₀ ) FA 对胚胎发生的影响通过眼睛面积、体长和卵黄囊面积进行评估。0.5 μg/mL 或更少的 FA 处理未显示任何不良反应，但 LC ₁₀FA 显着导致斑马鱼畸形。与对照组相比，发育不良个体存在器官疾病，包括心率缓慢、心包增大和肝萎缩。TUNEL分析表明畸形胚胎中的凋亡细胞是由FA产生的，并且增加剂量会加剧细胞凋亡。定量实时聚合酶链反应显示心脏发育相关转录因子、肝脏发育相关基因和凋亡调节基因表达异常。这些结果表明ZFET可用于FA毒性试验，低致死剂量的FA对斑马鱼胚胎发生有害，特别是在胚胎致癌和肝发生中。