Previous research in our laboratory showed that acetaminophen (ACE) induced embryonic mortality and abnormalities in zebrafish. Here, we examined the dose response of ACE (0.05–50 μg L⁻¹) in zebrafish embryos. Concentrations as low as 0.1 μg L⁻¹ significantly increased abnormalities, and all test concentrations significantly increased mortality rates. In mammals, ACE inhibits cyclooxygenase (COX) enzymes to decrease prostaglandin production. Here we report COX activity and expression of the cox-1, cox-2a, and cox-2b genes in zebrafish embryos. COX activity was significantly inhibited by specific mammalian cox-1 (SC-560) and cox-2 (DuP-697) inhibitors in unexposed and ACE-exposed embryos. COX activity declined with development time. Maternal transcripts of all cox genes were found at 1 -h post fertilization and embryonic expression began in gastrulation or early segmentation. Co-exposure of ACE and prostaglandin E2 abolished the ACE-induced effects. This strongly supports that ACE elicits embryo toxicity in zebrafish though the same molecular mechanism of action of their therapeutic effects in mammals.

我们实验室先前的研究表明，对乙酰氨基酚（ACE）会引起斑马鱼的胚胎死亡和异常。在这里，我们检查了斑马鱼胚胎中ACE的剂量反应（0.05–50μgL ^-1）。低至0.1μgL ^-1的浓度会显着增加异常，并且所有测试浓度均会显着提高死亡率。在哺乳动物中，ACE抑制环氧合酶（COX）酶以降低前列腺素的产生。在这里，我们报告斑马鱼胚胎中的COX活性和cox -1，cox -2a和cox -2b基因的表达。特定的哺乳动物cox -1（SC-560）和cox显着抑制了COX活性-2（DuP-697）抑制剂未暴露和ACE暴露的胚胎。COX活性随开发时间而下降。在受精后1小时发现所有cox基因的母本转录本，并且胚胎表达开始于胃形成或早期切分。ACE和前列腺素E2的共同暴露消除了ACE诱导的作用。这有力地支持了ACE在斑马鱼中引发胚胎毒性，尽管它们在哺乳动物中具有相同的治疗作用分子机制。