四种细胞毒性药物对斑马鱼的急性和亚慢性毒性
Acute and sub-chronic toxicity of four cytostatic drugs in zebrafish.
作者信息
Kovács Róbert, Bakos Katalin, Urbányi Béla, Kövesi Judit, Gazsi Gyöngyi, Csepeli Andrea, Appl Ádám János, Bencsik Dóra, Csenki Zsolt, Horváth Ákos
机构信息
Department of Aquaculture, Szent István University, 2100, Gödöllő, Páter Károly u. 1., Hungary.
出版信息
Environ Sci Pollut Res Int. 2016 Aug;23(15):14718-29. doi: 10.1007/s11356-015-5036-z. Epub 2015 Jul 24.
The acute and sub-chronic effects of four cytostatic drugs-5-fluorouracil (5-FU), cisplatin (CisPt), etoposide (ET) and imatinib mesylate (IM)-on zebrafish (Danio rerio) were investigated. Acute tests were carried out in a static system in accordance with the OECD guideline 203 for adult fish and the draft guideline for fish embryos (FET test) in order to find the LC50 values of the four cytostatic drugs. Early-life stage toxicity test on zebrafish was conducted according the OECD guideline 210 using the cytostatic drugs 5-FU and IM in a semistatic system with the objective of investigating the sub-chronic effects of the cytostatic drugs on fish. In adult fish, the cytostatic drugs 5-FU and ET did not pass the limit test, thus, are considered non-toxic. In case of cisplatin, LC50 was calculated at 64.5 mg L(-1), whereas in case of IM, LC50 was at 70.8 mg L(-1). In the FET test, LC50 of 5-FU at 72-h post fertilization (hpf) was 2441.6 mg L(-1). In case of CisPt, LC50 was 349.9 mg L(-1) at 48 hpf and it progressively decreased to 81.3 mg L(-1) at 120 hpf. In addition, CisPt caused a significant delay in the hatch of larvae. In case of ET, LC50 values were not calculable as they were higher than 300 mg L(-1) at which concentration the substance crystallized in the solution. LC50 values of IM were 48 hpf; 158.3 mg L(-1) , 72 hpf; 141.6 mg L(-1), 96 hpf; 118.0 mg L(-1), and 120 hpf; 65.9 mg L(-1). In the Early-life Stage Test with 5-FU, embryonic deformities were not detected during the tests. Regarding mortalities, the 10 mg L(-1) concentration can be considered as LOEC, as statistically significant difference in mortalities was detected in this group alone. Concerning dry body weight and standard length, 1 mg L(-1) is the LOEC. In case of IM, the highest tested concentration (10 mg L(-1)) can be considered LOEC for mortalities, however, the treatment did not have an effect on the other investigated parameters (dry and wet weight, standard length). All four cytostatic drugs were characterized by low toxicity in zebrafish in acute and sub-chronic tests.
研究了四种细胞毒性药物——5-氟尿嘧啶（5-FU）、顺铂（CisPt）、依托泊苷（ET）和甲磺酸伊马替尼（IM）对斑马鱼（Danio rerio）的急性和亚慢性影响。根据经合组织（OECD）针对成鱼的203号指南以及鱼类胚胎指南草案（FET试验），在静态系统中进行急性试验，以确定这四种细胞毒性药物的半数致死浓度（LC50）值。根据OECD 210号指南，在半静态系统中使用细胞毒性药物5-FU和IM对斑马鱼进行早期生命阶段毒性试验，目的是研究细胞毒性药物对鱼类的亚慢性影响。在成鱼试验中，细胞毒性药物5-FU和ET未通过极限试验，因此被认为无毒。顺铂的LC50计算值为64.5 mg L(-1)，而甲磺酸伊马替尼的LC50为70.8 mg L(-1)。在FET试验中，受精后72小时（hpf）时5-FU的LC50为2441.6 mg L(-1)。顺铂在48 hpf时的LC50为349.9 mg L(-1)，在120 hpf时逐渐降至81.3 mg L(-1)。此外，顺铂导致幼虫孵化显著延迟。对于依托泊苷，由于其在溶液中结晶的浓度高于300 mg L(-1)，因此无法计算LC50值。甲磺酸伊马替尼在48 hpf时的LC50值为158.3 mg L(-1)，72 hpf时为141.6 mg L(-1)，96 hpf时为118.0 mg L(-1)，120 hpf时为65.9 mg L(-1)。在5-FU的早期生命阶段试验中，试验期间未检测到胚胎畸形。关于死亡率，10 mg L(-1)的浓度可被视为最低观察效应浓度（LOEC），因为仅在该组中检测到死亡率有统计学显著差异。关于干体重和标准体长，1 mg L(-1)是LOEC。对于甲磺酸伊马替尼，最高测试浓度（10 mg L(-1)）可被视为死亡率的LOEC，然而，该处理对其他研究参数（干重和湿重、标准体长）没有影响。在急性和亚慢性试验中，所有四种细胞毒性药物在斑马鱼中的毒性均较低。
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