Evaluation of Macaca mulatta as a model for genotoxicity studies
Evaluation of Macaca mulatta as a model for genotoxicity studies
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DOI：
10.1016/j.mrgentox.2008.11.006
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发表时间：
2009-02-19
影响因子：
1.9
通讯作者：
Morris, Suzanne M.
中科院分区：
文献类型：
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作者：
Dobrovolsky, Vasily N.;Shaddock, Joseph G.;Morris, Suzanne M.
我们研究了使用非人灵长类（NHP）恒河猴（Macaca mulatta）的外周血作为突变检测的模型系统。恒河猴在代谢方面比大多数普通实验动物更接近人类，因此可能是危害识别和人类风险评估的相关模型。为了验证该模型，确定了体外选择和扩增常规静脉穿刺外周血中6-硫鸟嘌呤耐药（6-TGr） HPRT突变体和ProAERr耐药（ProAERr）猪- a突变体淋巴细胞的条件。此外，流式细胞术方法被开发用于快速检测猪- a突变红细胞。猪- a突变红细胞的流式细胞分析是基于通过糖基磷脂酰肌醇（GPI）锚定点计算细胞膜表面标记缺失的细胞。在一段较长的时间内，研究人员在接受每日剂量的电解质补充剂Prang （NHPs中口服药物的常见载体）的雄性猴子的外周血中，以及在大约2岁时接受单次剂量50 mg/kg n -乙基-n -亚硝基脲治疗的一只雄性猴子的血液中，以及在大约3.5岁时接受另一类似注射的另一只雄性猴子的血液中，都发现了突变细胞。在接受Prang治疗的动物中，自发的猪- a和HPRT t细胞突变频率（MF）较低（0-8 × 10(-6)），而使用ENU治疗导致ProAERr和6-TGr淋巴细胞频率明显增加（分别接近28 × 10（-6）和30 × 10(-6)）。此外，enu治疗动物gpi缺陷红细胞的频率更高(治疗动物为46.5 × 10（-6)，对照组为7.8 +/- 4.2 × 10(-6)）。我们的研究结果表明，恒河猴可以作为一个有价值的模型，用于鉴定可能影响人类健康的诱变剂，并且猪- a基因可以作为检测白细胞和红细胞突变的有用靶点。Elsevier B.V.出版
We have investigated the use of peripheral blood from the nonhuman primate (NHP) rhesus monkey (Macaca mulatta) as a model system for mutation detection. The rhesus monkey is metabolically closer to humans than most common laboratory animals, and therefore may be a relevant model for hazard identification and human risk assessment. To validate the model, conditions were determined for in vitro selection and expansion of 6-thioguanine-resistant (6-TGr) HPRT mutant and proaerolysin-resistant (ProAERr) PIG-A mutant lymphocytes from peripheral blood obtained by routine venipuncture. Also, flow cytometric methods were developed for the rapid detection of PIG-A mutant erythrocytes. The flow cytometric analysis of PIG-A mutant erythrocytes was based on enumerating cells deficient in surface markers attached to the cellular membrane via glycosylphosphatidyl inositol (GPI) anchors. Mutant cells were enumerated over an extended period of time in peripheral blood of male monkeys receiving daily doses of the electrolyte replenisher Prang (TM) (a common carrier for oral delivery of drugs in NHPs), and in the blood of one male monkey treated with a single i.p. dose of 50 mg/kg of N-ethyl-N-nitrosourea at similar to 2 years of age and another similar injection at approximately 3.5 years of age. The spontaneous PIG-A and HPRT T-cell mutant frequency (MF) was low in animals receiving Prang (0-8 x 10(-6)), and treatment with ENU resulted in a clearly detectable increase in the frequency of ProAERr and 6-TGr lymphocytes (up to similar to 28 x 10(-6) and similar to 30 x 10(-6), respectively). Also, the ENU-treated animal had higher frequency of GPI-deficient erythrocytes (46.5 x 10(-6) in the treated animal vs. 7.8 +/- 4.2 x 10(-6) in control animals). our results indicate that the rhesus monkey can be a valuable model for the identification of agents that may impact upon human health as mutagens and that the PIG-A gene can be a useful target for detection of mutation in both white and red blood cells. Published by Elsevier B.V.