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目的测定自主建立的p53+/-基因敲除小鼠(B6-Trp53~(tm1)/NIFDC)在N-甲基-N-亚硝基脲(N-Methyl-Nnitrosourea,MNU)给药后体质量、脏器质量、血液学及血生化指标,为临床前药物安全评价致癌性实验短期体内替代试验候选遗传修饰动物模型提供背景性数据。方法共设计4个组:阴性对照组(野生型小鼠)给予生理盐水、溶媒对照组(B6-Trp53~(tm1)/NIFDC小鼠)给予枸橼酸缓冲液、MNU组1(B6-Trp53~(tm1)/NIFDC小鼠)给予75 mg/kg MNU、MNU组2(野生型小鼠)给予75 mg/kg MNU,阴性对照组和MNU组2每组野生型小鼠各20只,雌雄各半,溶媒对照组和MNU组1每组B6-Trp53~(tm1)/NIFDC小鼠各20只,雌雄各半,测定其体质量、主要脏器质量、相对脏器质量、血液学及血生化指标,并进行统计分析。结果 MNU组1、MNU组2动物体质量降低与阴性对照组、溶媒对照组相比都存在显著性统计学差异(P<0.05)。MNU组1、MNU组2动物心脏、肝脏、脾脏、肺脏、胸腺和颌下腺的绝对质量与阴性对照组、溶媒对照组相比有显著性统计学差异(P<0.05)。MNU组1和MNU组2动物心脏、肝脏、脾脏、肺脏、肾脏、脑、胸腺和颌下腺的相对质量与阴性对照组、溶媒对照组相比有显著性统计学差异(P<0.05)。MNU组1和MNU组2动物均发现NEU、LYM%、LUC%、RBC、HGB、HCT、MCV、MCHC、RDW、HDW、CHCM、CHDW、PDW、MPV及PLT等15个指标与阴性对照组和溶媒对照组相比有显著性统计学差异(P<0.05)。另外,MNU组1和MNU组2均发现TP、ALB、CREA、UREA、TCHO、TG、CA等7个指标与阴性对照组和溶媒对照组有显著性统计学差异(P<0.05),MNU组2的AST与阴性对照组和溶媒对照组有显著性升高(P<0.05),但MNU组1和MNU组2组间没有显著性统计学差异。结论本文测定并分析了自主建立的p53+/-基因敲除小鼠(B6-Trp53~(tm1)/NIFDC)和野生型小鼠分别给予MNU及枸橼酸缓冲液后的体质量、脏器质量、血液学及血生化指标,该模型有望将来用于临床前药物安全评价致癌性实验短期体内替代试验。
Objective To determine the body mass of self-established p53 +/- knockout mice (B6-Trp53 (tm1) / NIFDC) after administration of N-methyl-Nnitrosourea (MNU) , Organ quality, hematology and blood biochemical indicators, to provide background data for the preclinical drug safety evaluation carcinogenicity test short-term in vivo alternative test candidate genetically modified animal model. Methods A total of 4 groups were designed: negative control group (wild-type mice) with saline, vehicle control group (B6-Trp53 ~ (tm1) / NIFDC mice) with citrate buffer, MNU group 1 ~ (tm1) / NIFDC mice) were given 75 mg / kg MNU, MNU group 2 (wild type mice) were given 75 mg / kg MNU, negative control group and MNU group 2 each 20 wild-type mice, male and female Each half, vehicle control group and MNU group 1 each B6-Trp53 ~ (tm1) / NIFDC mice 20 each, male and female, the body mass, the quality of the main organs, the relative organ quality, hematology and blood Biochemical indicators, and statistical analysis. Results The decrease of body weight in MNU group 1 and MNU group 2 was significantly lower than that in negative control group and vehicle control group (P <0.05). The absolute quality of MNU group 1 and MNU group 2 animal heart, liver, spleen, lung, thymus and submandibular gland were significantly different from that of negative control group and vehicle control group (P <0.05). The relative quality of MNU group 1 and MNU group 2 animal heart, liver, spleen, lung, kidney, brain, thymus and submandibular gland were significantly different from those of negative control group and vehicle control group (P <0.05). 15 indicators including NEU, LYM%, LUC%, RBC, HGB, HCT, MCV, MCHC, RDW, HDW, CHCM, CHDW, PDW, MPV and PLT were found in both MNU group 1 and MNU group 2 animals compared with negative control group and There was significant difference between the vehicle control group and the control group (P <0.05). In MNU group 1 and MNU group 2, there were significant differences (P <0.05) between TPU, ALB, CREA, UREA, TCHO, TG and CA in the MNU group and the negative control group and the vehicle control group 2 AST significantly increased compared with the negative control group and the vehicle control group (P <0.05), but there was no significant difference between MNU group 1 and MNU group 2. CONCLUSIONS: We measured and analyzed the body mass, organ quality, and pathophysiology of spontaneous p53 +/- knockout mice (B6-Trp53 (tm1) / NIFDC) and wild-type mice after MNU and citrate supplementation , Hematology and blood biochemical indicators, the model is expected to be used in pre-clinical drug safety evaluation of carcinogenicity experiments short-term in vivo replacement test.