镉亚急性暴露对小鼠肝肾功能及甲基化水平的影响

发布时间：2018-01-28 18:21

本文关键词： 镉 DNA甲基化 Tet酶肝功能肾功能小鼠　出处：《环境与职业医学》2015年05期 　论文类型：期刊论文

【摘要】：[目的]初步探讨氯化镉(cadmium chloride,Cd Cl2)亚急性暴露(4周染毒)对小鼠肝肾功能、全基因组甲基化水平及去甲基化酶Tet1表达的影响。[方法]将48只SPF级KM小鼠(昆明小鼠,雌雄各半)随机分为4组:对照组(dd H2O)、Cd Cl2 17.5 mg/kg组、25 mg/kg组、35 mg/kg组。经口灌胃染毒(每天1次、每周5 d),共染毒4周,CO2麻醉法处死动物。测定肝脏和肾脏的脏器系数、血液常规及血液生化检查、肝肾组织病理学检查、全基因组DNA甲基化水平及Tet1酶表达水平。[结果]35 mg/kg染毒组小鼠活动度及精神状态较差。小鼠体重在各染毒周期和染毒剂量组间差异均有统计学意义,且存在交互作用(P0.05)。与对照组相比,雄性小鼠肝脏质量和肝脏脏器系数在25 mg/kg和35 mg/kg剂量组差异具有统计学意义(P0.05);血液常规检查结果显示,雌、雄性小鼠35 mg/kg染毒组血液白细胞(WBC)、血小板(PLT)、淋巴细胞(LYM)计数,均高于对照组(P0.05);雄性小鼠在各个染毒剂量组间,WBC、PLT、LYM、RBC计数差异有统计学意义(P0.05)。此外,血生化实验结果显示,各剂量组雄性和雌性小鼠中肝功能的主要指标谷丙转氨酶(ALT)、碱性磷酸酶(ALP)差异有统计学意义(P0.05),肾功能的主要指标尿酸(UA)、血尿素氮(BUN)、肌酐(CR)差异均有统计学意义(P0.05)。组织病理学分析发现25 mg/kg和35 mg/kg组雄性小鼠肝脏及肾脏呈现明显的病理性改变。Tet1 m RNA及其蛋白表达水平仅在雄性小鼠的肝脏、肾脏中表达的差异有统计学意义(P0.05)。焦磷酸测序结果显示,雄性小鼠肝脏、肾脏甲基化水平表达差异有统计学意义(P0.05),且其与Tet1 m RNA表达呈负相关(r=-0.473,P0.05;r=-0.134,P0.05)。[结论]Cd Cl2亚急性染毒可以诱导小鼠肝肾功能损伤,且对全基因组甲基化水平和去甲基化酶Tet1表达呈现出性别差异影响,雄性小鼠的肝肾组织Tet1表达参与调控全基因组DNA甲基化水平改变。
[Abstract]:[Objective] to study the effects of cadmium chloride on liver and kidney function of mice after subacute exposure to cadmium chloride (CDCL _ 2) for 4 weeks. Effect of genomic methylation level and Tet1 expression of demethylase. [Methods] 48 km mice of SPF grade (Kunming mice, half male and half female) were randomly divided into 4 groups: the control group was treated with CD Cl2 17.5 mg/kg. The animals in 25 mg/kg group were given intragastric administration (5 days a week, once a day, 5 days a week). The animals were killed by CO _ 2 anesthesia for 4 weeks. The organ coefficients of liver and kidney were measured. Blood routine and blood biochemical examination, liver and kidney histopathology, whole genome DNA methylation level and Tet1 enzyme expression level. [Results: the activity and mental state of the mice in the 35 mg/kg group were poor, and the weight of the mice was significantly different in the different exposure cycles and dose groups. And there was interaction between the two groups (P 0.05), compared with the control group. The difference of liver mass and liver organ coefficient between 25 mg/kg and 35 mg/kg group was statistically significant (P 0.05). The results of routine blood examination showed that WBC, PLT, and LYM were found in 35 mg/kg infected group of female and male mice. All of them were higher than the control group (P 0.05). There was significant difference in RBC count between different dose groups of male mice. In addition, the results of blood biochemistry test showed that the RBC counts of LYMN were significantly different among different dose groups. The main indexes of liver function in male and female mice were alanine aminotransferase (alt) and alkaline phosphatase (ALP). The main indexes of renal function were UAA, bun (bun). There were significant differences in creatinine creatinine (creatinine) (P 0.05). Histopathological analysis showed that the liver and kidney of 25 mg/kg and 35 mg/kg mice showed obvious pathological changes. The expression of RNA and its protein was found only in the liver of male mice. The difference in the expression of methylation in the kidney was statistically significant (P 0.05). The results of pyrosequencing showed that the expression of methylation in the liver and kidney of male mice was significantly different (P 0.05). And it was negatively correlated with the expression of Tet1 m RNA (P 0.05). R-0.134, P0.05. [Conclusion CD Cl2 subacute exposure can induce liver and kidney function injury in mice, and has a gender difference on the whole genome methylation level and the expression of demethylase Tet1. The expression of Tet1 in the liver and kidney of male mice is involved in the regulation of genomic DNA methylation.
【作者单位】：中山大学公共卫生学院预防医学系;广州市疾病预防控制中心毒理学检验部;
【基金】：国家自然科学基金(编号:81101562,81273099) 中央高校基本科研基金(编号:12ykpy13) 广东省自然科学基金(编号:s2012010009633) 广东省科技计划项目(编号:2012b060300005)
【分类号】：R114
【正文快照】： 镉(cadmium,Cd)及其化合物是多种工业生产中广泛应用的原料,1993年国际癌症研究中心(International Agency for Research on Cancer,IARC)及美国国家毒理学计划署(US National ToxicologyProgram)将其列为人类确定致癌物[1-2]。Cd也是一种潜在的致突变剂[3];可在哺乳动物细胞

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