二甲基甲酰胺短期重复染毒对雄性小鼠肝脏的影响  

Effect of short-term repeated exposures to N,N-dimethylformamide on liver in male mice

作　　者：王磊[1] 郑敏[1] 管明月[1] 张蔓[1] 吴智君[1] 赵文锦[1] 程娟[1] WANG Lei;ZHENG Min;GUAN Ming-yue;ZHANG Man;WU Zhi-jun;ZHAO Wen-jin;CHENG Juan(National Institute of Occupational Health and Poison Control,Chinese Center for Disease Control and Prevention,Beijing 100050,China)

机构地区：[1]中国疾病预防控制中心职业卫生与中毒控制所,北京100050

出　　处：《毒理学杂志》2018年第4期268-273,共6页Journal of Toxicology

基　　金：国家自然科学基金(81372963)

摘　　要：目的研究二甲基甲酰胺(DMF)短期重复染毒对雄性小鼠肝损伤的特点,为今后开展DMF慢性毒性研究提供实验依据。方法 SPF级健康成年雄性C57BL/6小鼠100只,随机分成空白对照组和染毒组(150 mg/kg·bw),每组50只。分别于染毒1、3、7、14和28 d 5个时间点处死10只对照组和10只染毒组动物。采尾静脉血检测血常规指标,摘眼球取血检测血生化指标和生物标志物N-甲基氨基甲酰加合物(NMHb)的含量。解剖取肝,记录肝重,计算脏器系数,苏木素-伊红(HE)染色进行肝组织病理学检查。结果与对照组相比,DMF连续染毒可抑制小鼠体重增长,1、3、14和28 d肝脏系数明显增大(P<0.05)。28 d白细胞计数明显升高(P<0.05)。14和28 d丙氨酸转氨酶(ALT)含量明显升高(P<0.05),7和28 d天冬氨酸转氨酶(AST)含量升高(P<0.05)。肝病理切片显示,染毒组出现不同程度的肝细胞水样变,局灶性细胞坏死伴有炎细胞浸润,严重程度随染毒时间延长逐渐加重。染毒28 d出现严重细胞水肿,肝小叶结构破坏,细胞核固缩或溶解。NMHb含量随染毒时间逐渐升高,对照组未检出。结论 DMF短期重复染毒可导致小鼠生长缓慢,肝损伤特点主要表现为肝肿大,从第7天开始,血清转氨酶明显升高,染毒前期(3 d)病理表现为肝细胞轻度水肿伴炎细胞浸润,后期主要以严重肝细胞水样变性为主,肝小叶结构受损,损伤程度随染毒时间逐渐加重。Objective To explore the hepatotoxicity of the repeated exposures to N,N-dimethylformamide（ DMF） for 28 consecutive days on liver in male mice. Methods One hundred male C57 BL/6 mice were divided into two groups randomly,which included one control group and one exposure group. In DMF exposure group,mice were administrated by gavage with DMF（ 150 mg/kg·bw） for continuous 28 days. Ten mice from control group and exposure group were sacrificed on the 1 st day,3 rd day,7 th day,14 th day,28 th day respectively.Tail venous blood was taken for hematology analysis and whole blood samples from eye were collected after euthanasia. The serum levels of ALT,AST,TG,CHOL,ALP,GLU were measured by blood biochemical analyzer and the biomarker N-methylcarbmoylated-hemoglobin（ NMHb） were detected by LC-MS/MS. Pathological changes of liver tissue were observed by HE staining. Result Exposure to DMF continuously inhibited the body weight growth and significantly increased liver weight. Significant increase was observed in white blood cell count on the 28 th day. Continuous DMF exposure result ed in a significant increase in serum ALT on the 14 th day,28 th day and increased AST on the 7 th day,28 th day respectively. Morphology evaluations showed a time-dependent increase in vacuolation of hepatocytes,and aggravated gradually on the 7 th day,14 th day,28 th day of DMF exposure. The most severe edema,hepatic lobule structure destruction,and nuclear condensation or dissolution in hepatocytes were observed on the 28 th day. The biomarker NMHb content gradually accumulated with the exposure time of DMF. Conclusion These result indicate that DMF exposure result in growth inhibition and liver enlargement. From the7 th day,serum aminotransferases were significantly increased. In the early stage（ on the 3 rd day） pathological manifestation of hepatocytes was mild edema accompanied with inflammatory cell infiltration. While severe liver edema,and hepatic lobule structure damage appeared mainly in the later stage.

关 键 词：二甲基甲酰胺 亚急性肝损伤 N-甲基氨基甲酰加合物 

分 类 号：R114[医药卫生—卫生毒理学]