低剂量莠去津暴露饮用水诱导小鼠肝损伤模型的建立及验证

Establishment and validation of a mouse liver injury model induced by chronic low-dose exposure to atrazine

目的 建立长期饮喂低剂量莠去津诱发小鼠肝损伤模型,并评价莠去津引起的肝毒性作用。方法 C57BL/6-N雄性小鼠随机分为对照组以及1.5 mg/L和150 mg/L剂量(ATR-L、ATR-H)组,于饮喂后第35天和63天检测血清肝功能生化指标和炎性因子水平,计算肝体比并对肝进行病理组织学和超微结构观察,检测肝组织中脂质过氧化水平和抗氧化能力,以及主要Ⅰ相代谢酶和Ⅱ相解毒酶的活性及相关蛋白表达。结果 与对照组相比,莠去津组AST/ALT比值,促炎性因子CCL2、TNF-α和IL-6,H2O2含量以及代谢酶NCR、CYT b5和UDPGT活性均有显著变化(P<0.05);150 mg/L剂量组肝功能GGT含量,过氧化物MDA水平及CYP1A2表达量极显著升高(P<0.01),而GSH含量显著降低(P<0.05),观察肝细胞损伤和线粒体空泡化更严重。结论 在建立低剂量莠去津诱导小鼠肝损伤模型时,1.5 mg/L和150 mg/L莠去津饮用水暴露均能够引起小鼠肝损伤,其中150 mg/L莠去津暴露63 d后引起的肝代谢毒性更强。

Objective To establish a model of long-term atrazine(ATR)-induced liver injury in mice and to evaluate the hepatotoxic effects induced by ATR.Methods C57BL/6-N male mice were randomly divided into a control group and 1.5 mg/L and 150 mg/L ATR dose(ATR-L,ATR-H)groups.After 35 and 63 days,serum liver function biochemical indexes and inflammatory factors were detected,the hepatosomatic ratio was calculated,and the histopathology and ultrastructure of the liver were observed.Lipid peroxidation levels and antioxidant capacity,the activities of major phase I metabolic enzymes and phase II detoxification enzymes,and the expression of related proteins in liver tissues were detected.Results Compared with the control group,the ATR groups showed significant changes in the AST/ALT ratio,levels of pro-inflammatory factors CCL2,TNF-αand IL-6,H2O2 content and activities of the metabolic enzymes NCR,CYT b5,and UDPGT(P<0.05).In the 150 mg/L ATR group,GGT content,peroxide levels(as indicated by malondialdehyde),and CYP1A2 expression were significantly increased(P<0.01),while GSH content was significantly decreased(P<0.05),and hepatocyte injury and mitochondrial vacuolation were more serious when compared to control and 1.5 mg/L groups.Conclusions In a mouse model of low-dose ATR liver injury,both 1.5 mg/L and 150 mg/L ATR exposure induced liver injury in mice,with 150 mg/L ATR inducing the maximum metabolic toxicity in the liver after 63 days.