塑化剂邻苯二甲酸酯暴露诱导活性氧水平升高对大鼠肝脏的毒性作用  

DEHP plasticizer-induced hepatotoxicity in rats:elevated reactive oxygen species levels as a mechanism

作　　者：朱学河 武杰[1] ZHU Xue-he;WU Jie(Emergency Surgery Affiliated Hospital of Inner Mongolia Medical University,Huhehaote 015000,China)

机构地区：[1]内蒙古医科大学附属医院急诊外科,呼和浩特015000

出　　处：《肝脏》2024年第6期719-724,共6页Chinese Hepatology

基　　金：2022年度自治区卫生健康科技计划项目(202201315);内蒙古医科大学实验室开放基金项目(2022KF02)。

摘　　要：目的 探讨塑化剂邻苯二甲酸酯暴露对肝脏的毒性作用。方法 50只SD大鼠随机分为空白对照组、溶媒对照组及DEHP低、中和高剂量组(DEHP 1 mg/kg、5 mg/kg和25 mg/kg)。染毒4周,染毒期间测定各组大鼠体重,结束染毒时测定各组大鼠血清生化指标、肝脏系数、肝脏组织氧化/还原指标。人正常肝细胞HL-7702分为空白对照组、溶媒对照组(DEHP 0μmol/L)和实验组(DEHP 0.1μmol/L、10μmol/L和100μmol/L),测定各组24、48和72 h细胞活力、细胞TG、TC和ROS水平,以及Nrf2/HO-1信号通路相关基因和蛋白表达水平。结果 染毒后1、2和4周时DEHP低剂量组、中剂量组和高剂量组大鼠体重均较溶媒对照组呈剂量依赖性降低(P<0.05)。治疗结束时DEHP低剂量组、中剂量组和高剂量组大鼠肝脏重量和肝脏系数均较溶媒对照组呈剂量依赖性升高(P<0.05);治疗结束时DEHP低剂量组、中剂量组和高剂量组大鼠血清AST、ALT和ALP均较溶媒对照组呈剂量依赖性升高(P<0.05);治疗结束时DEHP低剂量组、中剂量组和高剂量组大鼠肝脏组织中ROS和MDA均较溶媒对照组呈剂量依赖性升高(P<0.05),SOD、GSH均较溶媒对照组呈剂量依赖性降低(P<0.05);培养24、48和72 h时中剂量组和高剂量组HL-7702细胞活力均较溶媒对照组呈剂量依赖性降低(P<0.05);培养48 h中剂量组和高剂量组HL-7702细胞TG、TC和ROS水平均较溶媒对照组呈剂量依赖性升高(P<0.05);培养48 h中剂量组和高剂量组HL-7702细胞Nrf2、HO-1和NQO1 mRNA表达水平均较溶媒对照组呈剂量依赖性降低(P<0.05);培养48 h中剂量组和高剂量组HL-7702细胞Nrf2、HO-1和NQO1蛋白表达水平均较溶媒对照组呈剂量依赖性降低(P<0.05)。结论 塑化剂邻苯二甲酸酯暴露可对肝脏产生毒性作用,其作用机制可能与通过调节Nrf2/HO-1信号通路提高活性氧水平对肝脏产生氧化应激损伤有关。Objective To investigate the hepatotoxic effects of the plasticizer DEHP and explore its potential mechanism involving the elevation of reactive oxygen species.Methods A total of 50 Sprague-Dawley rats were randomly divided into five groups:blank control,vehicle contro,DEHP low dose(1 mg/k),DEHP medium dose(5 mg/kg),and DEHP high dose(25 mg/kg).Body weight was monitored during the treatment period.At the end of the treatment,serum biochemical indices,liver coefficients,and oxidative/reductive indices in hepatic tissues were measured.Human normal hepatocytes HL-7702 were divided into blank control,vehicle control(DEHP 0μmol/L)and experimental groups(DEHP 0.1μmol/L,10μmol/L and 100μmol/L).Cell viability was assessed at 24 h,48 h and 72 h,along with measurements of TG,TC and ROS levels,and the expression of genes and proteins related to the Nrf2/HO-1 signaling.Results(1)The body weights of rats in the DEHP low dose,middle dose and high dose groups decreased in a dose-dependent manner during the 1st 2nd and 4th weeks post-treatment(P<0.05).(2)At the end of treatment,the liver weight and liver coefficient of rats in the DEHP low dose,medium dose and high dose groups increased in a dose-dependent manner compared to the vehicle control group(P<0.05).(3)Serum AST,ALT and ALP levels in the DEHP low dose,medium dose,and high dose groups were elevated in a dose-dependent manner compared to the vehicle control group at the end of the treatment period(P<0.05).(4)The levels of ROS and MDA in hepatic tissues of rats in the DEHP low dos,medium dose,and high dose groups increased in a dose-dependent manner,while the levels of SOD and GSH decreased in a dose-dependent manner at the end of treatment(P<0.05).(5)The viability of HL-7702 cells in the DEHP medium dose and high dose groups decreased in a dose-dependent manner compared to the vehicle control group at 24 h,48 h,and 72 h post-cultivation(P<0.05),(6)The levels of TG,TC and ROS in HL-7702 cells in the DEHP medium dose and high dose groups increased in a dose-dependent ma

关 键 词：邻苯二甲酸酯 氧化应激 肝脏 活性氧 Nrf2/HO-1信号通路 

分 类 号：R114[医药卫生—卫生毒理学]