双酚A暴露诱导活性氧水平升高对肝脏脂质代谢的影响

Effect of the reactive oxygen species-induced by bisphenol A on liver lipid metabolism disorder

目的探索双酚A(bisphenol A,BPA)对肝脏脂质代谢的影响。方法﹐采用BPA染毒大鼠体内实验,结合人肝细胞系HL-7702体外染毒实验研究双酚A对肝脏脂质代谢的影响。将28只雄性SD大鼠随机分为4组:对照组及BPA亚急性染毒低[1 mg/(kgd)]、中[5 mg/(kg·d)]和高[25 mg/(kg·d)]剂量组,14d后从大鼠体重、肝脏脏器系数,肝脏病理组织切片、血清生化指标等方面评价BPA对肝脏的毒性效应。将人肝细胞系HL-7702,分为对照组及BPA低(0.16 μmol/L)、中(4 μmol/L)和高(100 μmol/L)浓度处理组,染毒24 h后检测细胞内甘油三酯和总胆固醇(totalcholesterol,TC)含量,活性氧簇(reactive oxygen species,ROS)水平,并通过荧光定量PCR检测脂代谢及氧化应激相关基因的转录水平。结果BPA 14 d亚急性染毒后,大鼠体重和肝脏脏器系数无明显变化,但肝脏病理切片发现BPA染毒可损伤肝脏的组织结构。血清生化指标中总胆汁酸在高剂量组显著降低,为(4.75±0.33)μmol/L;肌酐在中﹑高剂量组显著升高,分别为(18.00±0.76)和(18.83±0.75)μmol/L;TC,高密度脂蛋白胆固醇和低密度脂蛋白胆固醇在中,高剂量组均显著降低(P<0.05),分别为(1.44±0.10)、(1.14±0.10)mmol/L,(0.84±0.04)、(0.63±0.07)mmol/L和(0.21±0.04),(0.16±0.05)mmol/L。BPA染毒可使人肝细胞系HL-7702细胞内TC含量显著降低(P<0.05),ROS水平显著增加;PPARα及FABP1转录水平在高浓度处理组中显著升高;SOD1在中,高浓度处理组中均显著降低(P<0.05)。结论BPA可能通过诱导肝脏细胞内产生过量的ROS,导致肝脏损伤和体内脂质代谢紊乱,从而表现出肝脏毒性。

OBJECTIVE To explore the toxic effect of bisphenol A on the liver, as well as the influence effect on lipid metabolism. METHODS The toxic effects of bisphenols on human health were studied by using in vivo experiments of bisphenol A exposure in rats and in vitro experiments of human liver cell line HL-7702. Male SD rats were divided into control group(Ctrl), 1 mg/(kg·d) group(low), 5 mg/(kg·d) group(medium) and 25 mg/(kg·d) group(high) for 14 days subacute exposure of bisphenol A, to evaluate the toxic effect of bisphenol A on the liver in terms of body weight, liver organ index, liver pathological tissue sections, serum biochemical indicators. Then HL-7702 was divided into four groups: control group(Ctrl), low concentration treatment group(0.16 μmol/L), medium concentration treatment group(4 μmol/L) and high concentration treatment group(100 μmol/L). After 24 hours of exposure to bisphenol A, the contents of triglyceride(TG) and total cholesterol(TC) in cells, reactive oxygen species(ROS) levels were detected, and the transcription levels of genes related to lipid metabolism and oxidative stress were detected by fluorescent quantitative PCR. RESULTS The 14-day subacute exposure had no significant effect on rat body weight and liver body weight ratio, but liver pathological sections clearly showed that bisphenol A exposure can damage liver tissue structure. Serum biochemical indicator of total bile acid(TBA) was significantly reduced in the high-dose group, which was(4.75±0.33)μmol/L, creatinine(Cr) was significantly increased in the medium and high-dose group, which were(18.00±0.76)μmol/L and(18.83±0.75)μmol/L, respectively. TC, high-density lipoprotein(HDL-C) and low-density lipoprotein(LDL-C) were significantly reduced in the middle-and high-dose groups(P<0.05), which were(1.44±0.10),(1.14±0.10)mmol/L;(0.84±0.04),(0.63±0.07)mmol/L and(0.21±0.04),(0.16±0.05)mmol/L, respectively. Bisphenol A exposure could significantly reduce the content of TC in hepatocytes(P<0.05). BPA treatment could significantly increase ROS levels in HL-7702 cells. The transcription level of PPARα was significantly increased in the high concentration group, FABP1 was significantly increased in the high concentration group, SOD1 was significantly decreased in the medium and high concentration group(P<0.05). CONCLUSION Bisphenol A may cause oxidative stress by inducing excessive ROS production in liver cells, leading to liver damage and disorder of lipid metabolism in the body, thereby showing liver toxicity.