8种多环芳烃联合暴露致大鼠肝脏毒性及BMDL推导

Hepatotoxicity and BMDL derivation in rats under combined exposure to eight kinds of polycyclic aromatic hydrocarbons

目的探究8种多环芳烃(PAH8)联合暴露的大鼠肝脏毒性,利用基准剂量法(BMD)获得PAH8致肝脏毒性的基准剂量95%置信区间下限值(BMDL)。方法雄性SD大鼠随机分为5组,每组10只,分别按照0、10、50、250和1000μg/kg·BW剂量的PAH8连续染毒30 d后处死大鼠,计算脏器系数,进行肝脏病理学检测和油红O染色,检测血清谷丙转氨酶、谷草转氨酶、丙二醛、谷胱甘肽过氧化物酶(GSH-Px)、甘油三酯(TG)、总胆固醇(TC)的水平及肝脏TG、TC含量。选择具有统计学意义、毒理学意义和剂量效应趋势的肝脏毒性数据,利用BMDS 3.2软件进行BMD分析,选择最佳拟合模型得到BMDL值。结果1000μg/kg·BW剂量组大鼠肝脏系数较对照组显著升高(P<0.05)。PAH8染毒后部分大鼠肝脏出现细胞水肿、炎性浸润、脂肪变性等病理改变。10~250μg/kg·BW剂量组血清GSH-Px较对照组显著升高(P<0.01),但1000μg/kg·BW剂量组GSH-Px显著降低(P<0.001)。肝脏中TC含量呈现剂量效应趋势,1000μg/kg·BW剂量组较对照组显著升高(P<0.001)。其他指标与对照组相比均无显著性差异(P>0.05)。利用肝脏TC含量进行BMD分析,选择Hill模型得到PAH8致大鼠肝脏毒性的BMDL和BMD分别为47.61和213.52μg/kg·BW。根据肝脏TC含量得到PAH8的未观察到有害作用水平(NOAEL)和观察到有害作用的最低水平(LOAEL)分别为250和1000μg/kg·BW。结论PAH8联合暴露引起肝脏脂质异常蓄积,致大鼠肝脏毒性的BMDL为47.61μg/kg·BW,低于相应的NOAEL/LOAEL值。

Objective To investigate the hepatotoxicity induced by the combined exposure of eight types of PAHs(PAH8)in rats,the lower limit of the 95%confidence interval of benchmark dose(BMDL)of PAH8-induced hepatotoxicity was determined using the benchmark dose(BMD)method.Methods Male SD rats were randomly divided into five groups(10 rats in each group)and were exposed to PAH8 at doses of 0,10,50,250,and 1000μg/kg·BW,respectively.Rats were sacrificed after 30 d,and organ coefficients were calculated.Liver pathological examination and oil-red O staining were performed.Serum alanine aminotransferase,aspartate aminotransferase,malondialdehyde,glutathione peroxidase(GSH-Px),triglyceride(TG),total cholesterol(TC)levels,and liver TG and TC levels were measured.Hepatotoxicity data with statistical significance,toxicological significance,and dose-effect trend were selected.BMD analysis was performed using the BMDS 3.2 software.BMDL values of PAH8-induced hepatotoxicity in rats were obtained by choosing the optimal fitting model.Results The liver coefficient of the 1000μg/kg·BW group was significantly higher than that in the control group(P<0.05).After PAH8 exposure,some rats showed pathological changes,such as cell edema,inflammatory infiltration,and liver steatosis.Serum GSH-Px in the 10-250μg/kg·BW group was significantly higher than that in the control group(P<0.01)but significantly decreased in the 1000μg/kg·BW group(P<0.001).The TC content in the liver showed a dose-dependent trend and increased significantly in the 1000μg/kg·BW group(P<0.001).No significant changes in other indexes were observed compared with the control group(P>0.05).Liver TC content was used for BMD analysis,and the BMDL and BMD of PAH8 based on the Hill model were 47.61 and 213.52μg/kg·BW,respectively.The non-observed adverse effect level and lowest observed adverse effect level of PAH8 were 250 and 1000μg/kg·BW,respectively.Conclusion Combined exposure to PAH8 caused abnormal lipid accumulation in the liver,and the BMDL value of liver toxicity in PAH8 rats was 47.61μg/kg·BW,which was lower than the NOAEL/LOAEL.