正己烷亚急性吸入染毒致大鼠肝肾毒性的机制

Mechanism of liver and kidney toxicity in rats induced by subacute inhalation of n-hexane

[背景]国内外正己烷的毒理学主要研究方向在神经系统毒性,对肝肾毒性研究较少。正己烷的主要代谢器官是肝脏,主要排泄器官是肾脏。正己烷暴露是否影响肝肾功能以及可能的机制,是值得探究的问题。[目的]观察正己烷亚急性吸入染毒致雌性大鼠的肝肾毒性,初步探讨其可能机制。[方法]将40只雌性SD大鼠随机分为4组,设1个对照组和3个染毒组,分别静式吸入0、4212、12637、37910mg·m^(-3)正己烷,每天4h,连续染毒28d。测定染毒后大鼠体重和肝肾脏器系数。观察肝脏和肾脏组织病理学改变。测定血清中丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的活力,以及血清肌酐(Scr)和尿素氮(BUN)的含量。采用实时荧光定量PCR法检测肝脏中CYP1A2基因和肾脏中CHOP基因的mRNA表达水平。[结果]与对照组相比,37910 mg·m^(-3)正己烷组大鼠体重下降(P<0.05),各染毒组肝脏和肾脏的脏器系数变化无统计学意义(P>0.05)。随着染毒剂量升高,光镜下大鼠肝脏和肾脏组织可观察到明显的病理损伤。与对照组比较,37910 mg·m^(-3)正己烷组血清AST活力升高[(93.63±6.84)U·L^(-1)vs(72.88±11.59)U·L^(-1),P<0.05];各染毒组中血清的Scr和BUN的含量变化无统计学意义(P>0.05)。与对照组比较(1.00±0.06、1.00±0.04),各染毒剂量组肝脏组织CYP1A2 mRNA的水平表达下调(0.01±0.00、0.08±0.07、0.14±0.09,P<0.05),肾脏组织CHOP mRNA的水平均上调(2.22±0.19、2.05±0.02、2.95±0.28,P<0.05)。[结论]正己烷亚急性暴露引起雌性大鼠肝脏损害并可能触发大鼠肾组织内质网应激反应,可改变肝脏CYP1A2和肾脏CHOP的mRNA表达。

[Background]n-Hexane has been widely studied for its neurotoxicity at home and abroad rather than its hepatorenal toxicity.The main metabolizing organ of n-hexane is the liver,and the main excretory organ is the kidney.Whether n-hexane exposure affects hepatic and renal functions and what is the possible mechanism are wo rth interrogating.[Objective]This experiment is designed to observe the hepatorenal toxicity in female rats induced by subacute inhalation of n-hexane and preliminarily explores its possible mechanism.[Methods]Forty female SD rats were randomly divided into four groups,namely one control group and three exposure groups which were exposed to n-hexane at 0,4212,12637,and 37910 mg·m^(-3)respectively by static inhalation,4 h a day,for continuous 28 d.The rat body weight and liver and kidney organ coefficients after exposure were determined.The pathological changes of liver and kidney were observed.The activities of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in serum,as well as the contents of serum creatinine(Scr)and urea nitrogen(BUN)were determined.Real-time fluorescence quantitative PCR was used to detect the mRNA expression levels of CYP1A2 gene in liver and CHOP gene in kidney.[Results]Compared with the control group,the body weight of rats in the 37910 mg·m^(-3)n-hexane group decreased(P<0.05),and the changes in the organ coefficients of liver and kidney in each exposure group had no significant difference(P>0.05).With increasing exposure dose,obvious pathological changes were observed in rat liver and kidney tissues under light microscope.Compared with the control group,the serum AST level in the 37910 mg·m^(-3)n-hexane group increased[(93.63±6.84)U·L^(-1)vs(72.88±11.59)U·L^(-1),P<0.05];the Scr and BUN levels in each exposure group were not significantly different(P>0.05).Compared with the control group(1.0010.06 for CYP1A2,1.0010.04 for CHOP),the expression of CYP1A2 mRNA in liver tissue of each exposure group was down-regulated(0.01±0.00,0.08±0.07,and 0.14±0.09,respectively;P<0.05),and the expression of CHOP mRNA was up-regulated(2.2210.19,2.0510.02,and 2.9510.28,respectively;P<0.05).[Conclusion]Subacute exposure to n-hexane causes liver damage in female rats,possibly triggers endoplasmic reticulum stress in rat kidney tissues,and changes the mRNA expressions of CYP1A2 in liver and CHOP in kidney.