硝基苯对公鸭肝脏损伤机制的研究
摘要
硝基苯(NB)是一种应用广泛的重要化工有机合成原料,但同时也是环境中重要的污染物之一,并被美国环保局规定为环境中优先监测污染物。已有研究表明,NB的长期接触对人体及动植物危害极大,可以引起机体发生氧化损伤、细胞凋亡、坏死等病理变化,但目前NB的毒理学研究主要集中在哺乳动物和鱼类,对于禽类的研究较少。本试验以育成公鸭为研究对象,对其进行不同浓度NB灌胃染毒,通过对受试公鸭肝脏显微结构和超微结构的观察、细胞凋亡率、肝微粒体P450酶系的活性和含量及其相关基因表达情况、血清或/和肝脏的抗氧化功能、血清肝功能和肝脏酶组织化学的检测,研究了硝基苯对育成公鸭肝脏结构和功能,以及肝脏P450酶系、抗氧化功能和细胞凋亡的影响,并对其毒性作用机理进行了初步探讨,为全面评价NB对禽类的生态毒理效应提供科学依据。研究结果表明:
1.通过剖检变化、显微和超微结构的观察,以及血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、总蛋白(TP)、白蛋白/球蛋白(A/G)、总胆红素(TBIL)、直接胆红素(DBIL)、间接胆红素(IBIL)和总胆汁酸(TBA)等肝脏功能指标活性或含量的检测,说明NB能够损伤公鸭的肝脏组织;
2.通过血清和肝脏抗氧化功能的检测,表明NB能够诱导公鸭肝脏组织发生氧化应激,导致谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)活性和还原型谷胱甘肽(GSH)含量降低,丙二醛(MDA)含量升高,并且影响肝脏中一氧化氮(NO)含量和一氧化氮合酶(NOS)活性,从而破坏机体抗氧化防御系统及清除自由基功能,造成公鸭肝脏组织发生氧化损伤,这可能是NB对肝脏的损伤机制之一;
3.通过肝脏酶组织化学的检测,说明NB能够改变酸性磷酸酶(ACP)、碱性磷酸酶(ALP)、Mg2+激活的三磷酸腺苷酶(Mg2+-ATPase)、Ca2+激活的三磷酸腺苷酶(Ca2+-ATPase)、葡萄糖-6-磷酸酶(G-6-Pase)的活性,进而影响肝脏的正常功能;
4.通过TUNEL法对肝脏细胞凋亡的检测,表明NB经口染毒可以使肝脏细胞凋亡指数显著升高,诱导公鸭肝脏细胞发生凋亡,这可能是NB对肝脏损伤作用的重要诱导因素;
5.通过肝微粒体P450酶系的活性及其基因表达情况的检测,显示NB能够影响肝微粒体细胞色素P450和b5的含量、NADPH-细胞色素C还原酶(CR)、氨基吡啉-N-脱甲基酶(AND)、红霉素-N-脱甲基酶(ERND)和7-乙氧基香豆素O-脱乙氧基酶(ECOD)的活性,及其相关基因CYP1A5和CYP3A37 mRNA的表达,从而干扰P450酶系的正常功能,加剧机体内的氧化损伤,说明P450酶系与机体内的氧化应激作用共同参与NB对肝脏的损伤过程。
综上所述,NB可以影响公鸭肝脏P450酶系、抗氧化功能和肝组织酶活性,改变肝脏的正常生理功能,导致氧化应激的发生,并诱导肝脏细胞发生凋亡,造成肝脏组织的病理损伤,从而发挥其毒性作用。
Nitrobenzene (NB) is an important chemical industrial raw material generally used, however, it is also a considerable environmental pollutant which has been preferentially monitored by American Environmental Protection Bureau. It has been demonstrated that NB jeopardize people, animals and plants, and could cause oxidative damage, apoptosis, cellular necrosis of organism because of long-term exposure. However, most studies on NB toxicology were about mammals and pisces, the studies on poultry were rare. This experiment selected drakes as experiment animals, which were given different concentration NB by intragastric administration, and studied the effect of NB on liver structure, function, cytochrome P450, oxidative damage and apoptosis by the observation of microstructure and ultrastructure of liver, and the detection of apoptosis ratio, activity and contents of cytochrome P450 and its relative gene expression, antioxidant function, hepatic function and enzymohistochemistry in liver and / or serum. At the same time, it was initial to discuss the action mechanism of NB toxcity, and provide the scientific evidence for overall assessment of the ecotoxicology effect of NB on birds. The results showed as follows:
1.By the observation of microstructure and ultrastructure of liver, and the detection of hepatic function such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin / globulin (A/G), total bilirubin (TB), direct bilirubin (DBIL), indirect bilirubin (IBIL) and total bile acid (TBA), it was proved that NB could cause the damage on liver;
2. By the detection of antioxidative function of liver, it was shown that NB could induce the oxidative stress in liver, decrease the activity of glutathion peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT), and the contents of reduced glutathione (GSH), increase the contents of malonaldehyde (MDA), and change the contents of nitrogen monoxidum (NO) and the activity of nitricoxide synthase (NOS). Accordingly, the antioxidative defence system of organism was destroyed and the free radical could not be removed, which further caused oxidative damage, and affected normal physiological function in drake liver;
3. By the detection of liver enzymohistochemistry, it was discovered that NB could change the activity of Acid phosphatase (ACP), Alkaline phosphatase (ALP), Mg2+-ATPase , Ca2+-ATPase and Glucose-6-phosphatase (G-6-Pase), and then influence and destroy the normal function of liver;
4. By the detection of the hepatic cell apoptosis, it was revealed that NB per os could obviously increase the apoptotic index of hepatic cells, and induce the hepatic cells apoptosis;
5. By the detection of the activity and contents of cytochrome P450 enzyme system and its relative gene expression, it was revealed that NB could affect the contents of cytochrome P450 and b5, and the activity of cytochrome C reductase (CR), aminopyrine-N-demethylase (AND), erythromycin- N-demethylase (ERND) and ethoxy coumarin dealkylase (ECOD), the expression of the relative gene CYP1A5 and CYP3A37 mRNA, accordingly interfere the fuction of cytochrome P450 enzyme system, aggravate the oxidative damage, which proved that both cytochrome P450 enzyme system and the oxidative stress of organism participated in the damage of NB on the liver.
In a word, NB could affect the activity and contents of cytochrome P450 enzyme system, antioxidative function and the enzymatic activity of liver, change the normal liver function, induce oxidation stress and apoptosis of liver, cause liver pathology damage, and then educe NB toxic action.
1.通过剖检变化、显微和超微结构的观察,以及血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、总蛋白(TP)、白蛋白/球蛋白(A/G)、总胆红素(TBIL)、直接胆红素(DBIL)、间接胆红素(IBIL)和总胆汁酸(TBA)等肝脏功能指标活性或含量的检测,说明NB能够损伤公鸭的肝脏组织;
2.通过血清和肝脏抗氧化功能的检测,表明NB能够诱导公鸭肝脏组织发生氧化应激,导致谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)活性和还原型谷胱甘肽(GSH)含量降低,丙二醛(MDA)含量升高,并且影响肝脏中一氧化氮(NO)含量和一氧化氮合酶(NOS)活性,从而破坏机体抗氧化防御系统及清除自由基功能,造成公鸭肝脏组织发生氧化损伤,这可能是NB对肝脏的损伤机制之一;
3.通过肝脏酶组织化学的检测,说明NB能够改变酸性磷酸酶(ACP)、碱性磷酸酶(ALP)、Mg2+激活的三磷酸腺苷酶(Mg2+-ATPase)、Ca2+激活的三磷酸腺苷酶(Ca2+-ATPase)、葡萄糖-6-磷酸酶(G-6-Pase)的活性,进而影响肝脏的正常功能;
4.通过TUNEL法对肝脏细胞凋亡的检测,表明NB经口染毒可以使肝脏细胞凋亡指数显著升高,诱导公鸭肝脏细胞发生凋亡,这可能是NB对肝脏损伤作用的重要诱导因素;
5.通过肝微粒体P450酶系的活性及其基因表达情况的检测,显示NB能够影响肝微粒体细胞色素P450和b5的含量、NADPH-细胞色素C还原酶(CR)、氨基吡啉-N-脱甲基酶(AND)、红霉素-N-脱甲基酶(ERND)和7-乙氧基香豆素O-脱乙氧基酶(ECOD)的活性,及其相关基因CYP1A5和CYP3A37 mRNA的表达,从而干扰P450酶系的正常功能,加剧机体内的氧化损伤,说明P450酶系与机体内的氧化应激作用共同参与NB对肝脏的损伤过程。
综上所述,NB可以影响公鸭肝脏P450酶系、抗氧化功能和肝组织酶活性,改变肝脏的正常生理功能,导致氧化应激的发生,并诱导肝脏细胞发生凋亡,造成肝脏组织的病理损伤,从而发挥其毒性作用。
Nitrobenzene (NB) is an important chemical industrial raw material generally used, however, it is also a considerable environmental pollutant which has been preferentially monitored by American Environmental Protection Bureau. It has been demonstrated that NB jeopardize people, animals and plants, and could cause oxidative damage, apoptosis, cellular necrosis of organism because of long-term exposure. However, most studies on NB toxicology were about mammals and pisces, the studies on poultry were rare. This experiment selected drakes as experiment animals, which were given different concentration NB by intragastric administration, and studied the effect of NB on liver structure, function, cytochrome P450, oxidative damage and apoptosis by the observation of microstructure and ultrastructure of liver, and the detection of apoptosis ratio, activity and contents of cytochrome P450 and its relative gene expression, antioxidant function, hepatic function and enzymohistochemistry in liver and / or serum. At the same time, it was initial to discuss the action mechanism of NB toxcity, and provide the scientific evidence for overall assessment of the ecotoxicology effect of NB on birds. The results showed as follows:
1.By the observation of microstructure and ultrastructure of liver, and the detection of hepatic function such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin / globulin (A/G), total bilirubin (TB), direct bilirubin (DBIL), indirect bilirubin (IBIL) and total bile acid (TBA), it was proved that NB could cause the damage on liver;
2. By the detection of antioxidative function of liver, it was shown that NB could induce the oxidative stress in liver, decrease the activity of glutathion peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT), and the contents of reduced glutathione (GSH), increase the contents of malonaldehyde (MDA), and change the contents of nitrogen monoxidum (NO) and the activity of nitricoxide synthase (NOS). Accordingly, the antioxidative defence system of organism was destroyed and the free radical could not be removed, which further caused oxidative damage, and affected normal physiological function in drake liver;
3. By the detection of liver enzymohistochemistry, it was discovered that NB could change the activity of Acid phosphatase (ACP), Alkaline phosphatase (ALP), Mg2+-ATPase , Ca2+-ATPase and Glucose-6-phosphatase (G-6-Pase), and then influence and destroy the normal function of liver;
4. By the detection of the hepatic cell apoptosis, it was revealed that NB per os could obviously increase the apoptotic index of hepatic cells, and induce the hepatic cells apoptosis;
5. By the detection of the activity and contents of cytochrome P450 enzyme system and its relative gene expression, it was revealed that NB could affect the contents of cytochrome P450 and b5, and the activity of cytochrome C reductase (CR), aminopyrine-N-demethylase (AND), erythromycin- N-demethylase (ERND) and ethoxy coumarin dealkylase (ECOD), the expression of the relative gene CYP1A5 and CYP3A37 mRNA, accordingly interfere the fuction of cytochrome P450 enzyme system, aggravate the oxidative damage, which proved that both cytochrome P450 enzyme system and the oxidative stress of organism participated in the damage of NB on the liver.
In a word, NB could affect the activity and contents of cytochrome P450 enzyme system, antioxidative function and the enzymatic activity of liver, change the normal liver function, induce oxidation stress and apoptosis of liver, cause liver pathology damage, and then educe NB toxic action.
引文
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