二甲基甲酰胺致工人肝脏损害及维生素E干预实验

发布时间：2018-05-05 22:25

本文选题：二甲基甲酰胺 + 肝脏损害　；参考：《山东大学》2013年硕士论文

【摘要】：背景：二甲基甲酰胺(dimethvlformamide, DMF)是一种重要化工原料,广泛用于纤维、皮革、医药等行业。随着现代工业发展,DMF消耗量不断增加,接触DMF职业人群不断扩大,DMF职业中毒报道不断增多[1]。动物实验证明DMF具有肝脏毒性,可致急性和慢性肝脏损害[2.3]。职业流行病学调查发现DMF暴露工人肝功能异常率升高[4-8],国内已有DMF致工人慢性重度肝病的报道[9]。因此,有必要探讨DMF接触工人肝脏损害情况及有关影响因素,提出防治措施。研究发现,DMF引起体内谷胱甘肽(glutathione, GSH)水平降低,机体抗氧化能力下降与肝脏损伤有关[10-15]。维生素E (Vitamin E, VE)具有抗氧化功能,动物实验和临床应用证明其具有较好保护肝脏效果[16-20],并且,细胞实验发现VE可显著提高细胞内GSH水平[21,22]。因此,用VE预防DMF肝脏损害值得研究。目的：了解DMF接触工人肝脏损害情况及有关影响因素,通过动物实验进行VE对DMF中毒的干预,提出预防DMF肝脏损害的对策。方法： 1、DMF致工人肝脏损害的调查选择某腈纶厂DMF接触男工152名为接触组,无任何毒物接触男工179名为对照组,进行职业卫生问卷调查。收集该厂DMF监测资料和工人健康监护资料,分析工人肝脏损害情况及影响因素。 2、VE干预实验急性实验：健康SPF级雄性昆明小鼠,随机分为5组,每组10只,分别为对照组(玉米油灌胃5天+蒸馏水灌胃1天)、VE对照组(10mg/kg· d VE灌胃5天+蒸馏水灌胃1天)、DMF中毒模型组(玉米油灌胃5天+2g/kg·d DMF(?)灌胃1天)和低(5mg/kg· d)、高(10mg/kg· d)剂量VE干预组(VE灌胃5天+2g/kg· d DMF灌胃1天)。亚慢性实验：健康SPF级雄性昆明小鼠,随机分为4组,每组10只,分别为对照组(蒸馏水+玉米油)、VE对照组(蒸馏水+5mg/kg· d VE)、 DMF中毒模型组(0.5g/kg· d DMF+玉米油)和VE干预组(0.5g/kg· d DMF+5mg/kg· d VE),连续干预30天。观察血清谷丙转氨酶(alanine amino transferase, ALT)、天冬氨酸转氨酶(aspartate aminotransferase, AST)和黄嘌呤氧化酶(xanthine oxidase,XOD)活力变化；观察肝脏GSH和丙二醛(malondialdehyde, MDA)含量变化；观察肝脏病理学变化。结果： 1、DMF致工人肝脏损害的调查 ①与对照组比较,接触组肝脏损害发生率显著升高(P0.05),主要表现为肝功能异常率显著升高(P0.01):ALT异常率显著升高(P0.01),谷氨酰胺转移酶(glutamyltransferase, GT)异常率显著升高(P0.01)。接触组肝脏B超异常率有高于对照组的趋势,但差异没有统计学意义(P0.05)。 ②影响DMF接触工人肝脏损害发生的危险因素有DMF浓度(OR=1.07,P0.05)、DMF接触工龄(OR=1.06,P0.05)和体重指数(OR=1.10,P0.05)。其中,影响DMF接触工人ALT异常率的危险因素有DMF浓度(OR=2.21,P0.05)和体重指数(OR=1.14,P0.05)；影响GT异常率的危险因素有DMF浓度(OR=2.62,P0.01)、DMF接触工龄(OR=1.11,P0.05)和饮酒(OR=3.91,P0.01)；而影响肝脏B超异常率的危险因素只有体重指数(OR=1.19,P0.01)。 2、VE干预实验急性实验： ①DMF中毒模型组与对照组比较,肝脏重量及肝脏系数均显著升高(P0.01)；VE干预组与对照组比较,肝脏重量及肝脏系数均无统计学差异(P0.05)：VE干预组与DMF中毒模型组比较,肝脏重量及肝脏系数均显著降低(P0.05)。 ②DMF中毒模型组与对照组比较,血清ALT、AST和XOD活力均显著升高(P0.05)；VE干预组与对照组比较,ALT、AST和XOD活力均无统计学差异(P0.05)；VE干预组与DMF中毒模型组比较,ALT、AST和XOD活力均显著降低(_P0.05)。 ③DMF中毒模型组与对照组比较,肝脏GSH含量显著降低(P0.05),而MDA含量显著升高(P0.01)；VE干预组与对照组比较,GGH含量无统计学差异(P0.05),而MDA含量显著升高(P0.01)；VE干预组与DMF中毒模型组比较,GSH含量显著升高(P0.05),且MDA含量显著降低(P0.01)。 ④DMF中毒模型组肝脏病理切片可见肝细胞局灶坏死、炎症细胞浸润,肝血窦扩张、淤血、出血；VE干预组肝脏病理切片正常。亚慢性实验： ①DMF中毒模型组和VE干预组与对照组比较,体重均明显降低(p0.01),而肝脏系数均明显升高(P0.01)；VE干预组体重有高于DMF中毒模型组的趋势,但差异不显著(P0.05)。 ②DMF中毒模型组和VE干预组与对照组比较,血清ALT、AST和XOD活力均显著升高(P0.05)；VE干预组与DMF中毒模型组比较,ALT、AST和XOD活力均显著降低(P0.05)。 ③DMF中毒模型组与对照组比较,肝脏GSH含量显著降低(P0.01),而MDA含量显著升高(P0.01)；VE干预组与对照组比较,GSH和MDA含量均显著升高(P0.01)；VE干预组与DMF中毒模型组比较,GSH含量显著升高(P0.01),且MDA含量显著降低(P0.05)。 ④DMF中毒模型组肝脏病理切片可见肝细胞核固缩,核周空泡,细胞水肿、变性、坏死,细胞界限不清；VE干预组肝脏病理切片正常。结论： 1、长期接触DMF作业能引起工人肝脏损害,主要表现为DMF接触工人肝功能异常率升高,而肝脏B超异常率升高不显著。 2、影响DMF接触工人肝脏损害发生率的因素有接触DMF浓度、接触DMF时间、体重指数和饮酒。 3、VE可降低DMF中毒小鼠血清肝功能酶水平,改善肝脏病理损害,保护肝脏。 4、VE可促进DMF中毒小鼠肝脏GSH水平升高和MDA水平降低,这可能是VE保护肝脏的一种机制。 5、建议DMF作业场所降低空气中DMF浓度,缩短工人接触DMF时间；倡导工人控制体重和减少饮酒,在饮食中补充VE,预防DMF肝脏损害。
[Abstract]:Background :

DMF ( DMF ) is an important chemical raw material widely used in industries such as fiber , leather , medicine and so on . With the development of modern industry , the consumption of DMF is increasing , and the number of DMF occupational poisoning is increasing . Animal experiments prove that DMF has liver toxicity , can cause acute and chronic liver damage , and has been found to increase the abnormal rate of liver function in DMF exposed workers . Therefore , it is necessary to study the liver injury situation of workers exposed to DMF and related factors , and put forward the prevention measures .

Vitamin E ( Vitamin E , VE ) has antioxidant function , animal experiment and clinical application show that it has better protection against liver injury .

Purpose :

To understand the liver damage and related factors of DMF exposure workers , the intervention of VE on DMF poisoning was carried out through animal experiments , and the countermeasures for prevention of liver damage in DMF were suggested .

Method :

1 . Investigation of liver damage induced by DMF

A survey was conducted to collect DMF monitoring data and health monitoring data of workers in order to analyze the liver injury of workers and the factors affecting workers ' liver injury .

2 . VE Intervention Experiment

Acute experiment : SPF male Kunming mice were randomly divided into 5 groups : control group ( corn oil enema for 5 days + distilled water for 1 day ) , VE control group ( 10 mg / kg 路 d VE for 5 days + distilled water for 1 day ) , DMF poisoning model group ( corn oil enema for 5 days + 2 g / kg 路 d DMF ( ? ) for 1 day ) and low ( 5 mg / kg 路 d ) , high ( 10 mg / kg 路 d ) dose VE intervention group ( VE enema for 5 days + 2 g / kg 路 d DMF for 1 day ) .

Subchronic experiment : SPF male Kunming mice were randomly divided into four groups : control group ( distilled water + corn oil ) , VE control group ( distilled water + 5 mg / kg 路 d VE ) , DMF poisoning model group ( 0.5g / kg 路 d DMF + corn oil ) and VE intervention group ( 0.5g / kg 路 d DMF + 5mg / kg 路 d VE ) for 30 days .

The changes of alanine amino transferase ( ALT ) , aspartate aminotransferase ( AST ) and xanthine oxidase ( XOD ) activity were observed .
The changes of GSH and MDA in liver were observed .
Liver pathology changes were observed .

Results :

1 . Investigation of liver damage induced by DMF

Compared with the control group , the incidence of liver injury in the contact group increased significantly ( P0.05 ) , and the abnormal rate of liver function increased significantly ( P0.01 ) . The abnormal rate of ALT was significantly increased ( P0.01 ) . The abnormal rate of liver B in the contact group was higher than that of the control group , but the difference was not statistically significant ( P0.05 ) .

( 2 ) DMF concentration ( OR = 1.07 , P0.05 ) , DMF exposure ( OR = 1.06 , P0.05 ) and body mass index ( OR = 1.10 , P0.05 ) . The risk factors influencing the abnormal rate of ALT in DMF exposed workers were DMF ( OR = 2.21 , P0.05 ) and body mass index ( OR = 1.14 , P0.05 ) .
DMF concentration ( OR = 2.62 , P0.01 ) , DMF exposure ( OR = 1.11 , P0.05 ) and alcohol consumption ( OR = 3.91 , P0.01 ) .
However , the risk factors that affect the abnormal rate of liver B were only the body mass index ( OR = 1.19 , P0.01 ) .

2 . VE Intervention Experiment

Acute Experiment :

( 1 ) Compared with control group , the weight of liver and liver coefficient increased significantly ( P0.01 ) .
There was no significant difference in liver weight and liver coefficient between the VE intervention group and the control group ( P0.05 ) . Compared with the DMF poisoning model group , the liver weight and liver coefficient decreased significantly ( P0.05 ) .

Compared with control group , the serum ALT , AST and XOD activity increased significantly ( P0.05 ) .
There was no statistical difference between the VE intervention group and the control group ( P0.05 ) .
The levels of ALT , AST and XOD in the VE intervention group were significantly lower than those in the DMF poisoning model group ( P < 0.05 ) .

( 3 ) Compared with control group , the content of GSH in liver decreased significantly ( P0.05 ) , while MDA content increased significantly ( P0.01 ) .
Compared with control group , there was no significant difference in GGH content ( P0.05 ) , but MDA content increased significantly ( P0.01 ) .
Compared with the DMF poisoning model group , the content of GSH increased significantly ( P0.05 ) , and the content of MDA decreased significantly ( P0.01 ) .

( 4 ) The pathological sections of liver pathological section of DMF poisoning model group showed focal necrosis , infiltration of inflammatory cells , dilatation of hepatic blood sinus , congestion and hemorrhage .
The liver pathological section of VE intervention group was normal .

Subchronic experiment :

( 1 ) Compared with control group , the weight of DMF poisoning model group and VE intervention group were significantly lower than that in control group ( P0.01 ) , but the liver coefficients increased significantly ( P0.01 ) .
The body weight of VE intervention group was higher than that of DMF poisoning model group , but the difference was not significant ( P0.05 ) .

( 2 ) The levels of ALT , AST and XOD in serum of DMF poisoning model group and VE intervention group were significantly higher than those in control group ( P0.05 ) .
The levels of ALT , AST and XOD in the VE intervention group were significantly lower than those in the DMF poisoning model group ( P0.05 ) .

( 3 ) Compared with control group , the content of GSH in liver decreased significantly ( P0.01 ) , while MDA content increased significantly ( P0.01 ) .
Compared with control group , the content of GSH and MDA increased significantly ( P0.01 ) .
Compared with the DMF poisoning model group , the content of GSH increased significantly ( P0.01 ) , and the content of MDA decreased significantly ( P0.05 ) .

( 4 ) The pathological section of liver pathological section of DMF poisoning model group can be seen in hepatocyte nuclear pyknosis , nuclear week vacuoles , cell edema , degeneration , necrosis , and unclear cell line ;
The liver pathological section of VE intervention group was normal .

Conclusion :

1 . Long - term exposure to DMF can cause liver damage to workers , mainly in DMF exposure , and the abnormal rate of liver function is not significant .

2 . Factors affecting the incidence of liver injury in DMF exposed workers were exposed to DMF concentration , exposure to DMF time , body mass index and alcohol consumption .

3 . VE can reduce the serum liver function enzyme level of mice poisoned by DMF , improve the pathological damage of liver and protect the liver .

4 . VE can promote the increase of GSH level and the level of MDA in liver of mice poisoned by DMF , which may be a mechanism for VE to protect the liver .

5 . It is recommended that DMF work place reduce DMF concentration in air and shorten worker ' s contact with DMF time ;
Promote workers to control body weight and reduce alcohol consumption , supplement VE in diet , prevent DMF liver damage .

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R131

【参考文献】