本文選題：二甲基甲酰胺 + 肝臟損害　； 參考：《山東大學(xué)》2013年碩士論文

【摘要】：背景： 二甲基甲酰胺(dimethvlformamide, DMF)是一種重要化工原料,廣泛用于纖維、皮革、醫(yī)藥等行業(yè)。隨著現(xiàn)代工業(yè)發(fā)展,DMF消耗量不斷增加,接觸DMF職業(yè)人群不斷擴(kuò)大,DMF職業(yè)中毒報(bào)道不斷增多[1]。動(dòng)物實(shí)驗(yàn)證明DMF具有肝臟毒性,可致急性和慢性肝臟損害[2.3]。職業(yè)流行病學(xué)調(diào)查發(fā)現(xiàn)DMF暴露工人肝功能異常率升高[4-8],國(guó)內(nèi)已有DMF致工人慢性重度肝病的報(bào)道[9]。因此,有必要探討DMF接觸工人肝臟損害情況及有關(guān)影響因素,提出防治措施。 研究發(fā)現(xiàn),DMF引起體內(nèi)谷胱甘肽(glutathione, GSH)水平降低,機(jī)體抗氧化能力下降與肝臟損傷有關(guān)[10-15]。維生素E (Vitamin E, VE)具有抗氧化功能,動(dòng)物實(shí)驗(yàn)和臨床應(yīng)用證明其具有較好保護(hù)肝臟效果[16-20],并且,細(xì)胞實(shí)驗(yàn)發(fā)現(xiàn)VE可顯著提高細(xì)胞內(nèi)GSH水平[21,22]。因此,用VE預(yù)防DMF肝臟損害值得研究。 目的： 了解DMF接觸工人肝臟損害情況及有關(guān)影響因素,通過(guò)動(dòng)物實(shí)驗(yàn)進(jìn)行VE對(duì)DMF中毒的干預(yù),提出預(yù)防DMF肝臟損害的對(duì)策。 方法： 1、DMF致工人肝臟損害的調(diào)查 選擇某腈綸廠DMF接觸男工152名為接觸組,無(wú)任何毒物接觸男工179名為對(duì)照組,進(jìn)行職業(yè)衛(wèi)生問(wèn)卷調(diào)查。收集該廠DMF監(jiān)測(cè)資料和工人健康監(jiān)護(hù)資料,分析工人肝臟損害情況及影響因素。 2、VE干預(yù)實(shí)驗(yàn) 急性實(shí)驗(yàn)：健康SPF級(jí)雄性昆明小鼠,隨機(jī)分為5組,每組10只,分別為對(duì)照組(玉米油灌胃5天+蒸餾水灌胃1天)、VE對(duì)照組(10mg/kg· d VE灌胃5天+蒸餾水灌胃1天)、DMF中毒模型組(玉米油灌胃5天+2g/kg·d DMF(?)灌胃1天)和低(5mg/kg· d)、高(10mg/kg· d)劑量VE干預(yù)組(VE灌胃5天+2g/kg· d DMF灌胃1天)。 亞慢性實(shí)驗(yàn)：健康SPF級(jí)雄性昆明小鼠,隨機(jī)分為4組,每組10只,分別為對(duì)照組(蒸餾水+玉米油)、VE對(duì)照組(蒸餾水+5mg/kg· d VE)、 DMF中毒模型組(0.5g/kg· d DMF+玉米油)和VE干預(yù)組(0.5g/kg· d DMF+5mg/kg· d VE),連續(xù)干預(yù)30天。 觀察血清谷丙轉(zhuǎn)氨酶(alanine amino transferase, ALT)、天冬氨酸轉(zhuǎn)氨酶(aspartate aminotransferase, AST)和黃嘌呤氧化酶(xanthine oxidase,XOD)活力變化；觀察肝臟GSH和丙二醛(malondialdehyde, MDA)含量變化；觀察肝臟病理學(xué)變化。 結(jié)果： 1、DMF致工人肝臟損害的調(diào)查 ①與對(duì)照組比較,接觸組肝臟損害發(fā)生率顯著升高(P0.05),主要表現(xiàn)為肝功能異常率顯著升高(P0.01):ALT異常率顯著升高(P0.01),谷氨酰胺轉(zhuǎn)移酶(glutamyltransferase, GT)異常率顯著升高(P0.01)。接觸組肝臟B超異常率有高于對(duì)照組的趨勢(shì),但差異沒(méi)有統(tǒng)計(jì)學(xué)意義(P0.05)。 ②影響DMF接觸工人肝臟損害發(fā)生的危險(xiǎn)因素有DMF濃度(OR=1.07,P0.05)、DMF接觸工齡(OR=1.06,P0.05)和體重指數(shù)(OR=1.10,P0.05)。其中,影響DMF接觸工人ALT異常率的危險(xiǎn)因素有DMF濃度(OR=2.21,P0.05)和體重指數(shù)(OR=1.14,P0.05)；影響GT異常率的危險(xiǎn)因素有DMF濃度(OR=2.62,P0.01)、DMF接觸工齡(OR=1.11,P0.05)和飲酒(OR=3.91,P0.01)；而影響肝臟B超異常率的危險(xiǎn)因素只有體重指數(shù)(OR=1.19,P0.01)。 2、VE干預(yù)實(shí)驗(yàn) 急性實(shí)驗(yàn)： ①DMF中毒模型組與對(duì)照組比較,肝臟重量及肝臟系數(shù)均顯著升高(P0.01)；VE干預(yù)組與對(duì)照組比較,肝臟重量及肝臟系數(shù)均無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)：VE干預(yù)組與DMF中毒模型組比較,肝臟重量及肝臟系數(shù)均顯著降低(P0.05)。 ②DMF中毒模型組與對(duì)照組比較,血清ALT、AST和XOD活力均顯著升高(P0.05)；VE干預(yù)組與對(duì)照組比較,ALT、AST和XOD活力均無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)；VE干預(yù)組與DMF中毒模型組比較,ALT、AST和XOD活力均顯著降低(_P0.05)。 ③DMF中毒模型組與對(duì)照組比較,肝臟GSH含量顯著降低(P0.05),而MDA含量顯著升高(P0.01)；VE干預(yù)組與對(duì)照組比較,GGH含量無(wú)統(tǒng)計(jì)學(xué)差異(P0.05),而MDA含量顯著升高(P0.01)；VE干預(yù)組與DMF中毒模型組比較,GSH含量顯著升高(P0.05),且MDA含量顯著降低(P0.01)。 ④DMF中毒模型組肝臟病理切片可見(jiàn)肝細(xì)胞局灶壞死、炎癥細(xì)胞浸潤(rùn),肝血竇擴(kuò)張、淤血、出血；VE干預(yù)組肝臟病理切片正常。 亞慢性實(shí)驗(yàn)： ①DMF中毒模型組和VE干預(yù)組與對(duì)照組比較,體重均明顯降低(p0.01),而肝臟系數(shù)均明顯升高(P0.01)；VE干預(yù)組體重有高于DMF中毒模型組的趨勢(shì),但差異不顯著(P0.05)。 ②DMF中毒模型組和VE干預(yù)組與對(duì)照組比較,血清ALT、AST和XOD活力均顯著升高(P0.05)；VE干預(yù)組與DMF中毒模型組比較,ALT、AST和XOD活力均顯著降低(P0.05)。 ③DMF中毒模型組與對(duì)照組比較,肝臟GSH含量顯著降低(P0.01),而MDA含量顯著升高(P0.01)；VE干預(yù)組與對(duì)照組比較,GSH和MDA含量均顯著升高(P0.01)；VE干預(yù)組與DMF中毒模型組比較,GSH含量顯著升高(P0.01),且MDA含量顯著降低(P0.05)。 ④DMF中毒模型組肝臟病理切片可見(jiàn)肝細(xì)胞核固縮,核周空泡,細(xì)胞水腫、變性、壞死,細(xì)胞界限不清；VE干預(yù)組肝臟病理切片正常。 結(jié)論： 1、長(zhǎng)期接觸DMF作業(yè)能引起工人肝臟損害,主要表現(xiàn)為DMF接觸工人肝功能異常率升高,而肝臟B超異常率升高不顯著。 2、影響DMF接觸工人肝臟損害發(fā)生率的因素有接觸DMF濃度、接觸DMF時(shí)間、體重指數(shù)和飲酒。 3、VE可降低DMF中毒小鼠血清肝功能酶水平,改善肝臟病理?yè)p害,保護(hù)肝臟。 4、VE可促進(jìn)DMF中毒小鼠肝臟GSH水平升高和MDA水平降低,這可能是VE保護(hù)肝臟的一種機(jī)制。 5、建議DMF作業(yè)場(chǎng)所降低空氣中DMF濃度,縮短工人接觸DMF時(shí)間；倡導(dǎo)工人控制體重和減少飲酒,在飲食中補(bǔ)充VE,預(yù)防DMF肝臟損害。
[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 .

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R131

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