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研究生:雷侑蓁
研究生(外文):Lei Yu-Chen
論文名稱:一、吸菸者DNA修補及代謝基因多形性與姊妹染色體交換頻率相關研究;二、氯乙烯暴露工人血中突變蛋白標記與基因多形性相關研究
論文名稱(外文):1. Effects on sister chromatid exchange frequency of polymorphisms in DNA repair gene XRCC1 in smokers; 2. Association of VCM exposure, plasma mutant oncoproteins, and genetic polymorphisms in polyvinyl chloride workers
指導教授:鄭尊仁鄭尊仁引用關係
指導教授(外文):Cheng Tsun-Jen
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:66
中文關鍵詞:氯乙烯姊妹染色體交換突變蛋白修補基因代謝基因
外文關鍵詞:vinyl chloridesister chromatid exchangep53K-rasXRCC1
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一、吸菸者DNA修補及代謝基因多形性與姊妹染色體交換頻率相關研究
過去研究證實抽菸引發之肺癌與代謝基因之相關,然而DNA修補基因多形性在癌症發生所扮演的角色並不清楚。本研究的目的欲探討代謝酵素基因mEH(microsomal epoxide hydrolase)、GST(Glutathione S-transferase)M1與DNA修補酵素基因XRCC1(X-ray repair cross complementing group 1)的基因多形性對於抽菸工人之姊妹染色體交換(SCE)頻率的影響。
本研究以台灣某家合成樹脂製造工廠61名男性員工為研究對象,利用周邊淋巴球進行姊妹染色體交換實驗,mEH、GSTM1及XRCC1基因多形性以聚合脢鍊鎖反應限制片段長度多形性分析(PCR-RFLP)反應分析,受訪員工均接受詳細問卷調查,包括基本資料和生活習慣(抽菸及喝酒情形等)及詳細工作史等。
研究結果顯示,抽菸者的姊妹染色體交換頻率顯著高於非抽菸者 (8.4 vs. 7.1, p < 0.05),每天平均吸菸數超過10支的工人中,具有XRCC1 Arg/Gln或Gln/Gln基因型者較具有XRCC1 Arg/Arg基因型者有較高的姊妹染色體交換頻率(9.0 vs. 7.9, p < 0.05)。研究亦發現吸菸與XRCC1基因多形性在姊妹染色體交換頻率的發生上具有交互作用 (p = 0.02)。代謝基因GSTM1與mEH與吸菸之間則無交互作用。本研究結果可提供流行病學上XRCC1在吸菸導致的癌症上扮演重要角色的證據。
二、氯乙烯暴露工人血中突變蛋白標記與基因多形性相關研究
過去研究指出,突變Asp13-K-ras及突變p53表現與氯乙烯相關癌症有關;本研究目的為比較p53與K-ras突變與氯乙烯暴露之相關,並進一步探討氯乙烯相關代謝酵素及DNA修補酵素在抑癌基因p53與致癌基因Asp13-K-ras突變上扮演之角色。研究對象是從五家聚氯乙烯工廠中,選取218名男性員工進行分析,血漿中 p53突變蛋白以及anti-p53抗體分別以酵素連結免疫吸附反應(enzyme-linked immunosorbent assay, ELISA)進行分析,血漿中突變Asp13-K-ras蛋白則以西方墨點法(enhanced chemiluminescence Western blotting)加以分析。CYP2E1、GSTT1、ALDH2及XRCC1基因型以聚合脢連鎖反應(polymerase chain reaction,PCR)加以判定。
結果顯示,血漿中 p53突變蛋白、anti-p53抗體及突變Asp13-K-ras蛋白陽性率分別為10.1%,5%及10.1%。累積暴露劑量大於40ppm-years之工人突變蛋白(p53, anti-p53 antibody及Asp13-K-ras)之表現顯著高於累積暴露劑量小於40ppm-years之工人 (OR=2.0, 95%CI=1.0-3.8)。高暴露組中,XRCC1 Gln/Gln較XRCC1 Arg/Arg 或Arg/Gln基因型者具有顯著較高之突變蛋白表現(OR=8.5, 95%CI=1.9-38.9);進一步分析發現氯乙烯暴露、XRCC1基因多形性與突變蛋白之表現存在交互作用 (p=0.06)。有趣的是,氯乙烯低暴露組工人中具有CYP2E1 c2c2基因型者,相較於氯乙烯低暴露組工人中具有CYP2E1 c1c1或c1c2者,也呈現p53過度表現的危險 (OR=3.1, 95%CI=0.3-37.8)。
進一步研究發現,p53過度表現與氯乙烯累積劑量有顯著相關 (OR=2.5, 95%CI=1.0-6.2),在調整吸菸、年紀、飲酒、肝炎感染的作用後,相較於具有XRCC1 Arg/Arg及Arg/Gln基因型的氯乙烯高暴露工人,具有XRCC1 Gln/Gln的氯乙烯高暴露工人,呈現明顯的p53過度表現的危險 (OR=17.0, 95%CI=4.3-198.5),而在低暴露組中,具CYP2E1 c2c2基因型者亦表現出顯著高於CYP2E1 c1c1或c1c2基因型者的危險性 (OR=19.9, 95%CI=1.6-253.2)。
有趣的是,突變Asp13-K-ras發生與氯乙烯累積暴露劑量的劑量反應關係並不明顯,反而與收集檢體前五年有無從事高暴露工作(手工清槽、水柱清槽、卸料及加料)有關 (OR=2.9, 95%CI=1.1-7.9),反應的可能是近期高暴露的指標。進一步分析發現,在五年內有從事高暴露工作者中,具有XRCC1 Gln/Gln基因型的工人,較XRCC1 Arg/Arg或Arg/Gln基因型的工人,有較高的突變Asp13-K-ras蛋白危險性 (OR=1.7, 95%CI=0.1-23.3),但未達統計顯著相關。同樣地,具有ALDH2 1-2或2-2基因型的工人較ALDH2 1-1基因型工人亦顯示較高的危險性 (OR=2.5, 95%CI=0.6-11.2)。具有GSTT1有效型的工人也較GSTT1無效型的工人具有顯著較高的危險性 (OR=5.1, 95%CI=1.1-24.1)。
本研究結果顯示,p53突變蛋白與突變Asp13-K-ras在氯乙烯工人中有不同的表現,突變Asp13-K-ras與近期暴露有關,一旦暴露停止即無法於血液中測得,反之,p53突變蛋白的形成與累積暴露劑量有關。推測可能的原因包括:突變p53基因提供的生長優勢,使得p53基因突變能持續存在細胞中,另外,含有突變Asp13-K-ras的細胞可能在癌化的過程中,因為p53的抑癌機制而進行細胞凋亡,以致於停止暴露後無法測得。p53過度表現與DNA修補及代謝基因的關係與我們之前的研究一致,而突變Asp13-K-ras與DNA修補基因XRCC1及代謝基因之關係在本研究中因為樣本數較少無法釐清,有必要進行進一步的回溯性世代研究以解釋相關機制。

Part I
The association between metabolic polymorphisms and cigarette smoking-induced cancers has been documented. However, the role of DNA repair polymorphism in carcinogenesis is less clear.
To investigate if the polymorphisms of metabolic traits and DNA repair modulate smoking-related DNA damage, we used sister chromatid exchange (SCE) as a marker of genetic damage to explore the relationship of microsomal epoxide hydrolase (mEH), glutathione S-transferase M1 (GSTM1), and x-ray cross-complementing group 1 (XRCC1) and cigarette smoking-induced SCE. Sixty-one workers without significant exposure to mutagens were recruited. Questionnaires were completed to obtain detailed occupational, smoking, and medical histories. SCE frequency in peripheral lymphocytes was determined using a standard cytogenetic assay and GSTM1, mEH (exon 3, eoxn 4), XRCC1 (codon 399) genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP).
Smokers had higher SCE frequency than nonsmokers (8.4 vs. 7.1, p < 0.05). Among workers who had smoked equal to or greater than 10 cigarettes each day, those with XRCC1 Arg/Gln + Gln/Gln had higher SCE frequency than those with XRCC1 Arg/Arg after adjusting for potential confounders (9.0 vs. 7.9, p < 0.05). The interaction of XRCC1 and cigarettes smoked per day on SCE frequency was also observed (p = 0.02). There was no significant interaction between cigarettes smoked per day with GSTM1 and mEH on SCE frequency.
Our results support previous epidemiological studies that XRCC1 may play a role in cigarette smoking-induced lung cancer.
Part II
The presence of mutant Asp13-K-ras protein, p53 overexpression and anti-p53 antibody have been reported to be associated with vinyl chloride monomer (VCM)-related cancers. The aim of this study was to compare the relationship between VCM-induced p53 and K-ras oncoproteins, and to further investigate the role of polymorphisms of metabolic and DNA repair genes on VCM-induced oncoprotein expression.
We examined the plasma samples of 218 male workers occupationally exposed to VCM. Plasma mutant p53 protein and anti-p53 antibody were detected with enzyme-linked immunosorbent assay (ELISA), and Asp13-K-ras proteins were detected using enhanced chemiluminescence Western blotting. Genotypes of cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2), glutathione S-transferase T1 (GSTT1) and X-ray repair cross-complementing group 1 (XRCC1, exon 10) were identified using the polymerase chain reaction (PCR).
The results revealed that the plasma mutant p53 protein was positive in 10.1% of workers, anti-p53 antibody was positive in 5% of workers and Asp13-K-ras protein was positive in 10.1% of workers. High VCM exposure group (>40 ppm-years) had significantly higher mutant oncoprotein (mutant p53 protein, anti-p53 antibody or Asp13-K-ras protein) expression as compared to low VCM exposure group (<40 ppm-years) (OR=2.0, 95%CI=1.0-3.8). Among high exposure workers, subjects with XRCC1 Gln/Gln genotypes demonstrated significantly higher risk of mutant oncoproteins expression as compared to those with XRCC1 Arg/Arg or Arg/Gln variants (OR=8.5, 95%CI=1.9-38.9) after adjusting for potential confounders. Moreover, there was an interaction between VCM exposure and XRCC1 polymorphisms on oncoprotein expression (p=0.06). In our further analysis, amongst low exposure workers, subjects with CYP2E1 c2c2 genotypes demonstrated greater risk than subjects with CYP2E1 c1c1 or c1c2 genotypes (OR=3.1, 95%CI=0.3-37.8). However, there was no interaction between VCM exposure and genotypes of CYP2E1, GSTM1, and ALDH2 on oncoproteins.
We found that p53 overexprssion was significantly associated with VCM cumulative dose (OR=2.5, 95%CI=1.0-6.2). After adjusted for smoking, age, drinking, and hepatitis infection, amongst high exposure workers, subjects with XRCC1 Gln/Gln demonstrated significantly greater risk of p53 overexpression than subjects with Arg/Arg or Arg/Gln (OR=17.0, 95%CI=4.3-198.5). Amongst low exposure workers, subjects with CYP2E1 c2c2 genotypes have significantly higher risk than CYP2E1 c1c1 and c1c2 genotypes (OR=19.9, 95%CI=1.6-253.2).
Mutant Asp13-K-ras oncoprotein was not associated with VCM cumulative exposure dose; however, it was significantly associated with current high exposure experience within 5 years of sample collection (OR=2.9, 95%CI=1.1-7.9). After further analysis, we found that subjects experiencing high exposure job within 5 years with XRCC1 Gln/Gln had greater risk of K-ras oncoprotein than those with XRCC1 Arg/Arg or Arg/Gln (OR=1.7, 95%CI=0.1-23.3) although didn’t reach statistical significance. Similarly, subjects with ALDH2 1-2 or 2-2 genotypes demonstrated greater risk than those with ALDH2 1-1 genotypes (OR=2.5, 95%CI=0.6-11.2). Further, subjects experiencing high exposure job within 5 years with GSTT1 non-null genotype revealed significantly higher risk than those GSTT1 null type.
Our results suggest that mutant p53 protein and mutant K-ras oncoprotein revealed differential expression in VCM-exposed workers. Mutant K-ras oncoprotein was associated with current exposure, and it became undetected when exposure ends. However, mutant p53 protein was associated with cumulative dose. One possible explanation is mutant p53 gene provide selective growth advantage which making mutant p53 protein sustained in the cell persistently. In contratst, K-ras mutants may be demolished by p53 through the apoptosis. Furthermore, the relationship between p53 overexpression and DNA repair gene and metabolic genes was consistent with our previous study, but the association of mutant K-ras oncoprotein and DNA repair gene and metabolic traits are not clear in this study because of small sample size. Therefore, further studies are needed to elucidate the exact mechanism.

content
1.intorduction
2.materials and methods
3.results
4.discussion

Part I
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Part II
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