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系統識別號 U0026-0812200914082978
論文名稱(中文) 戴奧辛類中毒者健康影響及其分子指標研究
論文名稱(英文) Health effect and molecular markers in humans exposed to dioxin-like chemicals
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 蔡佩倩
研究生(英文) Pei-Chien Tsai
電子信箱 s5890124@mail.ncku.edu.tw
學號 s5890124
學位類別 博士
語文別 中文
論文頁數 133頁
口試委員 指導教授-郭育良
召集委員-劉校生
口試委員-黃溫雅
口試委員-王應然
口試委員-李德章
口試委員-沈志陽
中文關鍵字 多氯聯苯  多氯呋喃  死亡率  基因表現  基因多型性 
英文關鍵字 PCBs  PCDFs  mortality  gene expression  gene susceptibility 
學科別分類
中文摘要 戴奧辛類化學物質包括多氯戴奧辛、多氯聯苯、多氯呋喃。在動物實驗中發現具有致毒性且調控基因之表現。但在人類研究中,暴露這些物質所造成的健康效應及分子指標尚未十分清楚。因此本研究即針對台灣中部一群因食用多氯聯苯及呋喃污染之米糠油中毒之油症個案進行調查,以期尋找基因多型性、潛在的暴露指標及早期健康效應指標,瞭解暴露與疾病之相關性。
因個體之基因表現或基因多型性,造成暴露後所產生之疾病有所差異,因此本研究期望尋找有意義的潛在分子指標,以便能及早偵測疾病或死亡的產生。所研究之問題包括:(一)暴露個案因疾病死亡,是否有異於背景族群;(二)AhR、CYP1A1、GST之基因多型性是否與多氯聯苯及呋喃引起之疾病易感性有關;(三)尋找其他有意義的潛在暴露及早期健康效應指標。
在死亡率的長期追蹤研究中,研究團隊自行政院衛生署取得台灣及暴露個案之死亡情形,調整年齡結構後,以標準死亡率(SMR)比較在不同時期,台灣居民與暴露個案因疾病死亡的情形的異同。在暴露後0-8年內,男性暴露個案因肝硬化而死亡的比率顯著增加。在暴露後8-24年內,女性暴露個案因全身性紅斑狼瘡而死亡的比率,比起台灣女性高出14.7倍。
除已利用電話訪問持續追蹤油症個案之皮膚症狀外,在這次研究中,也抽取自願暴露族群與對照族群之周邊淋巴球血液,利用聚合酶鏈鎖反應(PCR)及限制酶片段多型性(RFLP)進行個體基因多型性的分析。當暴露個案之多氯聯苯濃度達一定量時,GSTM1有缺失會比沒缺失的基因型,罹患皮膚過敏高出約三倍。此外,在高濃度族群,則發現CYP1A1 T6235C變異型及GSTM1缺失型組合基因型之暴露個案較易發生氯痤瘡。
以微矩陣實驗,測得暴露與對照兩組混和男性未抽菸個案之908個基因之表現。調整背景及管家基因後,以迴歸及集群分析判別其顯著性,並以即時定量PCR(Real-Time PCR)進行確認,尋找到一個有意義的基因:VHL。調整年齡因素後,暴露個案之VHL基因表現量較對照個案為低,且有皮膚問題之暴露個案VHL表現量也較為低。
本論文中發現暴露多氯聯苯/呋喃後,除會造成新的健康影響外,基因之易感性及暴露之潛在指標問題,也是造成皮膚問題的主要因素。該類化學物質之暴露仍有一些健康效應及其致病因子尚未為現今之科學所了解。因此,持續追蹤此暴露族群仍相當重要,癌症的死亡率、自體免疫發生之機轉、及其他生物指標等,均有待未來更進一步研究探討。
英文摘要 Dioxin-like chemicals include polychlorodibenzodioxin (PCDD), polychlorinated biphenyls (PCBs), and polychlorinated dibenzofurans (PCDFs). Toxicity of them has been broadly reported in animal studies. However, the health effect and molecular markers in human exposed to dioxin-like chemicals were still unclear. Therefore, a group of Yucheng cases in central Taiwan ingested cooking oil contaminated with PCBs/PCDFs have followed. Gene suscepbility, potential exposure markers, and early effect markers were studied for evaluating the relationship between exposure and diseases.
In this thesis, we followed up a group of people highly exposed to PCBs and PCDFs, and examined: (1) the difference in long term mortality between exposed group and background population; (2) whether genetic polymorphisms of AhR, CYP1A1 and GST affected susceptibility for developing skin manifestations in exposed people; and (3) potential exposure molecular markers for such exposure.
The overall and cause-specific mortality of the exposed group were compared to those of the Taiwan general population. An age-modified method was to calculate standardized mortality ratio (SMR). Between 0-8 years after exposure, mortality of chronic liver disease and cirrhoses was increased in the Yucheng men, but not in women. Between 8-24 years after the exposure, mortality of systemic lupus erythematosus (SLE) was increased significantly in Yucheng females (five deaths, SMR = 14.7)
Questionnaires with telephone interview were used to obtain occurrence of skin manifestations in Yucheng groups. Polymerase chain reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) was done for determination of gentic polymorphism. Among intermediately exposed individuals, GSTM1 null genotype was associated with skin allergy. Among highly exposed individuals, combined CYP1A1-MspI mutant genotype and GSTM1 null genotype were associated with increased risk of chloracne.
A cDNA microarray system consisted of 908 genes was used for pooled mRNA among non-smoking men exposed to PCBs/PCDFs and their reference in triplicates. After adjusting for background and housekeeping genes, genes with different expressions between exposure and reference groups were determined by both regression and cluster analysis, and further confirmed by real-time PCR. Von Hippel Lindau (VHL) was found reduced in Yucheng people by both methods, after adjusted for age. Among Yucheng people, those with abnormal nails had lower VHL expression than those without abnormal nails.
As new health outcomes were found among people highly exposed to PCBs/PCDFs, and genetic susceptibility and exposure markers were identified in this study, we believe further follow-up of these people is important. Further investigation on cancer mortality, mechanism of autoimmune diseases, and other biomarkers are warranted.
論文目次 中文摘要………………………………………………………………Ⅰ
英文摘要………………………………………………………………Ⅲ
誌謝……………………………………………………………………Ⅴ
目錄……………………………………………………………………Ⅶ
表目錄…………………………………………………………………Ⅹ
圖目錄…………………………………………………………………Ⅹ
附錄圖表 …………………………………………………………ⅩI
符號彙編 …………………………………………………………ⅩII
第一章、背景介紹
1.1. 研究緣起 …………………………………………………………1
1.2. 戴奧辛類化學物質………………………………………………2
1.3. 動物毒性之研究…………………………………………………7
1.4. 戴奧辛類污染物重大暴露事件之健康效應及基因影響回顧 15
1.4.1. 義大利Seveso戴奧辛中毒事件……………………………15
1.4.2. 日本Yusho多氯聯苯/呋喃中毒事件……………………23
1.5. 台灣1979年Yucheng多氯聯苯/呋喃中毒事件…………………29
1.6. 比較台灣Yucheng、日本Yusho及義大利Seveso中毒之異同 34
第二章 台灣油症中毒者死亡率之研究
2.1. 死亡情形…………………………………………………………35
2.1.1. 研究對象及方法 ………………………………………36
2.1.2. 研究結果 ………………………………………………37
2.1.3. 討論 ……………………………………………………37
第三章、分子指標之研究
3.1. AhR、CYP1A1及GST基因對皮膚問題的影響……………………40
3.1.1. 研究對象………………………………………………41
3.1.2. 研究方法:聚合酶鏈鎖反應及限制性片段多型性…42
3.1.3. 研究結果………………………………………………46
3.1.4. 討論……………………………………………………47
3.2. VHL基因對多氯聯苯中毒之健康影響 …………………………48
3.2.1. 研究對象………………………………………………………48
3.2.2. 研究方法:cDNA微矩陣及統計方法…………………………48
3.2.2.1. 微矩陣實驗步驟……………………………………48
3.2.2.2. 資料前處理-校正背景值及housekeeping基因…51
3.2.2.3. 統計方法……………………………………………51
3.2.2.4. 即時定量反轉錄聚合酶鏈鎖反應…………………52
3.2.3. 研究結果 ……………………………………………………54
3.2.4. 討論 …………………………………………………………55
第四章、總結及未來展望……………………………………………59
參考文獻………………………………………………………………60
附錄一、與本研究相關之發表及修業期間其他之發表……………114
附錄二、臺灣地區居民健康調查問卷………………………………131

表目錄
表1油症個案暴露時之年齡及至2003年的存活情形………………84
表2油症個案發生各種疾病之死亡率(依性別) …………………85
表3油症個案發生各種疾病之死亡率(依暴露後的時間) ………87
表4因紅斑性狼瘡死亡之五位女性暴露及基本資料 ………………89
表5 PCR實驗之引子、產物序列長度及RFLP所用之酵素 ………90
表6暴露組與對照組之五種基因型的對偶基因頻率 ………………91
表7暴露族群中,單一基因多型性與皮膚症狀之相關性 …………92
表8暴露族群中,多重基因多型性與皮膚症狀之相關性 …………93
表9微矩陣晶片上之基因種類與數目 ………………………………94
表10微矩陣晶片上14個Housekeeping基因之名稱及位置 ………95
表11微矩陣及Real-Time PCR實驗之個案基本資料 ………………96

圖目錄
圖1 PCB濃度與皮膚疾病發生率之相關 ……………………………97
圖2利用迴歸分析預測暴露與對照個案之基因表現相異之基因 …98
圖3利用集群分析,分類暴露與控制組之基因表現趨勢 …………99
圖4調整年齡因素後,暴露個案與對照個案之VHL表現量………100
圖5在油症族群中,VHL基因表現量與皮膚/牙齒問題的相關 ……101
圖6本研究探討之問題、重要發現、及未來研究方向……………102

附錄圖表
附表1台灣油症患者血液中多氯聯苯及呋喃之平均含量…………103
附表2台灣油症患者血中濃度含量最多的6個PCB同源物及2個PCDF
濃度值 ……………………………………………………………104
附圖1戴奧辛類化學物質之基本結構………………………………105
附圖2戴奧辛類化學物質之毒性致病機轉…………………………106
附圖3義大利Seveso中毒事件之分佈區域…………………………107
附圖4義大利Seveso中毒事件,與TCDD暴露相關之AhR機制……108
附圖5截至2005年止,日本油症患者各種癌症發生比率 …………109
附圖6台灣油症事件發生的主要暴露鄉鎮及罹病率分佈圖………110
附圖7台灣油症持續追蹤之個案數…………………………………111
附圖8微矩陣實驗之酵素呈色法原理………………………………112
附圖9微矩陣實驗之ScanAlyze計算訊號強度方式…………………113
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