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研究生：	鄭天浚 Cheng, Tain-Junn
論文名稱：	慢性砷暴露與腦血管疾病的關係-從流行病學到動物實驗證據 Chronic Arsenic Exposure and Cerebrovascular Disease-from Epidemiology to Animal Evidence
指導教授：	郭浩然 Guo, How-Ran
學位類別：	博士 Doctor
系所名稱：	醫學院 - 環境醫學研究所 Department of Environmental and Occupational Health
論文出版年：	2011
畢業學年度：	100
語文別：	英文
論文頁數：	98
中文關鍵詞：	腦血管疾病、砷、烏腳病流行區、死亡研究、粥狀動脈硬化、膽固醇脂化運輸蛋白、肝臟X接受器、膽固醇逆轉運
外文關鍵詞：	cerebrovascular disease, arsenic, blackfoot disease endemic area, mortality study, atherosclerosis, cholesteryl ester transfer protein, liver X receptor, reverse cholesterol transport
相關次數：	點閱：137 下載：11
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背景：烏腳病流行區位於台灣西南部沿海地區，包括嘉義縣的布袋鎮、義竹鄉、臺南縣的學甲鎮、北門鄉以及鹽水鎮，居住在該地區的居民曾經長期以含有高濃度無機砷的深井水作為飲用水。該地區的流行病學調查顯示具有較高的癌症、皮膚病變、以及心血管疾病等疾病的發生，但是對於腦血管疾病是否和長期過量的無機砷暴露有相關，則各研究的結果並不一致，值得進一步探討；本研究藉由流行病學數據分析來探討砷暴露與腦血管疾病的關係。此外，有研究顯示砷暴露會引發粥狀動脈硬化，而粥狀動脈硬化是引發腦、心血管疾病很重要的原因之一，但其機轉仍不清楚。本研究藉由動物模式來探討砷暴露與高膽固醇造成粥狀動脈硬化的機轉。

研究方法：在流行病學方面，分別以烏腳病流行區居民及蘭陽平原居民為兩個砷暴露族群，並以全臺灣居民以及合併嘉義縣及臺南縣居民作為兩個對照族群進行研究。以1971年到2005年臺灣內政部人口資料檔及死因資料檔為材料，將死亡原因符合國際疾病分類第九版代碼為431到439的個案視為腦血管疾病死亡病例計算粗死亡率，並以鄉鎮為單位估算各研究族群每年35歲以上男女各年齡層之腦血管疾病死亡率，進而計算直接標準化死亡率，以評估其各研究族群腦血管死亡率的趨勢。此外，在各研究族群間與性別間3年移動平均死亡率及35年總合死亡率進行間接標準化比較，以評估性別及砷暴露對腦血管疾病死亡的效應。在動物實驗方面，將基礎及2%高膽固醇食物分別餵食於原發性高血壓及Wistar-Kyoto大鼠。實驗組在不同年齡和次序，連續餵食含三氧化二砷飲用水共20週。在預定時間點量測高密度脂蛋白膽固醇、低密度脂蛋白膽固醇、總膽固醇、三酸甘油酯、熱休克蛋白70及高敏感C－反應蛋白的濃度。主動脈切片以蘇木和伊紅染色來証實粥狀動脈硬化，並量測肝臟膽固醇脂化運輸蛋白－1及肝臟X接受器β活性來探討對膽固醇代謝的影響。

結果：在流行病學研究方面，臺灣地區腦血管疾病死亡率呈下降趨勢，直接標準化死亡率由1971年的每千人每年2.46下降到2005年0.63。女性比男性有較低的死亡率，其間接標準化死亡比為0.8。慢性砷暴露地區族群不論在烏腳病流行區或蘭陽平原、無論男性或女性，都比對照組有較高的間接標準化死亡比，在男性為1.06~1.09，女性為1.12~1.14；而烏腳病流行區族群比蘭陽平原族群有較高的間接標準化死亡比，男性為1.05，女性為1.04。在動物實驗方面，不論單獨砷暴露或結合高膽固醇，均促發粥狀動脈硬化，並短暫增加熱休克蛋白70及高敏感C－反應蛋白。早期結合組的總膽固醇和三酸甘油酯濃度均無顯著改變，但高、低密度脂蛋白膽固醇比例顯著降低，並持續到30週齡。早期結合組亦出現最顯著的肝臟膽固醇脂化運輸蛋白－1及肝臟X接受器β活性抑制。

結論：臺灣地區腦血管疾病死亡率，不論女性與男性，在1971到2005間均呈下降趨勢，男性比女性有較高的腦血管疾病死亡率，而慢性飲水含砷暴露不論在女性與男性均會增加腦血管疾病死亡率。在實驗動物身上，砷可藉由抑制肝臟膽固醇脂化運輸蛋白－1及肝臟X接受器β的活性改變膽固醇逆轉運代謝進而誘發粥狀動脈硬化。因此，若減少早期生活環境中砷的暴露，應可降低砷暴露所造成粥狀動脈硬化有關的死亡率。

Background: Chronic arsenic exposure is associated with a variety of diseases, including cancer, peripheral vascular disease, cardiovascular disease, and diabetes. However, epidemiological studies on its association with cerebrovascular diseases (CVD) yielded inconsistent results. The first aim of this study is to explore this association in Taiwan using nationwide data. Furthermore, some studies suggested that arsenic exposure can induce atherosclerosis, which is one of the major causes of vascular diseases. The second aim of this study is to identify the mechanism of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process.

Materials and methods: We analyzed mortality data in Taiwan from 1971 to 2005 and chose two geographic areas with populations suffering from chronic exposure to arsenic in drinking water for study: the blackfoot disease endemic area (BFDEA) in the southwest and the Lan-Yang Basin (LYB) in the northeast part of Taiwan. The Chia-Yi and Tainan Counties, which surround the BFDEA, and the nation of Taiwan as a whole were used as reference populations. Eligible people over 35 years of age are enrolled. We identified the cases whose causes of death were coded between 431 and 439 according to the 9th Edition of the International Classification of Disease as CVD deaths. From 1971 to 2005, direct standardized mortality rates and gender-specific indirect standardized mortality ratios (SMR) were calculated for the four populations. To study the mechanisms of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process, we fed spontaneous hypertensive rats and Wistar Kyoto rats with basal diet or HCD and provided with them drinking water containing arsenic at different ages and orders for 20 consecutive weeks. We measured high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol, triglyceride, heat shock protein 70 (HSP 70), and high sensitive C-reactive protein (hs-CRP) at predetermined intervals and determined expressions of cholesteryl ester transfer protein-1 (CETP-1) and liver X receptor β (LXRβ) in the liver. Atherosclerosis was determined by examining the aorta with hematoxylin and eosin stain.

Results: The direct standardized mortality rate for CVD in Taiwan decreased from 2.46/103 person-year in 1971 to 0.63/103 person-year in 2005, and women had significantly lower mortality than men (SMR = 0.80; p < 0.05). The CVD mortality rates of populations with chronic arsenic exposure were significantly higher than those of the reference populations (SMR ranging from 1.06 to 1.09 in men and 1.12 to 1.14 in women, p < 0.05). The BFDEA had higher CVD mortality rates than the LYB, with SMR = 1.05 (p < 0.05) in men and SMR = 1.04 (p = 0.05) in women. From animal study, we found arsenic, alone or combined with HCD, may promote atherosclerosis formation with transient increases in HSP 70 and hs-CRP after 20 weeks of feeding. Early combination exposure decreased the HDL-C/LDL-C ratio without changing the levels of total cholesterol and triglyceride till 30 weeks old. Expressions of both CETP-1 and LXRβ were suppressed, most significantly in early combination exposure.

Conclusion: In Taiwan, CVD mortality decreased in both genders from 1971 to 2005, and men had higher CVD mortality than women. Chronic arsenic exposure from drinking water was associated with increased risks of CVD. Arsenic exposure may induce atherosclerosis in rats, through modifying reverse cholesterol transport in cholesterol metabolism and suppressing LXRβ and CEPT-1 expressions. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element.

博士論文口試合格證明…………………………………………………………I
Chinese abstract………………………………………………………………………II
Abstract………………………………………………………………………………VI
Acknowledgement……………………………………………………………X
Contents……………………………………………………………………………XIII
Table contents……………………………………………………………XVII
Figure contents…………………………………………………………XIX
Symbol list……………………………………………………………………XXI
1.	Introduction………………………………………………………………………1
1-1 Nature and chemical characteristics of arsenic………………………2
1-2 Human arsenic exposure………………………………………………………….3
1-3 Human health effects of arsenic exposure………………………………………4
1-3-1 Epidemiological evidences of carcinogenicity………………………4
1-3-1-1 Evidences of associations between arsenic exposure and cancers……4
1-3-1-2 Evidences of dose-response relationship………………………………5
1-3-2 Arsenic exposure and risks of PVD, CAD and CVD…………………6
1-4 Atherosclerosis: one of the causes of CVD and CAD………………8
1-4-1 Etiology of atherosclerosis…………………………………………………8
1-4-2 TNF-α and atherosclerosis………………………………………………9
1-4-3 CRP and atherosclerosis…………………………………………………10
1-4-4 Heat shock protein and atherosclerosis…………………………10
1-4-5 Cholesterol and atherosclerosis……………………………………12
1-5 Arsenic and atherosclerosis……………………………………………………14
1-6 Mechanisms of arsenic induce atherosclerosis…………………………15
1-6-1 Inflammation and oxidative stress in atherosclerosis...15
1-6-2 Human paraoxonases in atherosclerosis………………………15
1-6-3 Lipid metabolism in atherosclerosis……………………………16
2. Study Objectives……………………………………………………17
3. Materials and Methods……………………………………………………………19
3-1 Arsenic exposure and CVD mortality…………………………………………..20
3-1-1 Study population and data source……………………………………………20
3-1-2 Exposure assessment and data source……………………………………20
3-1-3 Outcome measurement and data source…………………………………21
3-1-4 Methods………………………………………………………21
3-1-5 Statistical analysis………………………………………22
3-2 Mechanisms of atherosclerosis after arsenic exposure from drinking water in the rats………………………………………………………………………23
3-2-1 Animal Preparation……………………………………………………………23
3-2-2 Determination of biochemistry indexes……………………………………24
3-2-3 Western blot analysis for CETP-1 and LXRβ proteins……24
3-2-4 Measurement of serum hs-CRP and HSP 70 levels…………………25
3-2-5 Hematoxylin and eosin stain of aorta………………………………………26
3-2-6 Statistical analysis……………………………………………………………27
4. Results………………………………………………………………………28
4-1 Arsenic exposure and CVD mortality…………………………………………29
4-1-1 Crude and direct standardized CVD mortality rates of study areas……………29
4-1-2 Differences in CVD mortality between men and women in four studied areas...29
4-1-3 Association between arsenic exposure from drinking water and CVD... ... ... 30
4-2 Mechanisms of atherosclerosis induced by arsenic exposure in drinking water in rats……………………………………………………………31
4-2-1 Lipid metabolism in different rat strains after arsenic exposure…………31
4-2-2 Atherosclerosis after arsenic and HCD exposure………………31
4-2-3 Atherosclerotic inflammatory markers in different exposure rats………31
4-2-4 Lipid profile/metabolism after arsenic and HCD exposure…......32
4-2-5 CETP-1 and LXRβ after arsenic and HCD exposure………………32
5. Discussion…………………………………………34
5-1 Arsenic exposure and CVD mortality…………………………………………35
5-1-1 Arsenic exposure from drinking water may increase the risk of CVD…………35
5-1-2 Arsenic exposure from air may increase the risk of lung cancer rather than CVD……………………………………………………………………………36
5-1-3 The CVD SMR of men in the BFDEA was significantly higher than that in the LYB…………………………………………………………………………….37
5-1-4 Arsenic as a risk factor of CVD in Taiwan……………………………37
5-1-5 Women had lower CVD mortality in Taiwan…………………………………38
5-2 Mechanisms of atherosclerosis induced in rats by arsenic exposure through drinking water…………………………………………………39
5-2-1 Different lipid profile changes in different rat strains after arsenic exposure…39
5-2-2 Inflammatory markers of atherosclerosis (HSP 70 and hs-CRP) increased after arsenic exposure………………………………………………39
5-2-3 Atherosclerosis induced in SHR rats by arsenic and HCD exposures……39
5-2-4 Arsenic has a more prominent effect on lipid metabolism under high cholesterol diet when the exposure occurs earlier in life…………………40
5-2-5 Arsenic induces atherosclerosis through modulating RCT by the suppressive effects on CETP-1 and LXRβ…………………40
5-2-6 The relationship of CETP and LXR activities with atherosclerosis, CVD, and CAD…………………………………………………41
5-2-7 CEPT-1 and LXRβ activities significantly decreased
after arsenic exposure and high cholesterol diet in early life………………………………43
6. Conclusions…………………………………………………44
7. Recommendations……………………………………46
8. References…………………………………………………48
9. Tables……………………………………………………………61
10. Figures.……………………………………………………76
11. Appendix……………………………………………………97
 
Table Contents

Table 1: The population, cerebrovascular deaths, and crude mortality rates (per 1000 person-year) from 1971 to 2005 in the blackfoot disease endemic area………...62
Table 2: The population, cerebrovascular deaths, and crude mortality rates (per 1000 person-year) from 1971 to 2005 in the Lan-Yang Basin………………………...63
Table 3: The population, cerebrovascular deaths, and crude mortality rates (per 1000 person-year) from 1971 to 2005 in the Chia-Yi and Tainan Counties…………..64
Table 4: The population, cerebrovascular deaths, and crude mortality rate (per 1000 person-year) from 1971 to 2005 in Taiwan……………………………………...65
Table 5: Male and female direct standardized cerebrovascular mortality rates in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan, 1971-2005……………66
Table 6: The 3-year cumulative standardized mortality ratio (SMR) of cerebrovascular disease between women and men and associated 95% confidence interval (CI) in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan…………………...68
Table 7: The 35-year cumulative standardized mortality ratio (SMR) of cerebrovascular disease between women and men and associated 95% confidence interval (CI) in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan…………………...70
Table 8: The 3-year moving average standardized mortality ratio (SMR) of cerebrovascular disease in men and associated 95% confidence interval (CI) in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan…………………………………71
Table 9: The 3-year moving average standardized mortality ratio (SMR) of cerebrovascular disease in women and associated 95% confidence interval (CI) in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan…………………………………73
Table 10: The 35-year cumulative standardized mortality ratio (SMR) of cerebrovascular disease and associated 95% confidence interval (CI) in women and men in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan…………………………75
 
Figure Contents
Figure 1: Locations of the blackfoot disease endemic area, Lan-Yang Basin, Chia-Yi and Tainan Counties combined, and whole Taiwan…………………………………77
Figure 2: Male direct standardized cerebrovascular mortality rates in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan from 1971-2005…………………………78
Figure 3: Female direct standardized cerebrovascular mortality rate in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan from 1971-2005…………………………79
Figure 4: The 3-year cumulative standardized mortality ratio (SMR) of cerebrovascular disease between women and men in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan……………………………………………………………………80
Figure 5: The 35-year cumulative standardized mortality ratio (SMR) of cerebrovascular disease between women and men in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan……………………………………………………………………82
Figure 6: The male 3-year moving average standardized mortality ratio (SMR) of cerebrovascular disease in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan……………………………………………………………………83
Figure 7: The female 3-year moving average standardized mortality ratio (SMR) of cerebrovascular disease in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan……………………………………………………………………85
Figure 8: The HDL-C/LDL-C ratio associated with arsenic exposure in WKY and SHR at indicated age in weeks…………………………………………………………...87
Figure 9: The changes in total cholesterol (TC) and triglyceride (TG) levels in arsenic rats……………………………………………………………………………….88
Figure 10: Aorta sections of spontaneous hypertensive prone rats with hematoxylin and eosin stain………………………………………………………………………..89
Figure 11: The HSP 70 levels in different groups of rats at various ages…………………91
Figure 12: The hs-CRP levels in different groups of rats at various ages…………………92
Figure 13: The HDL-C/LDL-C ratio in different groups of rats at various ages………….93
Figure 14: The total cholesterol (TC) levels in different groups of rats at various ages……………………………………………………………………….……...94
Figure 15: The triglyceride (TG) levels in different groups of rats at various ages……………………………………………………………………………...95
Figure 16: The activities of CETP-1 and LXRβ in liver tissue determined by western blot analysis in different groups of rats………………………………………………96
                                    

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