重金屬在生活環境中無所不在，人類經由飲食、空氣和水源暴露到重金屬後累積在人體內不易排出。近年來，台灣食安問題層出不窮，其中有不肖業者回收廚餘與地溝廢油，精煉後低價出售給攤販和餐廳，劣質油經重複回收和提煉後，會殘留重金屬砷、鎘和鉛，增加外食族群暴露到重金屬的機會。已有研究指出砷、鎘和鉛會與發炎和免疫反應相關的核受體(nuclear receptor)結合，干擾正常受體生理功能，可能會誘發發炎反應，引起急性發炎指標C-反應蛋白(C-reactive protein; CRP)分泌，導致心血管疾病(cardiovascular disease; CVD)發生。近十年來青壯年CVD死亡率有明顯增加，因此本研究探討外食青壯年暴露重金屬與生理數值和生活習慣之相關性，以及是否影響核受體基因表現，誘發發炎反應分泌CRP，進而促使CVD發生之可能性。
本研究招募100位18-45歲一天有兩餐正餐以上外食青壯年之尿液、血液樣本和問卷資料，以感應耦合電漿質譜分析儀(inductively coupled plasma mass spectrometry; ICP-MS)偵測尿液中砷、鎘和鉛濃度。以定量即時聚合酶鏈鎖反應法(quantitative real time polymerase chain reaction; qPCR)偵測血液中核受體基因表現，包含性激素受體基因(雄激素受體(androgen receptor; AR)、雌激素受體α (estrogen receptor α; ESR1)、ESR2和G蛋白偶聯雌激素受體(G protein-coupled estrogen receptor 1; GPER1))、脂肪代謝受體基因(過氧化物酶體增殖物活化受體α (peroxisome proliferator activated receptor α; PPARA)和PPARG)，以及外來物質代謝受體基因(類酯醇X受體(pregnane X receptor; NR1I2)及芳香基碳氫化合物受體(aryl hydrocarbon receptor; AHR))。利用酵素免疫分析法(enzyme-linked immunosorbent assay; ELISA)分析血液中CRP濃度。
研究結果發現尿液中砷與鎘、砷與鉛濃度有正相關性。常使用化妝品、吃海鮮、油炸食物者，尿液中砷濃度顯著較高；常使用線香、吃罐頭食品者，尿液中鎘濃度顯著較高；飲用飲水機水者，尿液中鉛濃度顯著較高。進一步依砷(29.72 μg/g cr)、鎘(0.29 μg/g cr)、鉛(2.60 μg/g cr)和CRP (268.0 µg/L)中位數濃度分為高和低兩組，以邏輯式迴歸分析結果顯示高砷暴露者GPER1、PPARG和NR1I2基因表現較低；高鎘暴露者AR、ESR2、GPER1和PPARG基因表現較高；高鉛暴露者AR基因表現較低，AHR基因表現較高；年齡較大或BMI較高者，CRP濃度較高；重金屬濃度與CRP則無相關性。此外，最小平方法-結構方程模型分析結果顯示，生理數值(年齡、臂圍、臀圍、BMI與血壓)較高者，CRP濃度較高(路徑係數0.485)；重金屬砷鎘鉛同時暴露較高者，AHR和NR1I2基因表現較高(路徑係數0.335)。TIA (transient ischemic attack)問卷與Rose問卷中有兩項以上CVD症狀者，有較高之尿液中鎘濃度及較低PPARA和NR1I2基因表現。
　　本研究發現不同生活與飲食習慣可能會暴露到不同之重金屬，外食青壯年暴露重金屬可能影響性激素受體(AR、ESR1、ESR2與GPER1)、脂肪代謝受體(PPARA與PPARG)及外來物質代謝受體(NR1I2與AHR)之基因表現，促使內皮細胞增生、改變脂肪分化及外來物質代謝之能力，導致發炎反應。雖然外食青壯年重金屬暴露與發炎指標CRP未達統計相關性，但體內鎘濃度較高者出現CVD症狀比率較高，推測鎘暴露可能降低PPARA基因表現，影響脂肪代謝能力，啟動發炎反應誘發CVD。因此應留意日常生活中可能之重金屬來源，減少暴露機會，避免健康危害。

Heavy metals exist ubiquitously in the living environment, and are very stable to accumulate in the food chain. Human are exposed to heavy metals by means of food, air and water. In recent years, there happened food safety scandals in Taiwan. The kitchen waste or gutter oil were recovered and refined by unscrupulous vendors, and sold to food stalls and restaurants. Diner-out has more chances to expose the heavy metals remained in the inferior oil after repetitive refining. Arsenic (As), cadmium (Cd) and lead (Pb) have been known as endocrine disrupting chemicals, which can bind with nuclear receptors to influence normal biological functions, and potentially induce inflammatory response to secret C-reactive protein (CRP) as a result of cardiovascular disease (CVD). In the decade, growth rate of CVD mortality of young adults has obviously increased. Therefore, this study aimed to investigate the correlation of urinary concentrations of heavy metals between physiological index and lifestyle, and whether heavy metals exposure affected gene expression of nuclear receptors genes to give rise to inflammatory response and trigger CRP secretion in dining-out young adults potentially for CVD development.
One hundred dining-out young adults aged 18-45 were recruited in this study, and informed consent to provide their urine and blood samples and questionnaire information. Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the urinary concentrations of As, Cd and Pb. Quantitative real time polymerase chain reaction was used to detect the gene expressions of nuclear receptors genes, including hormone-related receptors (androgen receptor (AR), estrogen receptor α (ESR1), ESR2, G protein-coupled estrogen receptor 1 (GPER1)), lipometabolism-related receptors (peroxisome proliferator activated receptor α (PPARA), PPARG), and xenobiotic detoxification-related receptors (NR1I2 and AHR)). Plasma CRP was determined using enzyme-linked immunosorbent assay.
This study found that there were correlations between As with Cd or Pb, and the young adults with higher frequency of cosmetics usage, seafood or fried food consumption had significant higher urinary arsenic levels. Study subjects who burned incense or consumed canned food more frequently were observed to have higher urinary Cd levels. Drinking water from water dispenser presented higher urinary Pb levels. Furthermore, urinary levels of heavy metals were divided by medians (As 29.72 μg/g cr, Cd 0.29 μg/g cr, Pb 2.60 μg/g cr), after logistic regression analysis, subjects with higher As exposure had the lower gene expressions of GPER1, PPARA and NR1I2. The higher Cd group had the higher gene expressions of AR, ESR2, GPER1 and PPARG. The higher Pb group had higher AHR and lower AR expressions. The CRP level was positively relevant to age and BMI. In addition, the results of partial least squares-structural equation modeling (PLS-SEM) indicated that young adults with higher levels of physiological indexes (age, arm, hip, BMI, and blood pressure) had higher CRP (path coefficient 0.485), and co-exposure of As, Cd and Pb presented higher gene expression of AHR and NR1I2 (path coefficient 0.335). Furthermore, the subjects with at least two potential CVD development syndromes inquired by TIA (transient ischemic attack) questionnaire and Rose questionaire had higher urinary Cd levels and decreased PPARA and NR1I2 expression.
The findings of this study suggested that exposure to heavy metals relied on various types of dietary and living habit. Exposure to As, Cd and Pb might affect gene expression of hormone-related receptors (AR, ESR1, ESR2 and GPER1), lipometabolism-related receptors (PPARA and PPARG), and xenobiotic detoxification-related receptors (NR1I2 and AHR) to induce inflammatory response. Even though there was no correlation between exposure levels of heavy metals and CRP levels, subjects with CVD syndromes were observed to have higher urinary Cd levels and lower PPARA expression, indicating that Cd exposure might reduce PPARA expression to cause inflammation for CVD development. Therefore, it is necessary to reduce the chance of heavy metal exposure to avoid adverse health effect.

摘要 VIII
Abstract X
第一章 緒論 1
第二章 文獻回顧 2
第一節 重金屬之物化特性與環境流佈 2
2.1.1 砷之特性與用途 2
2.1.2 鎘之特性與用途 3
2.1.3 鉛之特性與用途 4
第二節 重金屬相關食安事件與限量標準 5
第三節 砷之毒性與生物效應 8
第四節 鎘之毒性與生物效應 10
第五節 鉛之毒性與生物效應 11
第六節 重金屬之人體暴露 12
第七節 尿液重金屬的代表性 14
2.7.1 砷在生物樣本中的代表性 15
2.7.2 鎘在生物樣本中的代表性 15
2.7.3 鉛在生物樣本中的代表性 15
第八節 核受體種類與功能 16
2.8.1 雌激素受體 16
2.8.2 G蛋白偶聯雌激素受體1 19
2.8.3 雄激素受體 21
2.8.4 過氧化物酶體增殖物活化受體 22
2.8.5 類酯醇X受體與芳香基碳氫化合物受體 24
第九節 重金屬暴露與核受體之關聯性 27
2.9.1 砷暴露與核受體之關聯性 27
2.9.2 鎘暴露與核受體之關聯性 28
2.9.3 鉛暴露與核受體之關聯性 29
第十節 C反應蛋白簡介 29
第十一節 重金屬暴露與C反應蛋白濃度之關聯性 31
第三章 研究目的 33
第四章 研究材料與方法 35
第一節 化學藥品 35
第二節 研究對象 35
第三節 血液、尿液樣本收取與保存 36
第四節 尿液中重金屬分析 36
第五節 基因表現分析 41
第六節 以酵素結合免疫吸附法偵測C反應蛋白 43
第七節 統計分析 43
第五章 結果 45
第一節 ICP-MS檢測重金屬之品質管理 45
第二節 基本人口學資料、重金屬濃度及基因表現量 48
第三節 人口學資料與重金屬暴露之相關性 50
第四節 生活習慣對於重金屬暴露之勝算比 61
第五節 重金屬濃度與核受體基因表現之相關性 64
第六節 重金屬濃度對於核受體基因表現之勝算比 68
第七節 綜合探討重金屬對核受體基因表現之影響 79
第八節 生理數值與血液中CRP的相關性 82
第九節 重金屬濃度及核受體基因表現與CRP濃度之相關性 91
第十節 生理變項、重金屬濃度與核受體基因對CRP的勝算比 93
第十一節 探討所有變項間之相關性與預測模型建立 96
第十二節 重金屬濃度、核受體基因與CRP對於CVD症狀的影響 99
第六章 討論 103
第一節 各國尿液中重金屬濃度情形 103
第二節 生活習慣對於尿液中重金屬濃度之影響 104
6.2.1 砷暴露與化妝品使用習慣、海鮮類和油炸類食物食用頻率有關 104
6.2.2 鎘暴露與線香使用習慣、每日飲水量、罐頭食品食用頻率有關 107
6.2.3 鉛暴露與每日飲水量、飲用水來源有關 108
第三節 尿液中重金屬砷與鎘和鉛濃度間有正相關性 109
第四節 尿中砷濃度影響GPER1、PPARG和NR1I2基因表現量 109
第五節 尿中鎘濃度影響AR、ESR2、GPER1和PPARG表現量 113
第六節 尿中鉛濃度影響AR和AHR基因表現量 116
第七節 砷與鎘共暴露影響ESR1和ESR2基因表現量 118
第八節 尿中重金屬濃度影響CRP濃度及CVD症狀 118
6.8.1 重金屬暴露濃度與CRP濃度無相關性 118
6.8.2 鎘暴露導致CVD症狀出現 120
第七章 結論 122
參考文獻 123

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