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研究生:鄭如芳
研究生(外文):Ju-FangCheng
論文名稱:雙酚A及壬基酚共同暴露與男性成人芳香轉化酶及攝護腺疾病之相關性研究
論文名稱(外文):The study on association between concurrent exposure of bisphenol A and nonylphenol with aromatase and prostatic diseases in adult men
指導教授:李俊璋李俊璋引用關係
指導教授(外文):Ching-Chang Lee
學位類別:碩士
校院名稱:國立成功大學
系所名稱:環境醫學研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:118
中文關鍵詞:雙酚A壬基酚攝護腺性荷爾蒙芳香環化酶尿液
外文關鍵詞:Bisphenol Anonylphenolprostatereproductive hormonearomataseurinary
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近年來隨著科技、醫療進步,人口結構有逐漸邁向高齡化之趨勢,因而更需要對患有慢性疾病之中老年族群更加重視。研究發現,良性攝護腺肥大(Benign Prostatic Hyperplasia, BPH)、攝護腺癌症(Prostate Cancer, PCa)等泌尿系統疾病的發生率及盛行率逐年增加。2012年衛生福利部醫療統計顯示,台灣男性因BPH而就醫之就診人數及就診率隨著年齡增長,均有增加之趨勢。其中,PCa自2006-2012年連續七年位居台灣男性主要癌症死因第七位。誘發攝護腺相關疾病之危險因子包括年齡、種族及生活習慣以及環境中之內分泌干擾物質暴露等,均已被認為是重要之影響因素。動物及人類流行病學研究指出雙酚A(Bisphenol A, BPA)和壬基酚(Nonylphenol, NP)均會干擾人體內分泌系統之調控機制,可透過抗雄性激素作用進而導致生殖荷爾蒙失調、造成攝護腺細胞增生或攝護腺重量異常等,然其機制為何?尚無定論。此外,由於芳香轉化酶(Aromatase)為生殖荷爾蒙中調控雄性素(androgen)轉化為雌激素(estrogen)之重要酵素,當人體體內aromatase活性較高時,可觀察到有過多的睪固酮(Testosterone)轉換成雌二醇(Estradiol, E2),進而對於男性攝護腺疾病造成影響。
綜合上述可知,BPA和NP是否透過干擾體內aromatase之活性,進而對男性生殖荷爾蒙造成影響而導致攝護腺疾病之機制仍未明確。因此,本研究於國立成功大學附設醫院泌尿科門診進行研究族群篩選及招募,針對已罹患攝護腺疾病之男性成人尿液中BPA和NP濃度、血液中生殖荷爾蒙濃度與體內aromatase濃度之相關性進行探討。
本研究自國立成功大學醫學院附設醫院泌尿科招募45歲以上,經醫師診斷罹患BPH或PCa之男性成人為研究族群,經簽署受試者同意書後,以問卷調查其環境中BPA和NP暴露來源,並同時採集尿液及血液樣本,進行血液中13種生殖荷爾蒙檢測,並以高效能液相層析串聯式質譜儀(HPLC-MS/MS)分析尿液樣本中BPA和NP濃度。此外並收集受試者臨床診斷及檢查結果,包括攝護腺特異性抗原(Prostate specific antigen, PSA)、尿流速檢測(Voided volume、Maximum flow、Mean flow)、直腸超音波檢查(Transrectal ultrasonography, TRUS)、直腸觸診(Digital rectal examination, DRE)、國際攝護腺症狀評分(International prostate symptom score, IPSS)等。最後整合上述相關資料評估尿液中BPA和NP濃度與生殖荷爾蒙調控及攝護腺疾病之相關性。
參與本研究並完成所有流程及樣本分析之攝護腺疾病患者共有130位,受試者又可以分成BPH及PCa患者,BPH患者以攝護腺體積第33.3 %(29.37 mL)及66.7 %(43.20 mL)為切點進行三分位分組,合計共四組。但由於BPH與PCa間未能觀察到趨勢關係,推測PCa組受試者在被診斷患有PCa後大多皆以改變其生活作息型態,導致無法觀察到臨床診斷指標之趨勢,因此後續討論僅針對BPH患者(共118位)進一步探討。
結果顯示,三組間之PSA中位數濃度分別為1.44 ng/mL、2.13 ng/mL、6.32 ng/mL,達統計上顯著性差異(p 〈 0.001);膀胱攝護腺突出(Intravesical protruding)比率分別為5.26 %、25.7 %、76.9 % 達統計上顯著差異(p 〈 0.001)。BPH患者三分組之尿液中BPA及NP濃度不論是否經過creatinine校正,皆以重度BPH患者尿中BPA及NP濃度明顯高於其他組別。受試者血液中生殖荷爾蒙濃度之相關性分析之結果皆符合一般民眾體內之三組生理學變化趨勢。於BPH患者三組中,血液中荷爾蒙濃度LH、FSH、DHEA、DHT/TT與TT/AD皆以重度BPH患者較高。至於E2、SHBG、AD、E1、aromatate、E2/TT、AD/E1則以輕度BPH患者較高,除了E2具統計顯著差異(p = 0.029)與inhibin B具統計邊緣顯著差異(p = 0.051)外,其餘皆無統計上顯著差異。經校正年齡及BMI後之複迴歸分析顯示,則BPA與inhibin B、E1/E2呈顯著正相關(p 〈 0.01;p 〈 0.05);BPA與DHEA-S、DHEA呈現顯著負相關(p 〈 0.01;p 〈 0.05),與E2呈現邊緣顯著負相關(p 〈 0.1);NP與DHEA-S呈現顯著負相關(p 〈 0.01)在臨床檢測指標部分,NP與voided volume與max. flow rate呈現邊緣顯著正相關(p 〈 0.1)。亦即男性成人暴露BPA及NP後,可能藉由影響類固醇合成機制反應,進而影響E2之分泌。
As science, technology and medicine improving, the society towards the trend of aging. Diseases of urinary system were found that the incidence and prevalent rate of benign prostatic hyperplasia (BPH) and prostate cancer (PCa) increased year by year. Multiple risk factors including age, race, lifestyle and environmental toxicants might cause prostatic disorders. In above risk factors, endocrine disruptor is the most important factor up to now. The objectives in present research are to explore the association and active mechanism among bisphenol A (BPA) and nonylphenol (NP) exposure, steroid hormone, aromatase and prostate disease in elderly adult man.
130 men with prostate disease were recruited through urology clinics, and all were categorized based on the urologist' diagnoses. All BPH subjects were divided to three groups based on their prostate volume and one PCa group. However the trend among four groups were not found, we assumed that participants of PCa almost changed them lifestyle and resulted in the lower urinary BPA and NP were found. Therefore, only three BPH groups were discussed in the following analysis. The large-sized group had significantly higher PSA level and intravesical protruding ratio (p〈0.001). In three BPH groups who with larger prostate volume had higher urinary BPA and NP levels. LH, FSH, DHEA, DHT/TT and TT/AD were the highest in largest-sized prostate group of BPH subjects. E2, SHBG, AD, E1, aromatate, E2/TT and AD/E1 were the highest in small-sized prostate group of BPH subjects. The significant difference of E2 was found among three BPH groups (p=0.029) and inhibin B showed borderline significant among three BPH group (p=0.051). After adjusting age and BMI, urinary BPA was positively associated with inhibin B and E1/E2 (p〈0.01; p〈0.05) and negatively associated with DHEA and DHEA-S (p〈0.01, p〈0.05); urinary BPA were borderline negatively significantly associated with E2 (p〈0.1); urinary NP was negatively associated with DHEA-S (p〈0.01) and borderline significantly associated with voided volume and mean flow rate (p〈0.1). In conclusion, BPA and NP exposure were significantly associated with steroid hormones. Due to the size of subjects in present research is small, further study is needed to collect more subjects to explore the active mechanism between BPA and NP exposure and prostatic disease.
摘 要 I
Extended Abstract III
致謝 VI
目 錄 VII
表目錄 IX
圖目錄 XI
第一章 緒 論 1
1-1. 研究背景 1
1-2. 研究目的 3
第二章 文獻回顧 4
2-1. 攝護腺與生殖荷爾蒙調控 4
2-1-1. 攝護腺介紹與相關疾病盛行率調查 4
2-1-2. 攝護腺診斷及檢查流程 5
2-1-3. 攝護腺疾病之危險因子 7
2-1-4. 攝護腺與生殖荷爾蒙調控 10
2-2. 雙酚A、壬基酚暴露與生殖荷爾蒙調控 14
2-2-1. 雙酚A、壬基酚之暴露與代謝 14
2-2-2. 成人體內雙酚A、壬基酚濃度調查 18
2-2-3. 動物與細胞毒性測試 19
2-2-4. 流行病學研究 21
2-3. 雙酚A、壬基酚暴露與攝護腺疾病之相關影響 21
2-4. 尿液中雙酚A及壬基酚分析方法 23
第三章 材料與方法 24
3-1. 研究架構 24
3-2. 研究對象選取與流程 24
3-2-1. 研究個案招募 24
3-2-2. 良性攝護腺肥大與攝護腺癌分組標準 25
3-3. 尿液樣本採樣及雙酚A及壬基酚分析方法 25
3-3-1. 尿液樣本採集 25
3-3-2. 尿液中雙酚A及壬基酚分析方法 25
3-3-3. 尿液分析方法之品保品管 27
3-4. 血液樣本採樣及分析 30
3-4-1. 血液樣本採集 30
3-4-2. 生殖荷爾蒙分析 30
3-4-3. 攝護腺特異性抗原指標檢查 31
3-4-4. 血液中芳香轉化酶(Aromatase)濃度分析 31
3-5. 環境中雙酚A、壬基酚暴露來源及生活品質調查評估標準化問卷 32
3-6. 男性成人雙酚A、壬基酚每日暴露劑量推估 34
3-7. 資料處理與統計分析 34
第四章 結果與討論 35
4-1. 液相層析質譜儀分析條件與前處理測試結果 35
4-1-1. 液相層析質譜儀條件 35
4-1-2. 前處理測試結果 38
4-2. 護腺臨床診斷指標分布情形 39
4-3. 攝護腺臨床診斷指標差異及相關性 39
4-4. 攝護腺疾病患者環境中雙酚A及壬基酚暴露來源及生活品質調查評估之標準化問卷結果解析 41
4-4-1. 攝護腺疾病患者基本資料、生活習慣與身心健康狀況 41
4-4-2. 攝護腺疾病患者家戶環境與個人衛生用品使用情形 42
4-4-3. 攝護腺疾病患者日常飲食使用塑膠用品習慣調查結果 43
4-4-4. 攝護腺疾患外食塑膠用品使用習慣調查分析結果 43
4-4-5. 攝護腺疾病患者飲食習慣情形 44
4-4-6. 攝護腺疾病患者五大類食品攝取量調查結果 45
4-5. 尿液中雙酚A與壬基酚濃度分布 46
4-5-1. 尿液中雙酚A與壬基酚濃度之品保及品管結果 46
4-5-2. 尿液中雙酚A與壬基酚濃度分布 47
4-5-3. 尿液中雙酚A及壬基酚濃度差異 48
4-5-4. 攝護腺疾病患者雙酚A及壬基酚暴露來源探討 48
4-6. 攝護腺疾病患者血液中生殖荷爾蒙濃度分析結果 49
4-6-1. 血液中生殖荷爾蒙濃度分布情形 49
4-6-2. 血液中生殖荷爾蒙濃度之差異 50
4-6-3. 血液中生殖荷爾蒙濃度之相關性分析 50
4-7. 綜合探討雙酚A及壬基酚共同暴露對芳香轉化酶、生殖荷爾蒙及攝護腺疾病之相關性分析 52
4-8. 攝護腺疾病患者雙酚A及壬基酚每日暴露劑量推估 56
第五章 結論與建議 57
5-1. 結論 57
5-2. 建議 58
第六章 參考文獻 59
附件一 人體試驗委員會同意證明 114
附件二 臨床試驗同意書 115
附件三 攝護腺疾患塑化劑暴露評估標準化問卷 118
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