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系統識別號 U0026-2707201516404500
論文名稱(中文) 鄰苯二甲酸酯暴露與生殖荷爾蒙調控及攝護腺疾病之相關性研究
論文名稱(英文) Associations among phthalate exposure, steroid hormone and prostatic disease in adult man
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 103
學期 2
出版年 104
研究生(中文) 盧瀅安
研究生(英文) Yin-An Lu
學號 S76021038
學位類別 碩士
語文別 中文
論文頁數 128頁
口試委員 召集委員-張志欽
口試委員-陳秀玲
口試委員-蔡育賢
指導教授-李俊璋
中文關鍵字 鄰苯二甲酸酯類  生殖荷爾蒙  攝護腺疾病  攝護腺特異性抗原  攝護腺體積 
英文關鍵字 Phthalates esters  Steroid hormone  Prostatic disease  PSA  Prostate volume 
學科別分類
中文摘要 隨著醫療及社會進步,因國民壽命延長與出生率降低,使得我國中老年人口(中年為45-65歲及老年為65歲以上)及其比率呈顯著增加。近年來,各國研究皆發現良性攝護腺肥大及攝護腺癌的發生率及盛行率有逐年增加的趨勢。影響攝護腺疾患之危險因子除年齡、基因、種族及生活習慣外,荷爾蒙失衡及環境毒物或內分泌干擾物的暴露已被認為是重要之影響因子,但其對攝護腺之致病機制為何?仍尚需進一步研究。鄰苯二甲酸酯(Phthalate esters, PAEs)為已知的內分泌干擾物質,經常添加於塑膠產品中,作為增塑劑;在化妝品及衛生用品上,則作為溶劑及定香劑使用。動物及體外研究指出PAEs及其代謝物,可透過抗雄性激素作用干擾雄性內分泌系統,導致睪固酮降低及雌激素上升;亦會促使攝護腺細胞增生,導致攝護腺重量異常。然而,PAEs是否透過對生殖荷爾蒙調控之影響進而導致攝護腺疾病風險增加,其影響機制尚無人體研究結果可循。因此,本研究擬探討男性成人PAEs暴露與生殖荷爾蒙調控及攝護腺疾病之相關性。
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,經醫師診斷罹患良性攝護腺肥大或攝護腺癌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PAEs暴露來源,並同時採集尿液及血液樣本,進行血液中12種生殖荷爾蒙檢測,及以高效能液相層析串聯式質譜儀(HPLC-MS/MS)分析尿液樣本中11種PAEs代謝物濃度。此外,亦收集受試者臨床診斷及檢查結果,包括攝護腺特異性抗原(PSA)、尿流速檢測(Voided volume、Maximum flow、Mean flow)、直腸超音波檢查(TRUS)、直腸觸診(DRE)、國際攝護腺症狀評分(IPSS)等。最後整合上述相關資料評估PAEs代謝物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85位,研究結果以受試者之攝護腺體積第33.3 % (27.13 mL) 及66.7 % (41.00 mL) 為臨界點進行三分位分組。結果顯示,不同攝護腺體積之分組間,攝護腺體積最大組之PSA 中位數濃度 (1.03 vs. 2.89 vs. 7.36 ng/mL)、膀胱攝護腺突出 (Intravesical protruding) 所佔比率 (0.00 % vs. 18.8 % vs. 64.0 %) 均顯著高於其他兩組 (P < 0.001)。至於血液中生殖荷爾蒙濃度,僅E2/ TT在三組間具統計上之顯著差異 (P = 0.039),E2具邊緣性顯著差異 (P = 0.057)。尿液中PAEs代謝物濃度分析結果則顯示,經Creatinine校正後,MMP、MnBP、MEHP、MBzP、ΣDBP之濃度在三組間達統計上顯著差異 (P<0.05)。而MMP (3.93 vs. 4.64 vs. 5.22)、MiBP (4.12 vs. 3.44 vs. 4.43)、MnBP (9.00 vs. 7.17 vs. 10.7)、MEHHP (6.00 vs. 7.50 vs. 11.1)、MEOHP (4.19 vs. 6.12 vs. 6.29)、MECPP (8.55 vs. 10.1 vs. 13.9)、MEHP (2.27 vs. 2.84 vs. 4.54) 於攝護腺體積最大組者均高於其他兩組。受試者血液中生殖荷爾蒙、臨床檢測結果與PAEs代謝物濃度之相關性,經校正年齡、BMI及抽血時間後以複迴歸分析表示,尿液中MnBP和MBzP與LH呈統計上顯著負相關 (P < 0.05);MEP與E2達統計上之顯著負相關 (P < 0.05);MINP、MIDP與DHEA-S具統計上顯著負相關 (P < 0.01、P < 0.05);MiBP、ΣDBP與PSA呈統計上之顯著正相關 (P < 0.05);MMP、MEHP與Prostate volume具統計上之顯著正相關 (P < 0.05);MMP、MnBP與Voided volume具統計上之顯著負相關 (P < 0.05)。綜合上述統計分析結果可知,PAEs暴露濃度的增加可能連帶影響類固醇荷爾蒙合成機制,亦可能使 LH、E2濃度下降,進而使體內其他荷爾蒙濃度之平衡亦受到影響。而PAEs暴露濃度的增加亦和攝護腺體積的增加具顯著正相關性,推測PAEs可能使細胞中雌激素受體α (ER-α) 的活性增加,導致攝護腺產生異常增殖等現象。進一步評估本研究族群其PAEs暴露與雌激素受體及雄激素受體之結合及拮抗效應指標,結果顯示攝護腺體積最大組其雌激素受體與PAEs之結合效應值,及雄激素受體與PAEs之拮抗效應值皆有偏高情形,顯示PAEs除可能透過與雌激素受體α之結合效應,及與雄激素受體之拮抗效應來影響男性生殖荷爾蒙之平衡外,亦可能藉由增加ER-α之結合效應,使攝護腺肥大的風險上升,但因本研究樣本數較低,其影響機制仍待進一步收集更多樣本以釐清之。
英文摘要 The objectives of present study are to asses the relationships between steroid hormones and prostatic disease, then to explore the association and active mechanism among phthalate exposure, steroid hormone and prostatic disease in adult man. 85 men with prostate disease were recruited through urology clinics, and all were categorized based on the urologist’ diagnoses. Clinical examination, steroid hormones and urinary concentrations phthalate metabolites were measured in 85 men. The subjects were divided to 3 groups (group 1: prostate volume ≤ 33.3% (27.13 mL), group 2: prostate volume 33.3% - 66.7% and group 3: prostate volume ≥ 66.7% (41.00 mL)).The group 3 subjects had a significant higher PSA levels and intravesical protruding ratio (P < 0.001). E2/TT ratio showed significant difference among three groups (P = 0.039). MECPP had the highest urinary concentrations of all PAEs. Urinary MMP, MnBP, MEHP, MBzP, ΣDBP showed significant difference among three groups (P < 0.05). After adjusting age, BMI and time of blood drawing, urinary MnBP, MBzP were significantly negatively associated with LH. MEP was significantly negatively associated with E2. MINP, MIDP were significantly negatively associated with DHEA-S. MiBP, ΣDBP were significantly positively associated with PSA. MMP, MEHP were significantly positively associated with prostate volume. MMP, MnBP were significantly negatively associated with voided volume. The subjects with larger prostate volume had higher estrogen receptor binding effect and androgen receptor antagonistic effect than the other two groups. In conclusion, phthalates exposure were significantly associated with increased prostate volume. Due to the size of subjects is small, further study is needed to collect more subject to explore the active mechanism between phthalates exposure and prostatic disease.
論文目次 摘要I
Extended AbstractIII
致謝VI
表目錄XII
圖目錄XIV
第一章 緒論1
1-1.研究背景1
1-2.研究目的及意義3
第二章 文獻回顧4
2-1.攝護腺相關疾病4
2-1-1.攝護腺相關疾病介紹及其盛行率調查4
2-1-2.良性攝護腺肥大及攝護腺癌診斷及檢查流程5
2-1-3.攝護腺疾病之危險因子7
2-2.男性固醇類生殖荷爾蒙分泌回饋機制13
2-3.生殖荷爾蒙調控與攝護腺發育15
2-3-1.生殖荷爾蒙對攝護腺發育之影響15
2-3-2.生殖荷爾蒙與攝護腺疾病之相關性17
2-4.鄰苯二甲酸酯之物化特性及暴露途徑22
2-5.鄰苯二甲酸酯代謝機制及ㄧ般民眾尿中代謝物濃度調查23
2-6.鄰苯二甲酸酯暴露對生殖荷爾蒙分泌回饋機制影響26
2-6-1.動物實驗與體外毒性測試26
2-6-2.人類流行病學研究27
2-7.鄰苯二甲酸酯暴露對攝護腺之相關影響30
第三章 材料與方法32
3-1.研究架構32
3-2.研究對象選取與流程32
3-3.環境中內分泌干擾物質暴露來源及生活品質調查評估之標準化問卷 33
3-4.血液樣本採樣及分析35
3-4-1.血液樣本採集35
3-4-2.生殖荷爾蒙分析35
3-4-3.攝護腺特異性抗原指標檢查36
3-5.尿液樣本採樣與尿液中 PAEs 代謝物分析36
3-5-1.尿液樣本採集36
3-5-2.尿液中PAEs 代謝物分析方法36
3-5-3.尿液分析方法之品保品管38
3-6.男性成人PAEs每日暴露劑量推估41
3-7.PAEs與雌激素受體及雄激素受體之效應評估42
3-8.資料處理與統計分析42
第四章 結果與討論43
4-1.受試者攝護腺臨床診斷指標分析結果43
4-1-1.攝護腺臨床診斷指標分布情形43
4-1-2.攝護腺臨床診斷指標差異及相關性44
4-2.受試者基本資料之問卷結果分析45
4-2-1.受試者基本資料分布情形45
4-2-2.受試者之生活習慣統計46
4-3.受試者血液中生殖荷爾蒙濃度分析結果47
4-3-1. 血液中生殖荷爾蒙濃度分布情形 47
4-3-2.血液中生殖荷爾蒙濃度之差異47
4-3-3.血液中生殖荷爾蒙濃度之相關性分析48
4-4.受試者血液中生殖荷爾蒙濃度與臨床檢測結果之相關性分析49
4-5.受試者尿液中PAEs代謝物濃度分析結果50
4-5-1.尿液中PAEs代謝物分析之品保及品管結果50
4-5-2.尿液中PAEs代謝物及經肌酸酐校正過之PAEs代謝物濃度分布51
4-5-3.尿液中PAEs代謝物濃度差異52
4-6.受試者血液中生殖荷爾蒙、臨床檢測結果與尿液中經肌酸酐校正PAEs代謝物濃度之相關性分析53
4-7.受試者PAEs日暴露劑量推估及PAEs暴露與雌激素受體及雄激素受體之效應指標分析56
4-8.受試者環境中鄰苯二甲酸酯類暴露來源及生活品質調查評估之問卷結果分析58
4-8-1.受試者之身心健康狀態分析58
4-8-2.受試者之家戶環境調查及建材調查結果58
4-8-3.受試者之居家衛生用品使用情形分析結果59
4-8-4.受試者日常飲食使用塑膠用品習慣調查結果59
4-8-5.受試者外食塑膠用品使用習慣調查分析結果 60
4-8-6.受試者之飲食攝取習慣調查分析結果61
4-8-7.受試者之五大類食品攝取量調查結果62
第五章 結論與建議64
5-1.結論64
5-2.建議67
第六章 參考文獻68
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