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研究生:李思萱
研究生(外文):Sih-SyuanLi
論文名稱:具生育能力及不孕男性鄰苯二甲酸酯暴露、生殖荷爾蒙調控與類胰島素3基因表現之相關性探討
論文名稱(外文):Associations among phthalate exposure, reproductive hormones and INSL3 expression in fertile and infertile 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:2013
畢業學年度:101
語文別:中文
論文頁數:109
中文關鍵詞:鄰苯二甲酸酯生殖荷爾蒙類胰島素3男性不孕
外文關鍵詞:Phthalate estersReproductive hormonesInsulin-like 3Male infertility
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鄰苯二甲酸酯類 (Phthalate esters, PAEs)常添加於PVC產品,以提高產品之彈性及延展性;亦添加於化妝品及個人衛生用品中作為定香劑,使香味持久、穩定。人體可能於上述產品使用過程中,經由食入、吸入及皮膚吸收暴露PAEs。動物實驗及人類流行病學資料顯示,PAEs具有抗雄性素的活性及作用,可能造成睪丸不全症 (Testicular Dysgenesis Syndrome, TDS) (如:睪丸發育不全及睾丸畸形等)、隱睪症、生殖器發育異常 (尿道下裂等)、尿道至肛門口距離 (Anogential distances, AGD)縮減、肝臟損傷、荷爾蒙分泌異常、精液品質惡化及生育力降低等,甚至導致睪丸癌或畸胎;另外PAEs暴露亦會影響Leydig cells中類胰島素3 (Insulin-like 3, INSL 3)表現量及活性,而INSL 3與睪固酮共同調控生殖系統發育,且於精母細胞成熟上扮演重要的角色。
為了解PAEs暴露對男性成人體內生殖荷爾蒙及INSL 3之影響機制,本研究依據篩選條件,自成大醫院婦產科及某婦幼中心之不孕症門診招募研究對象,初步經WHO定義判斷為不孕納入為病例組,但此族群中仍有嚴重情況不同者,因此為避免錯誤分組而進一步由醫師對精液品質之臨床診斷再更精確的區分為不孕及低生育力兩組,另再招募自然受孕婦女之20-50歲男性配偶為具生育力之對照族群。研究對象簽署同意書後,以標準化問卷進行環境中PAEs暴露來源及生活品質調查,並同時使用玻璃器皿採集尿液及血液樣本以分析個人尿液中PAEs代謝物濃度、血液中生殖荷爾蒙及INSL3濃度。
參與本研究之男性成人共152位,其中不孕男性為84位,低生育力男性為53位,具生育力男性則有15位。尿液中PAEs代謝物經creatinine校正後之幾何平均濃度分別為MMP:3.86 μg/g-cre、MEP:20.31μg/g-cre、MiBP:8.53 μg/g-cre、MnBP:15.84 μg/g-cre、MBzP:0.88 μg/g-cre、MEHP:4.65 μg/g-cre、MEOHP:7.58 μg/g-cre、MEHHP:16.06 μg/g-cre、MECPP:16.97 μg/g-cre、MiNP:2.10 μg/g-cre、MiDP:0.10 μg/g-cre;其中以MEP最高,MiDP最低;且不孕男性族群體內PAEs代謝物濃度有高於低生育力及具生育力男性之趨勢,但未達統計上顯著差異(P〉0.05)。
關於PAEs暴露與生殖荷爾蒙之相關性分析顯示尿液中MMP與SHBG為正相關,迴歸係數β值為0.017且達統計上顯著相關 (95% CI:-0.002, 0.036;P〈0.05)。另在尿液中MEHP、MEOHP、MEHHP和MECPP及sum of DEHP代謝物總和皆與Inhibin B呈負相關,其中又以MEOHP、MECPP和sum of DEHP代謝物總和達統計上顯著負相關 (P 〈0.05);在校正年齡、BMI和抽血季節等因子後進行線性迴歸分析發現,MBzP與Free testosterone及FT/LH均呈現負相關,其迴歸係數β分別為-0.122及-0.167,且達統計上顯著意義 (P〈0.05);此外,MEHP%與INSL 3亦存在負相關性,迴歸係數β值為-0.016且達統計上顯著意義 (95% CI:-0.030, -0.001;P〈0.05)。
上述結果說明,PAEs暴露不論對Leydig cells或Sertoli cells均會造成影響,造成細胞數量減少或功能受損,並干擾男性成人體內各生殖荷爾蒙的運作使其正常調控機制紊亂,進而影響其生殖功能且降低生育能力。

Abstract
Phthalate esters (PAEs), a group of man-made chemicals widely used as plasticizers in the manufacture of flexible vinyl plastic, and also used as fixatives in personal care products. As the result of the ubiquitous use of phthalates in personal care and consumer products, human exposure is widespread. Exposure through ingestion, inhalation and dermal contact is considered important exposure routes for the general population. Mountain evidences indicated that phthalates exposure cause several detrimental reproductive defects through exhibiting anti-androgenic activity, including testicular dysgenesis syndrome (TDS), cryptorchidism, hypospadias, decreased of anogential distances (AGD), reproductive hormone alternation, deterioration of semen quality and decreased infertility among males. And also alternated Insulin-like 3 (INSL 3) expression in Leydig cells. However, it still debated with the adverse effects on human male reproduction.
The aim of this study is to investigate the associations of hormone circulation and INSL 3 expression with phthalate exposure in adult men. The subjects were recruited from clinics of Obstetrics and Gynecology Department of Cheng Kung University Hospital and women and children clinics, aged 20-50 years old. After signed informed consent, the recruited subjects were categorized into infertile, subfertile and fertile groups according to obstetrician diagnosis through semen quality and WHO selection criteria. Blood and urine samples were collected and stored with phthalate free containers and questionnaire interview were conducted for demographic characteristics and exposure profile of phthalates in all subjects. Levels of phthalate monoesters in urine samples and INSL 3 concentrations and reproductive hormones in serum samples of all subjects were measured. All of the data mentiond above were integrated to assess the correlations among reproductive hormones, INSL 3, and phthalate exposure.
There were 152 subjects recruited in this study, 84 subjects were infertile group, 53 subjects were subfertile group and 15 subjects were fertile men. Data show that average levels of urinary PAEs metabolites (creatinine adjusted) were MMP:3.86 μg/g-cre, MEP:20.31 μg/g-cre, MiBP:8.53 μg/g-cre, MnBP:15.84 μg/g-cre, MBzP:0.88 μg/g-cre, MEHP:4.65 μg/g-cre, MEOHP:7.58 μg/g-cre, MEHHP:16.06 μg/g-cre, MECPP:16.97 μg/g-cre, MiNP:2.10 μg/g-cre, and MiDP:0.10 μg/g-cre, respectively. According above, the highest concentration of MEP and the lowest concentration of MiDP were found.
The results show that there were significant positive relationship between MMP and SHBG, regression coefficient (β) is 0.017 (95% CI:-0.002, 0.036;P〈0.05). Negative association between urinary DEHP metabolites and sum of DEHP and Inhibin B were founds. In addition, we used linear regression to evaluate the relationship between phthalate exposure and reproductive hormone alternation after adjusting of confounding factors such as age, BMI, and season of blood collected. Significant negative correlations between MBzP and Free testosterone (β=-0.122, P〈0.05) and FT/LH ((β=-0.167, P〈0.05) were found, respectively. In addition, significant negative correlations between MEHP% and INSL 3 concentration was found (β=-0.016, P〈0.05).
In conclusions, the Leydig cells and Sertoli cells may dysfunction after PAEs exposure. Besides, the normal feedback mechanism of reproductive hormones in adult men maybe disrupted, and then debated with the adverse effects on human male reproduction.

摘要 I
Abstract III
誌謝 V
目錄 VI
表目錄 VIII
圖目錄 IX
第一章 前言 1
1-1 背景 1
1-2 目的 3
1-3 研究意義 4
第二章 文獻回顧 5
2-1 Phthalate ester (PAEs)的物化特性及應用 5
2-2 PAEs暴露途徑與代謝 6
2-3 PAEs暴露對雄性生殖系統之影響 7
2-3-1 雄性生殖系統簡介 7
2-3-2 PAEs暴露對生殖系統之影響 8
2-4 PAEs暴露對生殖荷爾蒙分泌機制之影響 9
2-4-1 生殖荷爾蒙分泌回饋機制介紹 9
2-4-2 PAEs暴露對生殖荷爾蒙分泌回饋機制之影響 10
2-5 PAEs暴露對睪丸中類胰島素3 (Insulin-like 3, INSL 3)之影響 12
2-5-1 INSL 3與INSL3/RXFP2 signaling system 12
2-5-2 Insulin-like 3與生殖荷爾蒙之相關性 13
2-5-3 PAEs暴露對Insulin-like 3之影響 13
第三章 材料與方法 15
3-1 研究架構 15
3-2 研究對象選取 15
3-3 樣本採集 16
3-4 血液中荷爾蒙與類胰島素3 (INSL 3)分析 17
3-5 尿液中PAEs代謝物分析 19
3-6 統計分析 23
第四章 結果與討論 25
4-1研究對象基本資料 25
4-1-1研究對象招募及基本資料分析 25
4-2 PAEs暴露來源調查評估之標準化問卷結果解析 26
4-2-1 個人衛生用品使用情形 26
4-2-2 家戶環境及家具建材調查結果 26
4-2-3 身心健康狀態 27
4-2-4 飲食狀況 27
4-3生殖荷爾蒙濃度分布情形 28
4-4 男性成人尿液中PAEs代謝物濃度分析結果 29
4-4-1 品保品管執行結果 29
4-4-2 尿液中PAEs代謝物濃度分析結果 30
4-4-3 具生育力、低生育力及不孕男性尿液中PAEs代謝物濃度之比較 31
4-5 男性成人體內INSL3分析結果 32
4-5-1 品保品管執行結果 32
4-5-2 血清中INSL3分析結果 32
4-6 體內生殖荷爾蒙與INSL 3濃度之相關性分析 33
4-7 PAEs代謝物濃度與生殖荷爾蒙濃度之相關性分析 34
4-8 PAEs暴露對Testicular function調控機制之影響 35
第五章 結論與建議 38
5-1 結論 38
5-2 建議 40
參考文獻 41
附件一 人體試驗委員會同意臨床試驗證明書 83
附件二 參與意願調查問卷-基本問卷 84
附件三 男性成人環境中PAEs暴露來源及生活品質調查評估之標準化問卷 86

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