近年來研究指出，成年男性體內睪固酮濃度與精液品質皆有逐年下降的趨勢，可能造成生育率的降低甚至不孕症（infertility）。在不孕症案例中因男性因素導致不孕者約佔30-50%，其危險因子包括生理（年齡、BMI）、心理（情緒壓力）、基因（種族）、生活習慣（抽菸、飲酒、個人衛生用品使用）或環境毒物暴露等因素。環境因子中鄰苯二甲酸酯（Phthalate esters, PAEs）已被證實為內分泌干擾物質，具低揮發性、低蒸氣壓及高脂溶性等特性，常用於日常生活塑膠製品及個人衛生用品。動物研究指出PAEs會透過抗雄性激素及雌激素之毒性效應導致動物之生長發育等生殖危害，包括睪丸缺陷症候群、生殖荷爾蒙失調、精液品質降低、睪丸癌等。人類流行病學研究結果，顯示暴露PAEs可能會導致生殖荷爾蒙改變及精液品質降低，其中芳香轉化酶（Aromatase）為生殖荷爾蒙調控中參與雄激素轉換成雌激素反應之重要酵素，能影響雌激素代謝與精子生成。然而，目前研究關於PAEs暴露對體內aromatase活性之影響尚無定論，而人類流行病學研究對於aromatase活性目前多利用睪固酮與雌二醇之比值（T/E2）表示，並未有實際量測aromatase濃度之結果。綜上可知，目前對於PAEs暴露是否影響人體aromatase之研究付之闕如，且其機制亦不明確。因此，本研究擬探討男性成人PAEs暴露對體內aromatase之影響機制。本研究自國立成功大學附設醫院及安安婦幼中心不孕症門診共招募298位研究對象，包含259位不孕男性及39位具生育力男性，經簽屬同意書後，進行標準化之問卷調查、血液及尿液樣本採集，並分析血液中生殖荷爾蒙與aromatase濃度、尿液PAEs代謝物濃度，整合相關研究數據後探討生殖荷爾蒙濃度、尿液PAEs代謝物濃度以及aromatase濃度之相關性，以評估男性成人PAEs暴露對aromatase之影響。研究對象共區分為具生育力男性、不孕且精液品質正常男性及不孕且精液品質異常男性三組，結果顯示不孕且精液品質異常之男性成人尿液中MMP （3.00 vs. 3.48 vs. 3.59）、MEP （10.6 vs. 13.6 vs.15.3）、MiBP（6.00 vs. 5.93 vs. 6.98）、 MEHHP （9.54 vs. 10.2 vs. 10.5）、MECPP（12.3 vs. 12.9 vs. 14.1）、MEOHP（6.64 vs. 7.06 vs. 7.69）、MINP（0.12 vs. 0.22 vs. 0.26）及MIDP（0.13 vs. 0.20 vs.0.23）幾何平均濃度（µg/g-cre）皆高於不孕且精液品質正常男性及具生育力男性成人。其中，尿液中MINP濃度達統計上顯著差異（P=0.013）。血液中生殖荷爾蒙分析結果顯示，不孕且精液品質異常男性體內E2濃度顯著高於不孕且精液品質正常男性及具生育力男性，且三組呈顯著趨勢相關（Ptrend=0.001）。血液中aromatase濃度分析結果，不孕且精液品質異常男性體內aromatase濃度顯著高於不孕且精液品質正常男性及具生育力男性（P=0.001），且三組呈顯著趨勢相關（Ptrend=0.004）。經校正年齡、BMI及抽血季節後，以迴歸分析結果顯示尿液中MMP、MEP及MEOHP濃度與E2濃度呈顯著正相關；尿液中MMP和MEP濃度與TT/E2呈顯著負相關；尿液中MiBP、MnBP、MEHHP、MECPP、MEOHP濃度與aromatase濃度呈顯著正相關，尿液中MEP及MEHP濃度與aromatase濃度呈邊緣顯著正相關（P〈0.1）。由以上證據得知，男性成人暴露PAEs後，可能會增加體內aromatase濃度，進而促使TT轉化為E2，並可能與雌激素受體結合，干擾雌激素受體調控CYP19a1 gene，直接或間接導致男性成人體內E2濃度異常增加。此外，進一步估算PAEs對雌激素受體及雄激素受體之結合效應及拮抗效應指標，發現不孕男性於雄激素受體拮抗效應指標及雌激素受體結合能力效應指標均有較高情形，顯示PAEs可能透過與雌激素受體結合及拮抗雄激素受體之效應影響內分泌系統之正常運作。最後以尿液中PAEs濃度及參考劑量進行男性成人健康風險評估，在PAEs暴露對於生殖及發育、肝臟危害結果危害指標HI值均小於1，顯示目前針對PAEs之生殖危害所訂定之參考劑量仍有檢討之必要，可能需再降低之。

The objectives of present study are to assess the associations among urinary phthalate metabolites levels, reproductive hormones and serum aromatase concentrations in adult men, and to explore the active mechanisms of phthalate exposure on aromatase expression in adult men. Two hundred and ninety eight subjects were recruited from the infertile clinic of National Cheng Kung University Hospital (NCKUH) and AN-AN Women and Children Clinic, including two hundred and fifty nine infertile men and thirty nine fertile men. After signed informed consent, the present study conducted through the questionnaire interview, determination of reproductive hormones, aromatase, and urinary phthalate metabolites. Urinary phthalate metabolites were analyzed with HPLC-MS/MS. Serum aromatase concentrations were determined by enzyme-linked immunosorbent assay. Urinary MMP (3.00 vs. 3.48 vs. 3.59 µg/g-cre), MEP (10.6 vs. 13.6 vs.15.3), MiBP (6.00 vs. 5.93 vs. 6.98), MEHHP (9.54 vs. 10.2 vs. 10.5), MECPP (12.3 vs. 12.9 vs. 14.1), MEOHP (6.64 vs. 7.06 vs. 7.69), MINP（0.12 vs. 0.22 vs. 0.26）and MIDP (0.13 vs. 0.20 vs.0.23) in infertile men with abnormal semen quality were higher than infertile men with normal semen quality and fertile men. Urinary MINP showed significant difference among three groups（P=0.013）. Estradiol and serum aromatase concentrations in infertile men with abnormal semen quality were significant higher than infertile men with normal semen quality and fertile men（P=0.006, 0.001）respectively. The significant increasing trends were found in estradiol levels and serum aromatase concentrations among the three groups（Ptrend=0.001, 0.004）respectively. After adjusting for age, BMI and season of blood drawing, urinary MMP, MEP and MEOHP were significantly positively associated with estradiol. Urinary MMP and MEP were significantly negatively associated with the TT:E2 ratio. Urinary MiBP, MnBP, MEHHP, MECPP, MEOHP were significantly positively associated with serum aromatase concentrations. The infertile men with abnormal semen quality had higher estrogen receptor binding effect and androgen receptor antagonistic effect than infertile men with normal semen quality and fertile men. Risk assessment of phthalate exposure on reproduction and liver effects showed that all hazard index were below 1, suggesting that it is necessary to reassess the value of reference dose. In conclusion, phthalate exposure may increase serum aromatase concentrations, upregulation of CYP19a1 gene for the estrogen receptors, resulting in abnormally increase of estradiol levels by an estrogenic mode of action.

摘要 I
Extended Abstract III
致謝 VI
目錄 VIII
表目錄 XI
圖目錄 XIII
第一章 緒論 1
1-1 研究背景 1
1-2 研究目的 4
1-3 研究重要性 4
第二章 文獻回顧 5
2-1 雄性生殖與不孕症 5
2-1-1 雄性生殖系統 5
2-1-2 荷爾蒙調控與精子生成 5
2-1-3男性不孕症之定義及診斷 7
2-1-4男性不孕症之危險因子 8
2-1-5芳香轉化酶(Aromatase)與雄性生殖 8
2-1-5-1 Aromatase與CYP19基因 8
2-1-5-2 Aromatase與生殖荷爾蒙調控機制 9
2-1-5-3 Aromatase與精子生成及凋亡(apoptosis) 10
2-1-5-4人類流行病學研究 12
2-2 PAEs之暴露及代謝 12
2-2-1 PAEs之物化特性 12
2-2-2 PAEs之暴露途徑 13
2-2-3人體之PAEs代謝機制 14
2-3不孕與一般男性族群尿液中PAEs代謝物濃度調查研究 15
2-4 PAEs暴露對生殖荷爾蒙分泌回饋機制之影響 18
2-4-1細胞及動物實驗 18
2-4-2流行病學調查研究 19
2-5 PAEs暴露對芳香轉化酶(Aromatase)之影響 22
2-5-1細胞及動物實驗 22
2-5-2流行病學調查研究 24
第三章 材料與方法 26
3-1 研究架構 26
3-2 研究對象選取流程 26
3-3 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 27
3-4 樣本採集方法 29
3-4-1血液樣本採集 29
3-4-2尿液樣本採集 29
3-5 樣本分析方法 29
3-5-1血液中生殖荷爾蒙濃度分析 29
3-5-2血液中芳香轉化酶(Aromatase)濃度分析 30
3-5-3尿液中PAEs代謝物濃度分析 31
3-6男性成人PAEs日暴露劑量推估 35
3-7 PAEs與雌激素受體及雄激素受體之效應評估 36
3-8健康風險評估 37
3-9 統計分析方法 37
第四章 結果與討論 39
4-1 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結果解析 39
4-1-1男性成人之基本資料分布情形 39
4-1-2男性成人之生活習慣情形 40
4-1-3男性成人之家戶環境及建材調查結果 41
4-1-4男性成人之身心健康狀態分析結果 41
4-1-5男性成人之生殖健康狀態分析結果 42
4-1-6男性成人之個人衛生用品使用情形分析結果 42
4-1-7男性成人日常飲食使用塑膠用品習慣調查結果 43
4-1-8男性成人之飲食攝取習慣調查結果 44
4-1-9男性成人之外食塑膠用品使用習慣調查結果 45
4-1-10男性成人之五大類食品攝取量調查結果 46
4-2 男性成人血清中生殖荷爾蒙濃度分析結果 47
4-2-1血清中生殖荷爾蒙濃度分布情形 47
4-2-2血清中生殖荷爾蒙濃度之差異 47
4-3 男性成人尿液中PAEs代謝物濃度分析結果 48
4-3-1品保及品管執行結果 48
4-3-2尿液中PAEs代謝物濃度分析結果 49
4-3-3尿液中PAEs代謝物濃度差異 50
4-4 男性成人血液中Aromatase濃度分析結果 51
4-4-1品保及品管執行結果 51
4-4-2血液中Aromatase濃度分析結果 51
4-5 PAEs暴露源與尿液中PAEs代謝物濃度之相關性分析 52
4-6血液中生殖荷爾蒙與Aromatase濃度之相關性分析 55
4-7血液中生殖荷爾蒙、Aromatase濃度與尿液中PAEs代謝物濃度之相關性分析 56
4-8 PAEs暴露與雌激素受體結合能力效應指標及雄激素受體拮抗效應指標分析 59
4-9 PAEs暴露健康風險評估 60
第五章 結論與建議 63
5-1 結論 63
5-2 建議 65
第六章 參考文獻 66

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