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研究生: 鄭瓊婷
Cheng, Chiung-Ting
論文名稱: 新生兒出生前暴露到鄰苯二甲酸酯類與其固醇類荷爾蒙之間的關係
Association between prenatal phthalate exposure and steroid hormones in newborns
指導教授: 廖寶琦
Liao, Pao-Chi
學位類別: 碩士
Master
系所名稱: 醫學院 - 環境醫學研究所
Department of Environmental and Occupational Health
論文出版年: 2008
畢業學年度: 96
語文別: 中文
論文頁數: 72
中文關鍵詞: 生殖環境荷爾蒙荷爾蒙出生前暴露鄰苯二甲酸酯
外文關鍵詞: reproduction, endocrine disruptor, phthalate, prenatal exposure, hormones
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  • 鄰苯二甲酸酯類在動物實驗中已被認為具有生長以及生殖方面的毒性。目前出生前暴露到鄰苯二甲酸酯類對於新生兒所造成的生殖方面影響之相關資料仍是缺乏的。因此本研究的目的主要是去評估胎兒出生前受到鄰苯二甲酸酯類的暴露及新生兒固醇類荷爾蒙濃度兩者之間的關聯性。本研究的研究對象挑選條件如下 : a. 從台中區域醫院挑選的孕婦 b. 18~39歲的孕婦 c. 在2000,12,1~2001,11,30此段時間生產的孕婦 d. 孕婦沒有臨床併發症。共有182位孕婦在懷孕第三期時分別提供尿液以及血清樣本,並且於生產時提供臍帶血樣本。在本實驗室中建立一套自動化樣本淨化系統配合高液相層析質譜儀去分析尿液七種鄰苯二甲酸酯類代謝物的濃度,此分析方法之檢量線、方法偵測極限、回收率、精密度以及準確度皆有被加以描述。另外,利用放射免疫法去分析母親血清以及新生兒臍帶血中LH、FSH、fT、E2這幾個固醇類荷爾蒙的濃度。女嬰臍帶血中睪固酮的濃度和母親尿液中鄰苯甲酸(2-乙基己基)酯 (MEHP)的濃度呈現顯著負相關 (R= -0.293, P<0.05);女嬰臍帶血中睪固酮的濃度和母親尿液中鄰苯氫氧己基乙酯 (5OH-MEHP)的濃度呈現顯著負相關 (R= -0.260, P<0.05)。由我們的結果可知,於一般的暴露環境中,出生前暴露到鄰苯二甲酸二(2-乙基己基)酯 (DEHP) 可能會影響女嬰血清中睪固酮的濃度。

    Phthalate diesters are considered as developmental and reproductive toxicants in animal studies. Limited human data are available on the relationship between prenatal phthalate exposure and adverse health effects in newborns. The aim of this study is to evaluate the association between prenatal phthalate exposure and steroid hormones in newborns. The study subjects were pregnant women without clinical complication between the ages of 18 and 39, who delivered their babies during 2000.12.01 and 2001.11.30 in central Taiwan. Serum and spot urine samples were collected from 182 pregnant women at third trimester. Cord blood samples were collected from the same population. We estabolished an on-line solid-phase extraction(SPE)method, coupled with isotope dilution high-performance liquid chromatography/tandem mass spectrometry(HPLC-MS/MS)to simultaneously quantify 7 phthalate metabolites 【mono-methyl phthalate(MMP), mono-ethyl phthalate (MEP), Mono-butyl phthalate (MBP), Mono-benzyl phthalate (MBzP), Mono-(2-ethylhexyl) phthalate (MEHP), Mono-(2-ethyl-5-oxo-hexyl) phthalate (5oxo-MEHP), Mono–(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP)】. The calibration curve, detection limit, precision, and recovery of the analytical method were characterized. Luteinizing hormone(LH), follicle-stimulating hormone(FSH), free testosterone(TT)and estradiol (E2) were measured by radioimmunoassay in maternal serum and cord blood samples. After adjusting for maternal age, BMI, smoking and drinking status, urinary 5OH-MEHP, MEHP levels showed significantly negative association with cord blood TT levels [(MEHP: TT= -0.293, P<0.05), (5OH-MEHP: TT= -0.260, P<0.05)] in female newborns. According to the results, prenatal exposure to di-2-ethylhexyl phthalate (DEHP) at environmental levels could adversely affect free testosterone (TT) levels in female newborns.

    致謝 II 摘要 III ABSTRACT IV 中英文名稱對照表 XI 英文全名與縮寫對照表 XIII 第一章 序論 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 環境荷爾蒙 4 2-2 鄰苯二甲酸酯之簡介 4 2-2-1 物理化學特性 4 2-2-2 用途 5 2-2-3 年產量 6 2-2-4 環境流佈 6 2-2-5 人體暴露的方式 9 2-2-6 代謝 10 2-2-7 毒性 12 2-2-8 鄰苯二甲酸酯類影響內分泌的可能機制 14 2-2-9 相關法規 15 2-3 鄰苯二甲酸酯類之各種生物指標 16 2-4 過去分析尿液中PHTHALATE METABOLITES之方法 17 第三章 研究方法與材料 19 3-1 研究架構 19 3-2 研究材料 19 3-2-1 研究對象 19 3-2-2 問卷調查 21 3-2-3 孕婦尿液、血情及臍帶血樣本收集時間 22 3-2-4 分析儀器與設備 23 3-2-5 實驗材料 24 3-3 實驗設計 25 3-4 樣本前處理 27 3-5 質譜儀參數找尋 27 3-5-1 找尋分析物之前趨離子及產物離子 30 3-5-2 離子源參數之調整 30 3-6 自動化淨化系統架構及參數找尋 33 3-6-1 自動化淨化系統架構 33 3-6-2 MMP之水沖提時間參數找尋 33 3-6-3 水中Formic acid (FA) 比例最佳化 34 3-7 方法驗證程序 36 3-7-1 檢量線之製備標準 36 3-7-2 方法偵測極限 36 3-7-3 回收率 37 3-7-4 精密度 37 3-7-5 準確度 38 3-8 臍帶血分析 39 3-9 統計分析 39 第四章 結果與討論 40 4-1 七個PHTHALATE METABOLITES及其個自同位素內標準品之前驅離子及產物離子 40 4-2自動化淨化系統參數找尋結果 42 4-2-1 MMP之水沖提時間參數之最佳化 42 4-2-2 水中FA比例之最佳化 42 4-3 INTERLAB COMPARISON DATA 44 4-4 空白分析結果 48 4-4-1 試劑空白分析 48 4-4-2 尿液基質空白分析 48 4-5 方法驗證程序之結果 48 4-5-1 檢量線 48 4-5-2 方法偵測極限 51 4-5-3 回收率 51 4-6 孕婦尿液中PHTHALATE METABOLITES的濃度 54 4-7 孕婦血清中固醇類荷爾蒙濃度 54 4-8 新生兒臍帶血中固醇類荷爾蒙濃度 54 4-9 單一孕婦尿液樣本評估鄰苯二甲酸酯類暴露 57 4-10 尿液中PHTHALATE METABOLITES之關聯性 58 4-11 尿液中PHTHALATE METABOLITES和固醇類荷爾蒙之關聯性 59 4-11-1 孕婦尿液中phthalate metabolites與其固醇類荷爾蒙之關聯性…………..59 4-11-2 母親尿液中phthalate metabolites和新生兒固醇類荷爾蒙之關聯性 62 4-11-3 母親尿液中phthalate metabolites和男嬰固醇類荷爾蒙之關聯性 63 4-11-4 母親尿液中phthalate metabolites和女嬰固醇類荷爾蒙之關聯性 64 4-11-5 母親血液中固醇類荷爾蒙和新生兒固醇類荷爾蒙兩者之關聯性 66 第五章 結論 67 第六章 參考文獻 69

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