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標題: 探討環境中多環芳香烴碳氫化合物及戴奧辛之暴露對雌性激素醌類代謝物蛋白質胼合物之影響
Investigation of the effects of environmental exposure to PAHs and dioxin on the production of estrogen quinone derived- protein adducts
作者: 蔡晨熙
Tsai, Chen-Hsi
關鍵字: protein adducts;生物指標;biomarker;quinones;醌類化物
出版社: 環境工程學系所
引用: 一、中文部分 方茹萍 (2004) 「雌性激素 (17β-estradiol) 於人類乳癌細胞株誘發基因表現失衡及核酸氧化損壞作用之研究」 國立中興大學環境工程研究所碩士論文 盧秀卿 (2005)「發展一生物化學法分析雌性激素醌類化物之蛋白質胼合物」 國立中興大學環境工程研究所碩士論文 王姿文 (2006)「發展一修正MT分析法來探討萘醌類衍生物之蛋白質胼合物」 國立中興大學環境工程研究所碩士論文 楊喜男、王漢泉、劉鎮山、王世冠、彭瑞華、郭季華、楊禮源、李俊宏、徐美榕 (2002) 台灣河川水體、底泥及生物監測分析研究 行政院環保署環境檢驗所研究報告 陳元武、李慈毅、翁英明 (2002) 台灣地區一般環境空氣中戴奧辛監測(Ⅰ)行政院環保署環境檢驗所研究報告 鍾仁棋和潘復華 (2002) 台中地區農業土壤中戴奧辛背景值之探討 行政院環保署環境檢驗所研究報告 二、中文部分 Anonymous 2006. TOXICOLOGY AND CARCINOGENESIS STUDIES OF 2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN(TCDD) IN FEMALE HARLAN SPRAGUE-DAWLEY RATS. NATIONAL TOXICOLOGY PROGRAM , NIH Publication No. 06-4468. Anonymous 2000. Toxicology and Carcinogenesis Studies of Naphthalene (Cas no. 91-20-3) in F344/N Rats (Inhalation Studies). Natl. Toxicol. Program. Tech. Rep. Ser. , (500), 1-173. Abbott, B.D., Buckalew, A.R., DeVito, M.J. et al. 2003. EGF and TGF-Alpha Expression Influence the Developmental Toxicity of TCDD: Dose Response and AhR Phenotype in EGF, TGF-Alpha, and EGF + TGF-Alpha Knockout Mice. Toxicol. 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本研究之主旨係運用蛋白質胼合物(protein adduct)作為生物指標(biomarker),以雌性激素及萘之醌類化物與蛋白質形成之共價鍵結產物-蛋白質胼合物,作為推估雌性激素及萘之醌類化物於標的器官之組織劑量。並探討於多環芳香族碳氫化合物(Polycyclic aromatic hydrocarbons, PAHs)及影響雌性激素代謝活化之干擾物質,例如戴奧辛(2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD)之環境暴露下,對萘及雌性激素醌類化物與蛋白質反應形成蛋白質胼合物之影響。本研究係以TFAA (trifluoroacetic acid anhydride) 作為衍生劑,並於強酸環境下移除雌性激素及萘之醌類化物與蛋白質上cysteine之硫原子鍵結產生之胼合物,並經由溶劑萃取濃縮,再利用氣相層析負離子化學離子化質譜儀 (GC/NICI/MS),進行定量分析。此外運用高效能液相層析儀純化雌性激素及萘之醌類化物與N-acetyl-L-cysteine反應形成之胼合物,以製備定量所需之標準品;同時利用同位素內標準品,對待測物進行定性及定量分析。首先在萘醌類蛋白質胼合物之分析結果顯示,自美國Sigma-Aldrich公司購買之小牛血清白蛋白(Bovine serum albumin, BSA)、人類血清白蛋白 (human serum albumin, HSA)及台灣台南捐血中心提供之人類血清白蛋白分析結果中,HSA及台南捐血中心檢體中均測得萘醌類化物蛋白質胼合物之背景值,1,2-NPQ-Alb及1,4-NPQ-Alb分別為127~1352及21.5~172 pmol/g,而在BSA中則均未測得;萘醌類(1,2-NPQ及1,4-NPQ)於人體血清中二階反應速率常數(kr, Lg-1h-1)經推估分別為0.0044及0.0002 Lg-1h-1;組織劑量則為75.7~98.4及217~316 nM-h。在雌性激素醌類蛋白質胼合物之分析結果顯示,於BSA、HSA及台南捐血中心之三種血清白蛋白中均測得雌性激素醌類之蛋白質胼合物4-OHE2-2-Alb 及2-OHE2-4-Alb分別為74.7~121及384~858 pmol/g,且均無測得2-OHE2-1-Alb之生成。而在台南捐血中心提供之檢體,女性血清白蛋白中雌性激素醌類蛋白質胼合物4-OHE2-2-Alb及2-OHE2-4-Alb略高於男性。在統計分析方面,台南捐血中心提供之檢體中,萘醌類蛋白質胼合物1,2-NPQ-Alb及1,4-NPQ-Alb濃度與年齡無相關性,而雌性激素醌類蛋白質胼合物4-OHE2-2-Alb及2-OHE2-4-Alb濃度亦與年齡無相關。本研究預期此一蛋白質胼合物分析法,將能作為一高效率之生物指標,提供流行病學中評估PAHs及雌性激素代謝活化之干擾物質長期暴露族群之研究。

The objective of this research is to develop a biochemical assay using protein adducts as biomarker of environmental exposure to polycyclic aromatic hydrocarbons (PAHs) and modulators of estrogen homeostasis, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). This methodology ultilizes trifluoroacetic acid (TFAA) and methanesulfonic acid (MSA) as catalysts to cleave cysteinyl adducts of naphthalene- and estrogen-derived quinones on proteins. The cleaved adducts are recovered by organic solvent extractions and analyzed by gas chromatography- negative-ion-chemical-ionization-mass spectrometer (GC-NICI-MS). The isomeric forms of cysteinyl adducts of naphthoquinones, including 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) as well as estrogen quinones, including estrogen-2,3-quinones (2-OHE2) and estrogen-3,4-quinones (4-OHE2), are characterized by using isotopically-labelled bound internal standards after adducts cleavage by the TFAA/MSA derivatization procedure. Additionally, synthetic cysteinyl adducts of estrogen and naphthalene quinones were further purified by HPLC-UV and were used as standards to quantify the modified proteins. We applied this method to analyze the background levels of cysteinyl adducts of estrogen- and naphthalene-derived quinones on bovine serum albumin(BSA), human serum albumin(HSA) (purchased from Sigma-Aldrich), and human serum albumin derived from unexposed blood donors in Tainan, Taiwan. Results showed that the background levels of cysteinyl adducts of 1,2-NPQ and 1,4-NPQ on HSA and human serum albumin derived from blood donors in Tainan, Taiwan at levels ranging from 127~1352 and 21.5~172 pmol/g, respectively. Further investigation indicates that the second-order reaction rate constants of 1,2-NPQ and 1,4-NPQ with human serum were estimated to be 0.0044 and 0.0002 Lg-1h-1, respectively whereas tissue dose of naphthoquinones in human serum derived from blood donors in Tainan, Taiwan were estimated to be between 75.7~98.4 and 217~316 nM-h for 1,2-NPQ and 1,4-NPQ, respectively. In addition, cysteinyl adducts of 4-OHE2-2-Alb and 2-OHE2-4-Alb were detected in all three types of albumin at levels ranging from 74.7~121 and 384~858 pmol/g, respectively. On the average, the background levels of cysteinyl adducts of 2-OHE2-4-Alb and 4-OHE2-2-Alb in human serum albumin of male blood donor are lower than those of females. Further, we noticed that among the samples derived from blood donors in Taiwan levels of 1,2-/1,4-NPQ-Alb and 2-OHE2-4-Alb were not associated with age. Overall, we conclude that the methodology developed in this study may be applied to epidemiological study to serve as biomarkers of environmental exposure to PAHs and modulators of estrogen homeostasis.
其他識別: U0005-1308200715124600
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