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標題: 運用蛋白質胼合物為生物指標評估多環芳香族碳 氫化合物及戴奧辛之環境暴露對雌性激素之活性 醌類代謝物累積組織劑量之影響
Application of protein adducts as biomarkers to assess the effects of environmental exposure to polycyclic aromatic hydrocarbons (PAHs) and dioxin on the cumulative tissue does of quinonoid metabolites of endogenous estrogen
作者: 楊宗洲
Yang, Tsung-Chou
關鍵字: biomarker;蛋白質胼合物;protein adduct;estrogen;naphthalene;dioxin;polycyclic aromatic hydrocarbon;雌性激素;萘戴奧辛;多環芳香族碳氫化合物
出版社: 環境工程學系所
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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),進行定性分析。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。實驗結果分別敘述如下
(1)在濃度效應實驗結果顯示,其具有線性正關係,隨著每添加1nM之estrogen-2,3-quinones (E2-2,3-Q)會增加13.4及29.0pmole/g之2-hydroxyestradiol-1-albumin (2-OHE2-1-Alb) 及2-hydroxyestradiol -4-albumin (2-OHE2-4-Alb),而每添加1nM之estrogen-2,3-quinones (E2-2,3-Q)會增加109.5 pmole/g 之4-hydroxyestradiol-2-albumin (4-OHE2-2-Alb)之形成。而在時間效應實驗結果顯示E2-2,3-Q及E2-3,4-Q在十分鐘即達到最大鍵結量,而隨著時間加長並沒有顯著之差異
(2) 在人類乳癌細胞MCF-7以TCDD 預處理(10 nM, 72小時)後,添加雌性激素(10-1000 nM, 9小時),及共同添加COMT抑制劑(Ro41-0960)實驗中,添加COMT抑制劑會相較於單獨暴露雌性激素增加兩倍之雌性激素醌類蛋白質胼合物。
(3)A/J mice動物實驗測試分析結果,同時暴露TCDD+NNK會增加雌性激素醌類蛋白質胼合物之生成。
(4)乳癌病患之血清白蛋白分析結果中,測得萘醌類化物蛋白質胼合物之背景值,1,2-naphthoquinone (1,2-NPQ)及1,4-naphthoquinone (1,4-NPQ)分別為167-653及19.8-68.6 pmol/g。此外,在雌性激素醌類蛋白質胼合物之分析結果顯示,乳癌病患測得雌性激素醌類之蛋白質胼合物2-OHE2-1-Alb、2-OHE2-4-Alb及4-OHE2-2-Alb分別為ND(Not Detection)-183,115-1097及433-1436 pmol/g。此一結果顯示,乳癌病患相 較於正常人之控制組,其4-OHE2-Alb 之背景值約高出2-4倍。
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 (E2-2,3-Q) and estrogen-3,4-quinones (E2-3,4-Q), are characterized by using isotopically-labelled bound internal standards after adducts cleavage by the TFAA/MSA derivatization procedure. Results were summarized as follows:
(1) Results form in vitro experiments confirmed that the production of estrogen quinone-derived adducts on serum Alb increased with increased concentration of estrogen quinones (0-100 nM). Linear relationships were observed over the range of concentration. The average formation of estrogen quinone-derived cysteinyl adducts per unit concentration of estrogen quinones was estimated to be 13.4, 29.0 , and 109.5 (pmol/g Alb)/(nM) for 2-hydroxyestradiol-1-albumin, 2-hydroxyestradiol-4-albumin, and 4-hydroxyestradiol-2-albumin, respectively. Time-course experiments suggested that both E2-2,3-Q- and E2-3,4-Q-derived adducts rapidly reached maximum values at 5 min mark and remained constant thereafter.
(2) In human MCF-7 breast cancer cells, with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) pretreatment (10 nM for 72 h), production of estrogen quinone-derived protein adducts was detected in cells exposed to estrogen (10 - 1000 nM for 9 h). Co-treatment of Ro 41-0960, a catechol-o-methyl transferase (COMT) inhibitor, further the production of estrogen quinone-derived adducts in Co-treatment of Ro 41-0960 was 2-fold higher than exposed estrogen only.
(3) Results from the animal study showed that Co-treatment of TCDD and Nicotine-derived nitrosamine ketone (NNK) enhanced the production of estrogen quinone-derived adducts on hemoglobin derived from A/J mice.
(4) Results from the analysis of human serum albumin indicated that the background levels of cysteinyl adducts of 1,2-NPQ and 1,4-NPQ on human serum albumin derived from breast cancer patients in at levels ranging from 167-653 and 19.8-68.6 pmol/g, respectively. In addition, cysteinyl adducts of 2-OHE2-1-Alb, 2-OHE2-4-Alb and 4-OHE2-2-Alb were detected at levels ranging from ND-183, 115-1097 and 433-1436 pmol/g, respectively. Additionally, these finding indicated that levels of 4-OHE2-2-Alb in breast cancer patients were ~2-4 fold greater than healthy controls.
Overall, we concluded that the methodology developed in this study may be applied to epidemiological study to serve as biomarkers of environmental exposure to PAHs and other modulators of estrogen homeostasis.
其他識別: U0005-2607201016425300
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