臺灣博碩士論文加值系統

本研究利用連線固相萃取 (on-line SPE) 液相層析三段式四極柱串聯質譜儀 (LC-QqQ-MS) 建立基因鍵結體學 (DNA adductomics) 分析法。採用質譜技術的中性丟失模式 (constant neutral loss, CNL)， 以 2’-deoxyribose 作為分析特徵以大範圍量測 adducted 2’-deoxynucleosides。使用18種去氧核糖核苷混合標準品進行參數最佳化，包括電噴灑離子化的溫度 (heater temperature)、去簇電壓 (declustering potential, DP) 以及碰撞能量 (collision energy, CE) 提高了分析的敏感度。最終參數的設定為 : 電噴灑離子化溫度 400 °C 、DP 30伏特及CE 10-30伏特。
本研究將建立的方法運用至體外及體內暴露甲基化試劑的DNA 樣本，以全面量測 DNA 鍵結物。CNL模式下分析的數據經輸出並繪製成基因鍵結體地圖 (adductome map)，可完整呈現 DNA 損傷樣貌，並比對樣本間的訊號差異。此外，本研究在 (multiple reaction monitoring) 模式下搭配已知標準品平行定量暴露甲基化試劑的 DNA 樣本，驗證所開發的基因鍵結體學分析法。最後，為了推測目標訊號的分子結構，本研究嘗試以中性丟失方法 (CNL) 搭配資料依靠收集模式 (information dependent acquisition) 運用子離子掃描 (enhanced product ion) 取得目標訊號的斷片資訊。

We developed a DNA adductomics methodology using liquid chromatography-triple quadrupole tandem mass spectrometry (LC-QqQ-MS). By using the constant neutral loss (CNL) scanning mode, we are able to comprehensively detect the DNA adducts resulting from the CNL loss of 2’-deoxyribose. We firstly optimized the parameters of electrospray ionization (ESI)-QqQ-MS using a 18 nucleosides standard mixture solution. These parameters included ESI temperature, declustering potential (DP) and collision energy (CE). The optimized parameters are found to be: ESI temperature set at 400 °C, DP at 30 volts and CE at a range of 10-30 volts.
This DNA adductomic method is then applied in DNA samples measurement obtained from in vitro and in vivo experiments, in which the DNA samples were pre-treated with methylating agents. The obtained data were transferred and output to establish an adductome map to comprehensively show the DNA damages. Furthermore, in order to verify the DNA adductomic method, we also applied the quantitation method (using multiple reaction monitoring mode) to quantify the DNA adducts induced by the methylating agents.
Finally, in order to further identify the chemical structure of target analyte, we further employed an information dependent acquisition (IDA) method to trigger enhanced product ion (EPI) scan that can give information about the fragmentation pattern of unidentified nucleosides.

摘要 I
Abstract III
目錄 IV
表目錄 VII
圖目錄 VIII
第一章 緒論 1
1-1前言 1
1-2研究動機 2
1-3研究目的 3
第二章 文獻回顧 4
2-1 DNA adducts 的介紹 4
2-2 DNA adductomics 10
2-2-1中性丟失模式 (Constant Neutral Loss mode) 11
2-2-2 偽中性丟失模式 (Pseudo Constant Neutral Loss mode) 12
2-3 資料依靠收集模式 (Information Dependent Acquisition) 14
2-4 基因鍵結體地圖 (Adductome map) 17
第三章 材料與方法 20
3-1實驗架構 20
3-2化學藥品及試劑 22
3-3 DNA 樣本來源 25
3-3-1小牛胸腺樣本 25
3-3-2小鼠樣本 26
3-4 DNA 樣本製備 27
3-4-1 DNA 萃取 27
3-4-2 DNA 酵素水解 28
3-5連線固相萃取-液相層析-串聯質譜儀分析方法開發 28
3-5-1自動連線式固相萃取裝置 (on-line SPE) 28
3-5-2液相層析系統 (LC) 30
3-5-3電灑離子化串聯質譜儀 (electrospray ionization QqQ/MS) 32
3-5-4資料依靠收集模式 (information dependent acquisition) 33
第四章 結果與討論 34
4-1中性丟失模式建立能同時偵測 2’-deoxynucleosides 的分析方法 34
4-2利用不同層析時間之 2’-deoxynucleosides 進行區段校正 42
4-3質譜分析數據轉換輸出成 Adductome map 44
4-4應用 DNA adductomics分析法於暴露 MMS 之小牛胸腺DNA 47
4-5應用 DNA adductomics分析法於餵食亞硝胺的小鼠肝臟DNA 51
4-6應用資料依靠收集模式進行定性分析 58
第五章 結論 64
參考文獻 65
附錄 75
A. 縮寫對照表 75
B. on-line SPE LC管柱切換流程表 (舊) 76

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趙木榮，2015。質譜法發展新穎的基因鍵結體學 (DNA Adductomics) :
全面評估檳榔及香菸所造成的 DNA 鹼基修飾。中華民國科技部
專題研究計畫 (計畫編號 : NSC 100-2648-B-040-001-MY4)。