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研究生:李昇翰
研究生(外文):Sheng-Han Lee
論文名稱:應用核磁共振與質譜技術共同探討急性呼吸暴露奈米與微米粒徑之氧化鋅顆粒對大鼠呼吸系統之影響
論文名稱(外文):Coupling NMR-based Metabolomics with LC-MS-based Lipidomics to Examine Acute Rat Pulmonary Responses after Nano- and Fine-Sized ZnO Particle Inhalation Exposure
指導教授:林靖愉
口試委員:鄭尊仁唐川禾鄭美玲
口試日期:2018-04-17
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:環境衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:英文
論文頁數:143
中文關鍵詞:代謝體學脂質體學核磁共振質譜分子機制生物指標毒理學氧化鋅急性呼吸暴露大鼠
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急性呼吸暴露氧化鋅粒子雖已被證實會引發人類與實驗嚙齒類動物的諸多不良健康效應,但氧化鋅粒子造成的呼吸系統損傷的分子機制尚未能一虧全貌。有鑑於此,本研究結合核磁共振技術為基礎的代謝體學和質譜技術為基礎的脂質體學來量測大鼠呼吸暴露氧化鋅粒子後所誘發之呼吸系統的代謝擾動。
氧化鋅呼吸暴露的動物模式的建立以不同粒徑:奈米(35 nm)或微米(250 nm)、不同粒子濃度的氧化鋅粒子暴露於SD品系的雄性大鼠,並以呼吸過濾後空氣的同品系大鼠作為控制組。暴露實驗後二十四小時犧牲動物並收集肺沖洗液和肺部組織再分別以氫核磁共振光譜或質譜儀進行代謝體或脂質體的分析。肺沖洗液和肺部水溶性代謝物的核磁共振光譜中主成分分析和偏最小平方法的結果顯示暴露微粒粒徑的氧化鋅粒子的組別其代謝物擾動的程度有劑量反應關係,然暴露不同濃度奈米粒徑氧化鋅粒子組別的代謝物組成差異則較不明顯。微米粒徑暴露組別中特定代謝物量的改變:如肺沖洗液中牛磺酸(taurine)、甲酸鹽(formate)的下降以及肺組織中葡萄糖的下降或含磷酸膽鹼官能基脂質(phosphorylcholine-containing lipids)的增加等可能與抗氧化、能量代謝、DNA損傷以及細胞膜結構之穩定有關。
另一方面,透過統合一系列多變量與單變量統計方法不但可以探索因氧化鋅粒子暴露所引發之脂質擾動外,也可篩選出潛在的氧化鋅暴露的生物指標。肺部的質譜光譜中主成分分析和偏最小平方法的結果顯示微米粒徑各組與奈米粒徑高劑量暴露組的脂質組成與控制組、奈米粒徑的中低濃度的暴露組不甚相同。不同脂質的差異可能藉由抗氧化、細胞膜結構的改變以及訊息傳遞等機制來應對氧化鋅暴露所引發的氧化壓力與發炎反應。此外,此研究也篩選出兩個能反映出氧化鋅粒子暴露的脂質:PC(18:0/18:1)和PC(16:0/15:0)。綜合上述結果可知利用代謝體學和脂質體學的研究策略不但可以探索氧化鋅粒子所引發的分子毒理機制,也可以篩選出潛在的氧化鋅粒子暴露的生物指標。此外,此平台也可應用於研究其他肺部毒性反應或健康效應。
Zinc oxide (ZnO) particles induce acute occupational inhalation illness in humans and rats. However, the possible molecular mechanisms of ZnO particles on the respiratory system remain unclear. In this study, metabolic responses of the respiratory system of rats inhaled ZnO particles were investigated by a nuclear magnetic resonance (NMR)-based metabolomic approach coupling with a liquid chromatography-mass spectrometry (LC-MS)-based lipidomic approach.
Male Sprague–Dawley rats were treated with a series of doses of nano-sized (35 nm) or fine-sized (250 nm) ZnO particles. The corresponding control groups inhaled filtered air. After 24h, bronchoalveolar lavage fluid (BALF) and lung tissues were collected, extracted and prepared for 1H and J-resolved NMR analysis as well as LC-MS analysis, followed by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). PCA and PLSDA models from analysis of BALF and hydrophilic lung NMR spectra demonstrated that dose response trends were restricted to the 250 nm ZnO particle exposure group and were not observed in the 35 nm ZnO particle exposure group. Increased isoleucine and valine, as well as decreased acetate, trimethylamine n-oxide, taurine, glycine, formate, ascorbate and glycerophosphocholine, were recorded in the BALF of rats treated with moderate and high dose 250 nm ZnO exposures. Decreases in taurine and glucose, as well as an increase of phosphorylcholine-containing lipids and fatty acyl chains, were detected in the lung tissues from 250 nm ZnO-treated rats. These metabolic changes may be associated with cell anti-oxidation, energy metabolism, DNA damage and membrane stability.
On the other hand, PCA, PLS-DA, and the Mann-Whitney U test with false discovery rate control were conducted to explore the perturbed lipid species and discriminate a potential pulmonary biomarker signature after ZnO particle exposure. The PCA and PLS-DA models revealed that the fine-sized ZnO particle-treated groups and the high-dose nano-sized group were separated from the control groups as well as the low and moderate nano-sized groups. Furthermore, our results suggested that lipids involved in anti-oxidation, membrane conformation, and cellular signal transduction were altered in response to ZnO-induced oxidative stress and inflammation. Two lipids, PC(18:0/18:1) and PC(16:0/15:0), exhibited good performance (AUC> 0.8) of discriminative ability in distinguishing ZnO particle exposure from the control. These findings not only provide a foundation for the exploration of possible ZnO particle-mediated mechanisms but also suggest a lipid biomarker for ZnO particle exposure. In addition, using this integrated metabolomic and lipidomic approaches can be applied to study other pulmonary toxicity or diseases.
Table of contents
摘要 I
Abstract III
Introduction 1
Zinc oxide particles 1
Background and potential impacts 1
Adverse effects of ZnO particles on the biological systems 3
Debate of particle dependent toxicity in the respiratory system 5
Metabolomics and its application 11
Lipidomics and phosphorylcholine-containing lipids 17
Study aims 24
Materials and Methods 25
Experimental flow chart 25
ZnO inhalation exposure model 26
Animals 26
Exposure system of the ZnO particles 26
Acute inhalation exposure on rats 28
NMR-based metabolomics analysis 29
Sample preparation 29
Instrument analysis 30
Data processing 32
Data analysis 32
Metabolite identification 34
LC-MS-based lipidomics analysis 34
Sample preparation 34
Instrument analysis 35
Data processing 36
Data analysis 37
Lipid identification 38
Results 40
NMR-based metabolomic analysis 40
1H NMR spectroscopy of BALF and lung metabolites 40
Effects of ZnO particles on rat BALF metabolome 40
Effects of ZnO particles on rat lung hydrophilic metabolome 43
Effects of ZnO particles on rat lung hydrophobic metabolome 44
LC-MS-based lipidomic analysis 45
LC-MS spectroscopy of lung PC-CLs 45
Multivariate analysis of effects of ZnO particles on PC-CLs in rat lungs 46
Univariate analysis of effects of ZnO particles on individual PC-CLs in rat lung 47
Statistical evaluation of biomarkers of ZnO particle exposure in rat lung 49
Discussion 51
Possible roles of metabolite and lipid alteration in response to ZnO exposure 52
Protective roles against oxidative stress and inflammation induced by ZnO particles 53
Membrane reinforcement to adapt to ZnO-mediated environmental stress 57
ZnO particle-induced energetic disturbance 59
Replenishing of nucleonic acid to repair ZnO-induced DNA lesions 61
Roles in cellular signalling to modulate ZnO particle-induced pulmonary oxidative inflammation 62
Debate regarding particle dependent toxicity 64
Dose response effects of ZnO particle exposure 67
Potential pulmonary biomarker signatures for acute inhalation of ZnO particles 70
Limitations and future developments 75
Conclusion 79
References 81

List of figures
Figure 1. Structure of representative molecular species of (a) phosphatidylcholines and (b) sphingomyelins 97
Figure 2. A representative 600 MHz 1H NMR spectrum of BALF metabolome from rats treated by ZnO particles 98
Figure 3. A representative 500 MHz 1H NMR spectrum of lung hydrophilic metabolome from rats treated by ZnO particles 99
Figure 4. A representative 500 MHz 1H NMR spectrum of lung hydrophobic metabolome from rats treated by ZnO particles 100
Figure 5. The score plot of PCA model from the analysis of 1H NMR spectra of BALF from rats exposed to different ZnO particles (n=6 for each dose group) 101
Figure 6. The PC1 loading plot from the analysis of 1H NMR spectra of BALF from rats exposed to 35 nm and 250 nm ZnO particles 102
Figure 7. The score plot of PCA model from analysis of 1H NMR spectra of BALF from rats exposed to 250 nm ZnO particles (n=6 for each dose group) and their matched control groups (n=4 for each group) 103
Figure 8. The PC1 loading plot from the analysis of 1H NMR spectra of BALF from rats exposed to 250 nm ZnO particles 104
Figure 9. The score plot of the PLS-DA model from the analysis of the J-resolved NMR spectra of lung hydrophilic metabolites from rats exposed to 250 nm ZnO particles (n=6 for each dose group) with their matched control groups (n=4 for each group) 105
Figure 10. The LV1 loading plot from the analysis of the J-resolved NMR spectra of lung from rats exposed to 250 nm ZnO particles 106
Figure 11. A representative LC-MS spectrum for different phosphatidylcholines and sphingomyelins. 107
Figure 12. The PCA score plot from the analysis of LC-MS spectra of rat lung from rats exposed to 35 nm or 250 nm ZnO particles 108
Figure 13. The PLS-DA score plot from the analysis of the LC-MS spectra of the lung PC-CLs from rats exposed to 35 nm or 250 nm ZnO particles 109
Figure 14. A Framework of the critical lipid selection after the ZnO particle exposure. 110
Figure 15. Plausible ZnO particle-induced metabolic pathways in the rat respiratory system. 111
Figure 16. The score plot of PCA model from the analysis of 1H NMR spectra of BALF from rats of different control groups (n=4 for each dose group) 112
Figure 17. The score plot of PCA model from the analysis of J-resolved NMR spectra of lung hydrophilic metabolites from rats of different control groups (n=4 for each dose group) 113
Figure 18. The PC1 loading plot from the analysis of 1H NMR spectra of BALF from rats exposed to 35 and 250 nm control groups 114
Figure 19. The PC1 loading plot from the analysis of the J-resolved NMR spectra of lung from rats exposed to 35 and 250 nm control groups 115

List of tables
Table 1. The properties of series sizes and concentrations of ZnO particles for rat acute inhalationa 116
Table 2. Significant metabolic changes in the BALF of rats exposed to different sizes and doses of ZnO particles 117
Table 3. Whole metabolic changes in the BALF of rats exposed to different sizes and doses of ZnO particles 119
Table 4. Significant metabolic changes in the lung tissue of rats exposed to different sizes and doses of ZnO particles 121
Table 5. Whole metabolic changes in the lung tissue of rats exposed to different sizes and doses of ZnO particles 124
Table 6. Changes of phosphatidylcholine in the rat lungs exposed to various sizes and concentrations of ZnO particles 128
Table 7. Changes of sphingomyelin in the rat lungs exposed to various sizes and concentrations of ZnO particles 132
Table 8. Possible critical lipids in responses to ZnO particle exposure from the results of PLS-DA model 134
Table 9. Significant PC-CL changes among ZnO particle treated groups comparing 136
Table 10. The variables in projection (VIP) score and the area under the ROC curve (AUC) for receiver-operating characteristic (ROC) curves for the three potential biomarkers that discriminated ZnO particle exposure and control groups 138
Table 11. The correlations between the PC-CL biomarker candidate and BALF markers for lung inflammation, injury, and oxidative stress 139
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