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研究生:趙貞婷
研究生(外文):Jen-Ting Chao
論文名稱:柴油引擎微粒對中樞神經系統影響之時間軸研究
論文名稱(外文):Time Course Study of Central Nervous System Toxicity Induced by Diesel Exhaust Particles
指導教授:鄭尊仁鄭尊仁引用關係
口試日期:2017-07-25
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:79
中文關鍵詞:柴油引擎微粒(DEPs)氣管灌注(ITI)時間軸中樞神經毒性氧化壓力硝化壓力自噬作用
外文關鍵詞:diesel exhaust particles (DEPs)intratracheal instillation (ITI)time-courseoxidative stressnitrosative stressCNS toxicityautophagy
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過去許多研究指出空氣懸浮微粒透過呼吸系統進入體內後,會對呼吸系統、心血管系統及中樞神經產生危害。流行病學及毒理學研究皆指出,空氣懸浮微粒會造成中樞神經系統特別是退化性神經疾病,可能與發炎以及氧化壓力增加有關,近年來,科學家發現神經退化性疾病與腦中的自噬作用(macroautophagy)有關,當自噬作用功能受損,會導致腦中錯誤折疊蛋白的累積,進而引起阿茲海默症或是帕金森氏症。
過去,我們實驗團隊使用C57BL/6小鼠,氣管灌注柴油引擎微粒,在暴露後24小時犧牲,發現暴露組比起對照組大腦的促發炎細胞激素有顯著的增加,本研究以氣管灌注的方式,對C57BL/6小鼠暴露總劑量300 µg的柴油引擎微粒,並於最後一次暴露後不同的時間點犧牲(6小時、1天、3天、7天)。小鼠犧牲後,針對三個不同的腦區(小腦、海馬迴、大腦皮質)測定活性氧化物的去氧核糖核酸(deoxyribonucleic acid,DNA)損傷指標8-羥基-2-去氧鳥嘌呤核甘(8-hydroxy-2''-deoxyguanosine,8-OHdG)、活性氮氧化物的DNA損傷指標8-硝基鳥嘌呤(8-nitroguanine,NO2Gua),以及自噬作用的兩個指標Beclin-1及細胞微管相關蛋白1輕鏈3(microtubule-associated protein 1 light chain 3,LC3)。欲探討急性暴露柴油引擎微粒後,氧化壓力及自噬作用在腦中的變化,藉此更加了解懸浮微粒在中樞神經的毒理機制。
結果顯示,急性暴露DEPs後,8-OHdG及8-NO2Gua在不同犧牲時間點,三個不同腦區皆無顯著不同。自噬作用的結果發現,暴露後3天後,LC3在大腦皮質會有顯著的減少(p<0.05,Wilcoxon rank sum test),Beclin-1在三個腦區的四個不同的犧牲時間點皆無顯著差異。而肺部病理切片中則看到暴露組比起對照組有發炎的現象。
過去研究發現,LC3的減少可能跟活性氮氧化物增加有關,並且可能造成腦中受損胞器及蛋白質的累積,但本研究並未發現活性氮氧化物增加,未來需要更進一步的檢測柴油引擎微粒對自噬作用造成的影響以及機制。
本研究發現急性暴露柴油引擎微粒會造成大腦皮質自噬作用受損,本研究提供了懸浮微粒造成中樞神經疾病的可能機制。而懸浮微粒對自噬作用造成損害的機制、活性氧化物及活性氮氧化物與自噬作用的關係則需要更進一步的研究。
Research has shown that particulate matter (PM) would have adverse effects on respiratory, cardiovascular and central nervous system (CNS) in vivo. Many studies have shown that PM would induce inflammation effects and oxidative stress in CNS. Recently, macroautophagy (simply called “autophagy” hereafter) has been a popular issue associated with neurodegenerative disease. Impairment of autophagy may lead to accumulation of misfolding proteins and cause Alzheimer’s disease or Parkinson’s disease. However, the effects of autophagy after exposure to PM through respiratory tract are not clear.
In our previous study, C57BL/6 mice were exposed to diesel exhaust particles (DEPs) by intratracheal instillation (ITI) and the animals were sacrificed at 24 hours after the exposure. We found that pro-inflammatory cytokines increased significantly in the brain. In this study, C57BL/6 mice were exposed to diesel exhaust particles (DEPs, total dose: 300 µg/mice) by ITI. Animals were euthanized at four different time points (6 h, 1 day, 3 days, 7 days) after the last exposure. Cerebellum, hippocampus and cerebral cortex were used to measure deoxyribonucleic acid (DNA) damage marker of reactive oxygen species (ROS), 8-hydroxy-2''-deoxyguanosine (8-OHdG), and DNA damage marker of reactive nitrogen species (RNS), 8-nitroguanine (8-NO2Gua). Besides, we also measured two markers of autophagy, beclin-1 and microtubule-associated protein 1 light chain 3 (LC3). In this study, we wanted to explore more about CNS toxicity induced by PM.
Our results showed that the concentration of 8-OHdG and 8-NO2Gua in exposure groups didn’t have any differences compared to control groups at four time points (Wilcoxon rank sum test). The outcomes of autophagy expression showed that LC3, the biomarker of later stage of autophagy, decreased in cerebral cortex at the third post-exposure day (p<0.05, Wilcoxon rank sum test) and beclin-1 didn’t have significant differences between control and exposure groups in three brain regions at four different time points. The histopathology of lung indicated that there were inflammation effects in exposure groups.
Scientists have found that inhibition of LC3 may be associated with RNS and may cause accumulation of damaged organelles as well as proteins. Therefore, our results may be associated with inflammation in brain. However, the RNS levels didn''t have significant differences between control groups and exposure groups in our study. Further study should explore more about the influences of autophagy by DEPs in detail.
In conclusion, acute exposure of DEPs would impair autophagy in cerebral cortex. Our study revealed the possible mechanism of PM exposure and CNS diseases. Further study should explore the mechanism of how PM impact autophagy and the relationship between ROS/RNS and autophagy.
中文摘要 I
Abstract III
Chapter 1. Introduction 1
1.1 Background 1
1.2 Objectives 2
Chapter 2. Literature review 3
2.1 Health effects of PM 3
2.2 CNS effects of PM 5
2.3 Oxidative and nitrosative stress induced by PM 9
2.4 Autophagy induced by PM 13
2.5 Time course of CNS effects induced by PM 15
Chapter 3. Materials and Methods 16
3.1 Animals 16
3.2 Study design and PM exposure 16
3.3 Measurement of 8-OHdG and 8-NO2Gua 19
3.3.1 DNA extraction 19
3.3.2 Extraction of 8-OHdG 20
3.3.3 Extraction of 8-NO2Gua 21
3.3.4 Analysis of 8-OHdG and 8-NO2Gua by LC-MS/MS 21
3.3.5 Analysis of dG and Gua by HPLC-UV 23
3.4 Measurement of Beclin-1 and LC3 25
3.4.1 Protein extraction and determination 25
3.4.2 Western blot analysis 26
3.5 Histopathology 27
3.6 Statistics 28
Chapter 4. Results 29
4.1 ROS and RNS 29
4.1.1 8-OHdG 29
4.1.2 8-NO2Gua 30
4.2 Autophagy 31
4.2.1 Beclin-1 31
4.2.2 LC3 31
4.3 Histopathology 32
Chapter 5. Discussion 33
5.1 ROS and RNS 35
5.2 Autophagy 38
5.3 Pulmonary effects induced by DEPs 41
5.4 Limitations 42
Chapter 6. Conclusion 43
Chapter 7. Reference 44
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