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研究生:吳亦翎
研究生(外文):Yi-Ling Wu
論文名稱:細懸浮微粒之中樞神經系統毒性
論文名稱(外文):CNS Toxicity Induced by DEPs and Ambient Particles
指導教授:鄭尊仁鄭尊仁引用關係
口試委員:陳達夫林靖愉吳焜裕
口試日期:2016-07-18
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:2016
畢業學年度:104
語文別:英文
論文頁數:99
中文關鍵詞:大氣細懸浮微粒柴油引擎微粒退化性中樞神經疾病中樞神經毒性細胞激素莫氏水迷津氧化壓力空間學習空間記憶
外文關鍵詞:ambient particlesdiesel exhaust particlesMorris water mazeCNS toxicityoxidative DNA lesionsnutritive DNA lesionscytokinesneurodegenerative diseasesspatial learningspatial memory
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流行病學及毒理學研究指出大氣懸浮微粒可能會對中樞神經系統產生健康效應,但影響機制尚未明確,因此本研究先使用氣管灌注柴油引擎微粒,探討急性中樞神經系統毒性,之後使用本實驗室開發之大氣微粒暴露系統,長期呼吸暴露健康小鼠,探討大氣微粒亞慢性中樞神經系統毒性。
本研究之實驗一使用八週齡C57BL/6J公鼠,以氣管灌注方式暴露柴油引擎微粒,每週暴露一次,共暴露兩次,實驗動物隨機分派為控制組、總劑量100μg DEPs低暴露組以及總劑量300μg DEPs高暴露組,暴露後進行莫氏水迷津試驗,並測試不同腦區中,與發炎反應有關的細胞激素IL-1β、IL-6及TNF-α,以及測定不同腦區中DNA氧化損傷指標8-OHdG,與特定在發炎狀態的細胞中會產生的DNA氧化損傷指標8-NO2Gua。實驗二使用C57BL/6J公鼠,利用本實驗室開發的大氣微粒暴露系統,自四周齡開始進行一週七天,一天24小時暴露,為期約12周,控制組則是呼吸經HEPA過濾懸浮微粒之空氣, 暴露之後進行莫氏水迷津試驗,並測試不同腦區中,與發炎反應有關的細胞激素IL-1β、IL-6及TNF-α,以及DNA氧化損傷指標8-OHdG,與特定在發炎狀態的細胞中會產生的DNA氧化損傷指標8-NO2Gua。
在急性暴露DEPs後,高暴露組於第四天的逃脫時間的中位數(35.4秒)顯著高於控制組(14.2秒,P=0.036,Kruskal-Wallis test);細胞激素的分析發現,嗅球TNF-α顯著上升,小腦IL-1β及TNF-α顯著上升,大腦髓質以及大腦皮質IL-1β、IL-6顯著上升;氧化壓力分析結果顯示不同腦區中並無顯著不同;肺病理切片判讀結果顯示,暴露DEPs劑量越高,觀察到越明顯的發炎反應,但在腦病理切片並無發現相似結果。
在健康小鼠呼吸暴露期間之PM2.5平均質量濃度為11.9 μg/m3 (2014年12月至2015年3月)以及8.6 μg/m3 (2015年11月至2016年2月),暴露組於第三天逃脫時間的中位數為45.1秒,控制組則為27.6秒 (p=0.018,Wilcoxon rank sum test);腦部細胞激素部分,控制組小腦IL-1β、IL-6顯著上升,控制組海馬迴IL-1β顯著上升;氧化壓力分析結果顯示海馬迴中8-NO2Gua顯著上升(p<0.05,Student’s t-test),8-OHdG則是在嗅球、小腦、大腦髓質、海馬迴、大腦皮質皆顯著上升(p<0.05,Student’s t-test);肺以及腦病理切片發現暴露沒有顯著的發炎反應。
研究結果顯示急性暴露柴油引擎微粒以及亞慢性呼吸暴露大氣微粒,可能造成學習及記憶的下降,急性暴露柴油引擎微粒,使部分腦區之發炎細胞激素增加,顯示急性暴露柴油引擎微粒還是可以影響中樞神經,至於氧化壓力並沒有因急性暴露柴油引擎微粒而增加;亞慢性呼吸暴露大氣微粒後,腦區之發炎細胞激素並沒有增加,氧化壓力8-NO2Gua在海馬迴、8-OHdG則是在嗅球、小腦、大腦髓質、海馬迴、大腦皮質皆增加,因此氧化壓力也可能影響中樞神經系統,而導致學習功能降低。

Epidemiological and toxicological studies have shown that particulate matter (PM) may have adverse effects on the central nervous system (CNS). However, the underlying mechanisms remain unclear. Therefore, we conducted an experiment to explore the CNS toxicity induced by PM.
In the first experiment, 8-week old male C57BL/6J mice were exposed to diesel exhaust particles (DEPs) by intratracheal instillation (I.T.) twice within two weeks. PBS (control group), 50μg DEPs (total 100μg DEPs group) or DEPs 150μg DEPs (total 300μg DEPs group) were administered. In the second experiment, C57BL/6J mice were exposed to ambient air by inhalation for about 3 months from the age of 4-weeks. The control group was given HEPA-filtered air. MWM test were conducted to evaluate spatial learning and memory. In above experiments, Morris water maze (MWM) test was conducted to test the capacity of spatial learning and memory. Inflammatory cytokines including IL-1β, IL-6, TNF-α and oxidative stress marker of 8-OHdG and 8-NO2Gua were determined.
In the acute study, the median of escape latency in the total 300μg DEPs group was significantly longer than the control group in the fourth day (35.4 seconds vs. 14.2 seconds, P=0.036, Kruskal-Wallis test). In olfactory bulb (OB) and cerebellum (CE), the level of TNF-α was increased. The level of IL-1β was increased in CE, cerebral medulla (ME) and cortex (CO). The level of IL-6 was increased in ME and CO. In the inhalation study with healthy mice, the median of escape latency in the exposure group was significantly longer than the control group in the third day (45.1 seconds vs. 27.6 seconds, p=0.018, Wilcoxon rank sum test). Level of IL-1β and IL-6 were increased in the control group in CE. Level of IL-1β was increased in the control group in hippocampus (HI). 8-OHdG significantly increased in OB, CE, ME, HI and CO and 8-NO2Gua significantly increased in HI.
Our results showed that acute exposure to DEPs caused poor spatial learning and increases the level of pro-inflammatory in different brain partitions. Sub-chronic exposure to ambient particles also causes adverse effects on behavior performance. However, the pro-inflammatory cytokines were not increased. 8-OHdG and 8-NO2Gua in healthy young adult mice were increased. Sub-chronic exposure to non-concentrated ambient particles may have adverse effects on spatial learning by accumulation of oxidative stress in CNS.

中文摘要………………………..………………………………………………........I
Abstract..……….………………………………………………….……….....……..III
Contents……………….……………………………………...………….….....……..V
List of Tables ……………………………………………………………..….……VIII
List of Figures ………………………...……………………….…………..…..........IX

Chapter 1 Introduction
1.1 Research background…………………………………………………….......1
1.2 Objectives………………………………………………..............…………...3

Chapter 2 Literature reviews
2.1 Cardiopulmonary effects induced by particulate matter.................................4
2.2 CNS effects induced by particulate matter....................……….............…….5
2.3 Possible mechanism in CNS effects induced by particulate matter................8
2.4 Oxidative stress induced by particulate matter..............................................10

Chapter 3 Material and Methods
3.1 Exposure to DEPs by I.T.
3.1.1 Study design and schedule……………….............................................13
3.1.2 Animals..................................................................................................15
3.2 Exposure to ambient particles by inhalation
3.2.1 Study design and schedule…………….................................................16
3.2.2 Animals..................................................................................................17
3.2.3 Exposure to ambient particulate matter
3.2.3.1 TAPES.......................................................................................18
3.2.3.2 Exposure monitoring.................................................................19
3.2.3.3 Characterization of ambient particulate matter..........................20
3.3 Morris Water Maze........................................................................................22
3.4 Total protein..................................................................................................24
3.5 Bio-Plex Pro Cytokine Assay........................................................................24
3.6 Analysis of 8-OHdG and 8-NO2Gua
3.6.1 DNA isolation........................................................................................25
3.6.2 Extraction of 8-OHdG...........................................................................26
3.6.3 Extraction of 8-NO2Gua........................................................................27
3.6.4 LC-MS/MS Analysis.............................................................................27
3.6.5 HPLC-UV..............................................................................................31
3.7 Histopathology..............................................................................................33
3.8 Statistics.........................................................................................................34

Chapter 4 Results
4.1 Exposure to DEPs by I.T.
4.1.1 Morris water maze............................................................................35
4.1.2 Pro-inflammatory cytokines.............................................................35
4.1.3 8-OHdG and 8-NO2Gua...................................................................36
4.1.4 Histopathology.................................................................................37
4.2 Exposure to ambient particles by inhalation
4.2.1 Mean mass concentration of PM2.5...................................................38
4.2.2 Compositions of PM2.5.....................................................................38
4.2.3 Morris water maze............................................................................39
4.2.4 Pro-inflammatory cytokines………….............................................39
4.2.5 8-OHdG and 8-NO2Gua...................................................................40
4.2.6 Histopathology.................................................................................40



Chapter 5 Discussion
5.1 Characterization of PM2.5...............................................................................41
5.2 Effects of spatial learning and memory induced by DEPs and ambient particles..........................................................................................................43
5.3 Pro-inflammatory cytokines...........................................................................46
5.4 8-OHdG and 8-NO2Gua.................................................................................50
5.5 Histopathology of brain.................................................................................53
5.6 Pulmonary effects induced by DEPs and ambient particles..........................54

Chapter 6 Conclusions and suggestions.............................................................55

References...................................................................................................................56

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