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研究生:李洛堯
研究生(外文):Lo-Yao Lee
論文名稱:以口咽吸入多次暴露柴油引擎微粒對小鼠誘發神經毒性之研究
論文名稱(外文):Neurotoxicity induced by diesel exhaust particles with repeated oropharyngeal aspiration in mice
指導教授:鄭尊仁鄭尊仁引用關係
指導教授(外文):Tsun-Jen Cheng
口試委員:陳鑫昌莊校奇
口試委員(外文):Hsin-Chang ChenHsiao-Chi Chuang
口試日期:2018-07-23
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:2018
畢業學年度:106
語文別:中文
論文頁數:90
中文關鍵詞:柴油引擎微粒口咽吸入神經毒性神經退化性疾病氧化壓力中樞神經系統神經纖維纏結
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現今的空氣污染日益嚴重,空氣污染的暴露也會造成許多身體健康上的影響。研究指出暴露於空氣污染之中會造成呼吸系統、心血管疾病甚至影響中樞神經系統(central nervous system)。直至今日,大氣細懸浮微粒與神經退化性疾病(neuro-degenerative diseases)的關聯已經被確立了,然而其中的詳細機制仍舊不得而知。現今大都市中的空氣污染排放嚴重,柴油引擎微粒(diesel exhaust particles, DEPs)更是主要的污染物之一。柴油引擎微粒的神經毒性可能與神經退化性疾病的產生有所關聯。因此,我們希望藉由實驗動物模型暴露於柴油引擎微粒來觀察實驗動物是否在空間記憶、學習能力上有所改變。同時,我們也會蒐集與測量動物的腦部氧化壓力(oxidative stress)、腦中神經纖維纏結指標,以了解柴油引擎微粒對中樞神經系統的神經毒性。
本研究使用32隻C57BL/6母鼠,透過口咽吸入(oropharyngeal aspiration,OA)在三週內分6次暴露共300 μg的SRM 1650b型柴油引擎微粒。柴油引擎微粒購買自美國國家標準暨技術研究院,是由多種重型柴油引擎機具燃燒所排放出來的引擎微粒,適合代表使用柴油引擎的重型機具與車輛所產生的微粒。在暴露之後,其中一批小鼠會在24小時內犧牲(急性組);另一批則會給予3個月的恢復期(恢復組)並且進行莫式水迷津(Morris water maze)、被動迴避測驗(passive avoidance test)兩個動物行為實驗。小鼠犧牲後會取下全腦做為樣本並再分為小腦、海馬迴、大腦皮質三個腦區進行研究。這些樣本將會使用LC-MS/MS分析腦中脂質過氧化(lipid peroxidation)的指標丙二醛(malondialdehyde, MDA),也會使用西方點墨法(Western blot)檢測神經纖維纏結指標:total Tau、phosphorylated Tau蛋白。部分腦組織灌流後進行石蠟包埋、H&E染色與切片,透過專業獸醫師分析組織病理。

實驗結果表示,脂質過氧化指標MDA於急性組的暴露組小腦、海馬迴有顯著的上升,在其他組別與腦區則無差異;神經纖維纏結指標分析上發現,total Tau、phosphorylated Tau蛋白的表現量在急性組的暴露組大腦皮質顯著的高於控制組,其他組別與腦區同樣無差異。動物行為實驗的結果表示,恢復前與恢復後的莫式水迷津與被動迴避試驗控制組與暴露組間皆無差異。在病理切片的部份,在兩大組別的暴露組肺部有發現微粒的堆積與發炎反應的產生,不過腦部並沒有顯著的發炎與病變發生。
總結來說,急性暴露於柴油引擎微粒的神經毒性會造成腦部的氧化壓力、total Tau與phosphorylated Tau蛋白表現量上升,但是經過長期的恢復後並沒有在腦部發現任何病變與生物指標上升而且在動物行為實驗上也沒有差異。這種結果可能表示小鼠在三個月恢復期中,由於自身的清除機制消除柴油引擎微粒產生的神經毒性。再加上本次使用健康的成年小鼠暴露,比起易感受族群(嬰幼兒、年長者)更不易受到神經毒性的傷害且恢復快速。不過,本實驗也指出急性的柴油引擎微粒暴露能夠造成中樞神經系統的受損,若長期暴露之下所帶來的危害更不容小覷。本次實驗在建立完整的柴油引擎微粒毒性影響中樞神經系統機制仍缺乏部份證據來佐證,期望未來可以增加檢測自噬作用、乙型類澱粉蛋白亦或更多的相關生物指標或在實驗動物上使用基因轉殖動物達到完整的結果。
The association between ambient particles and neurodegenerative diseases has been acquired. However, the exact mechanisms remain unclear. Diesel exhaust particles (DEPs) are one of major sources of ambient particles and it is also related to neuro-degenerative diseases. Here, we investigated if DEPs’ neurotoxicity induced behaviour changes of learning and memory of mice. We also evaluated the level of oxidative stress and Tau protein expression in brain tissue of mice.
Female C57BL/6 mice were administered with 300μg of SRM 1650b DEPs in 3 weeks through multiple oropharyngeal aspiration (OA). SRM 1650b DEPs used in this study was purchased from National Institute of Standards and Technology. After exposure, one group was sacrificed at 24 hours, and the other group was allotted 3-months recovery time. Morris water maze test was conducted to study the spatial learning and memory of mice. Additionally, passive avoidance task was used to evaluate learning and memory. The cortex, hippocampus and cerebellum regions were sampled after the sacrifice. Lipid peroxidation was measured by assaying the malondialdehyde level with LC-MS/MS. As markers of neurofibrillary tangle, expression of total Tau protein and phosphorylated Tau protein were also tested by western blot. Brain tissues were stained by hematoxylin and eosin (H&E) for histopathology.
Our results showed that MDA concentration significantly increased in hippocampus and cerebellum of mice (p<0.01, Wilcoxon rank sum test), which sacrificed right after exposure in 24 hours. We also found that expression of total Tau and phosphorylated Tau protein were significantly higher in the cortex of the exposure than the control (p<0.05, Wilcoxon rank sum test) in the same group. Whereas, we didn’t find any noticeable increasing of MDA concentration and expression of Tau protein in 3-months recovery group. The results of the Morris water maze and passive avoidance test didn’t show any difference between control and exposure, either. The histopathology of 3 brain regions (olfactory bulb, hippocampus and cerebellum) had no histopathological changed, but mild inflammation in lung of exposed mice in both groups.
Previous reports show that DEPs caused an increase of oxidative stress and expression of Tau protein, but there was no deficit of spatial learning and memory of animals. In our study, we only found that DEPs induced oxidative stress up-regulation and higher expression of Tau protein in the CNS, but a spatial learning and memory defect after acute exposure were not observed. Therefore, we conclude that acute exposure to DEPs could cause damage to the CNS and 3-months of recovery time could nearly remove the neurotoxicity of DEPs. However, the underlying mechanism through which DEPs affects our CNS requires further studies including biomarkers of autophagy (LC3b), beta-amyloid (Aβ), and microglia activation (Iba-1).
In conclusion, acute exposure to DEPs could cause neurotoxicity in mice. Our study also indicated a possible link between neurotoxicity of DEPs and neurodegenerative diseases. However, further studies are needed to elucidate the relationship between DEPs and neurodegenerative diseases.
目 錄
中文摘要 I
Abstract III
第一章 背景與研究目的 1
第二章 文獻回顧 2
2.1空氣污染與健康效應 2
2.2 DEPs對於中樞神經毒性的可能途徑 4
2.2.1微粒直接進入中樞神經 4
2.2.2微粒表面之可溶性有毒物質 4
2.2.3全身性的發炎反應 5
2.3 DEPs對神經退化性疾病的影響與指標 6
2.3.1氧化壓力與脂質過氧化 6
2.3.2Tau蛋白與神經纖維纏結 7
2.3.3行為與記憶改變 8
第三章 材料與方法 10
3.1 實驗動物 10
3.2 實驗設計 10
3.3 柴油引擎微粒 12
3.4 口咽吸入法 - Oropharyngeal aspiration (OA) 12
3.5 脂質過氧化指標 - MDA 14
3.5.1 MDA標準品與DNPH溶液配製 14
3.5.2 MDA萃取 14
3.5.3檢量線與標準添加法 15
3.5.4 LC-MS/MS分析MDA 15
3.6西方點墨法-Tau蛋白表現量 17
3.6.1蛋白質萃取與濃度測定 17
3.6.2凝膠電泳 18
3.6.3電泳照膠分析 19
3.7 動物行為實驗 20
3.7.1 莫式水迷津實驗 – Morris water maze 20
3.7.2 被動迴避實驗 – Passive avoidance test 22
3.8 組織病理 23
3.8.1灌流方法 23
3.9 統計分析 23
第四章 結果 24
4.1脂質過氧化 - MDA 24
4.2西方點墨法 - Tau 蛋白測定 24
4.2.1 Total Tau表現量 24
4.2.2 P-Tau表現量 25
4.2.3 P-Tau與total Tau相對比例 25
4.3動物行為實驗 26
4.3.1莫式水迷津 26
4.3.2被動迴避實驗 26
4.4組織病理 27
第五章 討論 28
5.1腦部脂質過氧化 29
5.2腦部Tau蛋白表現量 31
5.3空間學習與記憶 34
5.4肺部與中樞神經組織病理特徵 36
5.5結論與建議 37
第六章 參考文獻 39


表目錄
表一、細懸浮微粒對中樞神經系統影響之研究 51
表二、柴油引擎微粒對動物中樞神經系統影響之研究 53
表三、SRM 1650b柴油引擎微粒PAH質量分數 55
表四、LC-MS/MS移動相濃度梯度比例 57
表五、串聯質譜儀離子源設定參數 57
表六、SRM參數 58
表七、各組別不同腦區的MDA濃度(nmol/mL) 59
表八、Total Tau與P-Tau在急性組不同腦區的表現量 60
表九、Total Tau與P-Tau在恢復組不同腦區的表現量 61
表十、莫式水迷津第一次知識採集階段 62
表十一、莫式水迷津第一次空間探索實驗 63
表十二、莫式水迷津第二次知識採集階段 64
表十三、莫式水迷津第二次空間探索實驗 65
表十四、第一次被動迴避實驗每日滯留時間 66
表十五、第二次被動迴避實驗每日滯留時間 66
表十六、病理組織切片評分 67


圖目錄
圖一、實驗設計圖 68
圖二、實驗暴露與犧牲流程 69
圖三、MDA-DNPH層析圖 70
圖四、MDA-DNPH標準品檢量線與標準添加法檢量線 71
圖五、各腦區MDA平均濃度 72
圖六、小腦total Tau與phosphorylated Tau表現量 73
圖七、海馬迴total Tau與phosphorylated Tau表現量 74
圖八、大腦皮質total Tau與phosphorylated Tau表現量 75
圖九、急性組P-Tau與total Tau表現量比值 76
圖十、恢復組P-Tau與total Tau表現量比值 77
圖十一、第一次莫式水迷津知識採集階段結果 78
圖十二、第一次莫式水迷津空間探索階段結果 79
圖十三、第二次莫式水迷津知識採集階段結果 80
圖十四、第二次莫式水迷津空間探索階段結果 81
圖十五、第一次被動迴避實驗滯留時間趨勢圖 82
圖十六、第二次被動迴避實驗滯留時間趨勢圖 82
圖十七、急性組:控制組與暴露組小腦組織病理切片 83
圖十八、急性組:控制組與暴露組海馬迴組織病理切片 84
圖十九、急性組:控制組與暴露組嗅球組織病理切片 85
圖二十、急性組:控制組與暴露組肺部組織病理切片 86
圖二十一、恢復組:控制組與暴露組小腦組織病理切片 87
圖二十二、恢復組:控制組與暴露組海馬迴組織病理切片 88
圖二十三、恢復組:控制組與暴露組嗅球組織病理切片 89
圖二十四、恢復組:控制組與暴露組肺部組織病理切片 90
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