奈米二氧化鈦對於中樞神經系列細胞(小鼠腦神經瘤細胞、小鼠神經微膠質細胞、小鼠星狀膠質細胞)的毒性研究

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研究生：	張家誠 Chang, Chia-Cheng
論文名稱：	奈米二氧化鈦對於中樞神經系列細胞(小鼠腦神經瘤細胞、小鼠神經微膠質細胞、小鼠星狀膠質細胞)的毒性研究 The Cytotoxic Studies of Nano-size Titanium Dioxide on Central Nervous System Series Cell (Neuro-2a, Microglia, and Astrocyte)
指導教授：	黃鈺軫 Huang, Yuh-Jeen
口試委員:	萬磊 Lei Wan 陳仁焜 Jen-Kun Chen
學位類別：	碩士 Master
系所名稱：	原子科學院 - 生醫工程與環境科學系 Department of Biomedical Engineering and Environmental Sciences
論文出版年：	2014
畢業學年度：	102
語文別：	英文
論文頁數：	151
中文關鍵詞：	奈米二氧化鈦、神經退化性疾病、共培養系統
外文關鍵詞：	Titanium dioxide (TiO2), Neurodegenerative diseases, Co-culture system
相關次數：	點閱：2 下載：0
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奈米二氧化鈦( TiO2 NPs )廣泛的被使用在工業及生醫領域，對生物卻存在潛在的風險。動物及細胞實驗可知誘發中樞神經系統造成細胞死亡、發炎、氧化壓力等等。在本研究中，我們直接暴露TiO2 NPs (3-5 nm 和30-50 nm)於有/無經內毒素 (LPS)前處理神經系列細胞(小鼠腦神經瘤細胞(N2A)、小鼠神經微膠質細胞(BV-2)、小鼠星狀膠質細胞(ALT))，探討TiO2 NPs的神經毒性與發炎反應的直接關係。再利用transwell建立共培養及三培養系統(兩株或三株細胞共存)，探討直接受TiO2 NPs微粒(5 nm)刺激的細胞(ALT或BV-2)所誘發的生物效應例如細胞死亡、氧化壓力、及細胞激素造成其他細胞(BV-2或N2A)的間接影響或傷害。
在直接效應，我們發現奈TiO2 NPs在高濃度情況下可以對BV-2和ALT造成細胞毒性，而對於N2A細胞則不會，顯示TiO2 NPs對於兩種膠質細胞的毒性大於神經細胞。而攝食TiO2 NPs能力，我們發現BV-2>N2A>ALT，所以我們推測在大腦中主要攝食清除奈米二氧化鈦的細胞為BV-2細胞。LPS可以誘使細胞發炎或活化，尤其是對BV-2細胞，使細胞可以攝食更多TiO2 NPs導致細胞增加活性氧化物種和發炎物質甚至死亡。我們發現小粒徑的TiO2 NPs可以誘使細胞產生較多的發炎物質，所以選用小粒徑TiO2 (3-5 nm)進行後續間接效應實驗。
間接效應實驗我們發現只有被暴露TiO2 NPs的細胞有明顯的細胞死亡，除了BV2-N2A這一組合。而在細胞攝食方面，也只有被暴露TiO2 NPs的細胞有明顯的攝食情形。我們發現當暴露TiO2 NPs和LPS時，膠質細胞會產生發炎物質和活性氧化物種，影響周圍的神經細胞和神經膠質細胞使得他們產生細胞型態改變、發炎物質、氧化壓力最後甚至使細胞死亡。
由上述結果我們認為當TiO2 NPs進入到中樞神經系統，被膠質細胞攝食，導致細胞發炎或死亡，釋放出有害的發炎物質影響神經元，使其受損、發炎甚至死亡，如此可能導致神經退化性疾病(阿茲海默症、帕金森氏症等)的產生。

With the development of nanotechnology, more and more nanomaterials have been produced. Titanium dioxide (TiO2) nanoparticle (NP) is one of the important nanoscale materials. Though TiO2 nanoparticles (NPs) have been widely used in industry and biomedical field, they would have some potential risk to human health. Furthermore, animal and cell experiments were found NPs can induce toxic effects against central nervous system, such as cell death, inflammation, and oxidative stress ... etc. In this study, we exposed central nervous system cells (Neuro-2a cell line (N2A), microglial cell line (BV-2), and astrocytes (ALT)) w/wo endotoxin (lipopolysaccharide (LPS)) to TiO2 NPs (5 nm and 30 nm) to investigate the direct effect of neurotoxicity of TiO2 on cells. We also established the co-culture/tri-culture systems, co-existence of two or three cell lines by transwell assay. Then, one of the cells (ALT or BV-2) were treated with TiO2 NPs to study the effects of cell-cell interaction through secreted cytokines and chemokines.
The results show that TiO2 NPs induce CNS series cells to generate inflammatory substances, and high concentration of TiO2 NPs have more cytotoxic to ALT and BV2 than N2A. Uptake ability of TiO2 NPs were BV-2 > N2A > ALT, so we speculate that BV-2 microglia is principal cells of uptaking TiO2 NPs in the brain. LPS pre-treatment can activate cells, especially BV-2 which can ingest more nanoparticles and result in more serious damage to the cells, such as cell death, inflammation, oxidative stress... etc. TiO2 NPs in smaller size can induce CNS series cell to release more inflammatory substances. Therefore, we will use 3-5 nm TiO2 NPs to do indirect effect of subsequent experiments.
We found that only direct contact with nanoparticles, the declined phenomenon in cell viability was observed except for BV2-N2A co-culture system. In terms of uptake of nanoparticles, the SSC value of the cells also only in contact with the nanoparticles have increased significantly. When exposed to TiO2 NPs and LPS, glia cells generate inflammatory substances and ROS, and these inflammatory substances affect other kinds of cells, such as glia cells and neuron, leading to cell morphology changed, inflammatory substances increased, oxidative stress, and even cells death.
We believe that when TiO2 NPs passed into the central nervous system, TiO2 NPs were ingested by ALT or BV-2 cells causing cell death, oxidative stress, inflammation, and these conditions may cause damage to the central nervous system and lead to the generation of neurodegenerative diseases (such as Alzheimer's disease, Parkinson's s disease) . This study provides important information for nano titanium dioxide effects on the central nervous system series cells, and the results can supply a reference for future animal and human experiments.

Abstract    I
摘要    II
謝誌    III
Contents    IV
List of Tables    VII
List of Figures    VIII
Chapter 1    1
Background and Introduction    1
1    Nanotoxicology    1
2    in vitro cytotoxicity    2
3    Neurotoxicology    2
4    Objects of this study    3
5 References    5
Chapter 2    7
Literature review    7
1 Nanomaterials    7
2 Nano-TiO2    8
2.1 Physico-chemical properties    8
2.1.1 Chemical Structure    8
2.1.2 Electronic properties    12
2.2 Applications    13
3 in vivo toxicity of TiO2    16
3.1 in vivo    16
3.2 Toxicity of nano-TiO2    16
4 in vitro Cytotoxicity of TiO2    19
4.1 Three Neuro-Cell Lines of Mouse    19
4.2 in vitro Cytotoxicity assays    23
4.3 Possible mechanisms of nanomaterials effect to biological tissue    24
4.4.Cytotoxicity studies of TiO2 nanoparticles    29
5 Concept of Nanoparticles Neurotoxicity    32
5.1 Neuron cell and Nervous system    32
5.2 Neurotoxicity of Nanomaterials    33
5.2.1 in vivo Studies    34
5.2.2 in vitro studies    35
5.2.3 in vitro Studies of TiO2    38
5.3 Nanoparticles and neurodegenerative diseases possible relationships (ex: Alzheimer's disease)    40
6 References    45
Chapter 3    55
Materials and methods    55
1 Experimental flow chart and materials    55
2 Nanoparticles characterization    58
2.1 Transmission Electron Microscopy (TEM)    58
2.2 X-ray diffraction (XRD)    59
2.3 Zetasizer    60
2.4 Flow cytometer    62
2.5 Inductively coupled plasma optical emission spectrometry (ICP-OES)    63
3 Three kinds of nerve cell culture    64
3.1 Astrocyte (ALT)    64
3.2 Microglial cell line(BV-2)    64
3.3 Neuro-2a neuroblastoma cell line (N2A)    65
4 Single culture and co-/tri-culture    65
4.1 Differentiation of N2A cell    65
4.2 Sample treatment    66
4.3 Single culture system    66
4.4 Co-culture system    66
4.5 Tri-culture system    67
5 Biological analysis methods    69
5.1 Cell morphology    69
5.2 Alamar Blue assay    69
5.3 ELISA    70
5.4 DCFH-DA    71
5.5 Uptake potential    72
5.6 Cytometric Beads Array    72
5.7 Statistics    73
6 Reference    74
Chapter 4    75
Physicochemical properties of TiO2 nanoparticles and its cytotoxicity to nerve cells    75
1 Alkali-modified TiO2 nanoparticles    75
2 Characterization of TiO2 nanoparticles    76
2.1TEM    76
2.2 DLS (hydrodynamic size and zeta potential)    78
2.3 XRD    80
2.4 ICP-OES    80
3 Cytotoxic effect of TiO2 nanoparticles on three kinds of nerve cells    81
3.1 Cell morphology    82
3.2 Cell viability    86
3.3 Uptake potential    91
3.4 Intracellular ROS    99
3.5 Cytokines secretion    105
4 Summary    112
5 Reference    114
Chapter 5    115
The influences of TiO2 nanoparticles on Central Nervous System (CNS) series cell    115
1 Co-culture System    115
1.1 Cell viability    116
1.2 Uptake potential    119
1.3 Intracellualr ROS    121
1.4 Production of Cytokines    125
2 tri-culture System    131
2.1 Cell viability    131
2.2 Uptake potential    133
2.3 Intracellualr ROS    134
2.4 Production of Cytokines    135
3 BV2-ALT-N2A tri-culture system    137
3.1 Cell viability    138
3.2 Uptake potential    140
3.3 Intracellualr ROS    141
3.4 Production of Cytokines    143
4 Summary    145
Chapter 6    150
Conclusions    150


                                

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Chapter 3
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