臺灣博碩士論文加值系統

摘要
前言：鄰苯二甲酸二（2－已基己基）酯（DEHP）目前被廣泛用於製造含有聚氯乙烯（PVC）的塑膠製品，由於不是以共價鍵方式結合，所以容易暴露於環境中。大部分的研究都是針對DEHP與生殖系統的相關研究，本實驗室之前研究發現，母體暴露DEHP會讓子代肺部的過敏性發炎變嚴重，由於樹突細胞在氣喘免疫機制中扮演重要的角色，是否DEHP對樹突細胞的恆定作用會造成影響，這部分目前還不清楚。因此本研究著重於樹突細胞的恆定在DEHP的作用中所扮演的角色
實驗方法：模擬人類暴露DEHP的方式，建立DEHP母體暴露之子代小鼠氣喘模式，分析子代脾臟裡樹突細胞與其中CD4＋樹突細胞和CD8＋樹突細胞的比例，並且觀察骨髓細胞中樹突前驅細胞比例，最後針對這些比例之變化，觀察是否因為細胞凋亡而導致的。
實驗結果：母體長期暴露低劑量DEHP會導致F1幼鼠在經OVA致敏化的情況，脾臟中典型樹突細胞的比例與細胞數顯著下降，在骨髓細胞中樹突前驅細胞的比例也有下降的趨勢，並誘發走向細胞凋亡，而在脾臟中CD4+CD8－典型樹突細胞比例顯著上升，在CD4－CD8+典型樹突細胞比例則明顯下降。在經OVA致敏化的F1成鼠，結果發現脾臟中典型樹突細胞的比例與細胞數顯著下降，骨髓細胞中樹突前驅細胞比例無差異，而樹突前驅細胞會偏向B220+的亞群，並且也會誘發樹突前驅細胞走向細胞凋亡，而在脾臟中CD4+CD8－典型樹突細胞比例顯著上升，在CD4－CD8－典型樹突細胞比例則明顯下降。
結論：本研究發現了母體暴露DEHP會影響F1小鼠之樹突細胞恆定作用，而這樣的變化可能是導致肺部發炎較嚴重的原因。

Abstract
Introduction: Di (2-ethylhexyl) phthalate (DEHP) is widely used in plastic products such as polyvinyl chloride plastics. DEHP is not covalently bound to the plastic matrix, so DEHP exposure to the environment is easy, resulting in contamination of the external environment. Our previous studies found that maternal exposure to DEHP enhanced the severity of airway allergic inflammation in the offspring as compared to the control.
Aim: The dendritic cell (DC) plays an important role in the pathogenesis of asthma, therefore, the aim of this study is to clarify the effect of maternal DEHP exposure on DC homeostasis in F1 offspring.
Method: To simulate the ways in which humans are affected by exposure to DEHP, we established an asthma model of offspring after maternal exposure to DEHP and analyzed the percentages and numbers of splenic DCs and subsets in F1 offspring. We also observed DC precursors in bone marrow of offspring. Finally, we analyzed the apoptosis of DCs and DC precursors.
Result: After low-dose and long-term exposure to DEHP, the OVA-immunized F1 neonate mice were observed. We found that the percentage and numbers of splenic cDCs were significantly decreased in DEHP-exposed F1 neonates. In addition, the percentages of bone marrow DC precursors were also decreased in DEHP group. This may be due to the increased apoptotic rates of DC precursors in DEHP F1 offspring. We also found that percentage of the CD4+CD8－ DCs was increased and the percentage of CD4－CD8+ DCs was decreased in the DEHP F1 spleen. In the immunized adult DEHP F1 mice, the percentage and cell number of splenic cDCs were also decreased. Although the percentage of DC precursors was not different in these two groups, the percentage of B220+ cells in DC precursors was increased in DEHP group. We also found that the percentage of apoptotic DC precursors was increased, the percentage of CD4+CD8－ DCs was also increased and the percentage of CD4－CD8－ DCs was decreased in DEHP F1 offspring.
Conclusion: These results indicate that maternal exposure to DEHP may influence the DC homeostasis and enhance the severity of allergic lung inflammation in the F1 offspring.

目錄
致謝 ii
摘要 iii
Abstract iv
前言 1
1. 氣喘（Asthma）: 1
1-1. 氣喘簡介 1
1-2. 氣喘之母體繼代現象 2
2. 氣喘之免疫機制 2
2-1. 氣喘之先天性免疫機制 2
2-2. 氣喘之後天性免疫機制 3
3. 樹突細胞（dendritic cell；DC） 4
3-1. 樹突細胞簡介 4
3-2. 樹突細胞之分化過程 6
3-3. 脾臟之樹突細胞類型 7
3-4. 典型樹突細胞亞群之功能 8
4. 內分泌干擾因子（Endocrine disruptor chemical；EDC） 9
4-1 環境內分泌干擾因子之簡介 9
4-2 鄰苯二甲酸二（2-乙基己基）酯（DEHP）之簡介 11
4-3 DEHP之人體暴露與代謝 11
4-4 DEHP對人體的影響 12
4-5 DEHP之母體暴露影響 13
4-6 DEHP與氣喘相關研究 14
研究目的 16
實驗材料及方法 17
1. 實驗用小鼠 17
2. DEHP暴露方式 17
3. 幼鼠氣喘－動物模式 18
4. 成鼠氣喘之動物模式 19
5. 脾臟細胞處理 19
6. 骨髓細胞處理 20
7. 細胞表面抗原染色 21
8. 脾臟樹突細胞類型分析（dendritic cell） 22
9. 骨髓細胞之樹突前趨細胞分析（DC precurosr） 22
10. 細胞凋亡分析（Annexin V） 23
11. 統計方法 23
12. 本實驗分析細胞分群所使用的抗體 24
實驗結果 25
母體長期暴露低劑量DEHP會影響F1小鼠的脾臟樹突細胞之比例與細胞數 25
母體長期暴露低劑量DEHP會影響F1小鼠骨髓細胞中樹突前驅細胞的比例 26
母體長期暴露低劑量DEHP會誘發F1小鼠骨髓細胞中樹突前驅細胞走向細胞凋亡 27
母體長期暴露低劑量DEHP會誘發F1小鼠脾臟典型樹突細胞亞群偏向CD4+典型樹突細胞 28
結論 30
討論 32
結果圖表 38
參考文獻 54

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