TNT經由ROS介導之內質網壓力及粒線體失衡誘導人類肝臟細胞凋亡

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黃暐婷(Wei-Ting Huang) 查詢紙本館藏

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生命科學系

論文名稱

TNT經由ROS介導之內質網壓力及粒線體失衡誘導人類肝臟細胞凋亡
(2, 4, 6-Trinitrotoluene induces apoptosis by ROS-mediated endoplasmic reticulum (ER) stress and mitochondrial dysfunction in HepG2 cells)

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摘要(中)

三硝基甲苯 (2, 4, 6,-trinitrotoluene,TNT)，又稱作黃色炸藥。目前被人們廣泛使用於工業開發、軍事等用途。但有許多文獻指出，TNT在其製造、爆炸等過程中，恐會對環境或是生物體造成汙染，引發造血、生殖、神經系統方面的損傷，甚至是肝癌的發生。然而，TNT造成肝毒性的分子機制仍需要被進一步探討。因此，本研究選擇使用人類肝癌細胞株(HepG2)，觀察TNT對其所造成之影響，並更進一步探討其致毒機制。
在本研究中，我們發現TNT會導致細胞存活率明顯降低，且有基因損傷(DNA damage)的發生。利用RNA-seq觀察經由不同濃度TNT處理24小時前、後的細胞基因發現TNT會誘導細胞基因發生變異。而參考KEGG資料庫顯示：其恐造成包括線粒體功能障礙、內質網壓力和細胞生長週期停滯等影響。因此，本研究利用JC-1染劑測定粒線體膜電位，證實了TNT確實會破壞粒線體膜電位，導致粒線體功能障礙的發生。此外，TNT也會造成蛋白Bax/Bcl-2的比率上升、procaspase 9/3的表現量降低，促使細胞凋亡。而藉由觀察到內質網壓力信號基因BiP、PDI、PERK、CHOP和oxidase 1 like α (Erol-Lα)信號的提升，也證實了內質網壓力的發生。
最後，我們也研究了活性氧化物質(ROS)對於TNT誘導細胞毒性的作用機制，TNT進入細胞後在代謝的過程中，恐產生大量的ROS。除此之外，轉錄因子CHOP能誘導Ero1α的轉錄作用，進一步催化PDI的再氧化，增加胞內的氧化壓力。而藉由抗氧化劑N-acetyl-cysteine (NAC)的預處理能有效降低基因損傷、細胞凋亡和內質網傳遞途境訊號異常的比率。TNT所造成的HepG2細胞DNA損傷，是由於ROS所引起的內質網壓力和粒線體功能失衡所造成。

摘要(英)

2,4,6-Trinitrotoluene (TNT) has been commonly used as an explosive throughout the world. TNT was reported to cause numerous adverse effects including liver cancer. However, the detailed molecular mechanisms underlying TNT-induced liver toxicity still need to be elucidated. At first, we found that TNT significantly decreased cell viability and induced DNA damage. Thereafter, RNA-seq was utilized to detect the differential genes in comparison with cells before and after TNT (30 g/mL and 80 g/mL) treatment for 24 h. It was observed that TNT induced many differential genes, and the Kyoto Encyclopedia of Genes and Genome (KEGG) analysis showed that the diverse biological functions and metabolic pathways affected included mitochondrial dysfunction, ER signaling stress, and cell cycle arrest. Mitochondrial dysfunction was evidenced by the loss of mitochondrial membrane potential followed by the increase in the ratio of Bax/Bcl-2 and caspase 3/7 activity as well as the decreased expression of procaspase 9/3, indicating that apoptosis had occurred. In addition, the expressions of some ER stress-related signaling genes and proteins including BiP, PDI, PERK, CHOP, and oxidase 1 like α (Erol-Lα) had increased. Next, we investigated the role of ROS in TNT-induced cellular toxicity. The levels of DNA damage, apoptosis, and ER stress-signaling pathways were alleviated when the cells were pretreated with the ROS scavenger N-acetyl-cysteine (NAC). Notably, we also demonstrated that TNT induced ROS overproduction. These results indicated that TNT caused the ROS-dependent apoptosis via ER stress and mitochondrial dysfunction.

關鍵字(中)

★ 2,4,6-三硝基甲苯
★ 細胞凋亡
★ 線粒體功能障礙
★ 內質網壓力
★ 氧化壓力

關鍵字(英)

★ 2,4,6-trinitromethylbenzene
★ Apoptosis
★ Mitochondrial dysfunction
★ ER stress
★ ROS

論文目次

中文摘要 V
Abstract VI
目錄 VIII
圖目錄 X
表目錄 XIII
第一章緒論 1
1-1 三硝基甲苯 (2, 4, 6,-trinitrotoluene,TNT) 介紹 1
1-2 TNT的毒理特性 2
1-2-1 TNT之毒性 2
1-2-2 TNT之致癌性 2
1-2-3 TNT之基因毒性 3
1-3 氧化壓力 (Oxidative stress) 4
1-3-1 自由基 (Free radicals)介紹 4
1-3-2 TNT造成氧化壓力導致基因毒性之探討 5
1-3-3 TNT造成細胞氧化壓力與細胞毒性之探討 6
第二章實驗目的和實驗架構 9
第三章材料與方法 10
3-1 實驗材料 10
3-1-1 使用儀器及廠牌 10
3-1-2 常用藥品與試劑 10
3-2 實驗方法 13
3-2-1 細胞株與細胞培養（Cell cuture） 13
3-2-2 細胞計數（Trypan blue staining and cell counting） 15
3-2-3 細胞存活率分析（MTT assay） 16
3-2-4 細胞內活性氧化物質測定(Reactive oxygen species, ROS) 17
3-2-5 測定DNA損傷程度之彗星試驗(Comet assay) 19
3-2-6 細胞total RNA抽取 (RNA isolation) 21
3-2-7 反轉錄作用（Reverse Transcription） 22
3-2-8 DNA/RNA電泳 23
3-2-9 細胞總蛋白質萃取( Protein extraction) 24
3-2-10 蛋白質濃度測定(RC.DC protein assay) 25
3-2-11 蛋白質電泳 26
3-2-12 蛋白質轉漬： 28
3-2-13 西方免疫墨點法 (Western immune blotting) 28
3-2-14 細胞內粒線體膜電位分析 30
3-2-15 即時定量聚合酶連鎖反應 (qRT-PCR) 31
3-2-16 次世代定序(Next Generation Sequencing, NGS)………………………..33
第四章結果 344
4-1 TNT對於HepG2細胞之細胞存活率及造成細胞凋亡和DNA損傷之影響 34
4-2 TNT誘導內質網壓力、粒線體功能障礙和影響其他生理功能及路徑 34
4-3 TNT在HepG2細胞中誘導內質網壓力 35
4-4 TNT藉由粒線體功能障礙途徑誘導細胞凋亡 35
4-5 ROS的生成在DNA損傷、內質網壓力、粒線體功能障礙、細胞凋亡和死亡所扮演的角色 36
第五章討論 37
第六章圖表 41
第七章參考文獻 72
第八章附錄 78

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指導教授

陳師慶(Ssu-Ching Chen)

審核日期

2016-8-29

推文