博碩士論文 109821001 詳細資訊



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姓名 林儀臻(I-Chen Lin)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 研究雙特松對HepG2細胞之DNA修復的影響
(The impact on DNA repair in HepG2 cells treated with Dicrotophos)
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摘要(中) 有機磷類 (Organophosphate, OP) 是一種用於防治害蟲的殺蟲劑。由於其實用性高且對環境毒性低，它們被認為是使用最廣泛的殺蟲劑。雙特松 (Dicrotophos, Dic) 是一種含有有機磷的殺蟲劑，由於其目標害蟲之種類十分廣泛，故被大量地使用於各國。儘管其有效性已被證實，但已有推測認為Dic可能與人類的基因毒性作用、基因永久突變與疾病有關。然而，關於此基因毒性之損傷的機制卻尚未有詳細的闡述。先前，透過鹼性彗星試驗，我們揭露了Dic可能引起DNA單股斷裂的能力。為了進一步找出此單股斷裂可能造成的影響，我們從先前處理過Dic的細胞中獲取無細胞提取物 (cell-free extract)，再利用彗星試驗之體外DNA 修復檢測來評估其鹼基切除修復 (Base excision repair, BER) 和核苷酸切除修復 (Nucleotide excision repair, NER) 的活性。在有Dic處理過的組別中，其所產生的DNA尾巴之長度較未處理過之對照組短，說明BER和NER修復蛋白之切割能力皆受到了Dic的抑制。因此，我們可以得出BER和NER在Dic處理後均被抑制之結論。有鑑於未修復之單股斷裂有可能發展成DNA之雙股斷裂，我們進一步使用中性彗星試驗和H2AX之磷酸化 (γH2AX) 以檢測Dic處理後，細胞所產生之雙股斷裂的情形。兩種試驗皆顯示在Dic處理後，細胞雙股斷裂之情形有顯著升高的現象。為了進一步再探討細胞針對此雙股斷裂之情形的反應機制，我們分別利用了同源重組修復 (Homologous recombination, HR) 試劑與西方墨點法來評估HR與非同源性末端黏合之修復 (Non-homologous end joining, NHEJ) 的活性或修復蛋白之基因表現量。結果顯示，在HR活性試驗中，與未處理過之對照組相比，Dic顯著地抑制了HR之修復活性。此外，NHEJ之重要相關基因Ku80蛋白表現量，同樣在經Dic處理後也顯著降低。考慮到錯誤配對之DNA修復 (Mismatch repair, MMR) 是防止DNA複製與修復之錯誤的重要機制，我們再度進一步利用西方墨點法測定了在Dic處理後，MMR之重要相關基因msh2和mlh1的基因表現情形。結果顯示，在Dic處理過之細胞中，其MSH2和MLH1之蛋白表現量皆有顯著下調的趨勢，表示MMR修復之效能有可能在Dic處理過後發生改變。總結來說，我們揭示了在Dic處理後所引起的基因毒性可以對多個DNA修復途徑之活性產生負面的影響。本研究針對雙特松之潛在負面影響提供了更詳細的分子機制，可有助於調節人體健康的發展。
摘要(英) Organophosphates (OP) are a group of insecticides used for pest control. Due to their high level of utility, yet relatively low environmental toxicity, they are considered the most widely used insecticides. Dicrotophos (Dic), an OP insecticide, is extensively used due to its broad spectrum of target pests. Despite its effectiveness, Dic has been speculated to be asso-ciated with genotoxic effects, gene mutagenicity, and diseases in humans. However, the mechanism in terms of genotoxic insults has not been fully explicated. Previously, by using the alkaline comet assay, we revealed Dic could induce DNA sin-gle-strand breaks (SSBs). To further determine the response of SSBs, we assessed the activity of Base excision repair (BER) and Nucleotide excision repair (NER) via the comet-based in vitro DNA repair assay, utilizing a cell-free extract derived from cells that were formerly subjected to Dic. In the Dic-treated groups, the length of the DNA tail was shorter compared to the non-exposed groups, indicating the incision ability of BER/NER repair enzymes was decreased by Dic. Thus, we concluded that both BER and NER were suppressed after Dic exposure. Given the fact that unrepaired SSBs could potentially develop into DNA double-strand breaks (DSBs), we further evaluate the extent of DSBs following Dic exposure by implementing the neutral comet assay, along with the assessment of the expression level of the phosphorylated form of H2AX (γH2AX). Both assays revealed a notable increase in the level of DSBs after Dic ex-posure. To determine the response of DSBs, homologous recombination (HR) activity and non-homologous end joining (NHEJ) were evaluated via the HR assay kit and western blot, respectively. Our results showed Dic significantly attenuated the HR repair activity com-pared to the non-exposed control. Moreover, the expression level of the NHEJ-associated gene, Ku80 was also significantly reduced after Dic exposure. Considering that Mismatch repair (MMR) is a vital mechanism for preventing errors in DNA replication and repair, we were prompted to investigate the expression of MMR-associated genes, msh2 and mlh1, fol-lowing Dic exposure. Our results showed that both MSH2 and MLH1 protein expression were notably downregulated in Dic-treated cells, suggesting the alteration of the MMR effi-cacy might occur after Dic exposure. Collectively, we highlighted that genotoxicity caused by Dic exposure negatively modulates the activity of multiple DNA repair pathways. This present study provides a more detailed mechanism into the potential adverse effects of Di-crotophos, which may further help in modulating health complications.
關鍵字(中) ★ 雙特松
★ DNA損傷
★ DNA修復
★ BER
★ NER
★ MMR
★ HR
★ NHEJ
★ HepG2		 關鍵字(英) ★ Dicrotophos
★ DNA damage
★ DNA repair
★ BER
★ NER
★ MMR
★ HR
★ NHEJ
★ HepG2
論文目次 中文摘要 i
Abstract iii
Acknowledgments v
Table of contents vi
List of figures ..ix
Chapter 1 Introduction 1
1-1 Background 1
1-1-1 Organophosphate insecticide - Dicrotophos (Dic) 1
1-1-2 Pesticide and DNA damage response (DDR) 2
1-1-3 Pesticide and the repair of Single-Strand DNA damage 3
1-1-4 Pesticide and the repair of Double-Strand DNA damage 4
1-1-5 Pesticide and Mismatch repair (MMR) 5
1-2 Specific aim 6
1-3 Research Framework 6
Chapter 2 Material and Methods 8
2-1 Cell cultures 8
2-2 Cell counting 9
2-3 Chemical 10
2-4 MTT assay 10
2-5 Neutral comet assay 10
2-6 Comet-based in vitro DNA repair assay 12
2-7 Protein extraction 13
2-8 Bradford protein assay 14
2-9 Protein sample preparation 14
2-10 Protein electrophoresis 15
2-11 Western blot 16
2-12 Plasmid DNA isolation 16
2-13 Homologous recombination activity assay 17
2-14 Cell cycle analysis 18
2-15 Apoptosis assay 19
2-16 Statistical analysis 20
Chapter 3 Results 21
3-1 Dic suppressed the cell viability in HepG2 cells 21
3-2 Dic decreased the BER repair capacity in HepG2 cells 21
3-3 Dic decreased the NER repair capacity in HepG2 cells 22
3-4 DNA double-strand breaks were provoked after Dic exposure in HepG2 cells 23
3-5 Dic impaired the HR activity in HepG2 cells 24
3-6 Dic altered the expression level of NHEJ-related gene, Ku80 25
3-7 Dic altered the expression of MMR-related genes, MSH2 and MLH1 25
Chapter 4 Discussion and Conclusion 26
4-1 The selection of cell line 26
4-2 The toxicology of Dic in HepG2 cells 26
4-3 The impact of Dic on both BER and NER activity in HepG2 cells 27
4-4 The genotoxic impact, especially the induction of double-strand breaks caused by Dic 30
4-5 The impact of Dic on both HR and NHEJ in terms of double-strand breaks formation
32
4-6 The impact of Dic on MMR repair in HepG2 cells 34
4-7 The impact of Dic on apoptosis in HepG2 cells 35
4-8 The impact of Dic on Cell cycle in HepG2 cells 35
4-9 Conclusion 36
Chapter 5 References 38
Chapter 6 Figures 46
Chapter 7 Appendices 55
Appendix 7-1 Supplementary Figure 1 55
Appendix 7-2 Supplementary Figure 2 56
Appendix 7-3 List of materials and reagents 57
Appendix 7-4 Solution preparation 58
Appendix 7-5 List of antibodies 60
Appendix 7-6 List of assay kits 61
Appendix 7-7 SDS-PAGE gel recipe 61
Appendix 7-8 Experimental setup for HR assay 62
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指導教授 陳師慶 粘仲毅(Ssu-Ching Chen Chung-Yi Nien) 審核日期 2023-8-16
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