博碩士論文 105881603 詳細資訊



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姓名 王伊娃(Eva Ari Wahyuni)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 單一與複合有機磷農藥對人類肝臟細胞和斑馬魚胚胎的細胞毒性與遺傳毒性之作用
(The cytotoxicity and genotoxicity of single and combined organophosphate pesticides in human liver cells and zebrafish embryos)
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摘要(中) 本研究使用人類肝臟細胞HepG2和斑馬魚胚胎評估單獨或混合有機磷農藥terbufos和fenthion的毒性，以確定遺傳毒性機制。我們使用單細胞凝膠電泳實驗和 H2AX 磷酸化 (γH2AX) 分析遺傳毒性，結果顯示細胞在與terbufos和/或fenthion相互混合時會導致 DNA 雙鍵斷裂 (DSB)。當濃度為40 µM，複合藥物幾乎沒有藥物毒性、基因毒性以及對同源重組 (HR) 活性的影響。在 HepG2 細胞，當細胞處理藥物後，同源重組(HR) 修復基因Xrcc2表達降低；另一方面，複合藥物也降低了非同重組NHEJ 修復基因Xrcc6的表達，此外，儘管只有 terbufos或fenthion可降低 XRCC2 蛋白表達，有機磷農藥仍可影響所有處理過的細胞Ku70的表達，無論是正調控還是負調控。在斑馬魚胚胎實驗中，暴露在有機磷農藥24 小時後，fenthion是造成 HR 基因（Rad51 和 Rad18）發生破壞的唯一有效物質；相比之下，複合藥物增加了 Rad51 和 Xrcc2（HR 基因）的表達水平，單獨使用terbufos或fenthion則阻礙了 Rad51、Rad18、Xrcc2 和 Xrcc6 基因表達。此外，fenthion或複合藥物降低斑馬魚的孵化率。總之，terbufos、fenthion和複合藥物在 HepG2 細胞和斑馬魚胚胎中誘導了 DNA 雙鍵斷裂。此外，我們發現terbufos和fenthion複合藥物顯示出拮抗作用並降低HepG2和斑馬魚胚胎的毒性，這是一個新發現。
摘要(英) The individual and combined pesticides of terbufos and fenthion were evaluated using human hepatoma cell line HepG2 and zebrafish embryos to specify the genotoxicity mechanism. To analyze the genotoxicity, the neutral comet assay and H2AX phosphorylation (γH2AX) were used and showed that exposed cells caused DNA double strand breaks (DSBs) when mixed with terbufos and/or fenthion. At the level of equimolar concentration (40 µM), the pesticide combination showed almost no toxicity, genotoxicity, and effects on homologous recombination (HR) activity. Within HepG2 cells, cells exposed to the individual and combined treatment showed decreased expression of Xrcc2, which is an HR repair gene; on the other hand, the combined pesticides decreased expression of one of the Non-homologous end joining (NHEJ) repair genes, called Xrcc6. Moreover, although only terbufos or fenthion managed to lessen XRCC2 protein expression, Ku70 affected all cells treated irrespective of up- or downregulation. In zebrafish embryos, fenthion was found to be the only effective substance to cause HR genes (Rad51 and Rad18) to experience disruption following exposure for 24 h; in contrast, the combined pesticides increased the level of Rad51 and Xrcc2 (HR genes) expression while at the same time impeding Rad51, Rad18, Xrcc2, and Xrcc6 genes with terbufos or fenthion only. Furthermore, fenthion or the pesticide combination impaired the hatching rate of zebrafish. To conclude, terbufos, fenthion, and the combined pesticides induced DSBs in the HepG2 cells and zebrafish embryos. Furthermore, we found terbufos and fenthion show antagonism in combination and reduce the toxicity in HepG2 or zebrafish embryos, this is a novel finding.
關鍵字(中) ★ NHEJ
★ HR
★ Terbufos
★ Fenthion
★ γH2AX		 關鍵字(英) ★ NHEJ
★ HR
★ Terbufos
★ Fenthion
★ γH2AX
論文目次 (A). Referred papers:iii
(B). Abstracts presented in meetings: iii
中文摘要iv
Abstract.vi
Acknowledgementsvii
Table of Contents .viii
List of Figuresxi
List of Tablesxiii
Abbreviations..xiv
Chapter 1: Introduction .. 1
1.1 Organophosphate pesticides (OPs) 1
1.1.1 OPs genotoxicity . 1
1.1.2 OPs and DNA repair 3
1.2 Single and mixture exposure of OPs 4
1.2.1 Additivity:.. 5
1.2.2 Synergism: . 5
1.2.3 Antagonism: .. 5
1.3 Terbufos and fenthion 6
1.4 DNA DSB repair 8
1.4.1 Homologous recombination (HR) 9
1.4.2 Non-homologous end joining (NHEJ) 10
1.5 Human liver cells 11
1.6 Zebrafish embryos 12
1.7 Specific aim of the thesis 13
Chapter 2: Materials and Methods 16
2.1 Cell culture. 16
2.2 Pesticide exposure . 16
2.3 Cell viability assay. 17
2.4 Zebrafish maintenance and embryo exposure 17
2.5 Comet assays. 18
2.6 HR assay.. 19
2.7 RNA isolation and qRT-PCR assays. 19
2.8 Western blotting . 20
2.9 Statistical analysis . 20
Chapter 3: Results. 21
3.1 Cellular response to cell viability and DNA damage after delivery
of terbufos, fenthion, and their combinations to human liver cells 21
3.2 The correlation of single or combined pesticide exposure in HR activity in HepG2 cells 22
3.3 The expression of repair genes and proteins related to HR and NHEJ repair pathways in HepG2 cells treated with terbufos,
fenthion, and their combination .. 23
3.4 The expression of repair genes to HR and NHEJ repair pathways in zebrafish embryos treated with terbufos, fenthion, and their
combination 25
3.5 Single exposure to terbufos or fenthion induced DNA damage in zebrafish embryos . 25
Chapter 4: Discussion . 27
4.1 To determine if HepG2 and L-02 cells are appropriate, a model was tested to detect the genotoxicity mechanism of OPs (terbufos
or fenthion). 27
4.2 Genotoxicity concentration of terbufos or fenthion. 28
4.3 Antagonistic interactions of the combined pesticides. 29
4.4 Terbufos or fenthion impacted gene and protein repair pathways 30
4.5 Zebrafish embryo used as in vivo model of OPs (terbufos or fenthion) .. 33
Summary . 35
References.. 36
Figures.. 54
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指導教授 陳師慶 喻秋華(Ssu-Ching Chen Chiou-Hwa Yuh) 審核日期 2021-10-12
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