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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 劉貞佑(Chen-Yu Liu) | |
| dc.contributor.author | Yun-Siang Jhang | en |
| dc.contributor.author | 張芸湘 | zh_TW |
| dc.date.accessioned | 2022-11-24T09:24:56Z | - |
| dc.date.available | 2022-11-24T09:24:56Z | - |
| dc.date.copyright | 2021-08-18 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-04 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81630 | - |
| dc.description.abstract | "前言：磷酸三丁酯（TBP）和磷酸三（2-丁氧基乙基）酯（TBEP）多應用於阻燃劑上。由於用途廣泛、易於釋放，已在環境甚至人體中被發現。雖然 TBP 和TBEP 半衰期短，因有可能在脂質中積累的特性，使大眾關注它們對健康所帶來的危害。現今對於 TBP 和 TBEP 對人體的相關研究仍不足，先前的研究顯示 TBP和 TBEP 會導致代謝紊亂、神經毒性、內分泌干擾和致癌等影響。特別是，TBP和 TBEP 可以影響基因表達，它們誘導 Caco-2 結腸癌細胞損傷，而 TBP 有可能通過非基因毒性機制誘導膀胱癌。這些證據讓我們想深入研究 TBP、TBEP 和結直腸癌之間的關聯。本研究目的為 (1) 找出與暴露 TBP 和 TBEP 有關 DNA 甲基化水平會改變的潛在基因，以及 (2) 基因 DNA 甲基化的改變是否與 TBP 和TBEP 暴露相關的健康危害有關。 研究方法：本研究是於彰化市的一項巢式病例對照研究（包含結直腸癌組、腺瘤組與對照組）， 並使用社區整合式篩檢數據進行分析。被診斷患有其他癌症或診斷日期在篩查日期之前的樣本將被排除在我們的研究之外。暴露物濃度分析由陳家揚教授實驗室進行測量。我們使用 Illumina MethylationEPIC BeadChip 微陣列測量血液樣本中 DNA 甲基化水平。晶片分析包括過濾、標準化以及針對細胞類型和批次效應做校正。研究人群將被分為兩組已進行後續分析，包含癌症相關研究人群（排除腺瘤組樣本）和代謝合併症相關研究人群（排除結直腸癌組樣本），暴露物濃度將進行對數轉換。差異甲基化探針分析（DMP）會應用三個回歸模型做分析，包括模型一是單變量，模型二針對性別和年齡進行校正，模型三則是針對性別、年齡和吸煙狀況進行校正。會選擇 p 值小於 5E-05、有對應到基因名並且出現在三個模型中的重複基因進行討論。p 值小於 0.005 且在未分組模型三找到的基因將進行 KEGG 路徑分析。我們利用 Bumhunter 方法中的置換（permutation）步驟來分析 742,496 個探針中的差異甲基化區域 (DMR)。將選擇每組中 p 值小於 0.05 的前三個 DMR 和於三組間重疊的 DMR 進行討論。表觀遺傳年齡的計算有五種方法，包括 Horvath、Hannum、Weidner、ELOVL2、FHL2。使用 SAS 9.4 和 R 3.6.3 軟體進行統計分析和繪圖。 研究結果：暴露與代謝合併症相關參數間的關聯性沒有統計顯著發現。在癌症研究人口的 DMP 分析裡，TBP 分析的模型 1 中發現 2 個基因（MYH10 、R3HDM2）， 而 TBEP 分析中則在三個模型間共同發現 5 個重疊基因（PDZRN3、ZNF521、TDRD1、 LHPP 、 LOC100128253）。 值得注意的是，TBEP 分析中發現 KCNMA1（cg23533270，β= 0.25，p 值= 3.14E-05（模型一）） 與 UBXN11（cg00852783，β= -0.77，p 值= 4.69E-05（模型三）），它們的 DNA 甲基化水平在結直腸癌與對照組間具有顯著差異（p 值= 0.045（KCNMA1）； p 值= 0.040（UBXN11））。在代謝合併症的研究人群裡，TBP 的分析中發現兩個重疊基因（PCDHGA2 和 CNTNAP1）。 在沒有校正暴露變相的回歸模型結果顯示 CNTNAP1 （cg21946667，β= -0.60，p 值= 2.67E-05 （模型一）） 的 DNA 甲基化水平與三酸甘油酯（p 值= 0.031（模型一））呈負相關，然而在回歸模型中調整暴露變項後，沒有 DMPs 達到統計顯著性。在 TBP 的 DMR 分析中。MIR886 和 RIBC2 在三個研究人群中被共同發現。在 TBEP 的分析則沒有重疊的 DMR 於三個不同的研究人群間。此外，癌症研究人群的 DMR 分析顯示 CAT（TBP：β= 0.042，p 值= 8.84E-04；TBEP：β= 0.033，p 值= 4.21E-03）在 TBP 和 TBEP 中均有發現且與致癌作用有關。路徑分析顯示大多數基因參與的途徑為致癌作用。在表觀遺傳年齡的分析裡，我們沒有發現暴露與年齡加速間有顯著相關。 討論與結論：我們的研究表明，有些基因甲基化水平與暴露（TBP 和 TBEP）有關。但由於暴露濃度較低，本研究並無發現暴露與代謝合併症參數之間有顯著關聯性，雖然在 DMPs 或 DMRs 中有找到一些基因與致癌作用或是與發炎、神經系統相關疾病有關。然而，有些基因的 DNA 甲基化改變與我們假設不一致且所造成的健康效應與我們研究試圖探索的健康影響無關。為了確認暴露對於健康的影響，未來仍須進一步探索暴露、DNA 甲基化水平和健康影響間之關聯性。 " | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T09:24:56Z (GMT). No. of bitstreams: 1 U0001-0408202110595000.pdf: 2593110 bytes, checksum: e10e158fe36627ea8a702c968d67e909 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 口試委員會審定書 i 誌謝 ii 摘要 iii Abstract vi Contents ix List of Figures xii List of Tables xiii Chapter 1 Introduction 1 1.1 Tributyl phosphate and tris(2-butoxyethyl) phosphate 1 1.1.1 Usage 1 1.1.2 Environmental distribution 1 1.1.3 Metabolism 3 1.1.4 Health effects 4 1.2 Colorectal cancer 6 1.2.1 The incidence of colorectal cancer in Changhua community 6 1.2.2 The association between exposure and colorectal cancer 7 1.3 DNA methylation 8 1.4 DNA methylation age 9 1.5 Study aims 11 Chapter 2 Materials and methods 12 2.1 Study population 12 2.1.1 Study design 12 2.1.2 Data collection 13 2.2 Exposure measurement of TBP and TBEP 14 2.2.1 Qualitative exposure assessment 14 2.2.2 Quantitative exposure assessment 14 2.2.3 Validation testing 15 2.3 Analysis of DNA methylation 16 2.3.1 DNA extraction and quality control 16 2.3.2 Microarray for DNA methylation analysis 17 2.4 DNA methylation age 17 2.5 Statistical analysis 18 2.5.1 ChAMP analysis 20 Chapter 3 Results 29 3.1 Descriptive statistics 29 3.2 The potential health effects were associated with exposure 31 3.3 ChAMP data analysis 32 3.3.1. Differential methylated probes (DMPs) 33 3.3.2. Pathway analysis 37 3.3.3. Differentially methylated regions (DMRs) 38 3.4 DNA methylation age 40 Chapter 4 Discussion 42 4.1 The comparison of exposure concentration with other studies 42 4.2 The genes related to exposure in previous studies 43 4.3 The function of differential methylated probes (DMPs) found in our study 46 4.3.1. Tributyl phosphate 46 4.3.2. Tris(2-butoxyethyl) phosphate 50 4.4 The function differential methylated region found in our study 54 4.4.1. Tributyl phosphate 54 4.4.2. Tris(2-butoxyethyl) phosphate 59 4.5 The association between exposure and DNA methylation age acceleration 63 4.6 Strengths and limitations 64 Chapter 5 Conclusions 67 Reference 68 Supplements 101 | |
| dc.language.iso | en | |
| dc.subject | 磷酸三丁酯（TBP） | zh_TW |
| dc.subject | 彰化 | zh_TW |
| dc.subject | DNA 甲基化 | zh_TW |
| dc.subject | 磷酸三（2-丁氧基乙基）酯（TBEP） | zh_TW |
| dc.subject | 表觀遺傳學 | zh_TW |
| dc.subject | Changhua | en |
| dc.subject | Epigenetics | en |
| dc.subject | tris(2-butoxyethyl) phosphate (TBEP) | en |
| dc.subject | Tributyl phosphate (TBP) | en |
| dc.subject | DNA methylation | en |
| dc.title | 暴露磷酸三正丁酯與磷酸三(2-正丁氧乙基) 酯對彰化地區民眾基因甲基化與健康效應的影響 | zh_TW |
| dc.title | Effects of Tributyl Phosphate (TBP) and Tris(2-butoxyethyl) Phosphate (TBEP) on DNA Methylation Levels and Health Effects in the Changhua Communities | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳美蓮(Hsin-Tsai Liu),潘文驥(Chih-Yang Tseng),盧子彬 | |
| dc.subject.keyword | 磷酸三丁酯（TBP）,磷酸三（2-丁氧基乙基）酯（TBEP）,表觀遺傳學,DNA 甲基化,彰化, | zh_TW |
| dc.subject.keyword | Tributyl phosphate (TBP),tris(2-butoxyethyl) phosphate (TBEP),Epigenetics,DNA methylation,Changhua, | en |
| dc.relation.page | 109 | |
| dc.identifier.doi | 10.6342/NTU202102068 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2021-08-05 | |
| dc.contributor.author-college | 公共衛生學院 | zh_TW |
| dc.contributor.author-dept | 環境與職業健康科學研究所 | zh_TW |
| Appears in Collections: | 環境與職業健康科學研究所 | |
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|---|---|---|---|
| U0001-0408202110595000.pdf Restricted Access | 2.53 MB | Adobe PDF |
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