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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58596完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳惠文(Huei-Wen Chen) | |
| dc.contributor.author | Szu-Yao Lien | en |
| dc.contributor.author | 連思堯 | zh_TW |
| dc.date.accessioned | 2021-06-16T08:21:27Z | - |
| dc.date.available | 2018-01-20 | |
| dc.date.copyright | 2014-02-25 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-01-28 | |
| dc.identifier.citation | 1. Lamb JCt, Chapin RE, Teague J, Lawton AD, Reel JR. Reproductive effects of four phthalic acid esters in the mouse. Toxicology and applied pharmacology 1987;88:255-69.
2. Chauvigne F, Menuet A, Lesne L, et al. Time- and dose-related effects of di-(2-ethylhexyl) phthalate and its main metabolites on the function of the rat fetal testis in vitro. Environmental health perspectives 2009;117:515-21. 3. Hauser R. Urinary phthalate metabolites and semen quality: a review of a potential biomarker of susceptibility. International journal of andrology 2008;31:112-7. 4. Hauser R, Meeker JD, Singh NP, et al. DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites. Hum Reprod 2007;22:688-95. 5. Cobellis L, Latini G, De Felice C, et al. High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis. Hum Reprod 2003;18:1512-5. 6. Colon I, Caro D, Bourdony CJ, Rosario O. Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environmental health perspectives 2000;108:895-900. 7. Rusyn I, Peters JM, Cunningham ML. Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Critical reviews in toxicology 2006;36:459-79. 8. Karle VA, Short BL, Martin GR, et al. Extracorporeal membrane oxygenation exposes infants to the plasticizer, di(2-ethylhexyl)phthalate. Critical care medicine 1997;25:696-703. 9. Gillum N, Karabekian Z, Swift LM, Brown RP, Kay MW, Sarvazyan N. Clinically relevant concentrations of di (2-ethylhexyl) phthalate (DEHP) uncouple cardiac syncytium. Toxicology and applied pharmacology 2009;236:25-38. 10. Posnack NG, Swift LM, Kay MW, Lee NH, Sarvazyan N. Phthalate exposure changes the metabolic profile of cardiac muscle cells. Environmental health perspectives 2012;120:1243-51. 11. Martinez-Arguelles DB, McIntosh M, Rohlicek CV, Culty M, Zirkin BR, Papadopoulos V. Maternal in utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate affects the blood pressure of adult male offspring. Toxicology and applied pharmacology 2013;266:95-100. 12. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity. Cancer research 1987;47:943-6. 13. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of immunological methods 1983;65:55-63. 14. Nakao K, Yamada T, Itoh H, et al. Possible antagonistic relationship between atrial natriuretic peptide (ANP)-brain natriuretic peptide (BNP) system and brain renin-angiotensin system in central control of body fluid and cardiovascular function. Clinical and experimental hypertension Part A, Theory and practice 1988;10:1289-91. 15. Gardin JM, Wagenknecht LE, Anton-Culver H, et al. Relationship of cardiovascular risk factors to echocardiographic left ventricular mass in healthy young black and white adult men and women. The CARDIA study. Coronary Artery Risk Development in Young Adults. Circulation 1995;92:380-7. 16. Starling MR. Left ventricular-arterial coupling relations in the normal human heart. American heart journal 1993;125:1659-66. 17. Georgakopoulos D, Mitzner WA, Chen CH, et al. In vivo murine left ventricular pressure-volume relations by miniaturized conductance micromanometry. The American journal of physiology 1998;274:H1416-22. 18. Yang B, Larson DF, Watson R. Age-related left ventricular function in the mouse: analysis based on in vivo pressure-volume relationships. American Journal of Physiology - Heart and Circulatory Physiology 1999;277:H1906-H13. 19. Pacher P, Nagayama T, Mukhopadhyay P, Batkai S, Kass DA. Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats. Nature protocols 2008;3:1422-34. 20. Mizuno Y, Yoshimura M, Harada E, et al. Plasma levels of A- and B-type natriuretic peptides in patients with hypertrophic cardiomyopathy or idiopathic dilated cardiomyopathy. The American journal of cardiology 2000;86:1036-40, A11. 21. Lopaschuk GD, Jaswal JS. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. Journal of cardiovascular pharmacology 2010;56:130-40. 22. Fabiato A, Fabiato F. Use of chlorotetracycline fluorescence to demonstrate Ca2+-induced release of Ca2+ from the sarcoplasmic reticulum of skinned cardiac cells. Nature 1979;281:146-8. 23. Nabauer M, Callewaert G, Cleemann L, Morad M. Regulation of calcium release is gated by calcium current, not gating charge, in cardiac myocytes. Science 1989;244:800-3. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58596 | - |
| dc.description.abstract | DEHP鄰苯二甲酸二(2-乙基己基)酯【Bis (2-ethylhexyl) phthalate】是一種常用的塑化劑，可以增加塑膠的延展性與彈性，為一種環境荷爾蒙。在哺乳類中， DEHP進入體內後會快速的代謝產生其代謝物鄰苯二甲酸- 單- 乙基己基酯 (MEHP, mono-ethylhexyl phthalate)和2-辛醇（2-ethylhexanol），在醫療環境下，血液樣本中都可測得DEHP及MEHP的濃度，在先前的許多文獻中以指出DEHP可於生殖系統造成毒性以並且增加罹患乳癌及子宮頸癌風險已被廣泛研究；然而鄰苯二甲酸鹽對於心臟的不利影響相關文獻報導有限。而這些塑化劑暴露是否會造成臨床上心臟功能的變化就是我們要探討的題目本研究為了瞭解心臟手術醫療環境中的塑化劑對心肌功能的影響。
從細胞層次，動物實驗二方面分析。然而鄰苯二甲酸鹽對於心臟的不利影響相關文獻報導有限。其中有文獻指出在暴露臨床相關濃度DEHP處理之下的新生大鼠心肌細胞以微陣列晶片分析基因表現，其結果顯示DEHP會造成與心律不整相關基因受到改變，並且造成心肌細胞中重要的連接蛋白connexin 43喪失造成心肌損傷，但影響機制仍然不明白。本研究主在探討臨床相關濃度的DEHP對於心臟功能之影響，以小鼠口服暴露DEHP 八週之後，以心臟超音波分析心臟功能，研究中發現暴露DEHP之下的小鼠心跳頻率(heart rate)及左心室收縮能力(Left-ventricular fractional shortening)與單純服用玉米 油控制組有統計意義上的差異，在第十六週以微導管測量舒張末期容積與壓力(pv-loop)，在pv-loop檢測下發現暴露DEHP的小鼠收縮功能下降，包括，在低劑量組及高劑量組別之收縮末期壓力 -容積關係(ESPVR)斜率比控制組小並且造成預緊搏出功(PRSW)及末期收縮壓的下降。在細胞實驗方面的研究結果顯示以大鼠心肌細胞暴露DEHP 及其代謝產物MEHP後造成胞內處主要儲存鈣離子胞器肌漿網(SR) 上回收鈣離子通道SERCA2(SR Ca2+-ATPase)表現量下降，進一步探討病理組織鑑定以確認經DEHP所造成的心肌受損程度，這可能導致心臟功能障礙，此研究顯示了長期暴露於DEHP具有在雌性小鼠的造成心血管不良影響的第一個證據。 | zh_TW |
| dc.description.abstract | Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer have been added to polyvinyl chloride (PVC) products to enhance PVC flexibility and durability. DEHP is a well- known endocrine-disrupting chemical. In mammals, DEHP is rapidly hydrolyzed to its monoester, mono-(2-ethylhexyl) phthalate (MEHP) by esterase. The level of DEHP and its metabolite MEHP could be detectable before and after cardiopulmonary bypass (CPB) in the blood sample. The developmental and reproductive toxicity of DEHP are well recognized, however, little is known about the potential adverse effects and the mechanism of phthalates on the heart. Here, the effects and mechanism of DEHP exposure on cardiomyocytes were examined in both in vitro and in vivo models. Our data showed that high dosage DEHP and MEHP (10-100 μM) treatment for 48hr could causes the reduce of the cells viability, as well as, the activity of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) in H9C2 cardiomyoblast. The mRNA and protein level of SERCA2 declined after treating with DEHP and MEHP. Most importantly, long term exposure of DEHP could significantly affect cardiac functions in female mice . Left ventricular (LV) pressure–volume analysis revealed that less steep ESPVR and PRSW was markly drecreased in DEHP-treated animals.Left ventricular end-systoloic pressure(ESP) was decreased in DEHP-treated mice compared with control group. All these indicated exposure to DEHP would causes cadiac dysfunction at the level readurable clincal medial of heart.Our data documented that exposure to DEHP can lead to cardiac toxicity effects by reducing cardiomyocytes viability and decreasing SERCA2 expression, which may lead to cadiac dysfunction . This is the first evidence showing that long term exposure to DEHP has adverse cardiovascular effects in the adult female mice. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T08:21:27Z (GMT). No. of bitstreams: 1 ntu-103-R00447009-1.pdf: 4545059 bytes, checksum: 03eb6be7cc9898dbf0ec8a1af9da2ae0 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 謝誌...................................................I
縮寫表(Abbreviations).................................II 中文摘要...............................................III 英文摘要.................................................V 目錄 ..................................................VI 圖目錄(List of Figures) ......................................................................................................VIII 表目錄(List of Tbles)............................................................................................................IX 第一部分DEHP對於心肌細胞之毒性探討..........................................................................1 第一章 緒論.............................................................................................................................2 1.1塑化劑磷苯二甲酸(2-乙基己基)酯 ....................................................... ................2 1.2塑化劑磷苯二甲酸(2-乙基己基)酯的毒理背景 .................................................... 3 1.3 醫療環境中暴露塑化劑磷苯二甲酸(2-乙基己基)酯 (DEHP) ............................. 4 1.4 DEHP與心血管疾病相關研究 .............................................................................. 5 1.5研究動機 ................................................................................................................ 5 第二章 實驗材料與方法.........................................................................................................7 2.1實驗材料 ................................................................................................................ 8 2.1.1一般藥品 .............................................................................................................. ......8 2.1.2細胞株培養(cell line)................................................................................................. 9 2.2細胞生長試驗(MTT assay) .............................................................................................. 9 2.3 蛋白質萃取 .................................................................................................................... 10 2.4西方墨點法(Western blot analysis).................................................................................10 2.4.1蛋白質轉印（Protein transfer）和免疫墨點法（immunoblot）...........................11 2.5核醣核酸(RNA)萃取及cDNA之製備... .................................................................... ..11 2.6定量RT-PCR (Quantitative Real-Time Polymerase Chain) ........................................... 12 2.7免疫螢光染色 ................................................................................................................. 12 2.8統計分析 ......................................................................................................................... 12 第三章 實驗結果(Results)....................................................................................................13 3.1 暴露臨床劑量DEHP及MEHP使大鼠心肌細胞株存活率下降 ....................... 14 3.2 暴露臨床劑量DEHP及MEHP使心臟毒性相關基因指標上升 ....................... 14 3.3 暴露臨床劑量DEHP及MEHP造成SERCA2a蛋白質及基因表現下降 ......... 14 第二部分 慢性暴露DEHP之動物模式探討DEHP於心血管方面影響.........................16 第一章 實驗動物模式...........................................................................................................17 1.1 動物模式 .................................................................................................... .........17 1.2實驗流程 .............................................................................................................. 17 VII 第二章 實驗材料與方法 Materials and Methods.............................................................18 2.1小鼠心臟超音波(In-Vivo Ultrasound Imaging System) ........................................ 18 2.2 小鼠壓容積環（Pressure-VolumeLoop, PV-Loop) ............................................. 18 2.2.1法蘭克－史達林機轉（The Frank-Starling Mechanism） .............................. 18 2.2.2 血壓容積環（Pressure-VolumeLoop, PV-Loop) ............................................ 19 2.2.3參數分析 ......................................................................................................... 20 2.3血液生化值分析 .................................................................................................. 21 2.4心臟切片之製備(Slice preparation) ...................................................................... 21 2.5 蘇木素及伊紅染色法(Hematoxylin & Eosin stain)................................................21 2.6 Masson trichrome (MT)染色 ................................................................................ 21 2.7 組織免疫化學染色(Immunohistochemistry) ..................................................... ..22 第三章 實驗結果 (Results)..................................................................................................23 3.1慢性暴露DEHP小鼠心臟超音波 ....................................................................... 23 3.2慢性暴露DEHP小鼠心臟之收縮能力 ............................................................... 23 3.3慢性暴露DEHP小鼠心臟纖維化增生 .............................................................. .25 3.4慢性暴露DEHP小鼠測量心肌受損指標之前腦排鈉利尿肽(pro-BNP)表現上升 ................................................................................................................................... 25 3.5 慢性暴露DEHP小鼠測量之主動脈血管厚度增加 ........................................... 25 第四章 討論(Discussion)......................................................................................................26 總結.........................................................................................................................................29 參考文獻.................................................................................................................................30 | |
| dc.language.iso | zh-TW | |
| dc.subject | 心肌細胞 | zh_TW |
| dc.subject | 鄰苯二甲酸二(2-乙基己基)酯 | zh_TW |
| dc.subject | cardiomyocytes | en |
| dc.subject | DEHP | en |
| dc.title | 鄰苯二甲酸酯類對於心臟毒性的探討-從細胞到動物模式 | zh_TW |
| dc.title | Phthalate ester -induced cardio toxicity in vitro and in vivo | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 紀乃新(Nai-Hsin Chi),李君儀(Jiun-Yi Li),陳文彬(Wen-Pin Chen) | |
| dc.subject.keyword | 鄰苯二甲酸二(2-乙基己基)酯,心肌細胞, | zh_TW |
| dc.subject.keyword | DEHP,cardiomyocytes, | en |
| dc.relation.page | 55 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-01-28 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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