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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 蔡懷楨(Huai-Jen Tsai) | |
dc.contributor.author | Chen-Che Su | en |
dc.contributor.author | 蘇陳則 | zh_TW |
dc.date.accessioned | 2021-06-08T00:33:23Z | - |
dc.date.copyright | 2013-07-03 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-06-26 | |
dc.identifier.citation | Agency UEP (2000) Perfluorooctyl Sulfonate: Proposed Significant New Use rule, (Agency vFRUSEP ed) pp 62319-62333.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17724 | - |
dc.description.abstract | 全氟碳化物是一群被廣泛應用於工業界的人工合成的穩定化學物質,並且被認為是內分泌的干擾因子,正因為如此才受到大家的關注。但有關於全氟碳化物中的PFUA、PFDoA、PFDS和PFBA毒性資料相當稀少,因此本研究的目標在於對PFUA、PFDoA、PFDS和PFBA等全氟碳化物做初步的毒理試驗並研究其藥物動力學。雄性SD大鼠(N=4)經單一胃管餵食暴露不同劑量,分別為0、0.5和 5 mg/kg。接下來收集88天的血液及尿液樣本並利用新開發的線上固相萃取液相層析串聯質譜儀(LC-MS/MS)方法進行分析。這些資料將被用來建構藥物動力學參數。大鼠血清中的雌激素、黃體素、睪固酮、膽固醇、LH、FSH則利用市售的ELISA試劑進行檢驗。PFUA和PFDoA在尿液中皆無法被偵測到。PFUA和PFBA的藥物動力學參數並沒有顯著差異,顯示在雄性大鼠中0.5到5 mg/kg之間的劑量呈現線性的藥物動力學,然而PFDoA則否,呈現非線性的藥物動力學。PFUA在高暴露組(5 mg/kg)發現雌激素顯著增加而黃體素顯著降低。PFDS睪固酮顯著降低,PFBA則呈現雌激素顯著下降,顯示PFUA、PFDS及PFBA可能會影響固醇類激素的生合成。這些結果顯露了PFUA、PFDS和PFBA為環境內分泌干擾物,值得我們更進一步研究全氟碳化物對人類健康影響的機制。 | zh_TW |
dc.description.abstract | Perfluorinated chemicals (PFCs), considered as endocrines disrupters and widely used in industries, are a group of stable man-made organic compounds. The potential health effects caused by PFCs exposures have been of great concerns. However, there is no toxicity-related study on PFUA, PFDoA, PFDS, and PFBA. Therefore, this study was aimed to study pharmacokinetics and preliminary toxicity test for PFUA, PFDoA, PFDS, and PFBA. Male SD rats (n=4) were treated with a single dose of PFUA by oral gavage at 0, 0.5 and 5 mg/kg. Subsequently, urine and serum samples were collected for 88 days and analyzed with a newly-developed on-line solid-phase extraction liquid chromatography tandem mass spectrometry (LC-MS/MS) method. These data were fit with pharmacokinetic models with the Win-Nonlin software. Concentration of serum estradiol, progesterone, testosterone, cholesterol, FSH and LH were measured by ELISA using commercial rat ELISA kits. PFUA and PFDoA were not detectable in urine. No significant differences were observed in PFUA and PFBA in pharmacokinetic parameters at 0.5 and 5 mg/kg to suggest linear pharmacokinetics. However, PFDoA presented non-linear pharmacokinetics. PFUA at the highest dose caused significant increase in serum estradiol levels but decrease in serum progesterone levels. PFDS at the highest dose caused significant decrease in serum testosterone levels. PFBA at the highest dose decrease in serum estradiol levels, implying that PFUA, PFDS and PFBA may affect steroidogenic hormone biosynthesis of male SD rats. These results first reveal that PFUA, PFDS and PFBA are environment endocrine disrupters and deserve further studies on its potential effects on human health. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T00:33:23Z (GMT). No. of bitstreams: 1 ntu-102-R00b43020-1.pdf: 8413349 bytes, checksum: c1b9bcc92741061b57bd1b8a67c59003 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 目錄
口試委員會審定書 i 致謝 ii 摘要 iii Abstract iv 第一章 前言 1 1.1全氟碳化物之物化特性 1 1.2 全氟碳化物的環境流布 1 1.2.1 水 2 1.2.2 大氣 2 1.2.3 食物 3 1.2.4 動物 3 1.3 全氟碳化物的流行病學研究 3 1.3.1 全氟碳化物的致癌性 5 1.3.2 全氟碳化物的生殖發育毒性 6 1.3.3 全氟碳化物的肝毒性 7 1.3.4 全氟碳化物造成荷爾蒙失調 7 1.4 全氟碳化物人體的暴露途徑以及暴露程度 9 1.5 全氟碳化物的代謝機制 11 1.6 全氟碳化物的藥物動力學研究 13 1.7 全氟碳化物的分析方法 15 1.8全氟碳化物的分析儀器介紹 16 1.8.1 線上固相萃取,On-Line SPE (Solid-phase extraction) 16 1.8.2 液相層析串聯質譜儀,LC-MS-MS (Liquid chromategraph-tandem mass Spectrometry) 16 1.9 藥物動力學概述 17 1.9.1 藥物動力學模式 17 1.9.2 藥物動力學參數 19 1.9.3 線性與非線性藥物動力學 21 第二章 目的 22 第三章 材料與方法 23 3.1樣本來源 23 3.1.1化學標準品 23 3.1.2實驗動物 23 3.2動物實驗 25 3.3檢體上機前處理 25 3.4 分析方法介紹 26 3.5 校正曲線配製 27 3.6 血清生化指標檢驗 27 3.7 應用軟體 27 第四章 結果與討論 28 4.1動物實驗 28 4.1.1實驗動物體重 28 4.1.2實驗動物解剖外觀 28 4.2樣品分析 30 4.2.1 全氟碳化物檢量線 30 4.2.2 全氟碳化物於血液及尿液樣本分析圖譜 30 4.3 全氟碳化物於大鼠血清及尿液中的濃度變化 31 4.3.1 PFBA 31 4.3.2 PFDS 31 4.3.3 PFUA 31 4.3.4 PFDoA 32 4.4 全氟碳化物的藥物動力學參數 33 4.4.1 PFBA 33 4.4.2 PFDS 33 4.4.3 PFUA 33 4.3.4 PFDoA 34 4.4 全氟碳化物的生化指標 35 4.4.1 PFBA 35 4.4.2 PFUA 35 4.4.3 PFDS 36 第五章 結論與建議 39 參考文獻 85 圖目錄 圖一、描述各種陰離子蛋白對全氟碳化物在肝臟的排泄過程扮演的角色 40 圖二、以胃灌食後大鼠的血液中PFBS濃度變化值 40 圖三、以靜脈注射後食蟹猴血液中PFBS濃度變化值 41 圖四、暴露PFBS的勞工體內血液濃度的變化 42 圖五、SD大鼠血液中PFNA濃度變化 42 圖六、CD1小鼠血液中PFNA濃度變化 43 圖七、PFOA和PFOS在大鼠體內PBPK model的架構 43 圖八、左圖暴露每公斤15毫克PFOS、右圖暴露於每公斤1毫克PFOS(雄鼠) 44 圖九、左圖暴露每公斤15毫克PFOS、右圖暴露於每公斤1毫克PFOS(雌鼠) 44 圖十、暴露每公斤25毫克的PFOA(雄鼠) 45 圖十一、暴露每公斤25毫克的PFOA(雌鼠) 45 圖十二、線上固相萃取液相層析串聯式質譜儀裝置圖 46 圖十三、三段式四極柱質譜儀示意圖 46 圖十四、動物實驗設計流程圖 47 圖十五、前處理步驟 48 圖十六、暴露PFUA後SD大鼠的體重變化 49 圖十七、暴露PFDoA後SD大鼠的體重變化 49 圖十八、暴露PFDS後大鼠體重變化情形 50 圖十九、大鼠解剖外觀 50 圖二十、高暴露組(5 mg/kg)大鼠腎臟外觀,箭頭處為明顯的水泡 51 圖二十一、PFUA血清基質檢量線(1 ~ 100 ng/mL) 51 圖二十二、PFUA血清基質檢量線(10 ~ 500 ng/mL) 52 圖二十三、PFDoA血清基質檢量線(1 ~ 100 ng/mL) 52 圖二十四、PFDoA基質檢量線(25 ~ 500 ng/mL) 53 圖二十五、PFDS血清基質檢量線(1 ~ 100 ng/mL) 53 圖二十六、PFDS血清基質檢量線(100 ~ 500 ng/mL) 54 圖二十七、PFBA血清基質檢量線(1~ 100 ng/mL) 54 圖二十八、PFBA血液基質檢量線(100~ 500 ng/mL) 55 圖二十九、PFBA尿液基質檢量線(1 ~ 100 ng/mL) 55 圖三十、PFBA尿液基質檢量線(100 ~ 500 ng/mL) 56 圖三十一、分析配製血清含PFBA標準品(10 ng/mL)質譜層析圖 56 圖三十二、分析配製血清含PFDS標準品(10 ng/mL)質譜層析圖 57 圖三十三、分析配製血清含PFUA標準品(10 ng/mL)質譜層析圖 57 圖三十四、分析配製血清含PFDoA標準品(10 ng/mL)質譜層析圖 58 圖三十五、分析配製尿液含PFBA標準品(10 ng/mL)質譜層析圖 58 圖三十六、分析PFUA(5 mg/kg)處理的大鼠血清樣本的層析圖譜 59 圖三十七、分析PFUA(0.5 mg/kg)處理的大鼠血清樣本的層析圖譜 59 圖三十八、分析PFUA控制組的大鼠血清樣本的層析圖譜 60 圖三十九、分析PFDoA(5 mg/kg)處理的大鼠血清樣本的層析圖譜 60 圖四十、分析PFDoA(0.5 mg/kg)處理的大鼠血清樣本的層析圖譜 61 圖四十一、分析PFDoA控制組的大鼠血清樣本的層析圖譜 61 圖四十三、分析PFDS(0.5 mg/kg)處理的大鼠血清樣本的層析圖譜 62 圖四十四、分析PFDS控制組的大鼠血清樣本的層析圖譜 63 圖四十五、分析PFBA(5 mg/kg)處理的大鼠血清樣本的層析圖譜 63 圖四十六、分析PFBA(0.5 mg/kg)處理的大鼠血清樣本的層析圖譜 64 圖四十七、分析PFBA控制組的大鼠血清樣本的層析圖譜 64 圖四十八、分析PFBA(5 mg/kg)處理的大鼠尿液樣本的層析圖譜 65 圖四十九、分析PFBA(0.5 mg/kg)處理的大鼠尿液樣本的層析圖譜 65 圖五十、分析PFBA控制組的大鼠尿液樣本的層析圖譜 66 圖五十一、大鼠經PFBA處理後其血清濃度隨時間變化圖 66 圖五十二、大鼠經PFBA處理後其尿液濃度隨時間變化圖 67 圖五十三、大鼠尿液中PFBA的累積排放量 67 圖五十四、PFDS高暴露組(5mg/kg)暴露24小時後的糞便層析圖 68 圖五十五、大鼠經PFUA處理後其血清濃度隨時間變化圖 68 圖五十六、大鼠經PFDoA處理後其血清濃度隨時間變化圖 69 圖五十七、固醇類激素生合成路徑 69 圖五十八、暴露PFUA後經H&E染色後的控制組肝臟組織切片 70 圖五十九、暴露0.5 mg/kg PFUA後經H&E染色後肝臟組織切片 70 圖六十、暴露5 mg/kg PFUA後經H&E染色後肝臟組織切片,箭頭處為脂肪滴 71 圖六十一、暴露PFUA後經H&E染色後的控制組睪丸組織切片 71 圖六十二、暴露0.5 mg/kg PFUA後經H&E染色後的控制組睪丸組織切片 72 圖六十三、暴露5 mg/kg PFUA後經H&E染色後的控制組睪丸組織切片 72 表目錄 表一、 不同國家水體中全氟碳化物的含量 73 表二、 不同國家空氣中全氟碳化物的含量 74 表三、 全氟碳化物在不同地區魚類體內含量 75 表四、 全氟碳化物在不同區域動物血液中的含量 76 表五、 全氟碳化物在不同生物體內的半衰期 77 表六、 各國居民血液樣本中全氟碳化物濃度 78 表七、全氟碳化物的質譜參數設定 79 表八、全氟碳化物分析梯度及質譜參數游離化最佳條件 80 表九、SD大鼠暴露PFUA後肝、腎及睪丸重量和其相對重量 81 表十、SD大鼠暴露PFDoA後肝、腎及睪丸重量和其相對重量 81 表十一、SD大鼠暴露PFDS後肝、腎及睪丸重量和其相對重量 81 表十二、SD大鼠暴露PFBA後肝、腎及睪丸重量和其相對重量 82 表十三、PFBA於不同劑量的藥物動力學參數 82 表十四、PFUA於不同劑量的藥物動力學參數 82 表十五、PFDoA於不同劑量的藥物動力學參數 83 表十六、PFBA於不同劑量的生化指標 83 表十七、PFUA於不同劑量的生化指標 84 表十八、PFDS於不同劑量的生化指標 84 | |
dc.language.iso | zh-TW | |
dc.title | 全氟碳化物對雄鼠之毒性及其藥物動力學研究 | zh_TW |
dc.title | Pharmacokinetics and toxicity of perfluorinated chemicals in male rats | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 吳焜裕(Kuen-Yuh Wu) | |
dc.contributor.oralexamcommittee | 鄭尊仁,江素瑛,陳家揚 | |
dc.subject.keyword | 全氟碳化物,藥物動力學,液相層析串聯質譜儀,線上固相萃取, | zh_TW |
dc.subject.keyword | Perfluorinated chemicals,pharmacokinetics,Liquid chromatography tandem mass spectrometry,On-line solid-phase extraction, | en |
dc.relation.page | 95 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2013-06-27 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
顯示於系所單位: | 分子與細胞生物學研究所 |
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