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研究生:林怡妏
研究生(外文):Lin, I-Wen
論文名稱:雙酚A影響內分泌細胞固醇類荷爾蒙生合成之訊息傳遞路徑
論文名稱(外文):Bisphenol A affects steroidogenic signaling pathway in endocrine cells.
指導教授:藍心婕
指導教授(外文):Lan, Hsin-Chieh
口試委員:應靜雯胡孟君
口試委員(外文):Ying, Ching-WenHu, Meng-Chun
口試日期:2012-05-25
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生物及解剖學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:51
中文關鍵詞:雙酚A固醇類荷爾蒙生合成訊息傳遞內分泌細胞
外文關鍵詞:Bisphenol A (BPA)SteroidogenesisCYP11A1P450sccc-JunEndocrine cells
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在日常生活中,某些化合物具有干擾內分泌系統的功能因而被稱為內分泌干擾物(EDCs)。其中一種內分泌干擾物是雙酚A(BPA),雙酚A是構成塑膠和樹脂的單體,這類化合物可以經由食物鏈累積,並可在動物或人體中被偵測到,在先前的研究發現,雙酚A在人體血清中的含量平均濃度約為1-100 nM。
目前已知雙酚A會參與在發育、生殖和惡性腫瘤的過程中,藉由模擬天然的荷爾蒙—雌二醇 (Esradiol)並經由雌激素受體干擾內分泌的調控機制,但近幾年許多的研究發現,雙酚A不僅藉由雌激素受體影響內分泌,也會改變細胞中固醇類荷爾蒙合成酵素的訊息和表現。我們檢測了老鼠腎上腺腫瘤細胞(Y1)和睪丸萊迪氏細胞(MA10)中的某些特定分子,用以瞭解雙酚A對荷爾蒙合成之訊息傳遞路徑的影響。從細胞活性檢測結果得知,當細胞處理200 μM 雙酚A 24小時後,將導致60%的細胞死亡,但在低濃度雙酚A (10 nM)處理長達96小時下,並不會影響細胞存活率。我們接著發現雙酚A會誘發CYP11A1的轉錄活性,如同受到cAMP的刺激一般。從免疫轉漬法的結果則發現,雙酚A會影響類固醇的訊息傳遞路徑,Y1與MA10細胞在低濃度長時間的雙酚A處理下,均會誘導細胞中P450scc的基因表現與c-Jun蛋白質磷酸化增加。除此以外,雖然Erk1/2的磷酸化也受到雙酚A的影響,但卻出現長效性與短效性的不同表現型態。並且經由抑制劑處理的實驗結果,更能確定BPA是透過JKK/c-Jun這條路徑影響細胞作用。由上述的實驗結果,本文證實內分泌細胞在長時間、低濃度的雙酚A處理下,會改變MAPK訊息路徑以及固醇類荷爾蒙的合成。
Some artificial chemicals that used in our life are classified as endocrine disrupting chemicals (EDCs) since they can interrupt the functions of endogenous hormone. One of EDCs is bisphenol A (BPA). BPA is monomer in polycarbonate plastic and constituent of resins used in food packaging and dentistry. This chemical can be accumulated along food chains and is detectable in tissues of both wildlife and humans. In the previous studies of human, BPA levels in serum are around 1-100 nM.
It is well known that BPA is involved in development, reproduction, and malignant diseases by mimicking the natural hormone 17β-estradiol (E2) and interfering with endocrine regulation though estrogen receptors (ERs) interaction. However in recent years, many studies have reported that expose of BPA not only disturbed endocrine via ER but also altered cell signaling and expression of steroidogenic enzymes. To investigate the influence of BPA on signaling transduction pathway of the steroidogenesis, we examined the effects of some target molecules in Y1cells (adrenal cortical cell of mouse) and MA10 cells (Leydig cell of mouse). From the results of cell viability assay, 200μM of BPA treatment for 24 hours lead to 60% cell death, and BPA would not affect cell viability with low concentration (10 nM) and long time treatment (96hrs). The data indicate that BPA would not cause cell death until over 100 μM which is much higher than the concentration detected in human serum. Then we found that the promoter activity of CYP11A1 could be induced by BPA just like cAMP stimulation in these two endocrine cells. From the immunoblotting results, we demonstrated that BPA would affect steroidogenic signaling pathway. It induce P450scc expression and c-Jun phosphorylation in both Y1 and MA10 cells. Furthermore, although Erk1/2 phosphorylation was affected by BPA treatment, it shows different pattern for long-time and short-time treatment. Thus, we demonstrated that low level and long time stimulation of BPA in endocrine cells might affect the MAPK signaling pathway and steroidogenesis.
『圖』『表』目錄………………………………………………………… II
中文摘要……………………………………………………………………III
Abstract …………………………………………………………………… IV
第一章、緒言………………………………………………………………1
第二章、材料與方法………………………………………………………11
第三章、結果………………………………………………………………16
第四章、討論………………………………………………………………23
第五章、參考文獻…………………………………………………………30
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