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| 題名: | 砷酸鈉在大白鼠嗜鉻細胞上毒性與機制的探討;Studies on the pentavalent arsenate toxicity in rat pheochromocytoma PC12 cells |
| 作者: | 王慧淇;Huei-Chi Wang |
| 貢獻者: | 中國醫藥大學醫學研究所 |
| 關鍵詞: | 砷;五價無機砷;arsenic;pentavalent arsenate |
| 日期: | 1993 |
| 上傳時間: | 2009-12-24 10:58:49 (UTC+8) |
| 摘要: | 中文摘要 砷普遍存在我們的日常生活環境當中。其主要來源為天然形成(如礦石、泥土、空氣和水等)與人造形成(如醫藥、農業使用和工業產生等)兩類。在台灣也有關於砷的污染的文獻報告。砷被視為致癌性類金屬物質，目前證實無機砷的暴露會引發皮膚、膀胱、肝與肺癌。 自然環境中，依其型態大致可以區分為有機砷(Organic arsenic)與無機砷(Inorganic arsenic)兩大類。在無機砷又以五價無機砷(pentavalent；As5+)含量最高，但以三價無機砷(Trivalent；As3+)的毒性最大，所以目前毒物與生物學方面的研究都偏重在三價無機砷相關機制的探討。有藉於此，所以本論文將研究重心放在五價砷的暴露對可能引發的毒性機制探討。 大鼠腎臟腺嗜鉻細胞(PC12 cells)，目前被廣泛應用於研究神經細胞的分化、退化機制與其他神經毒性探討，有文獻報告指出無機砷的暴露，依其細胞種類或暴露劑量的不同，可能引發不同的毒性機制活，進而影響細胞生長、分化、凋亡。然而砷所引發細胞分子機制，對細胞影響目前仍然不明確。所以本論文以細胞體外培養方式(in vitro)細胞模式，給予砷酸鈉暴露，可能引發會引發相關機制的探討。 本論以未分化的PC12細胞做為實驗的模型，以評估五價無機砷的暴露對於PC12細胞引發的變化，也比較五價與三價無機砷暴露可能是否會引發MAPK Kinases的活化， 如(JNK與p38蛋白質)。在本論文實驗結果證實10μM作用24小時既可引發PC12細胞凋亡，且會隨劑量與時間增加細胞凋亡數量也會隨之增加(dose與time dependent)。此外，我們的實驗結果可觀察出，三價無機砷與五價無機砷的處理都可以引發JNK磷酸化；三價無機砷(10 μM處理6小時)JNK磷酸化現象會較五價無機砷明顯(10μM處理24小時)。然而，我們在五價無機砷處理卻直到10 μM作用36小時或是更高劑量五價砷的處理才看到p38磷酸化。在三價無機砷50 μM處理6小時既可引發p38磷酸化。其結果得知，未分化PC12細胞再給予五價或是三價無機砷作用而引發下游啟動的機制可能有重疊之處，但並非完全相同。與先前文獻報告三價砷導致神經細胞的凋亡是經由JNK與p38磷酸化，在本論文實驗結果為，五價無機砷引發PC12細胞的死亡是經JNK磷酸化，沒有p38磷酸化現象。然而，我們需要再進一步的探究其詳細機制。; 英文摘要 Arsenic is widely presented in the environment. Arsenic contamination of the environment could also result from industrial and agricultural uses, such as metal smelting, mining and pesticide applications. Incidents of arsenic contamination have also been reported in Taiwan. Arsenic exposure has been associated with increased risk for cancers of skin, bladder, liver and lung. Arsenic exposure also caused neurotoxic effects on the nervous system and apoptosis in cultured neuronal cells. It has been reported that the neurotoxicity caused by arsenic insult was involved with the increased generation of free radicals and the activation of the mitogen activated kinase pathways. The trivalent inorganic arsenic (arsenite) is the most potent poison of all the forms of arsenic. However, the predominant form of arsenic in nature is the pentavalent arsenate, yet most toxicological studies have been focusing on the toxicity of arsenite. Previous studies also indicated that the cytotoxic mechanisms underlying both trivalent arsenite and pentavalent arsenate might be different yet sometimes overlapping. It is apparent to us that studying and understanding the differential toxic mechanisms is very critical in assessing the risk from arsenic exposure. In this study, we used undifferentiated PC12 cells as our experimental model and assessed the effect of arsenate treatment on PC12 cell. We also investigated and compared the activation of MAPK kinases (JNK and p38 proteins) in response to arsenate and arsenite treatment. Our data have shown that 10 μM pentavalent arsenate treatment for 24 hours would be sufficient to cause significant amount of PC12 cell apoptosis. Besides, the rate of apoptosis is dose and time dependent. Further more, our data indicated that both trivalent and pentavalent arsenic treatment could cause the phosphorylation of JNK, with the trivalent arsenite more potent (10μM, 6hr treatment) than the arsenate (10 μM, 24hr treatment). However, we were not able to detect the phosphorylation of p38 by pentavalent arsenate till after 36 hours of 10μM or higher doses of arsenate treatment; while the trivalent arsenite significantly elicited p38 phosphorylation (50 μM) within 6 hours. Our data indicated that in undifferentiated PC12 cells, the mechanisms underlying both arsenite and arsenate action might be somewhat different. Unlike previously reported that trivalent arsenite caused neuronal apoptosis through phosphorylation of both JNK and p38, the current study implies that PC12 apoptosis induced by pentavalent arsenate might through the activation of JNK but not p38. However, we need further experiment to confirm this. |
| 顯示於類別: | [醫學研究所] 博碩士論文
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