2015-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658883摘要：天然環境中的重金屬砷，在外長期食入後已經證實與皮膚及其他臟器的癌症發生有 關。除了天然環境中的砷以外，高量的砷也存在於許多化學劑品中，因此可能會對於職 業中長期皮膚暴露的後造成不良影響。流行病學分析顯示職業性皮膚的砷暴露，會增加 皮膚癌，特別是在陽光曝曬位置的皮膚。此外，職業性的皮膚砷暴露，就算停止暴露後， 也可能在數十年後造成皮膚癌。對於皮膚砷暴露的急性皮膚影響，目前尚不明確。另外， 皮膚砷暴露造成皮膚癌的機轉也不清楚，因此仍無有效的預防方法。慢性發炎和許多臟 器的癌變有關，例如肝癌，大腸癌等。發炎是否與砷暴露後的急性及慢性病理機轉有關， 未曾被證實。我們的初步動物實驗顯示，相較於單獨砷暴露或單獨紫外光B照射，皮膚 在砷及紫外光B共暴露後，呈現相當明顯的表皮增厚及異常分化，其中未分化的角質細 胞大量增加。此外，DNA斷裂也較單一暴露明顯增加。我們發現到皮膚在砷及紫外光B 共暴露後會有較明顯的發炎反應，也觀察到有發炎體路徑的活化。利用特定基因剔除小 鼠以抑制發炎實驗中，這些共暴露後對表皮的急性不良影響有明顯的減少，甚至接近正 常。因此，我們假說，相較於單獨砷暴露或單獨紫外光B照射，砷及紫外光B共暴露 後可以協同性地透過活化發炎體而增加表皮細胞增生及擾亂其分化，而反覆的共暴露可 以增加皮膚癌變的機會。為測試此假說，我們在此計晝中有幾個目標需要達成：1.特化砷 及紫外光B共暴露對表皮細胞動態及分化的影響2.探討砷及紫外光B共暴露造成表皮 增生及表皮異常分化的分子機轉3.測試長期反覆的砷及紫外光B共暴露是否會增加皮 膚癌的機會，並研究透過調控與發炎相關的分子機轉是否可以減少皮膚癌發生。<br> Abstract: Long-term intake of arsenic has been shown to be associated with increased risks of various skin and internal malignancies. Epidemiological analysis showed that occupational skin exposure to arsenic increased risks of skin cancer formation, especially on the sun-exposed skin even decades after previous exposure. However, the acute effect of cutaneous arsenic exposure on skin has not been well characterized. In addition, how cutaneous arsenic exposure leads to skin carcinogenesis is unknown. Chronic inflammation has been shown to be associated with increased risk of carcinogenesis both in skin and other organs. However, whether inflammation is involved in the pathogenesis from arsenic exposure is unknown. Our preliminary animal study showed that, compared with cutaneous exposure to either arsenic or ultraviolet light B (UVB) along, single cutaneous co-exposure to arsenic and UVB was able to induce prominent epidermal hyperplasia and abnormal differentiation with expansion of undifferentiated keratinocytes. In addition, increased DNA damage was also observed. We also found that cutaneous co-exposure to arsenic and UVB induced an inflammatory response that was associated with activation of inflammasome pathway. In addition, inhibition of the inflammatory response in specific gene knockout mice abolished the detrimental effect on epidermis. Hence, we hypothesize that, compared with cutaneous exposure to either arsenic or ultraviolet light along, cutaneous co-exposure to arsenic and ultraviolet light synergistically increases epidermal proliferation and perturbs keratinocyte differentiation through activating inflammasome pathway and repeated co-exposure can enhance skin cancer formation. To test our hypothesis, there are several aims to be achieved in this proposal: 1. To characterize the effect of cutaneous co-exposure to arsenic and UVB on epidermal cell dynamic and differentiation 2. To identify the underlying molecular mechanisms that perturb keratinocyte differentiation and proliferation 3. To test whether long-term repeated cutaneous co-exposure to arsenic and UVB enhances skin carcinogenesis and to prevent skin carcinogenesis by modulating the underlying molecular mechanisms associated with inflammation.砷紫外光共暴露皮膚癌發炎預防arsenicultraviolet lightco-exposureskin cancerinflammationprevention