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標題: | 以核磁共振為主的代謝體學探討合成皮作業勞工暴露二甲基甲醯胺對其體內代謝體之影響 Characterization of the Urinary Metabolic Patterns from N,N-Dimethylformamide Exposed Workers in the Synthetic Leather Factory by 1H NMR-based Metabolomic |
作者: | Pai-Chen Cheng 鄭百宸 |
指導教授: | 林靖愉(Ching-Yu Lin) |
關鍵字: | 二甲基甲醯胺,代謝體學,核磁共振,毒性,腎臟傷害, N, N-dimethylformamide,metabolomics,nuclear magnetic resonance (NMR),toxicity,renal injury, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 二甲基甲醯胺(N, N-Dimethylformamide)是合成皮製程中最常使用的有機溶劑之一,過去許多的研究指出長期暴露於二甲基甲醯胺的職場中將對人體產生許多的不良反應,其中以肝臟細胞的損害最受到重視。過去針對二甲基甲醯胺的諸多相關研究中,均以生物偵測及空氣採樣的方法,分別測量尿液中(二甲基甲醯胺代謝物如NMF, HMMF)或血液中肝臟功能的相關指標 (ALT, AST) 及空氣中二甲基甲醯胺的濃度來推估濃度與真實暴露的相關性,並進一步提出能夠反映出真實暴露的生物指標。以最容易取得的生物液-尿液來說,這種只單一看外生性代謝物(NMF, HMMF)的方式確實能夠反映出二甲基甲醯胺真實的暴露,但卻無法瞭解二甲基甲醯胺對體內內生性代謝物所造成的擾動及可能的致毒機制。
本研究為瞭解職場中二甲基甲醯胺對於人體健康上的影響,遂以核磁共振為主的代謝體學配合尿液中外生性代謝物(NMF)等指標,分析合成皮勞工尿液中水溶性代謝物的改變,藉以探討二甲基甲醯胺暴露對人體尿液代謝體的影響,且進一步評估其造成的危害及可能機制,並試圖指出尿液樣本中可做為毒物暴露在健康效應上的探討及生物指標的開發。 研究結果顯示,在從事合成皮的勞工當中,DMF暴露程度的多寡將會使體內的能量代謝產生影響(2-oxo-isovalerate、3-hydroxybutyrate 在高暴露下顯著上升,citrate在高暴露下顯著下降),且可能造成腎臟傷害(dimethylamine、dimethylglycine在高暴露下顯著上升,creatinine在高暴露下顯著下降);而一天當中的工作暴露也可能對腎臟造成傷害(dimethylamine、dimethylglycine在高暴露下顯著上升)。另一方面,在代謝體與暴露溶劑的相關性探討中,我們透過線性迴歸的檢定發現DMF暴露濃度的多寡與體內能量代謝具有顯著相關性,但對於反應腎臟傷害的許多生物標記中並無發現有統計上顯著相關,且我們同時在甲苯與代謝體的相關性當中發現甲苯與DMF在體內能量代謝上均有一致的結果,所以我們認為合成皮工廠勞工體內代謝的改變,可能是由DMF與甲苯共同暴露所造成。代謝體學以二甲基甲醯胺暴露程度的樣本分類過程中,我們建議以生物偵測的方式為主,空氣採樣為輔,因生物偵測較能反映出身體實際的暴露,對於體內整體的代謝體變化較能無誤差的揭示。 根據整體研究設計而言,以非侵入性的樣本為主,將代謝體學應用於環境與職業衛生上是一種非常合適的方法,除了能與過去傳統方法獲得的結果相互對照之外,更能進一步找出毒物造成的危害及可能機制,且建議具有代表性的生物指標,本研究對於未來將代謝體學的方法應用在環境與職業衛生上將會有很大的發展與突破。 N,N-dimethyformamide (DMF) is one of organic solvents widely used in the production of synthetic leather. Previous studies have confirmed that DMF may cause various harmful effects in the occupational environment especially on the liver injury which has been most concerned. Measuring the urinary NMF (a metabolite of DMF) concentration and ambient DMF concentration by biological monitor and air sampling methods is the most common in the previous studies. The exposure biomarkers on reflecting the real DMF exposure have been confirmed. However, the metabolic effects caused by DMF and possible mechanism of DMF toxicity are still unknown. In order to realize the urinary metabolic patterns after the DMF exposure, NMR-based metabolomics approach was applied to investigate the perturbation of metabolome from workers of synthetic leather factory. The objective of this study is to elucidate the possible molecular mechanism of DMF induced adverse effects and attempt to discover candidate biomarkers on the health effect perspective especially in the non-invasive urine sample. Results indicated that high level of DMF exposure in the occupational environment may cause the energy disturbance (increased level of 2-oxo-isovalerate and 3-hydroxybutyrate and decreased level of citrate) and potentially give adverse effects on kidney (increased level of dimethylamine and dimethylglycine) while the daily exposure of DMF is relating to the kidney injuries (increased level of dimethylamine and dimethylglycine). The correlation between NMF and other solvent exposure and changes of metabolome has also been examined. Based on regression coefficient, we discovered that changes of energy related metabolites are depending on DMF and toluene exposure level while the metabolites biomarkers on the renal injury are not statistic significant. We also conclude that the metabolic changes are a consequence mainly resulted from the combination exposure of DMF and toluene in the synthetic leather factory. Proceeding the classification of the DMF exposure in metabolomics, we suggested that the biological monitor data gave the unbiased estimation on real exposure level than air sampling data. These results may facilitate the application on different occupational environment for biomarker development and mechanistic study in the future. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47253 |
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顯示於系所單位: | 環境衛生研究所 |
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