基因多型性對職業苯暴露生物偵測之影響

李曉雯

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基因多型性對職業苯暴露生物偵測之影響

Effects of genetic polymorphism on the biological monitoring of occupational exposure to benzene

李曉雯 , Masters　　Advisor：張火炎　　

繁體中文

NQO1 ； GST ； CYP2E1 ；基因多型性；苯；生物偵測； S-PMA ；血液異常；動力學曲線； Benzene ； genetic polymorphism ； S-PMA ； biological monitoring ； hematopoetic abnormality ； GST ； CYP2E1 ； kenetics ； NQO1

Abstract │ Reference (71) │ Times Cited (1) │ Altmetrics

Abstract 〈TOP〉

苯為工業上常用的有機溶劑，目前苯的生物暴露偵測為量測尿中S-phenylmercapturic acid（S-PMA），而由苯本體代謝至S-PMA所需的酵素包括CYP2E1（Cytochrome P450 2E1）和GST（Glutathione S-transferase），另外過去文獻指出苯毒性主要是苯代謝過程之中間產物benzoquinone所致，其中間產物會導致骨髓毒性（myelotoxicity），影響benzoquinone代謝之酵素為NQO1之調控基因（NAD(P)H:Quinone Oxidoreductase）。CYP2E1、GST及NQO1等酵素之調控基因在人群中皆有基因多型性。因此個體間此類酵素之基因多型性，將可能影響體內苯的代謝情形及健康效應。本研究目的是探討苯代謝酵素CYP2E1以及GST之不同基因多型性對苯暴露之生物指標S-PMA之生物偵測與動力學曲線影響，並探討苯作業員工NQO1之基因多型性對苯暴露造成造血系統不正常所導致之前驅因子之關係。本研究選取國內之職業苯暴露石化業74位員工進行採樣，環境中苯暴露偵測是利用被動式採樣器採集個人作業現場空氣中苯，並以氣相層析儀（GC）火焰離子偵測器（FID）進行分析;生物偵測則是收取苯暴露員工血液、下班前尿液以及部分員工收取工作期間8小時與工作後24小時連續尿液，以高效能液相層析儀結合電灑法串聯式質譜儀 (high performance liquid chromatography- electrospray ionization tandem mass spectrometry, HPLC-ESI-MS/MS)分析尿中苯代謝物S-PMA之濃度，血液樣本則進行血液常規檢查及利用RFLP（Restriction fragment length polymorphism）判定CYP2E1及NQO1基因型，GSTT1及GSTM1則利用PCR（Polymerase chain reaction）進行基因型判定。研究結果發現1.空氣中苯濃度與尿中S-PMA濃度皆呈現對數常態分佈，幾何平均濃度分別為6.52ppb與0.39μg/g Cr，皆遠低於法規容許濃度值或BEI值，說明本研究之員工為低苯暴露族群。2.全部受測員工之空氣中苯濃度與下班前尿中單點S-PMA濃度值呈現顯著線性相關（r=0.39，P<0.01）。3.有參與上班8小時連續尿液收集者空氣中苯濃度與上班8小時期間尿中S-PMA之AUC（area under curve)呈現顯著相關（r=0.62，P <0.05），但與下班前單點尿中S-PMA濃度無關。4.下班後連續24小時尿中S-PMA之AUC在吸煙習慣不同者達顯著差異（P<0.05）。5. CYP2E1、GSTT1、GSTM1及NQO1的allele 頻率與文獻中臺灣人或中國人並無顯著差異，推論所選取的樣本尚足以代表台灣族群。6.下班前尿中S-PMA濃度與苯濃度之自然對數比值其GSTT1有效基因型(non-null）較無效基因型(null)顯著為高（P<0.05）。7. 尿中S-PMA濃度高低與各項血液常規檢查異常並無相關。 8. NQO1雙套變異型T/T較野生型C/C和單套變異型C/T紅血球數目異常之相對危險比顯著較高 (OR＝24.4, 95%CI=3.4-173.4, P<0.05)。因此本研究之結論為1.發現苯的體內總負荷量與空氣中的苯濃度明顯較以單一下班前尿中S-PMA之關係為佳，因此未來在進行低苯暴露的生物偵測可考慮以一段時間之生物指標AUC來評估，較能獲得苯在體內完整的暴露劑量。2.有吸煙習慣者體內的下班後24小時之S-PMA之AUC濃度與職場中空氣中苯濃度暴露相關性甚低(P=0.42)，因此在未來進行低苯暴露之生物偵測時應將員工的吸煙行為加以考慮，以免對低苯暴露者之生物指標產生誤判。3.在基因多型性的研究方面，本研究發現在CYP2E1、GSTM1、GSTT1及NQO1四種基因多型性中，只有GSTT1基因多型性會對下班前單一尿中的生物指標S-PMA造成顯著影響，不同基因多型性對體內連續苯暴露8小時S-PMA之AUC並未有任何顯著影響，可能歸因於連續完整尿液樣本取得不易，導致樣本數過少所致。4.在低苯暴露對體內造血功能的傷害方面，本研究並未發現任何血液常規檢查項目與體內的苯暴露劑量有顯著相關。可能原因為；本研究族群屬於低苯暴露，尚未能產生健康效應；或基因多型性不同所影響。5. NQO1雙套變異型在所有血液檢查項目中對紅血球數異常(不足)影響最為敏銳，因此未來探討造血系統病變的前驅因子時可考慮以紅血球數變化作為造成造血系統異常之早期生物效應指標。

Parallel Abstract 〈TOP〉

Benzene is a common organic solvent used in industry. One of the current biomarkers of benzene exposure is urinary S-phenylmercapturic acid (U-SPMA) at post-shift. Cytochrome P450 2E1 (CYP2E1) and glutathione-S-transferase (GST) are involved in the biotransformation of S-PMA. Moreover, benzene intoxication was mainly due to its active intermediate metabolites. Among them, benzoquinone was documented to be responsible for its myelotoxicity and NAD(P)H:quinone oxidoreductase (NQO1) was the key enzyme during this metabolic pathway. Thus, the genetic polymorphism of aforementioned enzymes could affect the biotransformation of exposed benzene and the health effects. The purpose of this study is to investigate the effects of various genetic polymorphisms on S-PMA kinetics and the change of hematopoetic precursors. Seventy-four petrochemical workers directly exposed to benzene were environmentally monitored by breathing zone sampling coupled with gas chromatography analysis. Urine samples were collected at post-shift, during 8-hour complete work-shift and during 24-hr post-exposure since the end of the exposure. S-PMA in urine was analyzed by high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Blood samples were collected from each participants and were used to determine their genetic polymorphisms of CYP2E1, GST, and NQO1 by PCR (Polymerase Chain Reaction) as well as hematopoetic precursors. We found: 1. Airborne benzene and urinary S-PMA measurements were shown as log-normally distributed and their geometric means were 6.52 ppb and 0.39 μg/g Cr., respectively, far below the current permissible exposure limit and biological exposure index; 2. Significant association between airborne benzene concentrations and U-SPMA at post-shift was found (r=0.39，P<0.01). 3. For those who were determined for their S-PMA throughout 8-hr complete work-shift and post-shift, significant association of airborne benzene concentrations with AUCS-PMA (area under curve) (r=0.62，P <0.05), but not with S-PMA at post-shift, was found; 4. AUCS-PMA at 24-hr post-shift were found significantly different between smokers and non-smokers (P<0.05); 5. The frequency distributions of CYP2E1, NQO1 and GSTT1/M1 in our study were not different from those for Taiwanese or Chinese in literature; 6. The natural-transformed ratios of S-PMA to airborne benzene in those subjects with non-null GSTT1 type were significantly higher than those with null type; 7. No any hemetopoeitic parameter disorders were associated with the S-PMA levels in urine; 8. The risk of RBC count abnormality for those who with T/T type of NQO1 was significantly higher than those with T/C and C/C (OR=24.4, 95%3.4-173.4, P<0.05). We concluded that 1. Because the AUC of S-PMA within 8-hr work-shift was better correlated with benzene exposure levels than S-PMA concentrations at post-shift, the biological monitoring of benzene exposure might consider using AUC to calibrate the total body burden while benzene exposure is low; 2. Cigarette smoking should be taken into consideration of biological monitoring of benzene exposure; 3. GSTT1 genetic polymorphism might affect the S-PMA levels and possibly due to insufficient sample size, this study was unable to determine the effect of the genetic polymorphism on S-PMA AUC; 4. Possibly owing to the benzene exposure was too low or other factors including genetic polymorphism, this study found no association between benzene exposure and hematopoetic precursor abnormality; 5. NQO1 genetic polymorphism was found only associated with RBC count abnormality, indicating the RBC count could be one of the most sensitive precursors for the determination of hematopoetic abnormality.

Reference ( 71 ) 〈TOP〉

1. Alexandrie, A. K.; Rannug, A.; Juronen, E.; Tasa, G.; and Warholm, M.: Detection and characterization of a novel functional polymorphism in the GSTT1 gene. Pharmacogenetics., 12(8): 613-9, 2002.
連結：
2. Ambrosone, C. B.; Coles, B. F.; Freudenheim, J. L.; and Shields, P. G.: Glutathione-S-transferase (GSTM1) genetic polymorphisms do not affect human breast cancer risk, regardless of dietary antioxidants. Journal of Nutrition., 129(2S Suppl): 565S-568S, 1999.
連結：
3. Andrews, L. S.; Sasame, H. A.; and Gillette, J. R.: 3H-Benzene metabolism in rabbit bone marrow. Life Sciences., 25(7): 567-72, 1979.
連結：
4. Arand, M.; Muhlbauer, R.; Hengstler, J.; Jager, E.; Fuchs, J.; Winkler, L.; and Oesch, F.: A multiplex polymerase chain reaction protocol for the simultaneous analysis of the glutathione S-transferase GSTM1 and GSTT1 polymorphisms. Analytical Biochemistry., 236(1): 184-6, 1996.
連結：
5. Baak, Y. M.; Ahn, B. Y.; Chang, H. S.; Kim, J. H.; Kim, K. A.; and Lim, Y.: Aplastic anemia in a petrochemical factory worker. Environmental Health Perspectives., 107(10): 851-3, 1999.
連結：

Times Cited (1) 〈TOP〉

黃昇華(2008)。苯暴露勞工尿中代謝物對苯二酚與NQO1基因多型性及血液指標之相關性探討。成功大學環境醫學研究所學位論文。2008。1-81。

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