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The Influence of Metabolic Gene Polymorphisms on Urinary 1 中国科技论文在线 http://www.paper.edu.cn Science of the Total Environment 381 (2007) 38–46 The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers ⁎ ⁎ Bo Chen a,1, Yunping Hu a,c,1, Taiyi Jin a, , Daru Lu b, , Minhua Shao b, Lixing Zheng a, Qiangyi Wang a, Yue Shen a, Hongliang Liu b, Yanhong Liu b, Yuanfen Zhou a a Department of Occupational Health and Toxicology, School of Public Health, Fudan University, Shanghai, 200032, PR China b State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200433, PR China c Department of Pathology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA Received 21 November 2006; received in revised form 2 February 2007; accepted 19 February 2007 Available online 11 May 2007 Abstract Urinary 1-hydroxypyrene (1-OHP), a biomarker of polycyclic aromatic hydrocarbons (PAHs) exposure, may be influenced by metabolic gene polymorphisms. Such knowledge could benefit us in understanding the inter-individual difference in the mechanism of PAHs-induced carcinogenesis. We investigated the influence of gene polymorphisms on urinary 1-OHP concentrations in 447 coke oven workers from two coking plants in south China. After adjustment for age, plant, level of occupational exposure, body mass index, level of education, alcohol consumption, cigarette smoking and respirator usage, AhR R554K (rs2066853), UGT1A1 −3263TNG (rs4124874) and GSTP1 I105V (rs1695) were associated with urinary 1-OHP excretion with the p-value of 0.053, 0.006 and 0.021, respectively. The concentrations of urinary 1-OHP (Geometric mean, μmol/mol creatinine) in the homozygous major variant carriers and homozygous minor variant carriers for AhR R554K, UGT1A1 −3263TNG and GSTP1 I105V were listed as follows: 4.20 and 5.12, 5.11 and 3.92, 4.93 and 2.91, respectively. GSTT1 present carriers had a significantly higher urinary 1-OHP level than that in null carriers in the case with AhR R554K GA/AA carriers (5.17 vs. 3.64 μmol/mol creatinine, p=0.038), as well as in the case with UGT1A1 −3263TNG TG/GG carriers (5.67 vs. 3.38 μmol/mol creatinine, p=0.001). These results showed that AhR, UGT1A1, GSTP1 and GSTT1 polymorphisms were associated with urinary 1-OHP concentrations in Chinese coke oven workers. No influence was found in the association between urinary 1-OHP and other genetic polymorphisms such as CYP1A1, CYP1A2, CYP1B1, CYP2E1, EPHX1, EPHX2 in this population. © 2007 Elsevier B.V. All rights reserved. Keywords: 1-Hydroxypyrene; Polycyclic aromatic hydrocarbons; Coke oven workers; Gene polymorphism 1. Introduction ⁎ Corresponding authors. Jin is to be contacted at School of Public Coke oven workers are regularly exposed to coke oven Health, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, emissions, which are mainly comprised of a wide variety PR China. Tel./fax: +86 21 6417 8160. Lu, State Key Laboratory of of volatile organic compounds and particulates, especially Genetic Engineering, School of Life Sciences, Fudan University, polycyclic aromatic hydrocarbons (PAHs) (IARC, 1984). Shanghai 200433, PR China. Tel./fax: +86 21 65642799. E-mail addresses: [email protected] (T. Jin), [email protected] Some PAHs are proved to be probably or possibly car- (D. Lu). cinogenic (IARC, 1983, 1987). Epidemiological studies 1 Bo Chen and Yunping Hu contributed equally to this work. have implicated an elevated incidence of lung cancer 0048-9697/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.scitotenv.2007.02.021 转载 中国科技论文在线 http://www.paper.edu.cn B. Chen et al. / Science of the Total Environment 381 (2007) 38–46 39 among coke oven workers (WHO, 1987). 1-Hydroxypyr- 70s and had 4 and 6 coke ovens, respectively. 197 male ene has been recommended as a suitable biomarker of workers from Plant I and 250 from Plant II participated internal dose to assess recent exposure to PAHs (Jacob in this study. The study was undertaken with the and Seidel, 2002). Due to the high exposure to PAHs in permission of the local authority and the Ethics coke oven workers, an occupational exposure limit (OEL) Committee of School of Public Health, Fudan Univer- of 2.3 μmol/mol creatinine in urinary 1-OHP level has sity, China. Informed consent was obtained from each been recommended by Jongeneelen (1992), which was subject. Subjects completed a structured questionnaire corresponding to a unit risk of 1.3 on lung cancer by the to elicit information about demographic characteristics, epidemiological study (Jongeneelen, 1992). including age (empirical half, ≤36 or N36), BMI At least two major metabolic pathways are involved (normal, ≤25; overweight, N25), level of education in the biotransformation of PAHs (Grover, 1986). Phase I (high school or below, college or above), alcohol enzymes such as CYP1A1, CYP1A2 and CYP1B1 are consumption (nondrinker or drinker), cigarette smoking known to catalyze the formation of reactive intermedi- habit (nonsmoker; moderate-smoker, ≤10; heavy-smok- ates of some carcinogens, whereas phase II enzymes er, N10) and respirator usage (yes or no) and job such as glutathione S-transferases (GSTs) are mainly classification. Coke oven workers were classified into found to participate in the detoxification of these inter- four subgroups according to their job classifications as mediates through the conjugation with glutathione. follows: extremely high exposure group including Some of these genes are also known to be transcription- lidman, tar chaser and whistler; high exposure group ally up-regulated by the activation of Aryl hydrocarbon including larry car operator, benchman at coke side and Receptor (AhR) when exposure to PAHs. In addition, benchman at pusher side; moderate exposure group little but still available information has also been pro- including machine operator at coke side, pusher machine vided on other genes coding enzymes involved in the operator, quenching car operator, oven repairman, metabolism of PAHs. CYP2E1 is expressed at higher temperature controller and heater; low exposure group levels in Asians than in Caucasians, therefore was including screening station operator, supervisor and thought to be responsible for the metabolism of pyrene in electrician. All these job classifications had been Asian people (Nan et al., 2001). Epoxide hydrolases described in our previous study (Chen et al., revised by (EHs) convert epoxides to more water-soluble trans- American Journal of Industrial Medicine, AJIM-06- dihydrodiols, which has been found to be an important 0232.R1). Categorized by exposure situation, our step of the activation of benzo[a]pyrene (Seidegard and previous study had found a positive trend arising from Ekstrom, 1997). UDP-glucuronosyltransferase (UGT) is the referents to extremely high exposure group (linear another phase II enzyme detoxifying PAHs in vivo trend test, pb0.001). (Bock, 1991). It is known that most genes coding enzymes involved 2.2. Determination of 1-hydroxypyrene in the metabolism of PAHs are polymorphic. Therefore, the study on the polymorphisms of metabolizing enzymes Participants were asked to provide a sample of spot will benefit us in understanding the inter-individual dif- urine (20 mL) at the end of working shift. All samples ference in the rate of activation or detoxification of car- were kept at − 20 °C until analysis. Determination of cinogens related to PAHs and underlining the possible 1-OHP was performed using HPLC according to Li et al. molecular mechanism of their carcinogenesis. The present (2003), a method that was also described by Leng et al. study examined the associations between selected poly- (2004) and Liu et al. (2006). The detection limit of morphisms in a number of genes coding PAHs metabo- urinary 1-OHP was 0.15 ng/mL. All samples were above lizing enzymes and urinary 1-OHP concentrations in coke this limit. Urine specimen from each subject was oven workers from two large coking plants in south analyzed in duplicate. Quality control samples were China. analyzed after each twenty of measurements. The recovery rates from the entire procedure were 89.1%, 2. Material and methods 88.8% and 91.6% at 5, 20 and 100 μg/L, respectively. The intraday relative standard deviation (RSD) values 2.1. Subjects were 5.0%, 5.3% and 7.2% at 5, 20 and 100 μg/L, respectively, and the interday RSD values were 6.7%, This study was conducted in May, 2003 at Coking 8.3% and 10.2%, respectively. Urinary 1-OHP concen- plant I in Xinyu, Jiangxi province and in Dec, 2003 at trations were adjusted by urinary creatinine excretion Coking plant II in Shanghai, both of which started in the (μmol/mol creatinine). 中国科技论文在线 http://www.paper.edu.cn 40 B. Chen et al. / Science of the Total Environment 381 (2007) 38–46 2.3. Determination of genotype Table 1 Subject characteristics and their influence on urinary 1-hydroxypyrene levels Genomic DNA was isolated from the whole blood using a DNA isolating kit (Qiagen, USA). Genetic poly- N (%) GM (GSD) p-value morphisms were determined using Taqman® based assays Plant I 197 (44) 5.18 (3.87) (Applied Biosystems, USA) for all single nucleotide II 250 (56) 4.21 (2.46) 0.053 polymorphisms (SNPs). GSTM1 and GSTT1 deletion Occupational Low 31 (7) 1.56 (3.31) exposure Moderate 166 (37) 2.89 (2.53) 0.001 polymorphisms were analyzed using a multiple PCR High 144 (32) 5.88 (2.89) b0.001 procedure (Arand et al., 1996). Except for the CYP2E1 Extremely high 106 (24) 9.44 (2.42) b0.001 DraI- polymorphism (78%), GSTM1 and GSTT1 deletion Age (years) ≤36 217 (49) 4.96 (3.53) polymorphisms (88%), 93–99% of samples at each N36 230 (51) 4.31 (2.66) 0.186 2 ≤ polymorphism site were successfully genotyped.
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