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Associations of Genetic Variations in Metabolism Enzymes Genes and DNA Damage in Coke Oven Workers

Author: HuangGuoXiang
Tutor: ZuoTangChun
School: Huazhong University of Science and Technology
Course: Occupational and Environmental Health
Keywords: Coke oven workers Polycyclic aromatic hydrocarbons BPDE- albumin adduct Matrix-assisted laser desorption ionization time-of-flight mass spectrometry DNA damage SNPs Metabolizing enzymes
CLC: R131
Type: PhD thesis
Year: 2011
Downloads: 42
Quote: 0
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Polycyclic aromatic hydrocarbons (polycyclic aromatic hydrocarbons, PAHs) coke oven emissions (coke oven emission, COE) in the most important and the most important cancer-causing ingredients, can lead to the organism DNA damage, DNA damage in the incidence of lung cancer in coke oven workers the main reason. PAHs and polycyclic aromatic hydrocarbons receptor (aryl hydrocarbon receptor, AhR) binding, cause AhR space structure change, into the nucleus to induce the synthesis of a variety of xenobiotics metabolizing enzymes, such as the I-phase metabolic enzyme cytochrome P4501A1 (cytochrome P4501A1 , CYP1A1), cytochrome P4501B1 (cytochrome P4501B1, CYP1B1), cytochrome P4502B6 (cytochrome P4502B6, CYP2B6), cytochrome P4502E1 (of cytochrome P4502E1 CYP2E1). PAHs after metabolizing enzymes in the metabolic activation of carcinogenic, its toxicity is related to their physical and chemical properties, and genetic variation between individuals. Occupational epidemiological studies of cancer risks, a key enzyme in vivo metabolism of carcinogens PAHs CYPs, a member of the subfamily of CYP1A1, CYP1B1, CYP2B6 and CYP2E1 catalytic PAHs carcinogen benzopyrene (benzo [a ] pyrene, B [a] P) of CYPs catalytic metabolic end product of benzo (a) pyrene dihydrodiol epoxide (benzo [a] pyrene-7 ,8-dihydrodiol-9 ,10-epoxide BPDE) This final product forming a covalent adduct with DNA and plasma albumin and inducing DNA damage. As far as we know, the current domestic and international research are used 1-OHP markers as PAHs occupational exposure, due to the relatively short biological half-life of 1-OHP, can only reflect the short-term exposure levels of PAHs, and the vast majority of urine involved in DNA damage was minimal, so there are limitations. Plasma BPDE-albumin adduct higher levels in the blood, a longer biological half-life, may reflect the the PAHs long-term exposure levels, plasma BPDE-albumin adducts in coke oven workers have been reported, but not yet See related research as PAHs exposure markers reported, therefore, the study attempts to study on plasma BPDE-albumin adduct in coke oven workers by metabolizing enzymes in coke oven workers plasma BPDE-albumin adducts and DNA damage associated was exposed as PAHs feasibility of markers, as well as find and coke oven workers PAHs exposure and cancer risk potentially sensitive factors on the basis of genetics, hazard prevention and control to provide a scientific basis for occupational exposure to coke oven workers. The study is divided into the following three parts: the first part of the study by occupational epidemiology survey methodology, selected 202 cases of male coke oven workers as exposed group as the control group, 96 cases of male organ from the same factory management personnel as well as medical personnel . The study population through questionnaires general information, such as age, length of service, smoking and drinking. Color Pu (reverse phase-high performance liquid chromatography, RP-HPLC) method using RP-HPLC determination of plasma BPDE-albumin adduct levels and alkaline single-cell gel electrophoresis assay comet tail moment (Olive Tail Moment , OTM). The results show that the two groups of the study population in terms of age, length of service, smoking and drinking is not a significant difference (P gt; 0.05). Coke oven workers exposed to plasma BPDE-albumin adduct level (after the conversion of the natural logarithm) in the exposed group (3.55 (2.37-4.11)) was significantly higher than that of the control group (3.06 (1.47-2.85)), the difference significant (P lt; 0.01); peripheral blood lymphocytes OTM value (after conversion of the natural logarithm) in the exposed group (1.25 ± 1.09) was significantly higher than that of the control group (0.55 ± 0.93), there are significant differences (P lt; 0.01). The partial results suggest that exposure markers plasma BPDE-albumin adduct levels in coke oven workers in PAHs and peripheral blood lymphocyte the OTM value and the control group compared with the significant difference. The second part of metabolic enzyme gene polymorphism with plasma BPDE-albumin adducts associated coke oven workers plasma BPDE-albumin adduct chemical properties, its formation may be affected by many factors such as the level of exposure to PAHs extracellular environment the role of metabolic enzymes in the body, as well as smoking, drinking, diet and lifestyle. This section BPDE-albumin adduct levels in the metabolic enzyme gene polymorphism with plasma factors that affect coke oven workers plasma BPDE-albumin adduct formed association studies to explore the coke oven workers plasma BPDE-albumin adducts as PAHs exposure of the feasibility of the markers. I the phase metabolic enzyme in four key gene 12 mark single nucleotide polymorphisms (tagging single nucleotide polymorphism of tagSNPs) selected database according to the international human genome HapMap (International HapMap project, HapMap) matrix-assisted laser desorption ionization time-of-flight mass spectrometry, were genotyped 298 coke oven workers, found that by correcting the factors of age, length of service, smoking and drinking in the exposed group, the CYP2B6 gene rs3760657 locus GA AA gene type carriers plasma BPDE-albumin adduct levels (3.31 (2.01-4.07)) was significantly lower than the GG genotype (3.59 (2.67-4.27)), the difference was statistically significant (P lt; 0.05). Haplotype analysis showed that, in the control group, CYP2E1 gene GC / GT haplotype carriers lowest plasma BPDE-albumin adduct levels (3.00 (0.96-3.73)), and the population distribution of the most widely used the CG / CG haplotype compared to (3.63 (2.97-4.25)), the difference was statistically significant (P lt; 0.05). This section results suggest that metabolic enzyme genetic variants affect BPDE-albumin adduct levels in coke oven workers plasma major factor in the coke oven workers plasma BPDE-albumin adducts as PAHs exposure markers. The third part of the metabolic enzyme gene polymorphism and DNA damage in coke oven workers, the relevance of the body of carcinogens of PAHs in (carcinogenic strongest B [a] P as the representative), generally the first phase I metabolism enzyme CYPs role of oxidation, reduction, hydrolysis, to change the functional groups of the poison, so that degradation or into pro electronic polar group and carcinogenic effects, the metabolite BPDE and in vivo DNA and / or protein form a covalent adduct, resulting in DNA damage. However, epidemiological studies related metabolic enzyme genetic variation and DNA damage associated with research poorly, and disputes between various conclusions. Therefore, we assume that the metabolic enzyme genes and genetic variation plays an important role in the process of DNA damage in coke oven workers to explore the association of the metabolic enzyme genetic variation and DNA damage. The second part of the metabolic enzyme gene 12 tagSNPs genotyping data, divided into tertiles were logarithmically transformed plasma BPDE-albumin adduct levels in the low exposure group, in the exposed group and the high exposure group 3 groups. The results found in the high-exposure group, the the CYP2B6 gene rs1042389 locus TC genotype peripheral blood lymphocytes OTM values ??(1.04 ± 1.06) was significantly lower than the TT genotype (1.51 ± 1.05), the difference was statistically significant (P lt; 0.05). No significant association between genetic variations of the CYP1A1 gene, CYP1B1 gene and CYP2E1 gene DNA damage coke oven workers. In summary, the results of this study suggest that coke oven workers exposed to PAHs after exposure markers plasma BPDE-albumin adducts water were significantly increased, and the metabolic enzyme gene polymorphism is the main factors that affect the formation, so we think coke oven workers plasma BPDE-albumin adducts as PAHs exposure markers; important related the PAHs associated metabolic enzyme DNA damage effects of coke oven workers, individual susceptibility differences on the genetic effects . The innovation of this study is to: (1) for the first time found especially metabolic enzyme gene CYP2B6 gene polymorphism reduces the plasma BPDE-albumin adduct levels; (2) to explore the metabolic enzyme genetic variants the degree of correlation of DNA damage, and found that the genetic variation of the CYP2B6 gene significantly reduced the level of DNA damage in coke oven workers. Limitations, as well as areas for in-depth study of this topic: (1) of PAHs in the metabolic process is complex, involving a variety of metabolic enzyme genes, these genes may be, there are a large number of SNPs, the study is only a preliminary study phase I metabolism enzymes of CYP1A1, CYP1B1, CYP2B6 and CYP2E1 four, the 12 SNPs in genes with PAHs induced DNA damage associated PAHs caused by the body's other metabolic enzyme gene polymorphism, and how to evaluate the overall metabolism of the coke oven workers complex process, the joint role of genes and genes, between genes and environment combined effects, further research is needed. Therefore we explore metabolic enzyme gene polymorphism of PAHs body effects in risk impact is inadequate; (2) With the implementation of genome-wide association study (genome-wide association studies, GWAS), the small number of genes the study of the few sites in the interpretation of scientific hypothesis is not enough, it is necessary to verify the positive results obtained in this study in a larger sample; (3) In addition, the SNPs in the cell functional studies, as can be reporter gene transfection, gel mobility shift assay technologies such depth validation of the functional changes of the promoter region SNPs.

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