| Benzene is commonly used to synthesize organic chemicals and used as an important component of many organic solvents. The major industries using benzene are those involving in the production of rubber, paint, shoes, lubricants, dyes, detergents, drugs, and pesticides. Long term exposure to benzene could result in chronic benzene poisoning (CBP) characterized by hematotoxicities, mainly pancytopenia, aplastic anemia, myelodysplastic syndrome, and acute myeloid leukemia. Catalyzed by toxicant-metabolizing enzymes, inhaled and absorbed benzene is converted to benzene oxide, which is ultimately metabolized to phenol, catechol, hydroquinone and benzoquinone. Previous studies have demonstrated that benzene toxicity mainly resulted from its intermediate reactive metabolites which lead to DNA damage by directly oxidative damage and covalently binding to DNA. Then the repair systems will complete repair of damaged DNA by means of base excision repair (BER), nucleotide excision repair (NER), double strands break (DSB) repair and mismatched repair (MMR). During period of DNA repair, a great many of DNA repair genes related to repair oxidative damage, adduct damage, single-strand break damage and double-strand break of DNA are involved in. A number of single nucleotide polymorphisms (SNPs) have been identified in these genes, some of which are relatively common and can result in change of enzyme activity or the configuration, the quantity of expressed mRNA as well, which will affect their capability of repairing damaged DNA and the risk of CBP.In order to elucidate their roles in human susceptibility to CBP and effects of benzene exposure duration and life styles, a case-control study was designed and conducted. 152 CBP patients come from Shanghai, Guangzhou, Hangzhou and Maanshan and 152 workers without poisoning manifestations but occupationally exposed to benzene were investigated. The cumulative exposure level was estimated with method described by Dosmeci, and the lifestyles such as cigarette smoking and alcohol consumption were also explored. The results of occupational epidemiology showedthat there was no statistic difference for distribution of sex, race, age, workage and cumulative exposure level in case and control groups, which indicated that it was comprehensive equilibrium for the case and control groups.To determine these SNPs that could not compose sites recognized by restriction enzymes with adjacent sequences effectively, we investigated technique of introducing mismatched bases to create restriction site combined with restriction fragment length polymorphism (CRS-RFLP)and its application. The results suggested that this method is good for identifying found single nucleotide polymorphisms extensively existing in sequence of genes.With method of polymerase chain reaction-restriction fragments length polymorphism (PCR-RFLP) and CRS-RFLP, SNPs in XRCC1, XRCC2, XRCC3, ADPRT, APE1, XPD, hMTH1, hOGG1 and hMYH were genotyped. And the associations of these genetic polymorphisms with risk of developing CBP and the modifying effects of intensity of benzene exposure and life styles were also investigated in this case-control study. The results indicated that:(1) No variant allele was detected for polymorphisms of XRCC2 Arg188His, XPD Met199Ile and XPD Tyr201His. The frequencies of the variant allele for polymorphisms of XRCC3 Thr241Met, XPD Asp312Asn, hMTHl Val83Met and hOGGl Ser326Cys were different from these reported in studies with foreign population, and the frequencies of the variant allele for polymorphisms of XPD Asp312Asn, hOGGl Ser326Cys and ADPRT Val762Ala were not consisted with these reported in other domestic researches.(2) The proportion of XRCC1c. 194Arg/Trp+Trp/Trp genotypes in the case group was lower than that of the control group (50.69% vs 62.22%), and there was a 0.60-fold reduced risk of CBP for individuals carrying XRCC1c.194Arg/Trp+Trp/Trp genotypes (ORadj=0.60, 95%CI: 0.37-0.98, P=0.04) compared with the subjects carrying Arg/Arg allele. The proportion of XPDc. 312Asp/Asn+Asn/Asn genotypes in the case group was also lower than that of the control group (26.90% vs 36.50%). Compared with the subjects carrying XPDc.312Asp/Asp allele, the risk of CBP for the individuals carrying XP Dc.312Asp/Asn+Asn/Asn also decreased (ORad=0.59, 95%CI: 0.35-0.99, P<0.05).(3)The proportion of XRCC1c.280Arg/His+His/His, hMTH1c.83Val/Met+Met/Met and hOGG1c.326 Cys/Cys genotypes in the case group was higher than that of thecontrol group (52.08% vs 36.03%, 16.78% vs 7.30% and 62.68% vs 44.91%, respectively). There was a 1.91-fold increased risk of CBP for the individuals carrying XRCC1c.280 Arg/His+His/His genotypes compared with the subjects carrying Arg/Arg allele (ORadj=1.91,95%C7: 1.17-3.10, p=0.01). Compared with the subjects carrying hMTH1c.83Val/Val allele, there was a 2.51-fold increased risk of CBP for individuals carrying hMTHlc.83Val/Met+Met/Met genotypes (ORadj=2.51, 95%C7: 1.14-5.49, P=0.02). Compared with the subjects carrying hOGG1c.326 Ser/Cys+ Ser/Ser genotypes, there was a 2.49-fold increased risk of CBP for the individual carrying hOGG1c. 326 Cys/Cys allele (ORadj=2.49, 95%CI: 1.52-4.07, P<0.01).(4) Potential interactions were found among smoking and polymorphism of hMYH His335Gln (xh2=4.59, p=0.03), alcohol consumption and polymorphism of APE1 Aspl48Glu (xh2=6.93, P=0.01), intensity of benzene exposure and polymorphism of XPD Asp312Asn (xh2=8.45, p=0.02). Compared with individuals with hMYHc.335 His/His genotype together with habit of smoking, there was a 0.20-fold decreased risk of CBP for the subjects carrying genotypes of hMYHc.335His/Gln+Gln/Gln and smoking at the same time (OR=0.20, 95%CI: 0.05-0.77, p=0.02). There was a 4.13-fold increased risk of CBP for the drinker with genotype of APE1c. 148Asp/Asp compared with these with genotype of APE1c.148AsplAsp without habit of alcohol consumption(OR=4.13, 95%CI: 107-15.85, p=0.03). However, due to the relative few smokers and alcohol users in the subjects, further study needed to elucidate interactions among lifestyles and different polymorphisms. In the low intensity of benzene exposure group, compared with these with XPD c.3\2Asp/Asp, the risk of CBP for these carrying XPDc.312Asp/Asn+Asn/Asn genotypes further decrease (OR=0.19, 95%CI: 0.07-0.53, p<0.01).(5) Stratified analysis of different genetic polymorphisms suggested that there are potential interactions among different genetic polymorphisms (XRCCl Arg280His and XPD Asp312Asn, XRCCl Arg399Gln and hMYH His335Gln, ADPRT Val762Ala and hMYH His335Gln, XPD Asp312Asn and hOGG1 Ser326Cys, hOGG1 Ser326Cys and hMYH His335Gln, respectively). The risk of CBP may decrease for the individuals carrying genotypes of XRCC1c.399Arg/Arg and hMYHc.335His/Gln+Gln/Gln (OR=0.36, 95%CI:0.16-0.83, p=0.02), XRCC1c.399Arg/Gln+Gln/Gln and hMYHc.335 His/His (OR=0.39, 95%CI: 0.16-0.91, p=0.03), hOGG1c.326Ser/Ser+ Ser/Cys and hMYHc.335His/Gln+Gln/Gln (OR = 0.38,95%C/.0.18-0.79, P<0.01) at the same time, respectively. Alternatively, the risk of CBP may further increase for the subjects with...
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