Genetic Susceptibility Of DNA Damage Induced By VCM-exposure

Vinyl chloride monomer (CH2=CHCl, VCM) is widely used in industry primarily,95% of the vinyl chloride was polymerized to polyvinyl chloride. In 1997, the worldtotal annual production was 27,000,000 tons. In 1970's, China began to produce PVC,and the annual output was 3 millions tons in 2003. VCM is a certain human carcinogen. In a more recent epidemiological study,VCM has been proved to be a multi-organ and multi-system carcinogen in exposedworkers, and an increased incidence of malignant tumors was documented afterlong-term exposure to VCM. In China, the technique for producing VC/PVC made agreat progress in reducing exposure concentration of VCM at the end of 1980s. Theexposure level of workers was lower than the national occupational health standard(before 2002, the MAC was 30 mg/m3, since June 2002 the STEL and TWA has beenrevised to 25 mg/m3 and 10 mg/m3 respectively in China). The permissible exposurelimit of VCM in developed country is 1 ppm (2.79 mg/m3), while the MAC in Chinabefore 2002 was 11-fold higher than that in the U.S. This study analyzed occupational health hazards among workers exposed toVCM whose exposure level was lower than the national occupational health standard.Earlier studies about genetic susceptibility of workers exposure to VCM focused onpolymorphisms of xenobiotic metabolizers and effects of vinyl chloride. Morerecently there have been few studies done on the association between DNA damageand polymorphisms of DNA damage repair genes; there is also no report about theassociation between DNA damage and the expression of metabolizing enzymes, DNArepair enzymes and tumor suppressor protein. The study evaluated the relationship between the cumulative exposure dose andoccupational hazards based on exactly calculated cumulative exposure dose of theworkers exposed to VCM. Occupational epidemiological study and animalexperiment were performed to investigate the relationship between DNA damage 3复旦大学博士学位论文 氯 乙 烯 致 DNA 损 伤 的 遗 传 易 感 性 研 究 中文摘要induced by VCM and polymorphisms of metabolizing enzymes and DNA damagerepair genes, to detect the association between DNA lesions and expression of DNArepair enzymes, metabolizing enzymes and tumor suppressor protein, and to explorethe mechanism of cancer induced by VCM, and also to provide scientific evidence toscreen susceptible workers and to protect workers exposed to VCM.In the field study it was found that the incidence of the liver lesions increased in accordance withincrease of cumulative exposure dose. Under the same working environment and VCM-exposedlevel, only some VCM-exposed workers had got liver lesions and DNA damages, which indicatedthat there were genetic susceptible differences among the workers. The occupationalepidemiological results also revealed that the degree of DNA damage in VCM exposure group washigher than that in the control. In individuals having a high or low cumulative exposure dose, aprominent risk increasing of DNA damage was observed. Then we designed a case-control studyamong the exposure workers according to DNA damage in order to investigate the associationbetween the polymorphisms of metabolic enzymes genes, DNA repair genes and DNA damageexpressed by lymphocyte comet cells. In the case-control study, PCR-RFLP was used to detect SNPs of xenobioticmetabolizers and DNA repair genes. Univariate analysis showed that CYP2E1c1c2/c2c2 and XPD 751 Lys/Gln and Gln/Gln genotypes were significantly associatedwith DNA damages. It was also found that the incidence of DNA damages was higherin workers with XRCC1 194 Arg/Trp and Trp/Trp genotypes than the workers withArg/Arg homozygous, but did not have statistical difference (P=0.071), while theXRCC1399 Arg/Gln and Gln/Gln genotypes may have protection effect (P<0.05).Logistic regression analysis was employed to m...