Correlation of chromosome damage and promoter methylation status of the DNA repair genes MGMT and hMLH1 in Chinese vinyl chloride monomer (VCM)-exposed workers.

OBJECTIVE: To explore the association of the methylation status of MGMT and hMLH1 with chromosome damage induced by vinyl chloride monomer (VCM). MATERIALS AND METHODS: Methylation of MGMT and hMLH1 was measured in 101 VCM-exposed workers by methylation-specific PCR. Chromosome damage in peripheral blood lymphocytes was measured by the cytokinesis-block micronucleus assay. The subjects were divided into chromosome damaged and non-damaged groups based on the normal reference value of micronuclei frequencies determined for two control groups. RESULTS: MGMT promoter methylation was detectable in 5 out of 49 chromosome damaged subjects, but not in the chromosome non-damaged subjects; there was a significant difference in MGMT methylation between the two groups (p < 0.05). CONCLUSIONS: We detected aberrant promoter methylation of MGMT in a small number of chromosome damaged VCM-exposed workers, but not in the chromosome non-damaged subjects. This preliminary observation warrants further investigation in a larger study.

Genotoxicity in vinyl chloride-exposed workers and its implication for occupational exposure limit.

BACKGROUND: Vinyl chloride monomer (VCM) is a colorless gas under room temperature and has been mostly used to produce polyvinyl chloride (PVC) since the 1970s. It is classified by the International Agency of Research on Cancer (IARC) as a known human carcinogen (Group 1). In this study, genetic damage in VCM workers was evaluated in relation to their occupational cumulative exposure to VCM. METHODS: Cytokinesis-block micronucleus assay was conducted in 229 VCM workers and 138 controls to detect chromosome damage in peripheral blood lymphocytes. The cumulative exposure dose (CED) of VCM was calculated based on the job type and duration of each worker and the workplace VCM concentration. Dose-response relationships between VCM CED and micronucleus frequency or chromosomal damage were evaluated, and benchmark doses (BMDs) estimated. RESULTS: Dose-response relationships between VCM CED and chromosomal damage were obtained. The 95% lower confidence bound of BMD of VCM CED was 2.86 mg/m(3) -year for both genders combined, leading to an estimated exposure limit of 0.072 mg/m(3) assuming a work life of 40 years. CONCLUSIONS: VCM exposure may induce chromosomal damage at occupational exposure levels below the Chinese national occupational health standard. Further research is needed to better understand micronuclei as biomarker of VCM genotoxicity. Better dose-response assessment and BMD estimation are desirable in order to improve the quantification of occupational exposure limits for VCM with respect to non-cancer risk.

Genetic polymorphisms of XRCC1, HOGG1 and MGMT and micronucleus occurrence in Chinese vinyl chloride-exposed workers.

In this study, a group of 313 workers occupationally exposed to vinyl chloride monomer (VCM) and 141 normal unexposed referents were examined for chromosomal damage using the cytokinesis-blocked micronucleus (CBMN) assay in peripheral lymphocytes. We explored the relationship between genetic polymorphisms of XRCC1 (Arg194Trp, Arg280His and Arg399Gln), MGMT(Leu84Phe) and hOGG1 (Ser326Cys) and susceptibility of chromosomal damage induced by VCM. Polymerase chain reaction-restriction fragment length polymorphism techniques were used to detect polymorphisms in XRCC1, hOGG1 and MGMT. It was found that the micronuclei (MN) frequency of exposed workers (4.86 +/- 2.80) per thousand was higher than that of the control group (1.22 +/- 1.24) per thousand (P < 0.01). Increased susceptibility to chromosomal damage as evidenced by higher MN frequency was found in workers with hOGG1 326 Ser/Cys genotype [frequency ratio (FR) = 1.21, 95% confidence interval (CI): 1.02-1.46; P < 0.05], XRCC1 194 Arg/Trp (FR = 1.12, 95% CI: 1.00-1.25; P < 0.05) and XRCC1 280 Arg/His and His/His genotypes (FR = 1.12, 95% CI 1.00-1.26, P < 0.05). Moreover, among susceptibility diplotypes, CGA/CAG carriers had more risk of MN frequency compared with individuals with wild-type CGG/CGG (FR = 1.67, 95% CI: 1.19-2.23; P < 0.05). MN frequency also increased significantly with age in the exposed group (FR = 1.13, 95% CI: 1.00-1.28; P < 0.05). Thus, CB-MN was a sensitive index of early damage among VCM-exposed workers. Genotype XRCC1 Arg194Trp, Arg280His, hOGG1 Ser326Cys, diplotype CGA/CAG and higher age may have an impact on the chromosome damage induced by VCM.

Genetic polymorphisms in metabolizing enzymes and susceptibility of chromosomal damage induced by vinyl chloride monomer in a Chinese worker population.

OBJECTIVE: To evaluate whether polymorphisms in metabolizing enzymes contributed to susceptibility of chromosomal damage induced by vinyl chloride monomer (VCM). METHODS: Cytokinesis block micronucleus test was performed on 185 VCM-exposed workers and 41 control subjects to detect chromosomal damage in peripheral lymphocytes. The polymerase chain reaction and restriction fragment length polymorphism technique was applied to detect polymorphisms of GSTT1, GSTM1, GSTP1G/A, CYP2E1G/C, and CYP2D6G/C. Poisson regression analysis was performed. RESULTS: Sex, age, VCM exposure, GSTP1, and CYP2E1 genotype can influence chromosomal damage. There was a 1.51-fold increased micronucleus frequency for GSTP1GG genotypes individuals compared with those GSTP1AA/GA genotype individuals (P < 0.05), the effect of polymorphism in CYP2E1 gene was more pronounced for allele C compared with allele G (P < 0.05). CONCLUSIONS: Polymorphisms of GSTP1G/A and CYP2E1G/C, which are potential susceptibility biomarkers of chromosomal damage in VCM-exposed worker.

Prevalence and persistence of chromosomal damage and susceptible genotypes of metabolic and DNA repair genes in Chinese vinyl chloride-exposed workers.

Vinyl chloride (VC) was classified as a group 1 carcinogen by IARC in 1987. Although the relationship between VC exposure and liver cancer has been established, the mechanism of VC-related carcinogenesis remains largely unknown. Previous epidemiological studies have shown that VC exposure is associated with increased genotoxicity in humans. To explore chromosomal damage and its progression, and their association to genetic susceptibility, we investigated 402 workers exposed to VC, a 77 VC-exposed cohort and 141 unexposed subjects. We measured the frequencies of cytokinesis-block micronucleus (CBMN) to reflect chromosomal damage and conducted genotyping for six xenobiotic metabolisms and five DNA repair genes' polymorphism. Data indicate that 95% of the control workers had CBMN frequencies

[Polymorphisms of FAS and FASL genes and susceptibility of silicosis].

OBJECTIVE: To explore the relationship between polymorphisms of FAS and FASL genes and genetic susceptibility of silicosis. METHODS: A case-control study was conducted. The case group was 183 male patients with silicosis and the control group was 111 male silica-exposed but without silicosis miners. Data on total dust concentrations was collected to estimate cumulative total dust exposure (CTE) of each subject and each person's characteristics and work history were obtained from questionnaire. Polymerase chain reaction re-strained fragment length polymorphism technique (PCR-RFLP) was applied to detect the single nucleotide polymorphisms (SNPs) of FAS-1377, FAS-670 and FASL-844. Associations between polymorphisms and risk of silicosis and stages, interactions between polymorphisms, between polymorphisms and CTE and smoking and haplotypes were analyzed. RESULTS: There were no differences in the FAS-1377, FAS-670 and FASL-844 genotypes between the case group and the control group (P > 0.05). No association was observed between FAS-1377, FAS-670 and FASL-844 polymorphisms and silicosis and stages (P > 0.05). The frequencies of FAS-1377G/-670G haplotype in the cases (9.6%) were higher than those in the controls (3.6%) (P < 0.05). No interactions between the polymorphisms of different genes, the gene polymorphism and the total accumulative total dust, the gene polymorphism and smoking were observed (P > 0.05). CONCLUSION: FAS-1377, FAS-670 and FASL-844 polymorphisms are not susceptible factors of silicosis. The FAS-1377G/-670G haplotype might be a susceptibility marker of silicosis.