RESUMO
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.
Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Dano ao DNA , Exposição Ocupacional/efeitos adversos , Cloreto de Vinil/efeitos adversos , Adulto , China , Feminino , Humanos , Leucócitos Mononucleares , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Exposição Ocupacional/prevenção & controle , Adulto JovemRESUMO
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 =3 per thousand, whereas VC-exposed workers had the 3.73-fold increase compared with the controls. Among the cohort workers who were followed from 2004 to 2007, the mean CBMN frequency was higher in 2007 than in 2004 with ratio of 2.08. Multiple Poisson regression analysis showed that mean CBMN frequencies were significantly elevated for the intermediate and high exposure groups than the low. Exposed workers with CYP2E1 or XRCC1 variance showed a higher CBMN frequency than their wild-type homozygous counterparts, so did workers with GSTP1 or ALDH2 genotype. This study provides evidence that cumulative exposure dose of VC and common genetic variants in genes relevant to detoxification of carcinogens are the major factors that modulate CBMN induction in VC-exposed workers.
Assuntos
Cromossomos/efeitos dos fármacos , Reparo do DNA , Predisposição Genética para Doença , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Exposição Ocupacional , Adulto , Povo Asiático/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Fatores de Tempo , Cloreto de Vinil/toxicidadeRESUMO
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.
Assuntos
DNA Glicosilases/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Testes para Micronúcleos , Exposição Ocupacional , Polimorfismo Genético , Proteínas Supressoras de Tumor/genética , Cloreto de Vinil/toxicidade , Adulto , Sequência de Bases , China , Primers do DNA , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
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.
Assuntos
Proteína Ligante Fas/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Silicose/genética , Receptor fas/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de RestriçãoRESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cromossomos Humanos/efeitos dos fármacos , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , DNA/genética , Proteínas Nucleares/genética , Exposição Ocupacional/efeitos adversos , Polimorfismo Genético , Proteínas Supressoras de Tumor/genética , Cloreto de Vinil/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , China/epidemiologia , Cromossomos Humanos/genética , DNA/efeitos dos fármacos , Dano ao DNA , Metilases de Modificação do DNA/metabolismo , Reparo do DNA , Enzimas Reparadoras do DNA/metabolismo , Feminino , Humanos , Masculino , Metilação/efeitos dos fármacos , Testes para Micronúcleos , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteínas Nucleares/metabolismo , Doenças Profissionais/epidemiologia , Doenças Profissionais/genética , Reação em Cadeia da Polimerase , Proteínas Supressoras de Tumor/metabolismoRESUMO
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.