| Vinyl chloride monomer (CH2=CHCl, VCM) is widely used in industry,95% of which is used in polymerization to polyvinyl chloride (PVC). By Dec 2013,the production of PVC was 15.3 million ton in China, ranking the first in the world. VCM is a human carcinogen that has been proven to have multi-organ and multi-system effeets, multi-system effects. The mechanism of carcinogenesis was suggested to be related to the genetic damages by electrophilic metabolites of VCM. At present, the permissible exposure limit (PEL) of VCM in developed countries is 1 ppm(2.79mg/m3), and the PC-TWA in China is 10mg/m3.The permissible exposure limit is higher in China than that in developed countries, indicating that more researches are required to investigate the health effects and genetic toxicity caused by VCM-exposure under this condition. Epigenetic modifications, defined as heritable changes that do not alter the nucleotide sequence, emerge as key factors that regulate chromatin structure and gene expression and, together with genetic factors, provide the mechanistic basis to understand the biological effects of various classes of environmental carcinogens. It has recently been proposed that the analysis of aberrant methylation of DNA CpG islands, which are CpG dinucleotide rich areas located mainly in the promoter regions of many genes, will be helpful for illuminate the toxicity mechanism of VCM.This study evaluated the cumulative exposure doses based on exactly calculated cumulative exposure doses of the workers exposed to VCM. We measured the frequencies of cytokinesis-block micronucleus (CBMN) to reflect chromosomal damage, and evaluated the relationship between VC cumulate exposure doses and chromosomal damage. Methylation status of metabolic gene promoters were detected by Methylation Specific PCR (MSP), aimed to explore its relationship with chromosomal damage induced by VCM, to provide scientific evidence of the biomarkers to screen high-risk workers, and to explain the mechanism of cancer induced by VCM.The VCM concentration of air samples in workplace was almost under the PEL from 1990 to present in this study.3.60% of samples exceeded the Chinese occupational exposure limits in 1990-2007, and 1.55% in 2007-2013.139 VCM-exposed workers were the target population, and 95 healthy volunteers were used as control group for this cross-section study. The cumulative exposure doses were calculated according to VC air concentration data for different work sites, seniority, and life VC exposure. Based on the estimated cumulative exposure doses, the VC exposed subjects were further divided into high exposure(>12622.16mg), middle exposure (775.36mg-12622.16mg) and low exposure(≤775.36mg). CBMN results indicated that MN frequency in the exposed group was significantly higher than that of the control group, FR=239 (95%CI:2.08-2.71), P<0.05, and that there is a dose-response relationship between VCM-exposure and the frequency of MN. Also, ages was risk factors for the frequency of MN, FR=1.01 (95%CI:1.01-1.02), P<0.05. Therefore, the frequency of MN of peripheral blood lymphocyte can be used as an effect biomarker under low-level VCM exposure.Methylation status of GSTP1, GSTM1, GSTM3 and CYP1A1 genes promoter were detected by Methylation-Specific PCR in 139 VCM-exposed workers and 95 controls. The relationship between methylation and factors (such as sex, age, drinking and smoking) were analyzed by χ2 analysis and Poisson regression.In VCM-exposed group and controls, methylation ratios were 39.6%(55/139) and 13.7%(13/95), respectively, for GSTP1 promoter; 48.2%(67/139) and 35.8%(34/95), respectively, for GSTM1 promoter; 28.8%(40/139) and 15.8%(15/95), respectively, for GSTM3 promoter; 15.8%(22/139) and 22.1%(21/95), respectively, for CYP1A1 promoter. Only the rate of GSTP1 promoter methylation was significantly higher in VCM-exposed group than controls after binary Logistic regression, adjusting gender, age, smoking and drinking, OR=5.60 (95%C/:2.67-11.75), P<0.05. Promoter methylation of GSTM1, GSTM3 and CYP1A1 had no statistical correlation with the VCM exposure (P>0.05) under our study condition. Results of χ2test in exposed group indicated that age was a risk factor for promoter methylation of GSTP1,OR=1.18(95%CI:1.56-6.48),P<0.05. No does-response relationship was observed between cumulative VCM exposure and rate of GSTP1 promoter methylation.CBMN assay was performed to investigate the chromosomal damage of VCM-exposed workers. MN frequency of cases of GSTM1 methylation was significantly higher than that of cases of no GSTM1 methylation in exposed group, FR= 1.30(95%CI:1.15-1.47), P<0.05.Mutiple Poisson regression indicated that age, VC exposure and GSTM1 promoter methylation were risk facors for increased MN frequency, (FR= 1.01,95%C7:1.01-1.02, P<0.05); (FR=2.32,95%CI:2.02-2.66, P<0.05);(FR=122,95%CI:1.09-1.37, P<0.05), respectively.In summary, genetic damage induced by VC exposure still exists under current occupational exposure limit in China. Occupational VC exposure and promoter methylation of related metabolic genes may all impact the occurrence and development of chromosomal damage. |
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