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

Abstract

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. inactivation of tumor suppressor genes in human cancers. Several investigators have reported that CpG islands on the promoters of the MGMT and hMLH1 genes are hypermethylated in several malignancies and aberrant hypermethylation represses the expression of MGMT and hMLH1 [17][18][19][20]. A high frequency of p16 hypermethylationin was observed in vinyl chloride (VC)-associated hepatocellular carcinomas (HCC) [21]. Aberrant methylation of tumor suppressor genes might also act in the early stages of the multistep process of carcinogenesis [22]. Based on the information above, we hypothesized that epigenetic silencing of MGMT and hMLH1, by promoter hypermethylation, might be involved in VCM-exposureinduced chromosome damage which is the early stage in the process of liver angiosarcoma. In the present study, we attempted to identify the MGMT and hMLH1 promoter methylation status in genomic DNA isolated from peripheral blood lymphocytes from workers exposed to VCM using a methylation-specific polymerase chain reaction (MS-PCR) and to analyze the correlation between MGMT and hMLH1 gene promoter methylation and chromosome damage induced by VCM exposure. MATERIALS AND METHODS Study populationWorkers employed in a VCM polymerization plant in China were studied. Prior to the study, written informed consent had been obtained from each subject and a standardized questionnaire had been used to obtain personal information, smoking and alcohol habits, medication and occupational history. The subjects exposed to VCM for longer than one year were selected if the following criteria were met: detailed questionnaires had been completed, the CBMN test results and a blood sample had been provided and the MSP analysis for the MGMT and hMLH1 genes was completed successfully. A total of 101 workers met these criteria. Individuals who smoked once a day for

Evaluation of DNA Methylation Changes and Micronuclei in Workers Exposed to a Construction Environment

“…Previous studies of methylation levels on the same genes we studied have shown them to be altered in the blood of patients with lung cancer and leukocytes collected from blood-exposed populations to particulate matter [15,18]. A recent study of individuals exposed to arsenic in their water supply found increased DNA methylation levels of MLH1 and CDKN2A genes and decreased the methylation level of the repetitive sequence LINE-1 [17].…”

“…The methylation levels of the MLH1 gene were found to be significantly higher in individuals exposed to arsenic in their water supply [17]. In another study of MLH1 chromosomal instability, as evaluated by MNs, methylation of the MLH1 promoter region in workers exposed to vinyl chloride (plastic) was analyzed [18]. The authors found that methylation of the MLH1 gene was not significantly altered in exposed individuals, but there was increased chromosomal damage as determined by MNs.…”

“…Another study in a population with prolonged exposure to arsenic found an increase in DNA methylation levels in the p16 and MLH1 tumor-suppressor genes [17]. A study that assessed workers exposed to vinyl chloride detected promoter hypermethylation of DNA repair genes and increased chromosomal instability, as measured by evaluating the frequency of MNs [18].…”

GADD45α drives brown adipose tissue formation through upregulating PPARγ in mice

“…In mammals, three types of adipocytes, white, brown, and beige or brite adipocytes, have been identified 4 . Among them, white adipocytes store excess energy in lipid droplets 5 , while beige and brown adipocytes burn lipids to produce heat, thus counteracting obesity 6 , 7 . Unlike white adipocytes, beige and classical brown adipocytes are characterized by their unique ability to transform mitochondrial energy into heat via uncoupling protein 1 (UCP1) 8 , 9 .…”

The prevalence and persistence of aberrant promoter DNA methylation in benzene-exposed Chinese workers

“…Numerous studies have reported the elevated promoter methylation in cancer tissues, but to the best of our knowledge, none has reported the methylation status of two genes in benzene-exposed workers. Psofaki et al [45] found that MGMT presented a statistically significant increase in promoter methylation between the less- and more-tumorigenic forms of colorectal adenomas (tubular vs tubullovillous and villous adenomas), and Wu et al [48] previously observed in our lab that MGMT promoter methylation was elevated in vinyl chloride monomer-induced chromosome-damaged subjects. However, Duan et al [9] observed a PAH-related decrease in the methylation of the MGMT promoter, although their in vitro test found that MGMT was methylated in low-dose (2.5 lg/ml) coke oven emissions exposure groups and demethylated in high-dose groups.…”