| BACKGROUND: Arsenic is a naturally occurring metalloid and one of the most common naturally occurring environmental contaminants.Its highest accumulation is in water where the predominant.Chronic arsenic intoxication from drinking water and its adverse health effects,including the association with cancer risk have been well documented in numerous studies worldwide,residents consuming well water can be exposed to arsenic concentrations well above those set at safe levels.Well water sources used by small communities in Inner Mongolia,China run a greater risk of toxic arsenic consumption levels than surface water sources.Treatment of arsenicosis is unsatisfactory and is mostly symptomatic as specific chelation therapy has limited value.DNA methylation pattern disturbance leading to aberrant gene expression has been hypothesized as the mechanism for arsenic-induced carcinogenesis.METHODS: The objective of this study was to assess genome-wide DNA methylation in blood from Chronic arsenic exposure patients with skin cancer.A total of 18 patients were recruited and classified into two groups according to gender(6females as group S1;12males as group S2,).For comparative purposes,age and sex-matched non-cancerous patients belonging to non-exposed areas were also selected.We measured DNA methylation in blood using Illumina Human Methylation450 K Bead Chip,followed by quantitative validation using pyrosequencing.KEGG pathway enrichment analysis of Differentially Methylated Cytosine was performed by cluster profile package.RESULTS: In total,1,032 differentially methylated Cp G sites were identified in S1 group versus control group(p<0.05,|beta.difference|>0.1),the majority of which were hypermethylated(n=931;90%);573differentially methylated Cp G sites were identified in S2 group versus control group(p<0.05,|beta.difference|>0.1),the majority of which were hypermethylated(n=381;66%).Among them,83(8%)of the differentially methylated sites in the female patient group were located in the promoter region(including TSS1500,TSS200,5’UTR,1st Exon);the differentially methylated sites in the male patient group were located in the promoter region.There are 42(7%).Among the arsenic-associated Cp Gs,we observed significant enrichment of genes annotating to the NOTCH signaling path,Hedgehog signaling path,and pathway in cancer.Statistical analysis and bisulfite conversion method further verified that the methylation levels of three sites cg0440644(RPL34),cg13251750(SERPINA9),and cg16016951(DUT)in the disease group were higher than those in the control group,which may be used as biomarkers for chronic drinking water arsenic exposure An analysis of The Cancer Genome Atlas(TCGA)data provided support for our findings.CONCLUSION: There are multiple differentially methylated genes in patients with chronic drinking water arsenic exposure with skin cancer and the control group.Most of the differentially methylated genes are located in the gene body and non-coding regions and are related to chromosomal stability.The two-stage experiments showed that 3 The methylation levels of 1 locus(cg0440644,cg13251750,cg16016951)in drinking water arsenic-exposed patients with skin cancer were higher than those in normal controls.The genes RPL34,SERPINA9,and DUT where the three methylation sites are located may be involved in the pathogenesis of skin cancer associated with chronic drinking water arsenic exposure through Notch and Hedgehog signaling pathways.It may be a potential molecular marker for skin cancer associated with arsenic exposure in drinking water,and RPL34 and DUT may simultaneously be used as candidate biomarkers for other cancers induced by arsenic exposure in drinking water. |
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