Chen H, Li S, Liu J, Diwan BA, Barrett JC, Waalkes MP. Chronic inorganic arsenic exposure induces hepatic global and individual gene hypomethylation: implications for arsenic hepatocarcinogenesis. Carcinogenesis. 25: 1779-1786

Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Carcinogenesis (Impact Factor: 5.33). 10/2004; 25(9):1779-86. DOI: 10.1093/carcin/bgh161
Source: PubMed


Inorganic arsenic is a human carcinogen that can target the liver, but its carcinogenic mechanisms are still unknown. Global DNA hypomethylation occurs during arsenic-induced malignant transformation in rodent liver cells. DNA hypomethylation can increase gene expression, particularly when occurring in the promoter region CpG sites, and may be a non-genotoxic mechanism of carcinogenesis. Thus, in the present study liver samples of male mice exposed to 0 (control) or 45 p.p.m. arsenic (as NaAsO(2)) in the drinking water for 48 weeks were analyzed for gene expression and DNA methylation. Chronic arsenic exposure caused hepatic steatosis, a lesion also linked to consumption of methyl-deficient diets. Microarray analysis of liver samples showed arsenic induced aberrant gene expression including steroid-related genes, cytokines, apoptosis-related genes and cell cycle-related genes. In particular, the expression of the estrogen receptor-alpha (ER-alpha), and cyclin D1 genes were markedly increased. RT-PCR and immunohistochemistry confirmed arsenic-induced increases in hepatic ER-alpha and cyclin D1 transcription and translation products, respectively. Arsenic induced hepatic global DNA hypomethylation, as evidenced by 5-methylcytosine content of DNA and by the methyl acceptance assay. Arsenic also markedly reduced the methylation within the ER-alpha gene promoter region, as assessed by methylation-specific PCR, and this reduction was statistically significant in 8 of 13 CpG sites within the promoter region. Overall, in controls 28.3% of the ER-alpha promoter region CpG sites were methylated, but only 2.9% were methylated after chronic arsenic exposure. Thus, long-term exposure of mice to arsenic in the drinking water can induce aberrant gene expression, global DNA hypomethylation, and the hypomethylation of the ER-alpha gene promoter, all of which could potentially contribute to arsenic hepatocarcinogenesis.

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Available from: Carl Barrett, May 04, 2015
    • "One of the most studied compounds showing effects on global DNA methylation are arsenic (As) compounds. Genome-wide hypomethylation has been found after sodium arsenite exposure in rat liver cells (Zhao et al. 1997) as well as in livers from mice exposed to sodium arsenite via drinking water for 48 weeks (Chen et al. 2004). The hypomethylating effect of As in liver could be explained by its methylated metabolites, as metabolism involves SAM-dependent arsenic methyltransferases, thereby depleting the methyl pool for DNMTs (Hamdi et al. 2012). "
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    • "Tumor suppressor genes that are methylated in response to arsenic exposure include CDKN2A (Davis et al., 2000), tumor protein 53 (TP53) (Mass and Wang, 1997; Davis et al., 2000), von Hippel–Lindau tumor suppressor (VHL) (Zhong and Mass, 2001), RASSF1A (Cui et al., 2006a), DAPK (Chai et al., 2007), and reversion-inducingcysteine-rich protein with kazal motifs (RECK) (Huang et al., 2011). DNA methylation of oncogenes in response to arsenic include cyclin D1 (CCND1) (Chen et al., 2004), estrogen receptor alpha (ER-α) (Chen et al., 2004; Waalkes et al., 2004) and members of the RAS family of small G-proteins such as HRAS and KRAS (Benbrahim-Tallaa et al., 2005). Our group identified 183 differentially methylated promoters associated with arsenic exposure in adult subjects from Zimapan, Hildago, Mexico (Smeester et al., 2011), and out of this group were 17 tumor suppressor or tumor suppressor-associated genes with hypermethylated promoters. "
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    • "Despite most investigations indicating that arsenic affects the epigenetic status of cells and tissues, there is controversial regarding the exact effects. For example, Chen et al. reported a decreased global hepatic DNA methylation after administration of arsenic-containing drinking water to mice for 48 weeks (Chen et al., 2004). In contrast , Mass and Wang observed that arsenic increased both global DNA methylation as well as p53 promoter methylation in A459 human adenocarcinoma cells (Mass and Wang, 1997). "
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