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
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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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    ABSTRACT: Exposure to toxic metals poses a serious human health hazard based on ubiquitous environmental presence, the extent of exposure, and the toxicity and disease states associated with exposure. This global health issue warrants accurate and reliable models derived from the risk assessment process to predict disease risk in populations. There has been considerable interest recently in the impact of environmental toxicants such as toxic metals on the epigenome. Epigenetic modifications are alterations to an individual's genome without a change in the DNA sequence, and include, but are not limited to, three commonly studied alterations: DNA methylation, histone modification, and non-coding RNA expression. Given the role of epigenetic alterations in regulating gene and thus protein expression, there is the potential for the integration of toxic metal-induced epigenetic alterations as informative factors in the risk assessment process. In the present review, epigenetic alterations induced by five high priority toxic metals/metalloids are prioritized for analysis and their possible inclusion into the risk assessment process is discussed.
    Frontiers in Genetics 07/2014; 5:201. DOI:10.3389/fgene.2014.00201
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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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    ABSTRACT: Chronic exposure to arsenic may cause cancer. Many mechanisms have been suggested for arsenic carcinogenesis. Autophagy, an evolutionarily conserved cellular catabolic mechanism, has been implicated in cancer biology. Although being claimed as a type of cell death, autophagy may actually serve as a cell self-defense mechanism. In this review article, current understandings of the mechanisms of arsenic carcinogenesis, functions of autophagy and the role of autophagy in arsenic carcinogenesis are discussed.
    Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 07/2014; 66(4). DOI:10.1016/j.etp.2014.01.004 · 1.86 Impact Factor
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    • "Previous reports have demonstrated that carcinogen-induced demethylation of the genome in target organs is one of the main epigenetic responses to a range of wellknown chemical liver carcinogens, including arsenic, 2-acetylaminofuorene, and aflatoxin B 1 (Chen et al., 2004; Wu et al., 2013). In contrast, Chen et al. (2010; 2012) previously reported that exposure of male F344 rats to furan at 0.1 and 2.0 mg/kg bw/day for 28 days, or male Sprague Dawley rats to 30 mg/kg day/bw for 3 months did not alter the status of global DNA methylation in the livers. "
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    ABSTRACT: The presence of furan in common cooked foods along with evidence from experimental studies that lifetime exposure to furan causes liver tumors in rats and mice has caused concern to regulatory public health agencies worldwide; however, the mechanisms of the furan-induced hepatocarcinogenicity remain unclear. The goal of the present study was to investigate whether or not long-term exposure to furan causes epigenetic alterations in rat liver. Treating of male Fisher 344 rats by gavage 5 days per week with 0, 0.92, 2.0, or 4.4 mg furan/kg body weight (bw)/day resulted in dose- and time-dependent epigenetic changes consisting of alterations in DNA methylation and histone lysine methylation and acetylation, altered expression of chromatin modifying genes, and gene-specific methylation. Specifically, exposure to furan at doses 0.92, 2.0, or 4.4 mg furan/kg bw/day caused global DNA demethylation after 360 days of treatment. There was also a sustained decrease in the levels of histone H3 lysine 9 and H4 lysine 20 trimethylation after 180 and 360 days of furan exposure, and a marked reduction of histone H3 lysine 9 and H3 lysine 56 acetylation after 360 days at 4.4 mg/kg bw/day. These histone modification changes were accompanied by a reduced expression of Suv39h1, Prdm2, and Suv4-20h2 histone methyltransferases and Ep300 and Kat2a histone acetyltransferases. Additionally, furan at 2.0 and 4.4 mg/kg bw/day induced hypermethylation-dependent down-regulation of the Rassf1a gene in the livers after 180 and 360 days. These findings indicate possible involvement of dose- and time-dependent epigenetic modifications in the furan hepatotoxicity and carcinogenicity.
    Toxicological Sciences 03/2014; 139(2). DOI:10.1093/toxsci/kfu044 · 3.85 Impact Factor
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