Carcinogenesis Advance Access published online on April 8, 2004
Carcinogenesis, doi:10.1093/carcin/bgh161
© 2004 by Oxford University Press
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CARCINOGENESIS
1 Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institutes of Environmental Health Sciences, Research Triangle Park, NC, USA
* Corresponding author. E-mail: waalkes{at}niehs.nih.gov.
Received 6 January 2003
; revised 19 March 2004
; accepted 31 March 2004
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 nongenotoxic mechanism of carcinogenesis. Thus, in the present study liver samples of male mice exposed to 0 (control) or 45 ppm arsenic (as NaAsO2) 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 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-
Arsenic, chronic exposure, DNA methylation, ER-Chronic inorganic arsenic exposure induces hepatic global and individual gene hypomethylation: implications for arsenic hepatocarcinogenesis
2 Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, MD, USA
3 Basic Research Program, SAIC-Frederick, Frederick, MD, USA
(ER-), and cyclin D1 genes were markedly increased. RT-PCR and immunohistochemistry confirmed arsenic-induced increases in hepatic ER- 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- gene promoter region, as assessed by the 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- 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- gene promoter, all of which could potentially contribute to arsenic hepatocarcinogenesis., Cyclin D1
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