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Sodium arsenite administration via drinking water increases genome-wide and Ha-ras DNA hypomethylation in
R S Okoji1, R C Yu, R R Maronpot
1Center for Occupational and Environmental Health, UCLA School of Public Health, 650 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
Abstract:
Arsenic is an established human carcinogen. Deficiencies in available animal models have inhibited a detailed analysis of the mechanism of arsenic induced cancer. This study sought to determine the role of a methyl-deficient diet in combination with sodium arsenite on the genomic methylation status and Ha-ras methylation status of C57BL/6J male mice hepatic DNA. Mice were administered arsenic as sodium arsenite via drinking water at 0, 2.6, 4.3, 9.5 or 14.6 mg sodium arsenite/kg/day. Administration occurred 7 days a week for 130 days. Dose-related effects on the liver were evident in mice administered arsenic and methyl-deficient diets. Most prominent were observations of steatosis and microgranulomas. Sodium arsenite increased genomic hypomethylation in a dose dependent manner and methyl-deficiency and sodium arsenite reduced the frequency of methylation at several cytosine sites within the promoter region of the oncogenic gene, Ha-ras. Methylation changes were prominent in a 500 bp non-CpG island-like region of the Ha-ras promoter and less prominent in a 525 bp CpG island-like region. DNA methylation plays an important role in the physiological expression of many genes including Ha-ras. Significantly reduced methylation at a key regulatory region of Ha-ras in the mouse liver may have relevance to understanding arsenic-induced perturbations in the methylation patterns of cellular growth genes involved in the formation of tumors. These findings highlight the effect of sodium arsenite on inherent methylation processes within the hepatic cell.
Insights
Arsenic exposure, especially with a methyl-deficient diet, alters DNA methylation in mouse liver cells. This impacts the Ha-ras oncogene, potentially contributing to tumor formation.
Area of Science:
- Toxicology
- Epigenetics
- Carcinogenesis
Background:
- Arsenic is a known human carcinogen, but its cancer-causing mechanisms are not fully understood.
- Animal models are crucial for studying arsenic-induced cancer mechanisms.
Purpose of the Study:
- To investigate the combined effects of sodium arsenite and a methyl-deficient diet on genomic and Ha-ras methylation in mouse liver DNA.
- To explore the role of DNA methylation changes in arsenic-induced carcinogenesis.
Main Methods:
- C57BL/6J male mice were fed diets deficient in methyl donors and administered varying doses of sodium arsenite (0-14.6 mg/kg/day) for 130 days.
- Genomic DNA was analyzed for methylation status, focusing on the Ha-ras gene promoter region.
- Liver tissues were examined for dose-related effects.
Main Results:
- Sodium arsenite exposure led to dose-dependent genomic hypomethylation.
- A methyl-deficient diet combined with sodium arsenite reduced methylation frequency at specific cytosine sites in the Ha-ras promoter.
- Observed liver effects included steatosis and microgranulomas.
Conclusions:
- Arsenic exposure significantly alters DNA methylation patterns in mouse liver, particularly affecting the Ha-ras oncogene.
- These methylation changes, especially in non-CpG island regions of Ha-ras, may be relevant to arsenic-induced tumor development.
- The study highlights the impact of sodium arsenite on cellular methylation processes.
