Chronic Oral Exposure to Inorganic Arsenate Interferes with Methylation Status of p16INK4a and RASSF1A and Induces Lung Cancer in A/J Mice

Although inorganic arsenate (iAsV) or arsenite (iAsIII) is clearly a human carcinogen, it has been difficult to produce tumors in rodents. In the present study, we orally administered iAsV to A/J mice to examine arsenic carcinogenicity in rodent. A/J mice (male, n = 120) assigned to four groups were given drinking water containing 0, 1, 10, and 100 ppm iAsV for 18 months. At the end of experiment, the complete lungs were removed and used for examining histopathology and extracting RNA and DNA. Epige-netic effects of iAsV on DNA methylation patterns of p16INK4a and RASSF1A genes were determined by methylation-specific polymer-ase chain reaction. Changes of p16INK4a and RASSF1A at mRNA and protein levels were examined by reverse transcriptase– polymerase chain reaction and immunohistochemistry. Arsenic was accumulated dose dependently in the lung tissues of iAsV-exposed mice. Increase in lung tumor number and lung tumor siz