ToxSci Advance Access originally published online on March 16, 2006
Toxicological Sciences 2006 91(2):372-381; doi:10.1093/toxsci/kfj159
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Chronic Oral Exposure to Inorganic Arsenate Interferes with Methylation Status of p16INK4a and RASSF1A and Induces Lung Cancer in A/J Mice
* Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan; and Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan
Received January 25, 2006; accepted February 27, 2006
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. Epigenetic effects of iAsV on DNA methylation patterns of p16INK4a and RASSF1A genes were determined by methylation-specific polymerase 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 size was observed in iAsV-exposed mice compared to the control. Histopathological examination showed that the rate of poorly differentiated lung adenocarcinoma was much higher in iAsV-exposed mice than in the control. Methylation rates appeared to be higher in a dose-related tendency in lung tumors from iAsV-exposed mice compared to the control. Lower or loss of p16INK4a and RASSF1A expression was found in lung tumors from iAsV-exposed mice, compared to that in nontumor lung tissues from both control and iAsV-exposed mice, and this reduced or lost expression was in accordance with hypermethylation of the genes. In conclusion, iAsV exposure increased lung tumor incidence and multiplicity in A/J mice. Epigenetic changes of tumor suppressor genes such as p16INK4a and RASSF1A are involved in the iAsV-induced lung carcinogenesis.
Key Words: arsenic; epigenetics; DNA methylation; lung tumor; p16INK4a; RASSF1A; lung carcinoma.
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