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.
Toxicological Sciences (Impact Factor: 4.48). 07/2006; 91(2):372-81. DOI: 10.1093/toxsci/kfj159
Source: PubMed

ABSTRACT Although inorganic arsenate (iAs(V)) or arsenite (iAs(III)) is clearly a human carcinogen, it has been difficult to produce tumors in rodents. In the present study, we orally administered iAs(V) 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 iAs(V) 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 iAs(V) 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 iAs(V)-exposed mice. Increase in lung tumor number and lung tumor size was observed in iAs(V)-exposed mice compared to the control. Histopathological examination showed that the rate of poorly differentiated lung adenocarcinoma was much higher in iAs(V)-exposed mice than in the control. Methylation rates appeared to be higher in a dose-related tendency in lung tumors from iAs(V)-exposed mice compared to the control. Lower or loss of p16INK4a and RASSF1A expression was found in lung tumors from iAs(V)-exposed mice, compared to that in nontumor lung tissues from both control and iAs(V)-exposed mice, and this reduced or lost expression was in accordance with hypermethylation of the genes. In conclusion, iAs(V) 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 iAs(V)-induced lung carcinogenesis.

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