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.