| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
We are living in the environment with numerous natural and man-made carcinogens. Cancer development in human, therefore, is considered as a result of interaction with these factors. Thus carcinogenic response of radiation could be influenced by these factors. The aim of this study was to elucidate the mode and mechanism of the combined effect of radiation with chemicals, with special attention to the exposure sequence, using mouse model of T-cell lymphomas (TI).
Female B6C3F1 mice were either exposed weekly to whole body X-irradiation for consecutive 4 weeks or were given ENU in drinking water far consecutive 4 weeks. Mice were also exposed to both X-rays and ENU in different exposure sequence. The dose-response curve for X-ray-or ENU-induced TL was sigmoidal or linear both with threshold dose, respectively. Ikaros which is a critical tumor suppressor gene for TL, was frequently mutated. Ikaros mutations in X-rays-induced TL were characterized by frequent lass of heterozygosity (LOB), while those in ENU-induced TL were not accompanied with LOH. When mice were exposed to X-rays followed by ENU, the dose response of TL showed antagonism at doses lower than threshold, but synergism at doses higher than threshold. Ikaros mutations in TL after high dose X-rays combined with ENU were similar to those of ENU-induced TL or new types specific for combined exposure. On the other hand, the dose response after combined exposure to reverse sequence was additive despite X-ray dose. The Ikaros mutations were similar to those in X-ray-induced TL. Further, simultaneous-exposure resulted synergistic effect at doses more than threshold. Ikaros mutations were similar in those in ENU-induced TL. In addition, mutations specific to combined exposures were also identified. Taken together, it is concluded that the mode and mechanism of combined effect on lymphomagenesis depends on the sequence of exposure.
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