Principal Research Results

Acquisition of Radioresistance in Mice Induced by Low Dose-rate
Long Term Gamma Irradiation−Enhancement of Hematopoiesis and Reduction of DNA Damage−
BackgroundLow dose pre-irradiation would improve the survival of mice after acute high dose irradiation. The acquisition of radioresistance by low dose irradiation is called “radiation adaptive (or radioadaptive) response”, which emerged as a specific responses inanimals when treated with low dose radiation. However, it is almost observed when the mice were primed with “single low dose”
radiation. Therefore, it is necessary to clarify whether the adaptive response is induced and what its mechanism is under “low doserate long term” irradiation.

Objectives
To confirm the induction of adaptive response by low dose-rate long term irradiation, we focused on the hematopoieticsystem, which is most sensitive organ to radiation in mammalian body; survival rate of hematopoietic stem cells (HSCs) ＊ 1 after highdose irradiation, reduction of DNA damage and enhancement of antioxidants were estimated as an indicator of radiation resistance.

Principal Results
1. Mice were irradiated with gamma rays at 1.2mGy/hr for 30, 50, 60, 70 and 80 days. Immediately after the irradiation, high dose Xirradiation was carried out. Twelve days later, the number of colonies appearing on the surface of spleen, comprised to HSCs, wascounted. The survival of HSCs was increased at 30 or 60 days (Fig.1). It was indicated that low dose-rate long term irradiation
could induce adaptive response but it had a specific response.
2. Mice were irradiated at the low dose-rate for 30 days; then they were acutely irradiated with 0.5, 1 or 2 Gy of X-rays. Immediately
after the X-irradiation the spleen was removed and DNA damage in spleen cells consisting of HSCs was analyzed. The DNA
damage was less in the mice pre-irradiated and then X-irradiated compared to that in the mice irradiated with the X-rays only(Fig.2).
3. One of the antioxidants which can reduce reactive oxygen species was enhanced by low dose-rate irradiation (Fig.3). Reactive
oxygen species were known to DNA damaging agents. It is possible to contribute that the reduction of DNA damage by antioxidants finally improves the survival of HSC.
The results described above indicated that the low dose-rate long term irradiation activated certain types of bio-defense
mechanisms including an enhancement of antioxidants, reduction of DNA damage and improved HSC survival to prevent the death ofheavily irradiated mice.

Future Developments
Identify the molecules or genes that contribute to radiation adaptive response and confirm they are enhanced in humans inthe same manner.
Main Researchers:
Kensuke Otsuka, Research associate and Takaharu Nomura, Ph. D., Research Scientist,Low Dose Radiation Research Center, Nuclear Technology Research Laboratory
Reference
K. Otsuka, et.al., 2004, “Detection of DNA damage in mouse tissue cells induced by low dose or low dose-rate irradiation”, Technical
Report G03012 (in Japanese)
K. Otsuka, et.al., 2005, “Radiation adaptive response induced by prolonged low dose-rate irradiation”, Technical Report L04003 (inJapanese)＊1：Primordial cells which produce blood cells such as erythrocyte, leukocyte, lymphocyte and so on. Disorder of hematopoietic system by theloss of HSCs may cause death.

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C. Harmonization of energy and environment

Death

Fig.1 Effects oflowdose-rateirradiation on thesurvival of HSCs

Hematopoietic
DisorderLoss of HSC(above) The number ofHSCs was specificallyincreased at 60 days
irradiation.

Increase in
HSCs survival

Without pre-irradiation

With pre-irradiation

DNA damage(below) Appearance of thespleen of mice irradiated60 days at 1.2 mGy/hr.
Each colony (seemed as awhite nodule) derived fromone stem cell.

Fig.2 Reductionof DNA damage
by low dose-rateirradiation

Reduction ofDNA damage

DNAdamagewasincreased by increasing theX-ray dose. However,relative damage wassuppressed in the preirradiated mice.

ReactiveOxygenSpecies

Radiation

Enhancement ofantioxidants

Fig.3 Enhancement of antioxidative activity by low
dose-rate irradiation
Low dose-rate irradiation (0.6Gy at 1.2mGy/hr) could induced antioxidative
activity in mouse.

【Steps in radiation-induced disorder on hematopoietic system and their prevention by bio-defense mechanisms
enhanced by low dose-rate-irradiation】
Certain adaptive responses (shown by green arrows) suppress each radiation inductive disorder (blue).

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