To understand to what extent low-dose irradiations might be beneficial in humans, a better understanding of AR and other non-targeted effects is needed [15
]. The ‘Yonezawa Effect’ summarized a series of studies on radiation-induced AR at whole-body level in mice. In a series of comprehensive investigations, Yonezawa and colleagues verified the existence of AR under a variety of experimental conditions (varying doses of priming and challenge irradiations, varying intervals between priming and challenge exposures, and varying age and strain of the experimental mice) [7
]. These efforts helped to lay the cornerstone for an in vivo
AR model in mice. Based on the priming dose and on the interval between priming and challenge exposures, two different phenotypes of AR were observed that involved different mechanisms: the first phenotype was induced 2 weeks after a 0.3–0.5-Gy priming irradiation and was due to Trp53-dependent radioresistance in blood-forming tissues [10
]; the second phenotype was observed 2 months after a 0.05–0.1-Gy priming exposure and resulted from the interaction between blood-forming tissue and the central nervous system [17
]. The model for the first phenotype was applied to the present study.
Low doses of low-LET irradiations induce protective effects through mechanisms such as enhancement of antioxidative capacities, increase in cellular DNA double-strand break repair capacity leading to reduction of initial DNA damage in AR in mice in vivo
], and reduction of cell death, chromosomal aberrations, mutations and malignant transformation in vitro
]. These induced responses have been tightly conserved throughout evolution, suggesting that they are basic responses critical to life [4
]. In addition to the acute mouse killing effect in the AR animal model, examination of residual damage and late detrimental effects on the hematopoietic system, such as myelosuppression and delayed genotoxic effects, is of importance from the point of view of AR study and radiation protection. Well-designed animal experiments over extended periods of time have made studies on late effects possible. Because the biological effects produced by high-LET particulate irradiations were of some qualitative difference from those produced by low-LET photon exposures [22
], the existence of AR induced by low-LET irradiations against high-LET irradiations provides new clues for mechanistic studies. In the present study, the residual damage in surviving animals was studied in the mouse AR model after the 30-day survival test. Induction of AR in mice was performed using X-rays as priming irradiations in combination with challenge irradiations from either X-rays or accelerated carbon or neon ions with LET values of about 15 and 30 keV/μm, respectively. Results showed that in the surviving animals rescued by AR, the ratio of PCEs to the sum of PCEs and NCEs was significantly higher and the incidences of micronucleated PCEs and micronucleated NCEs were markedly lower than those in the survivors that received only the challenge dose. These findings indicated that a priming low dose of X-rays at 0.5 Gy significantly relieved myelosuppression and reduced residual damage in bone marrow cells induced by the challenge irradiations. In addition, the priming low dose of X-rays also markedly improved the blood platelet count in the surviving mice. Our blood platelet count results were consistent with previous results showing that rescue from bone marrow death was mainly due to priming irradiation-induced radio-resistance to challenge irradiation-induced Trp53-dependent apoptosis in hematopoietic stem cells [16
] and that the recovery of blood platelet count after exposure was one of the most important factors for restoration from bone marrow death [24
]. The results of blood platelet counts obtained in the present study were consistent with these previous studies.
The recovery ratio from potentially lethal damage is known to depend on the quality of radiation [25
]; cellular radio-sensitivity correlates with the frequency of residual chromatin breaks [26
], and high-LET irradiations have been shown to induce higher rates of residual chromatin breaks [27
]. Although high-LET heavy ions generally induce qualitatively different DNA damage (such as clustered DNA damage) in comparison with that of low-LET irradiations, the results of the present study suggested that the X-ray-induced biological defense mechanisms may be considered as effective countermeasures, being sufficient enough against the damage caused by high-LET challenge doses. In fact, mechanistic studies using cultured human fibroblasts reported that gene expression profiles following gamma radiation and decays of high-LET-like 125
I shared the majority of genes in common, indicating that both kinds of radiation elicited similar signal transduction pathways [28
]; thus, DNA double-strand breaks may not be the major factor modulating changes in gene expression following irradiation [29
]. In vitro
studies also showed that low doses of low-LET X-ray irradiations were effective in reducing chromosomal aberrations and mutation frequency induced by high-LET irradiations [21
]. These findings suggest that it may share at least to a large extent the same mechanisms against the damage caused by the high dose of challenge irradiations from low-LET X-rays and high-LET heavy ions.
Taken together, our results showed that a priming low dose of low-LET irradiations could relieve detrimental late effects (anhematopoiesis and delayed genotoxic effects) occurring in bone marrow cells. Results indicated the significance and possible application of AR to the reduction of genomic instability induced by high-dose irradiations from either low- or high-LET irradiations. These findings give new knowledge of the characterization of the ‘Yonezawa Effect’ by providing new insight into the mechanistic study of low-LET X-ray-induced AR against the detrimental effects of high-LET accelerated heavy ions in the mouse model of AR in vivo.