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Astronauts can develop psychological stress (PS) during space flights due to the enclosed environment, microgravity, altered light-dark cycles, and risks of equipment failure or fatal mishaps. At the same time, they are exposed to cosmic rays including high atomic number and energy (HZE) particles such as iron-56 (Fe) ions. Psychological stress or radiation exposure can cause detrimental effects in humans. An earlier published pioneering study showed that chronic restraint-induced psychological stress (CRIPS) could attenuate Trp53 functions and increase carcinogenesis induced by low-linear energy transfer (LET) γ rays in Trp53-heterozygous (Trp53+/–) mice. To elucidate possible modification effects from CRIPS on high-LET HZE particle-induced health consequences, Trp53+/– mice were received both CRIPS and accelerated Fe ion irradiation. Six-week-old Trp53+/– C57BL/6N male mice were restrained 6 h per day for 28 consecutive days. On day 8, they received total-body Fe-particle irradiation (Fe-TBI, 0.1 or 2 Gy). Metaphase chromosome spreads prepared from splenocytes at the end of the 28-day restraint regimen were painted with the fluorescence in situ hybridization (FISH) probes for chromosomes 1 (green), 2 (red) and 3 (yellow). Induction of psychological stress in our experimental model was confirmed by increase in urinary corticosterone level on day 7 of restraint regimen. Regardless of Fe-TBI, CRIPS reduced splenocyte number per spleen at the end of the 28-day restraint regimen. At 2 Gy, Fe-TBI alone induced many aberrant chromosomes and no modifying effect was detected from CRIPS on induction of aberrant chromosomes. Notably, neither Fe-TBI at 0.1 Gy nor CRIPS alone induced any increase in the frequency of aberrant chromosomes, while simultaneous exposure resulted in a significant increase in the frequency of chromosomal exchanges. These findings clearly showed that CRIPS could enhance the frequency of chromosomal exchanges induced by Fe-TBI at a low dose of 0.1 Gy.

Our previous study indicated that sodium orthovanadate (vanadate), a strong inhibitor of p53, effectively suppressed the lethality from the hematopoietic (HP) and gastrointestinal (GI) syndromes after 12 Gy total-body irradiation (TBI) in mice. This conclusion, however, was inconsistent with the fact that p53 plays a radioprotective role in the intestinal epithelium. The death after TBI of around 12 Gy was attributed to a combined effect of HP and GI syndromes. To verify the effect from prophylactic administration of p53 inhibitor on protection of HP and GI syndromes, in this study, the radioprotective effects from vanadate were investigated in TBI and lower half-body irradiation (partial-body irradiation: PBI) mouse models.

Space travel has advanced significantly over the last six decades with astronauts spending up to 6 months at the International Space Station. Nonetheless, the living environment while in outer space is extremely challenging to astronauts. In particular, exposure to space radiation represents a serious potential long-term threat to the health of astronauts because the amount of radiation exposure accumulates during their time in space. Therefore, health risks associated with exposure to space radiation are an important topic in space travel, and characterizing space radiation in detail is essential for improving the safety of space missions. In the first part of this review, we provide an overview of the space radiation environment and briefly present current and future endeavors that monitor different space radiation environments. We then present research evaluating adverse biological effects caused by exposure to various space radiation environments and how these can be reduced. We especially consider the deleterious effects on cellular DNA and how cells activate DNA repair mechanisms. The latest technologies being developed, e.g., a fluorescent ubiquitination-based cell cycle indicator, to measure real-time cell cycle progression and DNA damage caused by exposure to ultraviolet radiation are presented. Progress in examining the combined effects of microgravity and radiation to animals and plants are summarized, and our current understanding of the relationship between psychological stress and radiation is presented. Finally, we provide details about protective agents and the study of organisms that are highly resistant to radiation and how their biological mechanisms may aid developing novel technologies that alleviate biological damage caused by radiation. Future research that furthers our understanding of the effects of space radiation on human health will facilitate risk-mitigating strategies to enable long-term space and planetary exploration.

Background: Several factors found in foods are beneficial to human health and they may contribute to radiation protection. Taking food factors could be an easy way to reduce the effects of radiation after nuclear accidents, as well as secondary radiation risks after cancer radiotherapy or space missions. Here, diallyl disulfide (DADS), a component of garlic oil, was studied for its ability to mitigate radiation damage. Material/Methods: We investigated the effects of DADS on micronucleus (MN) formation and apoptosis in HepG2 cells by use of 4-Gy X-ray irradiation. We also assessed the effects of DADS on radiation damage in vivo by evaluating MN formation in bone marrow cells in mice (BALB/c, 8-week-old females) after oral intake of DADS prior to irradiation with 4 Gy. Several tissue effects were also investigated. Results: The presence of DADS inhibited MN formation, whereas DADS had no influence on the radiation-induced inhibition of cell cycle progression in HepG2 cells. An increase in apoptosis in HepG2 cells was induced after irradiation, and this effect was stronger in the presence of DADS than in its absence. In mice, when DADS was administered daily for 3 days prior to irradiation, MN formation in irradiated mice was decreased. The decrease in MN formation in mice was greater with 0.5% DADS compared to 1% DADS. Moreover, an increase in spleen weight observed 3 weeks after irradiation was suppressed in mice administered DADS. Conclusions: DADS is a potential radiation-protective agent that effectively mitigates DNA damage, and its effects in the spleen observed after irradiation may be related to inflammation and carcinogenesis

Purpose: Effect from post-exposure onset of diet restriction on genotoxicity induced by high LET iron particles was studied using total body irradiation (TBI) of mice and micronucleus frequency in bone marrow erythrocytes as the endpoint. Materials and Methods: C57BL/6J Jms strain female mice of 8 weeks old were irradiated with iron particles (initial energy=500 MeV/nucleon, LET=200 keV/μm; HIMAC) at a dose of 2.0 Gy. Induction of acute genotoxicity and late residual damage in the hematopoietic system was determined respectively at one and two months after TBI. After TBI, mice were either allowed to free access to a standard laboratory chow MB-1 (Funabashi Farm Co., Japan) or treated under a diet restriction (DR) to 75% of the amount that the animals took under free access. Results and Conclusions: Reduction of body weight gain after TBI was observed in the groups that were exposed to TBI alone, under DR alone, and under DR after TBI. TBI alone caused a significant increase in micronucleus induction. DR alone did not alter the micronucleus frequency. On the other hand, DR after TBI induced a significant decrease in micronucleus induction compared to the treatment by TBI alone. These findings indicated that post-exposure onset of diet restriction could relieve the genotoxicity induced by TBI to high LET iron particles. Acknowledgments: This work was partially supported by both the MEXT Grant-in-Aid for Scientific Research on Innovative Areas, Grant Number 15H05935 “Living in Space” and three HIMAC Research Project Grants (22B258, 14J286 and 16J295)., 日本放射線影響学会第63回大会

Astronauts develop psychological stress (PS) during space flight because of enclosed environment, zero gravity and altered light-dark cycles. At the same time, they are exposed to cosmic rays including high atomic number and energy (HZE) particles such as iron-56 (Fe) ions. A pioneering study showed that chronic restraint-induced PS (CRIPS) could attenuate Trp53 functions and increase carcinogenesis induced by low linear energy transfer (LET) gamma-rays in Trp53-heterozygous (Trp53+/-) mice. To elucidate possible modification effects from CRIPS on high LET HZE particles-induced health consequences, Trp53+/- C57BL/6N male mice (six-week-old) were restrained 6 hours per day for consecutive 28 days, and total-body irradiation (TBI) of Fe ions at a dose of 0.1 or 2 Gy was given on the 8th day. Chromosomal aberrations (CAs) in splenocytes were observed by fluorescence in situ hybridization (FISH) at the end of the 28-day restraint regimen. Induction of PS in our experimental model was confirmed by an increase in urinary corticosterone level. CRIPS reduced splenocyte number per spleen but Fe TBI. Fe TBI alone increased CAs significantly at 2.0 Gy but 0.1 Gy. Exposure to CRIPS alone didn’t induce CAs but concurrent exposure to CRIPS and Fe TBI showed a tendency of increase in the frequency of CAs as compared to exposure to Fe TBI alone. Further analyses are required to confirm the modification effects from CRIPS on Fe TBI-induced CAs. This work was partially supported by the MEXT Grant-in-Aid for, 日本放射線影響学会第62回大会

Radioadaptive response (RAR) was demonstrated in varied biosystems. In mice, the first model called “Yonezawa Effect” was established by Yonezawa and colleagues using X-rays as both the priming and the challenge doses, and rescue of bone marrow death as the endpoint. RAR is capable of reducing genotoxicity, cell transformation, mutation and carcinogenesis but the underlying mechanisms remain fragmented. The present work aimed to further characterize RAR in this mouse model. In a series of recent investigations, we demonstrated that existence of RAR using different types of ionizing radiation (IR) including high LET heavy ions; increase in the hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) measured as endogenous colony forming units-spleen under RAR; and reduction of delayed homologous recombination (HR) in the nucleated cells in hematopoietic tissues (bone marrow and spleen). These findings suggest that RAR in mice induced by different types of IR would share a common underlying mechanism: the priming IR-induced resistance in the blood forming tissues, leading to a protective effect on the HSCs/HPCs and rescuing the animals from bone marrow death. On the other hand, reduction of delayed HR may be at least a part of the mechanisms underlying decreased carcinogenesis by RAR. These findings provide a new insight into the mechanistic study on RAR in vivo and suggest that application of RAR would contribute to a more rigorous and scientifically-grounded system of radiation protection in radiotherapy. This work was partially supported by both the Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid for Scientific Research on Innovative Areas, Grant Numbers JP15K21745 and 15H05935 “Living in Space”. Keywords: Adaptive response, colony forming unites-spleen, homologous recombination, The 65th Annual Meeting of Radiation Research (RRS2019)に出席、ポスター発表を行う。タイトル:Study on Radioadaptive Response in a Mouse Model (Yonezawa Effect): Recent Progress

Background: Astronauts develop psychological stress (PS) during space flight because of enclosed environment, zero gravity and altered light-dark cycles. At the same time, they are exposed to cosmic rays including high atomic number and energy (HZE) particles such as iron-56 (Fe) ions. A pioneering study showed that chronic restraint-induced PS (CRIPS) could attenuate Trp53 functions and increase carcinogenesis induced by low linear energy transfer (LET) gamma-rays in Trp53-heterozygous (Trp53+/-) mice. Methods: To elucidate possible modification effects from CRIPS on high LET HZE particles-induced health consequences, Trp53+/- C57BL/6N male mice (six-week-old) were restrained 6 hours per day for consecutive 28 days, and total-body irradiation (TBI) of Fe ions at a dose of 0.1 or 2 Gy was given on the 8th day. Chromosomal aberrations (CAs) in splenocytes were observed by fluorescence in situ hybridization (FISH) at the end of the 28-day restraint regimen. Results/Conclusions: Induction of PS in our experimental model was confirmed by an increase in urinary corticosterone level. CRIPS reduced splenocyte number per spleen but Fe TBI. Fe TBI alone increased CAs significantly at 2.0 Gy but 0.1 Gy. Exposure to CRIPS alone didn’t induce CAs but concurrent exposure to CRIPS and Fe TBI showed a tendency of increase in the frequency of CAs as compared to exposure to Fe TBI alone, though the increases were not statistically significant. Further analyses are required to confirm the modification effects from CRIPS on Fe TBI-induced CAs. Acknowledgement: This work was partially supported by both the Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid for Scientific Research on Innovative Areas, Grant Numbers JP15K21745 and 5H05935 “Living in Space” and 3 HIMAC Research Project Grants (22B258, 14J286 and 16J295)., 学会The 16th International Congress of Radiation Research (ICRR2019)に出席し、ポスター発表を行う。 タイトル:Effects of chronic restraint-induced stress and Fe-particle irradiation on induction of chromosomal aberrations in Trp53-heterozygous mice

Astronauts develop psychological stress (PS) during space flight because of enclosed environment, zero gravity and altered light-dark cycles. At the same time, they are exposed to cosmic rays including high atomic number and energy (HZE) particles such as iron-56 (Fe) ions. A pioneering study showed that chronic restraint-induced PS (CRIPS) could attenuate Trp53 functions and increase carcinogenesis induced by gamma-rays in Trp53-heterozygous (Trp53+/-) mice. To elucidate possible modification effects from CRIPS on HZE particles-induced health consequences, Trp53+/- C57BL/6N male mice (six-week-old) were restrained 6 hours per day for consecutive 28 days, and total-body irradiation (TBI) of Fe ions at a dose of 0.1 or 2 Gy was given on the 8th day. Chromosomal aberrations (CAs) in splenocytes were observed by fluorescence in situ hybridization (FISH) at the end of the 28-day restraint regimen. Induction of PS in our experimental model was confirmed by an increase in urinary corticosterone level. CRIPS reduced splenocyte number per spleen but Fe TBI. Fe TBI alone increased CAs significantly at 2.0 Gy. CRIPS alone didn’t induce CAs but concurrent exposure to CRIPS and 0.1 Gy Fe TBI showed a significant increase in the frequency of CAs as compared to exposure to Fe TBI alone. This work was partially supported by MEXT Grant-in-Aid for Scientific Research on Innovative Areas, “Living in Space” (JP15K21745, 15H05944 and 5H05935)., 日本宇宙生物科学会第33回大会に出席して「Chromosomal aberrations induced in Trp53-heterozygous mice exposed to both chronic restraint-induced stress and Fe-particle irradiation」のタイトルでポスター発表を行う。

Both ionizing radiation (IR) and psychological stresses (PS) cause detrimental effects on humans. There is a great concern to understand if PS could cause any alterations in the response of human beings to IR. A pioneering study showed chronic restraint-induced PS (CRIPS) increased gamma-radiation-induced carcinogenesis in Trp53+/- mice. Prior to carcinogenesis study, to investigate the effects from PS on IR-induced health consequences, effects of Fe total body irradiation (Fe TBI) on the hematopoietic system in Trp53+/- mice under CRIPS were studied. Six-week-old male C57BL/6N mice were chronically restrained 6 hours daily for consecutive 28 days, being given Fe TBI (0.1 Gy or 2.0 Gy) on the 8th day. The peripheral blood and the bone marrow were collected for analysis of hematological abnormality and residual damage in the erythrocytes. Results showed that CRIPS alone hardly induce marked alteration in hematological parameters in the peripheral blood and the formation of micronucleated erythrocytes in the bone marrow while Fe TBI alone could induce significant hematological alteration and increased micronucleated erythrocytes. On the other hand, concurrent exposure of the animals to CRIPS and Fe TBI always showed a tendency of increased micronucleated erythrocytes when compared to the animals receiving only Fe TBI, and the increase was statistically significant for the mice receiving Fe TBI at 0.1 Gy., 新領域学術研究「宇宙に生きる」2018年度第2回全体会議

Background & Aim: Existence of radioadaptive response (RAR) was demonstrated in varied biosystems. RAR is capable of reducing genotoxicity, mutation and carcinogenesis but the underlying mechanisms remain fragmented. The first RAR mouse model (Yonezawa Effect) was established by Yonezawa et al. using low LET X-rays as both the priming and the challenge doses, and rescue of bone marrow death as the endpoint. The aim of this study was to characterize RAR in this model. Methods & Results: We demonstrated that existence of RAR using different types of ionizing radiation (IR) including high LET heavy ions; increase in the hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) measured as endogenous colony forming units-spleen under RAR; and reduction of delayed homologous recombination (HR) in the nucleated cells in hematopoietic tissues (bone marrow and spleen). Conclusions & Discussions: These findings suggest that RAR in mice induced by different types of IR would share a common underlying mechanism: the priming IR-induced resistance in the blood forming tissues, leading to a protective effect on the HSCs/HPCs and rescuing the animals from bone marrow death. On the other hand, reduction of delayed HR may be at least a part of the mechanisms underlying decreased carcinogenesis by RAR. These findings provide a new insight into the mechanistic study on RAR in vivo and suggest that application of RAR would contribute to a more rigorous and scientifically-grounded system of radiation protection in radiotherapy. Acknowledgement: This work was partially supported by MEXT Grant-in-Aid for Scientific Research on Innovative Areas, “Living in Space” (grant Nos. JP15K21745, 15H05944 and 15H05935)., 日本宇宙生物科学会第33回大会

Background: Existence of radioadaptive response (RAR) was reported in varied biosystems. RAR is capable of reducing genotoxicity, cell transformation, mutation and carcinogenesis but the underlying mechanisms remain fragmented. The first RAR mouse model called “Yonezawa Effect” was established by Yonezawa and colleagues using low LET X-rays as both the priming and the challenge doses, and rescue of bone marrow death as the endpoint. Aim: Characterization of RAR in this mouse model. Methods/Results: In a series of investigations, we further demonstrated that 1) existence of RAR using different types of ionizing radiation (IR) including high LET heavy ions; increase in the hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) measured as endogenous colony forming units-spleen (CFU-S) under RAR; and reduction of delayed homologous recombination (HR) in the nucleated cells in hematopoietic tissues (bone marrow and spleen) using the Rosa26 Direct Repeat-GFP homozygote mice. Conclusions/Discussions: These findings suggest that RAR in mice induced by different types of IR would share a common underlying mechanism: the priming IR-induced resistance in the blood forming tissues, leading to a protective effect on the HSCs/HPCs and rescuing the animals from bone marrow death. On the other hand, reduction of delayed HR may be at least a part of the mechanisms underlying decreased carcinogenesis by RAR. These findings provide a new insight into the mechanistic study on RAR in vivo and suggest that application of RAR would contribute to a more rigorous and scientifically-grounded system of radiation protection in radiotherapy. キーワード：Adaptive response, ionizing radiation, colony forming unites-spleen, homologous recombination, mice, The 16th International Congress of Radiation Research (ICRR2019）

近年、様々な機関が大学生を対象とした放射線防護の教育プログラムを実施している。原子力人材育成を目指した放射線防護教育において関連法令は必須項目であるが、業務経験のない受講者にとって一方向的な講義形式では法令に対する学習意欲が湧きにくく理解不足になりやすい。このような背景において、通常の講義に加え受講者参加型のグループワークを組み合わせたところ受講者の学習意欲改善に一定の効果を得たことが示唆された。, 第56回 アイソトープ・放射線研究発表会

放射線治療において処方できる線量は、正常組織への障害リスクによって強く制限される。この制限を克服する手段として、正常組織の耐容線量を高める放射線防護剤の開発が望まれている。我々はこれまでに、正常組織の放射線耐性を特異的に高めるいくつかのp53制御剤を見出してきた。そのなかでも、強力なp53阻害剤であるオルトバナジン酸ナトリウム（バナデート）は、骨髄死相当線量である8 Gyおよび腸死相当線量である12 Gyのマウス全身照射試験において、顕著な防護効果を示す化合物である。しかし、バナデートによるp53阻害を介した腸管保護効果は、p53が被ばく後の腸上皮幹細胞死に対する抵抗性因子として機能するという近年の知見と矛盾していた。 他の研究グループの研究では、腸死相当線量のマウス全身照射試験において骨髄移植が奏効したと報告されていることから、およそ12 Gyの全身照射モデルでは骨髄障害が腸死の進行に寄与していると考えられた。そこで本研究では、マウスの頭部および前脚部の骨髄を鉛で遮蔽防護し、骨髄死を回避した亜全身照射モデルによってバナデートの腸管保護効果を再検証した。 8週齢雌性ICRマウスにバナデート（20 mg/kg体重）または溶媒を腹腔内投与し、亜全身照射を行うことで、重度の骨障害を回避しつつ腸管死を誘導させた。溶媒投与群はX線18 Gyおよび21 Gy照射後、それぞれ20%および10%の生存率を示した一方、バナデート投与群は全てのマウスが死亡し、バナデートによる腸死の促進が認められた（P < 0.05）。また、18 Gy照射3.5日後の回腸組織では、バナデートおよび溶媒投与群のいずれも重度の絨毛萎縮と陰窩消失を示し、陰窩消失はバナデート投与群においてより顕著であった（P < 0.05）。他方、これらの組織障害はp53調節剤である5-クロロ-8-キノリノール（5CHQ）の投与によって効果的に抑制された（P < 0.05）。 以上の結果から、p53阻害剤であるバナデートの放射線防護効果は、骨髄症候群のみ、あるいは骨髄症候群と胃腸管症候群が複合的に誘導される全身被ばく状況下（～12 Gy程度）に限定される可能性があり、腹部領域への局所的被ばく状況下での使用は腸管障害を促進すると考えられた。, 第57回日本放射線腫瘍学会生物部会学術大会

近年の高精度放射線療法の進展は目覚ましく、線量集中性の向上によって高い治療効果が得られるようになった。しかしながら、周辺のリスク臓器に有害事象が生じないようにするため依然として正常組織障害が処方できる腫瘍線量の限界を決めている。分子標的創薬に基づいた正常組織選択的防護剤の開発は、放射線治療における線量限界を克服する有効な手段の一つと考えられ、リスク臓器防護による1回照射線量の増大と有害反応の抑制がもたらす寡分割照射の実現、あるいは処方線量の向上が期待される。 放射線防護上、代表的な急性障害は骨髄と腸上皮の放射線障害である。粒子線細胞死については、85 keV/µm以上の高LET放射線ではp53依存性を示さないことが固形腫瘍由来培養細胞を用いて明らかにされているが、骨髄や腸管の放射線高感受性を再現できる適切な培養細胞系はなく、マウス個体の生存率および組織解析が最も適切な防護活性評価方法と考えられた。一方、最近の研究により、p53は、骨髄死ではアポトーシスを促進する因子として、腸死では分裂死を防ぐ抵抗性因子として機能することが明らかとなった。 我々は、骨髄死を防ぐ化合物としてp53活性を抑制する「p53阻害剤」としてオルトバナジン酸ナトリウム（バナデート）を、また、腸死に有効な「p53調節剤」として5-クロロ-8-キノリノール（5CHQ）を発見した。本研究では、これらの化合物を用い、重粒子線に対するp53制御の有効性をマウス個体（8週齢雌性ICRマウス）の照射後の60日生存率を指標として評価した。線質については、培養細胞を用いた先行研究でp53依存的な致死作用を示した炭素線（14 keV/µm）と、p53非依存的な致死作用を示した鉄線（189 keV/µm）を用いた。 骨髄死相当線量の炭素線全身照射試験では、7.0 Gy、7.5 Gyでは溶媒投与群が8.3%、0%の生存率に対し、バナデート投与群が92%、83%生存し、有意な放射線防護活性を示した（p < 0.0001）。一方、腸死相当線量の炭素線を腹部照射したマウスでは、何れの照射線量群（12-15 Gy）においてもバナデートの防護効果が認められなかった。また、鉄線全身照射試験では、7.5 Gyでは溶媒投与群が56%の生存率に対し、バナデート投与群が92%生存し、溶媒投与群より高い生存率を示したが（p = 0.055）、8.0 Gyでは防護効果が認められなかった。以上より、バナデートは、腸死に対して有効ではないが、骨髄死においては炭素線に対して明確な防護効果を示した。鉄線による骨髄障害に対しては、線量のわずかな増加でバナデートの防護効果は失われてしまうが、p53阻害によってある程度軽減できることが明らかとなった。もう一方の5CHQの活性評価も進行中である。, 第57回放射線腫瘍学会生物部会

Ploy MVA was evaluated for its potential to protect mouse from radiation. Treatment of 8 Gy X-ray-irradiated mice with polyMVA increased survival rate to 100% 30 days after irradiation. The best effect was based on adequate absorption of ployMVA by a health mouse intestine. Doses higher than 8 Gy X-rays or 5.5 Gy carbon ions induce serious intestinal injury, which caused impedient absorption of ployMVA. We found simple ployMVA treatment was ineffective in protecting mice from carbon ion irradiation of doses higher than 5.5 Gy. However, the synergistic effect of ployMVA and Amifostine against irradiation deserves further exploration. In the FY 2018, we have plotted a credible survival fraction of the mice exposed to X-ray irradiation, which has laid the foundation for the heavy ion experiments., 平成30年度放射線医学総合研究所重粒子線がん治療装置等共同利用研究報告会