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16 pages, 3420 KiB

Open AccessArticle

Strong Shift to ATR-Dependent Regulation of the G₂-Checkpoint after Exposure to High-LET Radiation

by Veronika Mladenova, Emil Mladenov, Michael Scholz, Martin Stuschke and George Iliakis

Life 2021, 11(6), 560; https://doi.org/10.3390/life11060560 - 14 Jun 2021

Cited by 8 | Viewed by 2881

The utilization of high linear-energy-transfer (LET) ionizing radiation (IR) modalities is rapidly growing worldwide, causing excitement but also raising concerns, because our understanding of their biological effects is incomplete. Charged particles such as protons and heavy ions have increasing potential in cancer therapy, [...] Read more.

The utilization of high linear-energy-transfer (LET) ionizing radiation (IR) modalities is rapidly growing worldwide, causing excitement but also raising concerns, because our understanding of their biological effects is incomplete. Charged particles such as protons and heavy ions have increasing potential in cancer therapy, due to their advantageous physical properties over X-rays (photons), but are also present in the space environment, adding to the health risks of space missions. Therapy improvements and the protection of humans during space travel will benefit from a better understanding of the mechanisms underpinning the biological effects of high-LET IR. There is evidence that high-LET IR induces DNA double-strand breaks (DSBs) of increasing complexity, causing enhanced cell killing, owing, at least partly, to the frequent engagement of a low-fidelity DSB-repair pathway: alternative end-joining (alt-EJ), which is known to frequently induce severe structural chromosomal abnormalities (SCAs). Here, we evaluate the radiosensitivity of A549 lung adenocarcinoma cells to X-rays, α-particles and ⁵⁶Fe ions, as well as of HCT116 colorectal cancer cells to X-rays and α-particles. We observe the expected increase in cell killing following high-LET irradiation that correlates with the increased formation of SCAs as detected by mFISH. Furthermore, we report that cells exposed to low doses of α-particles and ⁵⁶Fe ions show an enhanced G₂-checkpoint response which is mainly regulated by ATR, rather than the coordinated ATM/ATR-dependent regulation observed after exposure to low doses of X-rays. These observations advance our understanding of the mechanisms underpinning high-LET IR effects, and suggest the potential utility for ATR inhibitors in high-LET radiation therapy. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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21 pages, 3728 KiB

Open AccessArticle

A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression

by Theodora-Dafni Michalettou, Ioannis Michalopoulos, Sylvain V. Costes, Christine E. Hellweg, Megumi Hada and Alexandros G. Georgakilas

Life 2021, 11(2), 115; https://doi.org/10.3390/life11020115 - 03 Feb 2021

Cited by 8 | Viewed by 3210

Abstract

The use of high linear energy transfer (LET) ionizing radiation (IR) is progressively being incorporated in radiation therapy due to its precise dose localization and high relative biological effectiveness. At the same time, these benefits of particle radiation become a high risk for [...] Read more.

The use of high linear energy transfer (LET) ionizing radiation (IR) is progressively being incorporated in radiation therapy due to its precise dose localization and high relative biological effectiveness. At the same time, these benefits of particle radiation become a high risk for astronauts in the case of inevitable cosmic radiation exposure. Nonetheless, DNA Damage Response (DDR) activated via complex DNA damage in healthy tissue, occurring from such types of radiation, may be instrumental in the induction of various chronic and late effects. An approach to elucidating the possible underlying mechanisms is studying alterations in gene expression. To this end, we identified differentially expressed genes (DEGs) in high Z and high energy (HZE) particle-, γ-ray- and X-ray-exposed healthy human tissues, utilizing microarray data available in public repositories. Differential gene expression analysis (DGEA) was conducted using the R programming language. Consequently, four separate meta-analyses were conducted, after DEG lists were grouped depending on radiation type, radiation dose and time of collection post-irradiation. To highlight the biological background of each meta-analysis group, functional enrichment analysis and biological network construction were conducted. For HZE particle exposure at 8–24 h post-irradiation, the most interesting finding is the variety of DNA repair mechanisms that were downregulated, a fact that is probably correlated with complex DNA damage formation. Simultaneously, after X-ray exposure during the same hours after irradiation, DNA repair mechanisms continue to take place. Finally, in a further comparison of low- and high-LET radiation effects, the most prominent result is that autophagy mechanisms seem to persist and that adaptive immune induction seems to be present. Such bioinformatics approaches may aid in obtaining an overview of the cellular response to high-LET particles. Understanding these response mechanisms can consequently aid in the development of countermeasures for future space missions and ameliorate heavy ion treatments. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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13 pages, 4850 KiB

Open AccessArticle

Repair Kinetics of DNA Double Strand Breaks Induced by Simulated Space Radiation

by Takashi Oizumi, Rieko Ohno, Souichiro Yamabe, Tomoo Funayama and Asako J. Nakamura

Life 2020, 10(12), 341; https://doi.org/10.3390/life10120341 - 10 Dec 2020

Cited by 8 | Viewed by 4283

Abstract

Radiation is unavoidable in space. Energetic particles in space radiation are reported to induce cluster DNA damage that is difficult to repair. In this study, normal human fibroblasts were irradiated with components of space radiation such as proton, helium, or carbon ion beams. [...] Read more.

Radiation is unavoidable in space. Energetic particles in space radiation are reported to induce cluster DNA damage that is difficult to repair. In this study, normal human fibroblasts were irradiated with components of space radiation such as proton, helium, or carbon ion beams. Immunostaining for γ-H2AX and 53BP1 was performed over time to evaluate the kinetics of DNA damage repair. Our data clearly show that the repair kinetics of DNA double strand breaks (DSBs) induced by carbon ion irradiation, which has a high linear energy transfer (LET), are significantly slower than those of proton and helium ion irradiation. Mixed irradiation with carbon ions, followed by helium ions, did not have an additive effect on the DSB repair kinetics. Interestingly, the mean γ-H2AX focus size was shown to increase with LET, suggesting that the delay in repair kinetics was due to damage that is more complex. Further, the 53BP1 focus size also increased in an LET-dependent manner. Repair of DSBs, characterized by large 53BP1 foci, was a slow process within the biphasic kinetics of DSB repair, suggesting non-homologous end joining with error-prone end resection. Our data suggest that the biological effects of space radiation may be significantly influenced by the dose as well as the type of radiation exposure. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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12 pages, 1695 KiB

Open AccessArticle

Iron Ion Particle Radiation Resistance of Dried Colonies of Cryomyces antarcticus Embedded in Martian Regolith Analogues

by Lorenzo Aureli, Claudia Pacelli, Alessia Cassaro, Akira Fujimori, Ralf Moeller and Silvano Onofri

Life 2020, 10(12), 306; https://doi.org/10.3390/life10120306 - 24 Nov 2020

Cited by 15 | Viewed by 2309

Abstract

Among the celestial bodies in the Solar System, Mars currently represents the main target for the search for life beyond Earth. However, its surface is constantly exposed to high doses of cosmic rays (CRs) that may pose a threat to any biological system. [...] Read more.

Among the celestial bodies in the Solar System, Mars currently represents the main target for the search for life beyond Earth. However, its surface is constantly exposed to high doses of cosmic rays (CRs) that may pose a threat to any biological system. For this reason, investigations into the limits of resistance of life to space relevant radiation is fundamental to speculate on the chance of finding extraterrestrial organisms on Mars. In the present work, as part of the STARLIFE project, the responses of dried colonies of the black fungus Cryomyces antarcticus Culture Collection of Fungi from Extreme Environments (CCFEE) 515 to the exposure to accelerated iron (LET: 200 keV/μm) ions, which mimic part of CRs spectrum, were investigated. Samples were exposed to the iron ions up to 1000 Gy in the presence of Martian regolith analogues. Our results showed an extraordinary resistance of the fungus in terms of survival, recovery of metabolic activity and DNA integrity. These experiments give new insights into the survival probability of possible terrestrial-like life forms on the present or past Martian surface and shallow subsurface environments. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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13 pages, 2462 KiB

Open AccessArticle

Combined Environment Simulator for Low-Dose-Rate Radiation and Partial Gravity of Moon and Mars

by Akihisa Takahashi, Sakuya Yamanouchi, Kazuomi Takeuchi, Shogo Takahashi, Mutsumi Tashiro, Jun Hidema, Atsushi Higashitani, Takuya Adachi, Shenke Zhang, Fady Nagy Lotfy Guirguis, Yukari Yoshida, Aiko Nagamatsu, Megumi Hada, Kunihito Takeuchi, Tohru Takahashi and Yuji Sekitomi

Life 2020, 10(11), 274; https://doi.org/10.3390/life10110274 - 06 Nov 2020

Cited by 6 | Viewed by 2562

Abstract

Deep space exploration by humans has become more realistic, with planned returns to the Moon, travel to Mars, and beyond. Space radiation with a low dose rate would be a constant risk for space travelers. The combined effects of space radiation and partial [...] Read more.

Deep space exploration by humans has become more realistic, with planned returns to the Moon, travel to Mars, and beyond. Space radiation with a low dose rate would be a constant risk for space travelers. The combined effects of space radiation and partial gravity such as on the Moon and Mars are unknown. The difficulty for such research is that there are no good simulating systems on the ground to investigate these combined effects. To address this knowledge gap, we developed the Simulator of the environments on the Moon and Mars with Neutron irradiation and Gravity change (SwiNG) for in vitro experiments using disposable closed cell culture chambers. The device simulates partial gravity using a centrifuge in a three-dimensional clinostat. Six samples are exposed at once to neutrons at a low dose rate (1 mGy/day) using Californium-252 in the center of the centrifuge. The system is compact including two SwiNG devices in the incubator, one with and one without radiation source, with a cooling function. This simulator is highly convenient for ground-based biological experiments because of limited access to spaceflight experiments. SwiNG can contribute significantly to research on the combined effects of space radiation and partial gravity. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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14 pages, 1653 KiB

Open AccessArticle

Simultaneous Exposure of Cultured Human Lymphoblastic Cells to Simulated Microgravity and Radiation Increases Chromosome Aberrations

by Sakuya Yamanouchi, Jordan Rhone, Jian-Hua Mao, Keigi Fujiwara, Premkumar B. Saganti, Akihisa Takahashi and Megumi Hada

Life 2020, 10(9), 187; https://doi.org/10.3390/life10090187 - 10 Sep 2020

Cited by 18 | Viewed by 2993

Abstract

During space travel, humans are continuously exposed to two major environmental stresses, microgravity (μG) and space radiation. One of the fundamental questions is whether the two stressors are interactive. For over half a century, many studies were carried out in space, [...] Read more.

During space travel, humans are continuously exposed to two major environmental stresses, microgravity (μG) and space radiation. One of the fundamental questions is whether the two stressors are interactive. For over half a century, many studies were carried out in space, as well as using devices that simulated μG on the ground to investigate gravity effects on cells and organisms, and we have gained insights into how living organisms respond to μG. However, our knowledge on how to assess and manage human health risks in long-term mission to the Moon or Mars is drastically limited. For example, little information is available on how cells respond to simultaneous exposure to space radiation and μG. In this study, we analyzed the frequencies of chromosome aberrations (CA) in cultured human lymphoblastic TK6 cells exposed to X-ray or carbon ion under the simulated μG conditions. A higher frequency of both simple and complex types of CA were observed in cells exposed to radiation and μG simultaneously compared to CA frequency in cells exposed to radiation only. Our study shows that the dose response data on space radiation obtained at the 1G condition could lead to the underestimation of astronauts’ potential risk for health deterioration, including cancer. This study also emphasizes the importance of obtaining data on the molecular and cellular responses to irradiation under μG conditions. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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14 pages, 1880 KiB

Open AccessArticle

Modelling Dose Effects from Space Irradiations: Combination of High-LET and Low-LET Radiations with a Modified Microdosimetric Kinetic Model

by Alejandro Bertolet and Alejandro Carabe

Life 2020, 10(9), 161; https://doi.org/10.3390/life10090161 - 23 Aug 2020

Cited by 5 | Viewed by 2382

Abstract

The Microdosimetric Kinetic Model (MKM) to predict the effects of ionizing radiation on cell colonies is studied and reformulated for the case of high-linear energy transfer (LET) radiations with a low dose. When the number of radiation events happening in a subnuclear domain [...] Read more.

The Microdosimetric Kinetic Model (MKM) to predict the effects of ionizing radiation on cell colonies is studied and reformulated for the case of high-linear energy transfer (LET) radiations with a low dose. When the number of radiation events happening in a subnuclear domain follows a Poisson distribution, the MKM predicts a linear-quadratic (LQ) survival curve. We show that when few events occur, as for high-LET radiations at doses lower than the mean specific energy imparted to the nucleus,

z_{F, n}

, a Poisson distribution can no longer be assumed and an initial pure linear relationship between dose and survival fraction should be observed. Predictions of survival curves for combinations of high-LET and low-LET radiations are produced under two assumptions for their comparison: independent and combined action. Survival curves from previously published articles of V79 cell colonies exposed to X-rays, α particles, Ar-ions, Fe-ions, Ne-ions and mixtures of X-rays and each one of the ions are predicted according to the modified MKM. We conclude that mixtures of high-LET and low-LET radiations may enhance the effect of individual actions due to the increase of events in domains provided by the low-LET radiation. This hypothesis is only partially validated by the analyzed experiments. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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12 pages, 1548 KiB

Open AccessArticle

Biologic Impact of Different Ultra-Low-Fluence Irradiations in Human Fibroblasts

by Masao Suzuki, Yukio Uchihori, Hisashi Kitamura, Masakazu Oikawa and Teruaki Konishi

Life 2020, 10(8), 154; https://doi.org/10.3390/life10080154 - 18 Aug 2020

Cited by 3 | Viewed by 2186

Abstract

In this study, we aimed to evaluate the cellular response of healthy human fibroblasts induced by different types of ultra-low-fluence radiations, including gamma rays, neutrons and high linear energy transfer (LET) heavy ions. NB1RGB cells were pretreated with ultra-low-fluence radiations (~0.1 cGy/7–8 h) [...] Read more.

In this study, we aimed to evaluate the cellular response of healthy human fibroblasts induced by different types of ultra-low-fluence radiations, including gamma rays, neutrons and high linear energy transfer (LET) heavy ions. NB1RGB cells were pretreated with ultra-low-fluence radiations (~0.1 cGy/7–8 h) of ¹³⁷Cs gamma rays, ²⁴¹Am–Be neutrons, helium, carbon and iron ions before being exposed to an X-ray-challenging dose (1.5 Gy). Helium (LET = 2.3 keV/µm), carbon (LET = 13.3 keV/µm) and iron (LET = 200 keV/µm) ions were generated with the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. No differences in cell death—measured by colony-forming assay—were observed regardless of the radiation type applied. In contrast, mutation frequency, which was detected through cell transformation into 6-thioguanine resistant clones, was 1.9 and 4.0 times higher in cells pretreated with helium and carbon ions, respectively, compared to cells exposed to X-ray-challenging dose alone. Moreover, cells pretreated with iron ions or gamma-rays showed a mutation frequency similar to cells exposed to X-ray-challenging dose alone, while cells pretreated with neutrons had 0.15 times less mutations. These results show that cellular responses triggered by ultra-low-fluence irradiations are radiation-quality dependent. Altogether, this study shows that ultra-low-fluence irradiations with the same level as those reported in the International Space Station are capable of inducing different cellular responses, including radio-adaptive responses triggered by neutrons and genomic instability mediated by high-LET heavy ions, while electromagnetic radiations (gamma rays) seem to have no biologic impact. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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Review

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13 pages, 1556 KiB

Open AccessReview

Hibernation as a Tool for Radiation Protection in Space Exploration

by Anggraeini Puspitasari, Matteo Cerri, Akihisa Takahashi, Yukari Yoshida, Kenji Hanamura and Walter Tinganelli

Life 2021, 11(1), 54; https://doi.org/10.3390/life11010054 - 14 Jan 2021

Cited by 12 | Viewed by 4790

Abstract

With new and advanced technology, human exploration has reached outside of the Earth’s boundaries. There are plans for reaching Mars and the satellites of Jupiter and Saturn, and even to build a permanent base on the Moon. However, human beings have evolved on [...] Read more.

With new and advanced technology, human exploration has reached outside of the Earth’s boundaries. There are plans for reaching Mars and the satellites of Jupiter and Saturn, and even to build a permanent base on the Moon. However, human beings have evolved on Earth with levels of gravity and radiation that are very different from those that we have to face in space. These issues seem to pose a significant limitation on exploration. Although there are plausible solutions for problems related to the lack of gravity, it is still unclear how to address the radiation problem. Several solutions have been proposed, such as passive or active shielding or the use of specific drugs that could reduce the effects of radiation. Recently, a method that reproduces a mechanism similar to hibernation or torpor, known as synthetic torpor, has started to become possible. Several studies show that hibernators are resistant to acute high-dose-rate radiation exposure. However, the underlying mechanism of how this occurs remains unclear, and further investigation is needed. Whether synthetic hibernation will also protect from the deleterious effects of chronic low-dose-rate radiation exposure is currently unknown. Hibernators can modulate their neuronal firing, adjust their cardiovascular function, regulate their body temperature, preserve their muscles during prolonged inactivity, regulate their immune system, and most importantly, increase their radioresistance during the inactive period. According to recent studies, synthetic hibernation, just like natural hibernation, could mitigate radiation-induced toxicity. In this review, we see what artificial hibernation is and how it could help the next generation of astronauts in future interplanetary missions. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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17 pages, 650 KiB

Open AccessReview

Relative Biological Effectiveness of High LET Particles on the Reproductive System and Fetal Development

by Bing Wang and Hiroshi Yasuda

Life 2020, 10(11), 298; https://doi.org/10.3390/life10110298 - 20 Nov 2020

Cited by 7 | Viewed by 2598

Abstract

During a space mission, astronauts are inevitably exposed to space radiation, mainly composed of the particles having high values of linear energy transfer (LET), such as protons, helium nuclei, and other heavier ions. Those high-LET particles could induce severer health damages than low-LET [...] Read more.

During a space mission, astronauts are inevitably exposed to space radiation, mainly composed of the particles having high values of linear energy transfer (LET), such as protons, helium nuclei, and other heavier ions. Those high-LET particles could induce severer health damages than low-LET particles such as photons and electrons. While it is known that the biological effectiveness of a specified type of radiation depends on the distribution of dose in time, type of the cell, and the biological endpoint in respect, there are still large uncertainties regarding the effects of high-LET particles on the reproductive system, gamete, embryo, and fetal development because of the limitation of relevant data from epidemiological and experimental studies. To safely achieve the planned deep space missions to the moon and Mars that would involve young astronauts having reproductive functions, it is crucial to know exactly the relevant radiological effects, such as infertility of the parent and various diseases of the child, and then to conduct proper countermeasures. Thus, in this review, the authors present currently available information regarding the relative biological effectiveness (RBE) of high-LET particles on the deterministic effects related to the reproductive system and embryonic/fetal development for further discussions about the safety of being pregnant after or during a long-term interplanetary mission. Full article

(This article belongs to the Special Issue Radiobiology in Space)

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