• dose and dose rate effectiveness factor
• fibroblasts
• low dose
• low dose rate
• radiation carcinogenesis

• Humans
• Dose-Response Relationship, Radiation
• Radiation, Ionizing
• Gamma Rays
• Fibroblasts/radiation effects
• Radiation Exposure/adverse effects

• biological effects
• cellular effects
• ionizing radiation
• linear energy transfer
• signal transduction
• transcriptomic analysis

• Apoptosis
• DNA damage
• Irradiated cell-conditioned media
• Media transfer
• Radiation dose
• Radiation-induced bystander effect

Understanding the differences in biological response to photon and particle radiation is important for optimal exploitation of particle therapy for cancer patients, as well as for the adequate application of radiation protection measures for astronauts. To address this need, we compared the transcriptional profiles of isolated peripheral blood mononuclear cells 8 h after exposure to 1 Gy of X-rays, carbon ions or iron ions with those of non-irradiated cells using microarray technology. All genes that were found differentially expressed in response to either radiation type were up-regulated and predominantly controlled by p53. Quantitative PCR of selected genes revealed a significantly higher up-regulation 24 h after exposure to heavy ions as compared to X-rays, indicating their prolonged activation. This coincided with increased residual DNA damage as evidenced by quantitative γH2AX foci analysis. Furthermore, despite the converging p53 signature between radiation types, specific gene sets related to the immune response were significantly enriched in up-regulated genes following irradiation with heavy ions. In addition, irradiation, and in particular exposure to carbon ions, promoted transcript variation. Differences in basal and iron ion exposure-induced expression of DNA repair genes allowed the identification of a donor with distinct DNA repair profile. This suggests that gene signatures may serve as a sensitive indicator of individual DNA damage repair capacity. In conclusion, we have shown that photon and particle irradiation induce similar transcriptional pathways, albeit with variable amplitude and timing, but also elicit radiation type-specific responses that may have implications for cancer progression and treatment

• DNA damage
• X-rays
• alternative splicing
• gene expression
• heavy ions
• immunity
• ionizing radiation
• p53

The existence of radiation-induced adaptive response (AR) was reported in varied biosystems. In mice, the first in vivo AR model was established using X-rays as both the priming and the challenge doses and rescue of bone marrow death as the end point. The underlying mechanism was due to the priming radiation-induced resistance in the blood-forming tissues. In a series of investigations, we further demonstrated the existence of AR using different types of ionizing radiation (IR) including low linear energy transfer (LET) X-rays and high LET heavy ion. In this article, we validated hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) measured as endogenous colony-forming units-spleen (CFU-S) under AR inducible and uninducible conditions using combination of different types of IR. We confirmed the consistency of increased CFU-S number change with the AR inducible condition. These findings suggest that AR in mice induced by different types of IR would share at least in part a common underlying mechanism, the priming IR-induced resistance in the blood-forming tissues, which would lead to a protective effect on the HSCs/HPCs and play an important role in rescuing the animals from bone marrow death. These findings provide a new insight into the mechanistic study on AR in vivo.

• adaptive response
• colony forming unites-spleen
• heavy ion
• ionizing radiation
• mice

• gene expression
• biomarker for high-let radiation
• α-radiation
• auger electron emitter
• ¹²³i-iododeoxyuridine exposure
• microarray analysis
• quantitative real-time pcr

• Alpha Particles
• Biomarkers/metabolism
• DNA/metabolism
• DNA Damage
• Down-Regulation/drug effects
• Down-Regulation/genetics
• Down-Regulation/radiation effects
• Gamma Rays
• Gene Expression Profiling
• Genetic Association Studies
• Histones/metabolism
• Humans
• Idoxuridine/pharmacology
• Jurkat Cells
• Signal Transduction/genetics
• Up-Regulation/drug effects
• Up-Regulation/genetics
• Up-Regulation/radiation effects

To compile a list of genes that have been reported to be affected by external ionizing radiation (IR) and to assess their performance as candidate biomarkers for individual human radiation dosimetry.

Eligible studies were identified through extensive searches of the online databases from 1978 to 2017. Original English-language publications of microarray studies assessing radiation-induced changes in gene expression levels in human blood after external IR were included. Genes identified in at least half of the selected studies were retained for bio-statistical analysis in order to evaluate their diagnostic ability.

24 studies met the criteria and were included in this study. Radiation-induced expression of 10,170 unique genes was identified and the 31 genes that have been identified in at least 50% of studies (12/24 studies) were selected for diagnostic power analysis. Twenty-seven genes showed a significant Spearman’s correlation with radiation dose. Individually, TNFSF4, FDXR, MYC, ZMAT3 and GADD45A provided the best discrimination of radiation dose < 2 Gy and dose ≥ 2 Gy according to according to their maximized Youden’s index (0.67, 0.55, 0.55, 0.55 and 0.53 respectively). Moreover, 12 combinations of three genes display an area under the Receiver Operating Curve (ROC) curve (AUC) = 1 reinforcing the concept of biomarker combinations instead of looking for an ideal and unique biomarker.

Gene expression is a promising approach for radiation dosimetry assessment. A list of robust candidate biomarkers has been identified from analysis of the studies published to date, confirming for example the potential of well-known genes such as FDXR and TNFSF4 or highlighting other promising gene such as ZMAT3. However, heterogeneity in protocols and analysis methods will require additional studies to confirm these results.

• Biomarkers/blood
• Carrier Proteins/blood
• Gene Expression Regulation/radiation effects
• Humans
• Nuclear Proteins/blood
• OX40 Ligand/blood
• RNA-Binding Proteins
• Radiation Injuries/blood
• Radiation, Ionizing
• Radiometry

• U19 AI067773 NIAID NIH HHS
• Center for High-Throughput Minimally-Invasive Radiation Biodosimetry

• Low-dose gamma radiation
• complete pooling
• lipid metabolism
• transcriptome profiling

The biological effects of low-dose ionizing radiation (LDIR) exposure in humans are not comprehensively understood, generating a high degree of controversy in published literature. The earliest stages of human development are known to be among the most sensitive to stress exposures, especially genotoxic stresses. However, the risks stemming from exposure to LDIR, particularly within the clinical diagnostic relevant dose range, have not been directly evaluated in human embryonic stem cells (hESCs). Here, we describe the dynamics of the whole genome transcriptional responses of different hESC lines to both LDIR and, as a reference, high-dose IR (HDIR). We found that even doses as low as 0.05 Gy could trigger statistically significant transient changes in a rather limited subset of genes in all hESCs lines examined. Gene expression signatures of hESCs exposed to IR appear to be highly dose-, time-, and cell line-dependent. We identified 50 genes constituting consensus gene expression signature as an early response to HDIR across all lines of hESC examined. We observed substantial differences in biological pathways affected by either LDIR or HDIR in hESCs, suggesting that the molecular mechanisms underpinning the responses of hESC may fundamentally differ depending on radiation doses.

• DNA microarray
• human embryonic stem cell
• ionizing radiation
• low dose exposure
• whole genome

Human pluripotent stem cells (hPSCs) represent heterogeneous populations, including induced pluripotent stem cells (iPSCs), endogenous plastic somatic cells, and embryonic stem cells (ESCs). Human ESCs are derived from the inner cell mass of the blastocyst, and they are characterized by the abilities to self-renew indefinitely, and to give rise to all cell types of embryonic lineage (pluripotency) under the guidance of the appropriate chemical, mechanical and environmental cues. The combination of these critical features is unique to hESCs, and set them apart from other human cells. The expectations are high to utilize hESCs for treating injuries and degenerative diseases; for modeling of complex illnesses and development; for screening and testing of pharmacological products; and for examining toxicity, mutagenicity, teratogenicity, and potential carcinogenic effects of a variety of environmental factors, including ionizing radiation (IR). Exposures to genotoxic stresses, such as background IR, are unavoidable; moreover, IR is widely used in diagnostic and therapeutic procedures in medicine on a routine basis. One of the key outcomes of cell exposures to IR is the change in gene expression, which may underlie the ultimate hESCs fate after such a stress. However, gaps in our knowledge about basic biology of hESCs impose a serious limitation to fully realize the potential of hESCs in practice. The purpose of this review is to examine the available evidence of alterations in gene expression in human pluripotent stem cells after genotoxic stress, and to discuss strategies for future research in this important area.

• Human pluripotent stem cells
• Gene expression alterations
• Genotoxic stress
• Ionizing radiation

Human stem cells (hSC) possess several distinct characteristics that set them apart from other cell types. First, hSC are self-renewing, capable of undergoing both asymmetric and symmetric cell divisions. Second, these cells can be coaxed to differentiate into various specialized cell types and, as such, hold great promise for regenerative medicine. Recent progresses in hSC biology fostered the characterization of the responses of hSC to genotoxic stresses, including ionizing radiation (IR). Here, we examine how different types of hSC respond to IR, with a special emphasis on their radiosensitivity, cell cycle, signaling networks, DNA damage response (DDR) and DNA repair. We show that human embryonic stem cells (hESCs) possess unique characteristics in how they react to IR that clearly distinguish these cells from all adult hSC studied thus far. On the other hand, a manifestation of radiation injuries/toxicity in human bodies may depend to a large extent on hSC populating corresponding tissues, such as human mesenchymal stem cells (hMSC), human hematopoietic stem cells (hHSC), neural hSC, intestine hSC, etc. We discuss here that hSC responses to IR differ notably across many types of hSC which may represent the distinct roles these cells play in development, regeneration and/or maintenance of homeostasis.

Existence of adaptive response (AR) was previously demonstrated in C57BL/6J mice. Irradiations were performed by delivering a priming low dose of X-rays (0.50 Gy) in combination with a challenge high dose of accelerated carbon or neon ion particles. AR was characterized by significantly decreased mortality in the 30-day survival test. This mouse AR model (‘Yonezawa Effect’) was originally established by using X-rays as both the priming and challenge irradiations. The underlying mechanism was due to radio-resistance occurring in blood-forming tissues. In this study, we verified the existence of AR and further investigated residual damage in the hematopoietic system in surviving animals. Results showed that the priming low dose of X-rays could relieve the detrimental effects on the hematopoietic system. We observed both an improvement in the blood platelet count and the ratio of polychromatic erythrocytes (PCEs) to the sum of PCEs and normochromatic erythrocytes (NCEs) and a marked reduction of the incidences of micronucleated PCEs and micronucleated NCEs. These findings suggest that the priming low dose of low linear energy transfer (LET) X-rays induced a protective effect on the hematopoietic system, which may play an important role in both rescue from acute lethal damage (mouse killing) and prevention of late detrimental consequences (residual anhematopoiesis and delayed genotoxic effects) caused by exposure to a high challenge dose from low-LET (X-ray) or high-LET (carbon and neon ion) irradiations. These findings provide new knowledge of the characterization of the Yonezawa Effect by providing new insight into the mechanistic study of AR in vivo.

• low dose
• radioadaptive response
• bone marrow micronucleated erythrocytes
• mice

• nitric oxide
• normal human fibroblast
• ionizing radiation
• dna microarray

• Benzoates
• Cell Line
• Dimethyl Sulfoxide
• Fibroblasts
• Free Radical Scavengers/metabolism
• Gamma Rays
• Gene Expression Profiling/methods
• Gene Expression Regulation/radiation effects
• Genome, Human/genetics
• Humans
• Imidazoles
• Nitric Oxide/metabolism
• Oligonucleotide Array Sequence Analysis
• Transcription, Genetic/physiology
• Transcription, Genetic/radiation effects

• Z01 CL060001 Intramural NIH HHS
• Z01 CL060001-12 Intramural NIH HHS
• Z99 CL999999 Intramural NIH HHS

Human embryonic stem cells, which are derived from the inner cell mass of the blastocyst, have become an object of intense study over the last decade. They possess two unique properties that distinguish them from many other cell types: (i) the ability to self-renew indefinitely in culture under permissive conditions, and (ii) the pluripotency, defined as the capability of giving rise to all cell types of embryonic lineage under the guidance of the appropriate developmental cues. The focus of many recent efforts has been on the elucidating the signaling pathways and molecular networks operating in human embryonic stem cells. These cells hold great promise in cell-based regenerative therapies, disease modeling, drug screening and testing, assessing genotoxic and mutagenic risks associated with exposures to a variety of environmental factors, and so forth. Ionizing radiation is ubiquitous in nature, and it is widely used in diagnostic and therapeutic procedures in medicine. In this paper, our goal is to summarize the recent progress in understanding how human embryonic stem cells respond to ionizing radiation exposures, using novel methodologies based on “omics” approaches, and to provide a critical discussion of what remains unknown; thus proposing a roadmap for the future research in this area.

Tumor suppressor p53 plays a key role in DNA damage responses in metazoa, yet more than half of human tumors show p53 deficiencies. Therefore, understanding how therapeutic genotoxins such as ionizing radiation (IR) can elicit DNA damage responses in a p53-independent manner is of clinical importance. Drosophila has been a good model to study the effects of IR because DNA damage responses as well as underlying genes are conserved in this model, and because streamlined gene families make loss-of-function analyses feasible. Indeed, Drosophila is the only genetically tractable model for IR-induced, p53-independent apoptosis and for tissue regeneration and homeostasis after radiation damage. While these phenomenon occur only in the larvae, all genome-wide gene expression analyses after irradiation to date have been in embryos. We report here the first analysis of IR-induced, genome-wide gene expression changes in wild type and p53 mutant Drosophila larvae. Key data from microarrays were confirmed by quantitative RT-PCR. The results solidify the central role of p53 in IR-induced transcriptome changes, but also show that nearly all changes are made of both p53-dependent and p53-independent components. p53 is found to be necessary not just for the induction of but also for the repression of transcript levels for many genes in response to IR. Furthermore, Functional analysis of one of the top-changing genes, EF1a-100E, implicates it in repression of IR-induced p53-independent apoptosis. These and other results support the emerging notion that there is not a single dominant mechanism but that both positive and negative inputs collaborate to induce p53-independent apoptosis in response to IR in Drosophila larvae.

• Animals
• Apoptosis/genetics
• Apoptosis/radiation effects
• DNA Damage/genetics
• Drosophila Proteins/genetics
• Drosophila Proteins/metabolism
• Drosophila melanogaster/genetics
• Drosophila melanogaster/metabolism
• Drosophila melanogaster/radiation effects
• Gene Expression Profiling
• Genome, Insect/genetics
• Humans
• Larva/genetics
• Larva/metabolism
• Larva/radiation effects
• Mutation
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• R01 GM087276 NIGMS NIH HHS
• T32 GM007135 NIGMS NIH HHS
• R01GM87276 NIGMS NIH HHS
• T32GM007135 NIGMS NIH HHS

• Apoptosis/radiation effects
• Cell Proliferation/radiation effects
• Cytosol/metabolism
• Cytosol/radiation effects
• Dose-Response Relationship, Drug
• Endothelial Cells/cytology
• Endothelial Cells/diagnostic imaging
• Endothelial Cells/metabolism
• Gene Expression Profiling
• Humans
• Proteome/metabolism
• Proteomics
• Radiography
• Time Factors

• Animals
• Binding Sites
• DNA-Binding Proteins/metabolism
• Early Growth Response Protein 3/metabolism
• Gamma Rays
• Gene Expression Regulation
• Liver/metabolism
• Liver/radiation effects
• Male
• Mice
• Mice, Inbred C57BL
• Models, Statistical
• NF-kappa B/metabolism
• Oligonucleotide Array Sequence Analysis
• Receptors, Aryl Hydrocarbon/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Sterol Regulatory Element Binding Protein 1/metabolism
• Transcription Factors/metabolism

• Animals
• Dose-Response Relationship, Radiation
• Gamma Rays
• Gene Expression Regulation
• Kidney/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Microarray Analysis
• Radiation
• Testis/metabolism

• Animals
• Dose-Response Relationship, Radiation
• Gamma Rays
• Gene Expression Regulation, Enzymologic/physiology
• Gene Expression Regulation, Enzymologic/radiation effects
• Liver/enzymology
• Liver/radiation effects
• Male
• Mice
• Mice, Inbred C57BL
• Radiation Dosage
• Thiosulfate Sulfurtransferase/metabolism
• Whole-Body Irradiation/methods