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Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 26961

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Special Issue Editors

Prof. Dr. Andreyan N. Osipov

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Guest Editor

State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), 123098 Moscow, Russia
Interests: DNA damage and repair; DNA double-strand breaks; cell death; cellular radiobiology; genotoxicity; carcinogenesis
Special Issues, Collections and Topics in MDPI journals

Dr. Dmitry Klokov

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Guest Editor

1. Institut de Radioprotection et de Sureté Nucléaire (IRSN), 92260 Fontenay-aux-Roses, France
2. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada
Interests: ionizing radiation; genotoxicity; DNA damage; DNA repair; mutagenesis; carcinogenesis; radioprotection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Evaluation of the health risks associated with exposures of humans to low-dose and low-dose-rate ionizing radiation is prone to uncertainties due to the lack of knowledge of molecular mechanisms that underlie long-term health effects. This Special Issue will highlight the latest research on cellular and molecular effects of low-dose and low-dose-rate ionizing radiation exposures, such as DNA damage and repair, signal transduction, translation regulation, epigenetic rearrangement, and how they convert to cancer and non-cancer disease. We therefore invite research articles presenting novel results, reviews, and/or perspectives addressing or systematizing pertaining knowledge in this area. The specific topics that can be covered include but are not limited to:

Links between initial DNA damage and subsequent mutagenesis and carcinogenesis;
Mechanisms of radioadaptive responses and hormetic effects;
The effect of dose rate on a choice of a DNA damage response pathway;
Molecular biomarkers of exposure and bioindicators of health risks;
Molecular responses to internal vs. external irradiation; radionuclide-specific effects;
Effects of chronic cosmic radiation exposures associated with long-term manned space missions;
Advances in molecular epidemiology;
Application of artificial intelligence/machine learning to decoding low-dose and low-dose-rate molecular mechanisms;
Consolidation of the knowledge of molecular mechanisms within the concept of adverse outcome pathways.

We look forward to your valuable contributions.

Prof. Dr. Andreyan N. Osipov
Dr. Dmitry Klokov
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

ionizing radiation
low dose
low dose rate
DNA damage and repair
molecular mechanisms
cellular radiation effects
radioadaptive response
radiation hormesis
bystander effect
biomarkers
molecular epidemiology
carcinogenesis
radioprotection

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Published Papers (9 papers)

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9 pages, 1138 KiB

Open AccessCommunication

Reduced Environmental Dose Rates Are Responsible for the Increased Susceptibility to Radiation-Induced DNA Damage in Larval Neuroblasts of Drosophila Grown inside the LNGS Underground Laboratory

by Antonella Porrazzo, Giuseppe Esposito, Daniela Grifoni, Giovanni Cenci, Patrizia Morciano and Maria Antonella Tabocchini

Int. J. Mol. Sci. 2022, 23(10), 5472; https://doi.org/10.3390/ijms23105472 - 13 May 2022

Cited by 5 | Viewed by 1664

Abstract

A large amount of evidence from radiobiology studies carried out in Deep Underground Laboratories support the view that environmental radiation may trigger biological mechanisms that enable both simple and complex organisms to cope with genotoxic stress. In line with this, here we show that the reduced radiation background of the LNGS underground laboratory renders Drosophila neuroblasts more sensitive to ionizing radiation-induced (but not to spontaneous) DNA breaks compared to fruit flies kept at the external reference laboratory. Interestingly, we demonstrate that the ionizing radiation sensitivity of flies kept at the LNGS underground laboratory is rescued by increasing the underground gamma dose rate to levels comparable to the low-LET reference one. This finding provides the first direct evidence that the modulation of the DNA damage response in a complex multicellular organism is indeed dependent on the environmental dose rate. Full article

(This article belongs to the Special Issue Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure)

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11 pages, 2635 KiB

Open AccessArticle

Effects of Concurrent Exposure to Chronic Restraint-Induced Stress and Total-Body Iron Ion Radiation on Induction of Kidney Injury in Mice

by Duling Xu, Hongyan Li, Takanori Katsube, Guomin Huang, Jiadi Liu, Bing Wang and Hong Zhang

Int. J. Mol. Sci. 2022, 23(9), 4866; https://doi.org/10.3390/ijms23094866 - 27 Apr 2022

Cited by 3 | Viewed by 2183

Abstract

Concurrent exposure to ionizing radiation (IR) and psychological stress (PS) may affect the development of adverse health consequences in scenarios such as space missions, radiotherapy and nuclear accidents. IR can induce DNA damage and cell apoptosis in the kidneys, thus potentially leading to renal fibrosis, which is the ultimate outcome of various chronic progressive nephropathies and the morphological manifestation of a continuous coordinated response after renal injury. However, little is known regarding the effects of concurrent IR exposure and PS on renal damage, particularly renal fibrosis. In this study, using a chronic restraint-induced PS (CRIPS) model, we exposed Trp53-heterozygous mice to total body irradiation with 0.1 or 2 Gy ⁵⁶Fe ions on the eighth day of 28 consecutive days of a restraint regimen. At the end of the restraint period, the kidneys were collected. The histopathological changes and the degree of kidney fibrosis were assessed with H&E and Masson staining, respectively. Fibronectin (FN) and alpha smooth muscle actin (α-SMA), biomarkers of fibrosis, were detected by immunohistochemistry. Analysis of 8-hydroxy-2 deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, was performed with immunofluorescence, and terminal deoxynucleotidyl transferase-mediated nick end labeling assays were used to detect apoptotic cells. Histopathological observations did not indicate significant structural damage induced by IR or CRIPS + IR. Western blotting revealed that the expression of α-SMA was much higher in the CRIPS + IR groups than the CRIPS groups. However, no differences in the average optical density per area were observed for FN, α-SMA and 8-OHdG between the IR and CRIPS + IR groups. No difference in the induction of apoptosis was observed between the IR and CRIPS + IR groups. These results suggested that exposure to IR (0.1 and 2 Gy ⁵⁶Fe ions), 28 consecutive days of CRIPS or both did not cause renal fibrosis. Thus, CRIPS did not alter the IR-induced effects on renal damage in Trp53-heterozygous mice in our experimental setup. Full article

(This article belongs to the Special Issue Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure)

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13 pages, 1885 KiB

Open AccessArticle

High-Accuracy Relative Biological Effectiveness Values Following Low-Dose Thermal Neutron Exposures Support Bimodal Quality Factor Response with Neutron Energy

by Laura C. Paterson, Amy Festarini, Marilyne Stuart, Fawaz Ali, Christie Costello, Chad Boyer, Ronald Rogge, Norma Ybarra, John Kildea and Richard B. Richardson

Int. J. Mol. Sci. 2022, 23(2), 878; https://doi.org/10.3390/ijms23020878 - 14 Jan 2022

Cited by 1 | Viewed by 2587

Abstract

Theoretical evaluations indicate the radiation weighting factor for thermal neutrons differs from the current International Commission on Radiological Protection (ICRP) recommended value of 2.5, which has radiation protection implications for high-energy radiotherapy, inside spacecraft, on the lunar or Martian surface, and in nuclear reactor workplaces. We examined the relative biological effectiveness (RBE) of DNA damage generated by thermal neutrons compared to gamma radiation. Whole blood was irradiated by 64 meV thermal neutrons from the National Research Universal reactor. DNA damage and erroneous DNA double-strand break repair was evaluated by dicentric chromosome assay (DCA) and cytokinesis-block micronucleus (CBMN) assay with low doses ranging 6–85 mGy. Linear dose responses were observed. Significant DNA aberration clustering was found indicative of high ionizing density radiation. When the dose contribution of both the ¹⁴N(n,p)¹⁴C and ¹H(n,γ)²H capture reactions were considered, the DCA and the CBMN assays generated similar maximum RBE values of 11.3 ± 1.6 and 9.0 ± 1.1, respectively. Consequently, thermal neutron RBE is approximately four times higher than the current ICRP radiation weighting factor value of 2.5. This lends support to bimodal peaks in the quality factor for RBE neutron energy response, underlining the importance of radiological protection against thermal neutron exposures. Full article

(This article belongs to the Special Issue Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure)

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17 pages, 2301 KiB

Open AccessArticle

Effect of Low-Dose Ionizing Radiation on the Expression of Mitochondria-Related Genes in Human Mesenchymal Stem Cells

by Svetlana V. Kostyuk, Elena V. Proskurnina, Marina S. Konkova, Margarita S. Abramova, Andrey A. Kalianov, Elizaveta S. Ershova, Vera L. Izhevskaya, Sergey I. Kutsev and Natalia N. Veiko

Int. J. Mol. Sci. 2022, 23(1), 261; https://doi.org/10.3390/ijms23010261 - 27 Dec 2021

Cited by 8 | Viewed by 3564

Abstract

The concept of hormesis describes a phenomenon of adaptive response to low-dose ionizing radiation (LDIR). Similarly, the concept of mitohormesis states that the adaptive program in mitochondria is activated in response to minor stress effects. The mechanisms of hormesis effects are not clear, but it is assumed that they can be mediated by reactive oxygen species. Here, we studied effects of LDIR on mitochondria in mesenchymal stem cells. We have found that X-ray radiation at a dose of 10 cGy as well as oxidized fragments of cell-free DNA (cfDNA) at a concentration of 50 ng/mL resulted in an increased expression of a large number of genes regulating the function of the mitochondrial respiratory chain complexes in human mesenchymal stem cells (MSC). Several genes remained upregulated within hours after the exposure. Both X-ray radiation and oxidized cfDNA resulted in upregulation of FIS1 and MFN1 genes, which regulated fusion and fission of mitochondria, within 3–24 h after the exposure. Three hours after the exposure, the number of copies of mitochondrial DNA in cells had increased. These findings support the hypothesis that assumes oxidized cell-free DNA as a mediator of MSC response to low doses of radiation. Full article

(This article belongs to the Special Issue Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure)

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14 pages, 1925 KiB

Open AccessArticle

The Use of ProteoTuner Technology to Study Nuclear Factor κB Activation by Heavy Ions

by Arif Ali Chishti, Christa Baumstark-Khan, Hasan Nisar, Yueyuan Hu, Bikash Konda, Bernd Henschenmacher, Luis F. Spitta, Claudia Schmitz, Sebastian Feles and Christine E. Hellweg

Int. J. Mol. Sci. 2021, 22(24), 13530; https://doi.org/10.3390/ijms222413530 - 16 Dec 2021

Viewed by 2251

Abstract

Nuclear factor κB (NF-κB) activation might be central to heavy ion-induced detrimental processes such as cancer promotion and progression and sustained inflammatory responses. A sensitive detection system is crucial to better understand its involvement in these processes. Therefore, a DD-tdTomato fluorescent protein-based reporter system was previously constructed with human embryonic kidney (HEK) cells expressing DD-tdTomato as a reporter under the control of a promoter containing NF-κB binding sites (HEK-pNFκB-DD-tdTomato-C8). Using this reporter cell line, NF-κB activation after exposure to different energetic heavy ions (¹⁶O, 95 MeV/n, linear energy transfer—LET 51 keV/µm; ¹²C, 95 MeV/n, LET 73 keV/μm; ³⁶Ar, 95 MeV/n, LET 272 keV/µm) was quantified considering the dose and number of heavy ions hits per cell nucleus that double NF-κB-dependent DD-tdTomato expression. Approximately 44 hits of ¹⁶O ions and ≈45 hits of ¹²C ions per cell nucleus were required to double the NF-κB-dependent DD-tdTomato expression, whereas only ≈3 hits of ³⁶Ar ions were sufficient. In the presence of Shield-1, a synthetic molecule that stabilizes DD-tdTomato, even a single particle hit of ³⁶Ar ions doubled NF-κB-dependent DD-tdTomato expression. In conclusion, stabilization of the reporter protein can increase the sensitivity for NF-κB activation detection by a factor of three, allowing the detection of single particle hits’ effects. Full article

(This article belongs to the Special Issue Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure)

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13 pages, 3191 KiB

Open AccessArticle

Differential Effects of Low and High Radiation Dose Rates on Mouse Spermatogenesis

by Min Ji Bae, Min Kook Kang, Yong Uk Kye, Jeong-Hwa Baek, Ye-Ji Sim, Hae-June Lee, Yeong-Rok Kang, Wol Soon Jo, Joong Sun Kim and Chang Geun Lee

Int. J. Mol. Sci. 2021, 22(23), 12834; https://doi.org/10.3390/ijms222312834 - 27 Nov 2021

Cited by 10 | Viewed by 2637

Abstract

The adverse effects of radiation are proportional to the total dose and dose rate. We aimed to investigate the effects of radiation dose rate on different organs in mice. The mice were subjected to low dose rate (LDR, ~3.4 mGy/h) and high dose rate (HDR, ~51 Gy/h) radiation. LDR radiation caused severe tissue toxicity, as observed in the histological analysis of testis. It adversely influenced sperm production, including sperm count and motility, and induced greater sperm abnormalities. The expression of markers of early stage spermatogonial stem cells, such as Plzf, c-Kit, and Oct4, decreased significantly after LDR irradiation, compared to that following exposure of HDR radiation, in qPCR analysis. The compositional ratios of all stages of spermatogonia and meiotic cells, except round spermatid, were considerably reduced by LDR in FACS analysis. Therefore, LDR radiation caused more adverse testicular damage than that by HDR radiation, contrary to the response observed in other organs. Therefore, the dose rate of radiation may have differential effects, depending on the organ; it is necessary to evaluate the effect of radiation in terms of radiation dose, dose rate, organ type, and other conditions. Full article

(This article belongs to the Special Issue Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure)

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15 pages, 923 KiB

Open AccessArticle

Increased Frequency of Copy Number Variations Revealed by Array Comparative Genomic Hybridization in the Offspring of Male Mice Exposed to Low Dose-Rate Ionizing Radiation

by Keiji Ogura, Yoshiko Ayabe, Chihiro Harada, Ignacia Braga Tanaka III, Satoshi Tanaka and Jun-ichiro Komura

Int. J. Mol. Sci. 2021, 22(22), 12437; https://doi.org/10.3390/ijms222212437 - 18 Nov 2021

Cited by 3 | Viewed by 1656

Abstract

There is very little information on the transgenerational or genetic effects of low dose-rate ionizing radiation. We report the detection of the transgenerational effects of chronic low dose-rate irradiation in mice, at the molecular level in the whole genome, using array comparative genomic hybridization technology. We observed that the number of the mice with de novo copy number variations (specifically, deletions) was significantly increased in the offspring of C57BL/6J male mice exposed to 20 mGy/day gamma-rays for 400 days (total dose: 8000 mGy), as compared to non-irradiated controls. We did not detect any difference in the size of the de novo deletions between the irradiated and the non-irradiated groups. An analysis of the life span of the offspring suggested a possibility that de novo copy-number variations may be associated with shorter life spans. Full article

(This article belongs to the Special Issue Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure)

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22 pages, 2255 KiB

Open AccessArticle

Effects of Chronic Low-Dose Internal Radiation on Immune-Stimulatory Responses in Mice

by Abrar Ul Haq Khan, Melinda Blimkie, Doo Seok Yang, Mandy Serran, Tyler Pack, Jin Wu, Ji-Young Kang, Holly Laakso, Seung-Hwan Lee and Yevgeniya Le

Int. J. Mol. Sci. 2021, 22(14), 7303; https://doi.org/10.3390/ijms22147303 - 7 Jul 2021

Cited by 12 | Viewed by 3658

Abstract

The Linear-No-Threshold (LNT) model predicts a dose-dependent linear increase in cancer risk. This has been supported by biological and epidemiological studies at high-dose exposures. However, at low-doses (LDR ≤ 0.1 Gy), the effects are more elusive and demonstrate a deviation from linearity. In this study, the effects of LDR on the development and progression of mammary cancer in FVB/N-Tg(MMTVneu)202Mul/J mice were investigated. Animals were chronically exposed to total doses of 10, 100, and 2000 mGy via tritiated drinking water, and were assessed at 3.5, 6, and 8 months of age. Results indicated an increased proportion of NK cells in various organs of LDR exposed mice. LDR significantly influenced NK and T cell function and activation, despite diminishing cell proliferation. Notably, the expression of NKG2D receptor on NK cells was dramatically reduced at 3.5 months but was upregulated at later time-points, while the expression of NKG2D ligand followed the opposite trend, with an increase at 3.5 months and a decrease thereafter. No noticeable impact was observed on mammary cancer development, as measured by tumor load. Our results demonstrated that LDR significantly influenced the proportion, proliferation, activation, and function of immune cells. Importantly, to the best of our knowledge, this is the first report demonstrating that LDR modulates the cross-talk between the NKG2D receptor and its ligands. Full article

(This article belongs to the Special Issue Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure)

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Review

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35 pages, 4017 KiB

Open AccessReview

Biomarkers of Genotoxicity in Medical Workers Exposed to Low-Dose Ionizing Radiation: Systematic Review and Meta-Analyses

by Clémence Baudin, Marie-Odile Bernier, Dmitry Klokov and Maria Grazia Andreassi

Int. J. Mol. Sci. 2021, 22(14), 7504; https://doi.org/10.3390/ijms22147504 - 13 Jul 2021

Cited by 14 | Viewed by 4045

Abstract

Medical staff represent the largest group of workers occupationally exposed to ionizing radiation (IR). Chronic exposure to low-dose IR may result in DNA damage and genotoxicity associated with increased risk of cancer. This review aims to identify the genotoxicity biomarkers that are the most elevated in IR-exposed vs. unexposed health workers. A systematic review of the literature was performed to retrieve relevant studies with various biomarkers of genotoxicity. Subsequent meta-analyses produced a pooled effect size for several endpoints. The search procedure yielded 65 studies. Chromosome aberrations (CA) and micronuclei (MN) frequencies were significantly different between IR-exposed and unexposed workers (θ_pooled = 3.19, 95% CI 1.46–4.93; and θ_pooled = 1.41, 95% CI 0.97–1.86, for total aberrant cells and MN frequencies, respectively), which was not the case for ring chromosomes and nucleoplasmic bridges. Although less frequently used, stable translocations, sister chromatid exchanges (SCE) and comet assay endpoints were also statistically different between IR-exposed and unexposed workers. This review confirms the relevance of CA and MN as genotoxicity biomarkers that are consistently elevated in IR-exposed vs. unexposed workers. Other endpoints are strong candidates but require further studies to validate their usefulness. The integration of the identified biomarkers in future prospective epidemiological studies is encouraged. Full article

(This article belongs to the Special Issue Biological Effects of Low-Dose and Low-Dose-Rate Ionizing Radiation Exposure)

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