|
1
|
Wang SY, Wu JX, An X, Yuan Z, Ren YF, Yu XF, Tian XD, Wei W. Structural and temporal dynamics analysis on immune response in low-dose radiation: History, research hotspots and emerging trends. World J Radiol 2025; 17:101636. [PMID: 40309477 PMCID: PMC12038408 DOI: 10.4329/wjr.v17.i4.101636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 12/19/2024] [Accepted: 03/27/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Radiotherapy (RT) is a cornerstone of cancer treatment. Compared with conventional high-dose radiation, low-dose radiation (LDR) causes less damage to normal tissues while potentially modulating immune responses and inhibiting tumor growth. LDR stimulates both innate and adaptive immunity, enhancing the activity of natural killer cells, dendritic cells, and T cells. However, the mechanisms underlying the effects of LDR on the immune system remain unclear. AIM To explore the history, research hotspots, and emerging trends in immune response to LDR literature over the past two decades. METHODS Publications on immune responses to LDR were retrieved from the Web of Science Core Collection. Bibliometric tools, including CiteSpace and HistCite, were used to identify historical features, active topics, and emerging trends in this field. RESULTS Analysis of 1244 publications over the past two decades revealed a significant surge in research on immune responses to LDR, particularly in the last decade. Key journals such as INR J Radiat Biol, Cancers, and Radiat Res published pivotal studies. Citation networks identified key studies by authors like Twyman-Saint Victor C (2015) and Vanpouille-Box C (2017). Keyword analysis revealed hotspots such as ipilimumab, stereotactic body RT, and targeted therapy, possibly identifying future research directions. Temporal variations in keyword clusters and alluvial flow maps illustrate the evolution of research themes over time. CONCLUSION This bibliometric analysis provides valuable insights into the evolution of studies on responses to LDR, highlights research trends, and identifies emerging areas for further investigation.
Collapse
Affiliation(s)
- Shu-Yuan Wang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Jia-Xing Wu
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Xian An
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Zhen Yuan
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Yi-Fan Ren
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Xiu-Feng Yu
- Department of General Medicine, Tuberculosis Hospital of Shaanxi Province, Xi’an 710105, Shaanxi Province, China
| | - Xiao-Dong Tian
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Wei Wei
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| |
Collapse
|
|
2
|
Nakamura N. An examination of the dose rate effect in mice assuming that the carcinogenic effect of radiation is life shortening resulting from a tissue reaction. Int J Radiat Biol 2025; 101:225-231. [PMID: 39746147 DOI: 10.1080/09553002.2024.2442690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 11/20/2024] [Accepted: 12/09/2024] [Indexed: 01/04/2025]
Abstract
PURPOSE Radiation exposures do not seem to increase the proportion of mice dying from tumors, but rather cause a shift in the appearance of spontaneous cancers, allowing them to appear earlier, and hence produce a life shortening effect. Then, it was possible to estimate the effect of the dose rate on the carcinogenic effects of radiation using life shortening effects as a measure. CONCLUSION The dose response for the induction of life shortening was linear under acute exposure conditions, which indicates that the response under chronic exposure conditions is also likely to be linear, and hence the dose rate factor (DRF) would be constant throughout the dose. Furthermore, the life shortening effect decreased sharply with an increase in age at exposure. To separate the dose rate effect from the effects of age under long-term exposure conditions, a thought experiment was designed which consisted of 8 repeated exposures to an acute 1 Gy dose at intervals of 50 days with an assumption that the effect is additive, and the results were compared with those observed in a chronic continuous exposure experiment (20 mGy per day for 400 days, for a total of 8 Gy: Tanaka et al. 2003). The results showed 211 days of life shortening in the former and 120 days in the latter, which provided a DRF of 1.8 (211/120). If one assumes that a tissue reaction is the primary cause of radiation carcinogenesis, the contrasting two concepts, radiation hormesis and linear-non-threshold model at low doses, would become compatible.
Collapse
Affiliation(s)
- Nori Nakamura
- Department of Radiation Biosciences, Radiation Effects Research Foundation, Hiroshima, Japan
| |
Collapse
|
|
3
|
Passelli K, Repáraz D, Kinj R, Herrera FG. Strategies for overcoming tumour resistance to immunotherapy: harnessing the power of radiation therapy. Br J Radiol 2024; 97:1378-1390. [PMID: 38833685 PMCID: PMC11256940 DOI: 10.1093/bjr/tqae100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/03/2024] [Accepted: 05/08/2024] [Indexed: 06/06/2024] Open
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; yet their efficacy remains variable across patients. This review delves into the intricate interplay of tumour characteristics contributing to resistance against ICI therapy and suggests that combining with radiotherapy holds promise. Radiation, known for its ability to trigger immunogenic cell death and foster an in situ vaccination effect, may counteract these resistance mechanisms, enhancing ICI response and patient outcomes. However, particularly when delivered at high-dose, it may trigger immunosuppressive mechanism and consequent side-effects. Notably, low-dose radiotherapy (LDRT), with its capacity for tumour reprogramming and reduced side effects, offers the potential for widespread application. Preclinical and clinical studies have shown encouraging results in this regard.
Collapse
Affiliation(s)
- Katiuska Passelli
- Centre Hospitalier Universitaire Vaudoise, Service of Radiation Oncology, Department of Oncology, University of Lausanne, AGORA Center for Cancer Research, Swiss Cancer Center Leman, 1012-Lausanne, Switzerland
| | - David Repáraz
- Centre Hospitalier Universitaire Vaudoise, Service of Radiation Oncology, Department of Oncology, University of Lausanne, AGORA Center for Cancer Research, Swiss Cancer Center Leman, 1012-Lausanne, Switzerland
| | - Remy Kinj
- Centre Hospitalier Universitaire Vaudoise, Service of Radiation Oncology, Department of Oncology, University of Lausanne, 1012-Lausanne, Switzerland
| | - Fernanda G Herrera
- Centre Hospitalier Universitaire Vaudois, Service of Radiation Oncology and Service of Immuno-oncology, Department of Oncology, University of Lausanne, Ludwig Institute for Cancer Research, Agora Center for Cancer Research, Swiss Cancer Center Leman, 1012-Lausanne, Switzerland
| |
Collapse
|
|
4
|
Seong SY, Kang MK, Kang H, Lee HJ, Kang YR, Lee CG, Sohn DH, Han SJ. Low dose rate radiation impairs early follicles in young mice. Reprod Biol 2023; 23:100817. [PMID: 37890397 DOI: 10.1016/j.repbio.2023.100817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 10/10/2023] [Accepted: 10/14/2023] [Indexed: 10/29/2023]
Abstract
Low-dose radiation is generally considered less harmful than high-dose radiation. However, its impact on ovaries remains debated. Since previous reports predominantly employed low-dose radiation delivered at a high dose rate on the ovary, the effect of low-dose radiation at a low dose rate on the ovary remains unknown. We investigated the effect of low-dose ionizing radiation delivered at a low dose rate on murine ovaries. Three- and ten-week-old mice were exposed to 0.1 and 0.5 Gy of radiation at a rate of 6 mGy/h and monitored after 3 and 30 days. While neither body weight nor ovarian area showed significant changes, ovarian cells were damaged, showing apoptosis and a decrease in cell proliferation after exposure to 0.1 and 0.5 Gy radiation. Follicle numbers decreased over time in both age groups proportionally to the radiation dose. Younger mice were more susceptible to radiation damage, as evidenced by decreased follicles in 3-week-old mice after 30 days of 0.1 Gy exposure, while 10-week-old mice showed reduced follicles only following 0.5 Gy exposure. Primordial or primary follicles were the most vulnerable to radiation. These findings suggest that even low-dose radiation, delivered at a low dose rate, can adversely affect ovarian function, particularly in the early follicles of younger mice.
Collapse
Affiliation(s)
- Se Yoon Seong
- Institute for Digital Antiaging Healthcare, Inje University, Gimhae 50834, Republic of Korea
| | - Min Kook Kang
- Department of Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 46033, Republic of Korea
| | - Hyunju Kang
- Institute for Digital Antiaging Healthcare, Inje University, Gimhae 50834, Republic of Korea
| | - Hae-June Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Seoul 01812, Republic of Korea
| | - Yeong-Rok Kang
- Department of Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 46033, Republic of Korea
| | - Chang Geun Lee
- Department of Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 46033, Republic of Korea
| | - Dong Hyun Sohn
- Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Seung Jin Han
- Institute for Digital Antiaging Healthcare, Inje University, Gimhae 50834, Republic of Korea; Department of Medical Biotechnology, Inje University, Gimhae 50834, Republic of Korea.
| |
Collapse
|
|
5
|
Averbeck D. Low-Dose Non-Targeted Effects and Mitochondrial Control. Int J Mol Sci 2023; 24:11460. [PMID: 37511215 PMCID: PMC10380638 DOI: 10.3390/ijms241411460] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/26/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023] Open
Abstract
Non-targeted effects (NTE) have been generally regarded as a low-dose ionizing radiation (IR) phenomenon. Recently, regarding long distant abscopal effects have also been observed at high doses of IR) relevant to antitumor radiation therapy. IR is inducing NTE involving intracellular and extracellular signaling, which may lead to short-ranging bystander effects and distant long-ranging extracellular signaling abscopal effects. Internal and "spontaneous" cellular stress is mostly due to metabolic oxidative stress involving mitochondrial energy production (ATP) through oxidative phosphorylation and/or anaerobic pathways accompanied by the leakage of O2- and other radicals from mitochondria during normal or increased cellular energy requirements or to mitochondrial dysfunction. Among external stressors, ionizing radiation (IR) has been shown to very rapidly perturb mitochondrial functions, leading to increased energy supply demands and to ROS/NOS production. Depending on the dose, this affects all types of cell constituents, including DNA, RNA, amino acids, proteins, and membranes, perturbing normal inner cell organization and function, and forcing cells to reorganize the intracellular metabolism and the network of organelles. The reorganization implies intracellular cytoplasmic-nuclear shuttling of important proteins, activation of autophagy, and mitophagy, as well as induction of cell cycle arrest, DNA repair, apoptosis, and senescence. It also includes reprogramming of mitochondrial metabolism as well as genetic and epigenetic control of the expression of genes and proteins in order to ensure cell and tissue survival. At low doses of IR, directly irradiated cells may already exert non-targeted effects (NTE) involving the release of molecular mediators, such as radicals, cytokines, DNA fragments, small RNAs, and proteins (sometimes in the form of extracellular vehicles or exosomes), which can induce damage of unirradiated neighboring bystander or distant (abscopal) cells as well as immune responses. Such non-targeted effects (NTE) are contributing to low-dose phenomena, such as hormesis, adaptive responses, low-dose hypersensitivity, and genomic instability, and they are also promoting suppression and/or activation of immune cells. All of these are parts of the main defense systems of cells and tissues, including IR-induced innate and adaptive immune responses. The present review is focused on the prominent role of mitochondria in these processes, which are determinants of cell survival and anti-tumor RT.
Collapse
Affiliation(s)
- Dietrich Averbeck
- Laboratory of Cellular and Molecular Radiobiology, PRISME, UMR CNRS 5822/IN2P3, IP2I, Lyon-Sud Medical School, University Lyon 1, 69921 Oullins, France
| |
Collapse
|
|
6
|
Janiak MK, Waligórski MPR. Can Low-Level Ionizing Radiation Do Us Any Harm? Dose Response 2023. [DOI: 10.1177/15593258221148013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The current system of radiological protection relies on the linear no-threshold (LNT) hypothesis of cancer risk due to humans being exposed to ionizing radiation (IR). Under this tenet, effects of low doses (i.e. of those not exceeding 100 mGy or 0.1 mGy/min. of X- or γ-rays for acute and chronic exposures, respectively) are evaluated by downward linear extrapolation from regions of higher doses and dose rates where harmful effects are actually observed. However, evidence accumulated over many years clearly indicates that exposure of humans to low doses of radiation does not cause any harm and often promotes health. In this review, we discuss results of some epidemiological analyses, clinical trials and controlled experimental animal studies. Epidemiological data indicate the presence of a threshold and departure from linearity at the lowest dose ranges. Experimental studies clearly demonstrate the qualitative difference between biological mechanisms and effects at low and at higher doses of IR. We also discuss the genesis and the likely reasons for the persistence of the LNT tenet, despite its scientific implausibility and deleterious social consequences. It is high time to replace the LNT paradigm by a scientifically based dose-effect relationship where realistic quantitative hormetic or threshold models are exploited.
Collapse
Affiliation(s)
- Marek K. Janiak
- Professor Emeritus of Medical Sciences, a retiree from the Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Michael P. R. Waligórski
- Centre of Oncology, Kraków Division and Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland
| |
Collapse
|
|
7
|
Gao Y, Dong J, Chen M, Wang T, Yang Z, He K, Li Y, Wang K, Jiang J, Zhang S. Protective effect of low-dose radiation on doxorubicin-induced brain injury in mice. Arch Biochem Biophys 2022; 729:109390. [PMID: 36067878 DOI: 10.1016/j.abb.2022.109390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/11/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND To investigate the protective effect of low-dose radiation (LDR) on brain injury in mice induced by doxorubicin (DOX). METHODS Sixty female BALB/C mice were randomly divided into the control (CTR) group, low-dose radiation (LDR) group, doxorubicin treatment (DOX) group and low-dose radiation before doxorubicin treatment (COM) group. After 72 h of exposure to 75 mGy, the mice were intraperitoneally injected with 7.5 mg/kg of doxorubicin and sacrificed 5 days later. Neuron-specific enolase (NSE), lactate dehydrogenase (LDH), adenosine triphosphate (ATP), neurotransmitters, inflammatory mediators, apoptosis- and oxidative stress-related mediators as well as mitochondrial dysfunction were examined. RESULTS Compared to the DOX group, the concentrations of DA, 5-HT, EPI and GABA in the COM group were significantly decreased, and the number of TUNEL-positive cells was decreased. In addition, the expression of proapoptotic proteins was downregulated in the COM group compared to the DOX group. Low-dose radiation in advance reduced reactive oxygen species and activated the SOD antioxidant defense system as indicated by significantly reduced GSH expression, increased GSSG expression, increased GPx expression and activation of the Nrf2 redox pathway. After low-dose radiation, the expression levels of ATP5f1, NDUFV1 and CYC1 were close to normal, and the mitochondrial respiratory control rate (RCR) and activity of respiratory chain complex enzymes also tended to be normal. Low-dose radiation upregulated the expression levels of IL-2 and IL-4 but downregulated the expression levels of IL-10 and TGF-β. CONCLUSION LDR has a protective effect on brain injury in mice treated with DOX. The mechanism is related to LDR alleviating mitochondrial dysfunction and oxidative stress, which promotes the production of antioxidant damage proteins, thus exerting an adaptive protective effect on cells.
Collapse
Affiliation(s)
- Yan Gao
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, 130021, China
| | - Jingyao Dong
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, 130021, China
| | - Mengmeng Chen
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, 130021, China
| | - Taiwei Wang
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, 130021, China
| | - Zhaoyun Yang
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, 130021, China
| | - Kang He
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, 130021, China
| | - Yuewei Li
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, 130021, China
| | - Kai Wang
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, 130021, China
| | - Jian Jiang
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, 130021, China.
| | - Shuang Zhang
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, 130021, China.
| |
Collapse
|
|
8
|
Hasan HF, Galal SM, Ellethy RA. Mitigative impact of bradykinin potentiating factor isolated from Androctonus amorexi scorpion venom and low doses of γ-irradiation on doxorubicin induced hepatotoxicity through Ang II/AMPK crosstalk. Toxicol Mech Methods 2022; 32:518-529. [PMID: 35253586 DOI: 10.1080/15376516.2022.2049941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Hesham Farouk Hasan
- Radiation Biology Department, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, Cairo, Egypt
| | - Shereen Mohamed Galal
- Health Radiation Research Department, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
| | - Rania A Ellethy
- Chemistry department, faculty of science, Helwan university, Cairo, Egypt
| |
Collapse
|
|
9
|
López-Nieva P, González-Vasconcellos I, González-Sánchez L, Cobos-Fernández MA, Ruiz-García S, Sánchez Pérez R, Aroca Á, Fernández-Piqueras J, Santos J. Differential molecular response in mice and human thymocytes exposed to a combined-dose radiation regime. Sci Rep 2022; 12:3144. [PMID: 35210498 PMCID: PMC8873405 DOI: 10.1038/s41598-022-07166-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 02/11/2022] [Indexed: 11/17/2022] Open
Abstract
In the quest for more effective radiation treatment options that can improve both cell killing and healthy tissue recovery, combined radiation therapies are lately in the spotlight. The molecular response to a combined radiation regime where exposure to an initial low dose (priming dose) of ionizing radiation is administered prior to a subsequent higher radiation dose (challenging dose) after a given latency period have not been thoroughly explored. In this study we report on the differential response to either a combined radiation regime or a single challenging dose both in mouse in vivo and in human ex vivo thymocytes. A differential cell cycle response including an increase in the subG1 fraction on cells exposed to the combined regime was found. Together with this, a differential protein expression profiling in several pathways including cell cycle control (ATM, TP53, p21CDKN1A), damage response (γH2AX) and cell death pathways such as apoptosis (Cleaved Caspase-3, PARP1, PKCδ and H3T45ph) and ferroptosis (xCT/GPX4) was demonstrated. This study also shows the epigenetic regulation following a combined regime that alters the expression of chromatin modifiers such as DNMTs (DNMT1, DNMT2, DNMT3A, DNMT3B, DNMT3L) and glycosylases (MBD4 and TDG). Furthermore, a study of the underlying cellular status six hours after the priming dose alone showed evidence of retained modifications on the molecular and epigenetic pathways suggesting that the priming dose infers a “radiation awareness phenotype” to the thymocytes, a sensitization key to the differential response seen after the second hit with the challenging dose. These data suggest that combined-dose radiation regimes could be more efficient at making cells respond to radiation and it would be interesting to further investigate how can these schemes be of use to potential new radiation therapies.
Collapse
Affiliation(s)
- Pilar López-Nieva
- Genome Dynamics and Function Program, Genome Decoding Unit, Severo Ochoa Molecular Biology Center, Madrid, Spain. .,Department of Biology, Madrid Autonomous University, 28049, Madrid, Spain. .,Institute of Health Research, Jiménez Díaz Foundation, 28040, Madrid, Spain.
| | - Iria González-Vasconcellos
- Genome Dynamics and Function Program, Genome Decoding Unit, Severo Ochoa Molecular Biology Center, Madrid, Spain. .,Department of Biology, Madrid Autonomous University, 28049, Madrid, Spain.
| | - Laura González-Sánchez
- Genome Dynamics and Function Program, Genome Decoding Unit, Severo Ochoa Molecular Biology Center, Madrid, Spain.,Institute of Health Research, Jiménez Díaz Foundation, 28040, Madrid, Spain.,Consorcio de Investigación Biomédica de Enfermedades Raras (CIBERER), Madrid, Spain
| | - María A Cobos-Fernández
- Genome Dynamics and Function Program, Genome Decoding Unit, Severo Ochoa Molecular Biology Center, Madrid, Spain.,Department of Biology, Madrid Autonomous University, 28049, Madrid, Spain
| | - Sara Ruiz-García
- Genome Dynamics and Function Program, Genome Decoding Unit, Severo Ochoa Molecular Biology Center, Madrid, Spain.,Department of Biology, Madrid Autonomous University, 28049, Madrid, Spain
| | - Raúl Sánchez Pérez
- Department of Congenital Cardiac Surgery, Hospital Universitario La Paz, 28046, Madrid, Spain
| | - Ángel Aroca
- Department of Congenital Cardiac Surgery, Hospital Universitario La Paz, 28046, Madrid, Spain
| | - José Fernández-Piqueras
- Genome Dynamics and Function Program, Genome Decoding Unit, Severo Ochoa Molecular Biology Center, Madrid, Spain.,Department of Biology, Madrid Autonomous University, 28049, Madrid, Spain.,Institute of Health Research, Jiménez Díaz Foundation, 28040, Madrid, Spain
| | - Javier Santos
- Genome Dynamics and Function Program, Genome Decoding Unit, Severo Ochoa Molecular Biology Center, Madrid, Spain.,Department of Biology, Madrid Autonomous University, 28049, Madrid, Spain.,Institute of Health Research, Jiménez Díaz Foundation, 28040, Madrid, Spain
| |
Collapse
|
|
10
|
Tanooka H. Radiation cancer risk at different dose rates: new dose-rate effectiveness factors derived from revised A-bomb radiation dosimetry data and non-tumor doses. JOURNAL OF RADIATION RESEARCH 2022; 63:1-7. [PMID: 34927198 PMCID: PMC8776691 DOI: 10.1093/jrr/rrab109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/14/2021] [Indexed: 06/14/2023]
Abstract
The dose rate of atomic bomb (A-bomb) radiation to the survivors has still remained unclear, although the dose-response data of A-bomb cancers has been taken as a standard in estimating the cancer risk of radiation and the dose and dose-rate effectiveness factor (DDREF). Since the applicability of the currently used DDREF of 2 derived from A-bomb data is limited in a narrow dose-rate range, 0.25-75 Gy/min as estimated from analysis of DS86 dosimetry data in the present study, a non-tumor dose (Dnt) was applied in an attempt to gain a more universal dose-rate effectiveness factor (DREF), where Dnt is an empirical parameter defined as the highest dose at which no statistically significant tumor increase is observed above the control level and its magnitude depends on the dose rate. The new DREF values were expressed as a function of the dose rate at four exposure categories, i.e. partial body low LET, whole body low linear energy transfer (LET), partial body high LET and whole body high LET and provided a value of 14 for environmental level radiation at a dose rate of 10-9 Gy/min for whole body low LET.
Collapse
Affiliation(s)
- Hiroshi Tanooka
- Corresponding author. National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Tel. +81-3-3542-2511, Ext. 3224; Fax. +81-3-3542-0623; E-mail address:
| |
Collapse
|
|
11
|
He CQ, Mao L, Yao J, Zhao WC, Huang B, Hu N, Long DX. The Threshold Effects of Low-Dose-Rate Radiation on miRNA-Mediated Neurodevelopment of Zebrafish. Radiat Res 2021; 196:633-646. [PMID: 34399425 DOI: 10.1667/rade-20-00265.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 07/29/2021] [Indexed: 11/03/2022]
Abstract
The biological effects and regulatory mechanisms of low-dose and low-dose-rate radiation are still rather controversial. Therefore, in this study we investigated the effects of low-dose-rate radiation on zebrafish neurodevelopment and the role of miRNAs in radiation-induced neurodevelopment. Zebrafish embryos received prolonged gamma-ray irradiation (0 mGy/h, 0.1 mGy/h, 0.2 mGy/h, 0.4 mGy/h) during development. Neurodevelopmental indicators included mortality, malformation rate, swimming speed, as well as the morphology changes of the lateral line system and brain tissue. Additionally, spatiotemporal expression of development-related miRNAs (dre-miR-196a-5p, dre-miR-210-3p, dre-miR-338) and miRNA processing enzymes genes (Dicer and Drosha) were assessed by qRT-PCR and whole mount in situ hybridization (WISH). The results revealed a decline in mortality, malformation and swimming speed, with normal histological and morphological appearance, in zebrafish that received 0.1 mGy/h; however, increased mortality, malformation and swimming speed were observed, with pathological changes, in zebrafish that received 0.2 mGy/h and 0.4 mGy/h. The expression of miRNA processing enzyme genes was altered after irradiation, and miRNAs expression was downregulated in the 0.1 mGy/h group, and upregulated in the 0.2 mGy/h and 0.4 mGy/h groups. Furthermore, ectopic expression of dre-miR-210-3p, Dicer and Drosha was also observed in the 0.4 mGy/h group. In conclusion, the effect of low-dose and low-dose-rate radiation on neurodevelopment follows the threshold model, under the regulation of miRNAs, excitatory effects occurred at a dose rate of 0.1 mGy/h and toxic effects occurred at a dose rate of 0.2 mGy/h and 0.4 mGy/h.
Collapse
Affiliation(s)
- Chu-Qi He
- School of Public Health, University of South China, Hengyang 421001, PR China.,Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang, Hunan 421001, China
| | - Liang Mao
- School of Public Health, University of South China, Hengyang 421001, PR China.,Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang, Hunan 421001, China
| | - Jin Yao
- School of Public Health, University of South China, Hengyang 421001, PR China.,Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang, Hunan 421001, China
| | - Wei-Chao Zhao
- School of Public Health, University of South China, Hengyang 421001, PR China.,Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang, Hunan 421001, China
| | - Bo Huang
- School of Public Health, University of South China, Hengyang 421001, PR China.,Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang, Hunan 421001, China
| | - Nan Hu
- Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, China
| | - Ding-Xin Long
- School of Public Health, University of South China, Hengyang 421001, PR China.,Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang, Hunan 421001, China
| |
Collapse
|
|
12
|
Ashoub AH, Abdel-Naby DH, Safar MM, El-Ghazaly MA, Kenawy SA. Ameliorative effect of fractionated low-dose gamma radiation in combination with ellagic acid on nicotine-induced hormonal changes and testicular toxicity in rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:23287-23300. [PMID: 33443739 DOI: 10.1007/s11356-020-12334-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 12/30/2020] [Indexed: 06/12/2023]
Abstract
Nicotine is an active pharmacological ingredient in cigarette smoke, which may negatively influence the male reproductive system and fertility. This study aims to investigate the effect of fractionated low-dose radiation (fractionated-LDR) and/or ellagic acid (EA) on nicotine-induced hormonal changes and testicular toxicity in rats. Nicotine was administrated orally (1 mg/kg) for 30 days, afterward, rats were treated with LDR (2 × 0.25 Gy/1-week interval), EA (10 mg/kg, 14 consecutive days p.o.), or a combination of both fractionated-LDR and EA. Rats were sacrificed 24 h after the last dose of treatment, then testes were dissected for histopathology examination, along with some biochemical parameters in serum and testicular tissue were evaluated. Nicotine-induced oxidative stress was evidenced by an increase in testicular thiobarbituric acid reactive substances (TBARS) and a decrease in reduced glutathione (GSH) content. Additionally, the activities of testicular androgenic enzymes were decreased, and the activity of serum lactate dehydrogenase (LDH) was significantly increased. The hormonal changes were verified by a noticeable reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone serum levels. Histological evaluation revealed that the testicular seminiferous tubules structure was distorted. On the contrary, fractionated-LDR plus EA attenuated the negative changes caused by nicotine observed through biochemical and histological findings. Accordingly, the exposure to fractionated-LDR combined with EA may be a promising candidate for treating hormonal changes and testicular toxicity caused by nicotine.
Collapse
Affiliation(s)
- Aliaa H Ashoub
- Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Atomic Energy Authority, 3 Ahmed El-Zomor Street, Nasr City, Cairo, Egypt
| | - Doaa H Abdel-Naby
- Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Atomic Energy Authority, 3 Ahmed El-Zomor Street, Nasr City, Cairo, Egypt
| | - Marwa M Safar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, Egypt
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt, Suez Desert Road, El Sherouk City, Egypt
| | - Mona A El-Ghazaly
- Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Atomic Energy Authority, 3 Ahmed El-Zomor Street, Nasr City, Cairo, Egypt
| | - Sanaa A Kenawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, Egypt.
| |
Collapse
|
|
13
|
Paunesku T, Stevanović A, Popović J, Woloschak GE. Effects of low dose and low dose rate low linear energy transfer radiation on animals - review of recent studies relevant for carcinogenesis. Int J Radiat Biol 2021; 97:757-768. [PMID: 33289582 PMCID: PMC9216178 DOI: 10.1080/09553002.2020.1859155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/20/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023]
Abstract
Purpose: Carcinogenic effects of radiation are often assumed to be universally understood, more often than, for example, carcinogenic effects of many different chemicals. This in turn leads to an assumption that any dose of radiation, delivered at any dose rate, poses a serious health challenge. This remains an issue of dispute and low dose radiation research is focused on understanding whether these exposures contribute to cancer incidence. This review is focused on the low linear energy transfer (low LET) radiation exposures for which the data is the most abundant in recent years. Materials and methods: Review of the literature between 2008 and today, highlighting some of the most diverse studies in low dose research. Results: Low dose and low dose rate, low LET ionizing radiation animal studies suggest that the effects of exposure very much depend on animal genotype and health status.Conclusions: Only the integration of all of the data from different models and studies will lead to a fuller understanding of low dose radiation effects. Therefore, we hope to see an increase in international archival efforts and exchange of raw data information opening the possibilities for new types of meta analyses.
Collapse
Affiliation(s)
- Tatjana Paunesku
- Department of Radiation Oncology, Northwestern University, Chicago, IL, USA
| | - Aleksandra Stevanović
- Multidisciplinary Studies of History and Philosophy of Natural Sciences and Technology, University of Belgrade, Belgrade, Serbia
| | - Jelena Popović
- Department of Radiation Oncology, Northwestern University, Chicago, IL, USA
| | - Gayle E Woloschak
- Department of Radiation Oncology, Northwestern University, Chicago, IL, USA
| |
Collapse
|
|
14
|
Saleeva DV, Mikhailov VF, Rozhdestvenskii LM, Shulenina LV, Raeva NF, Zasukhina GD. Changes in the Activity of Genes Involved in the Regulation of Hematopoiesis during Tumorigenesis in Irradiated Mice. DOKLADY BIOLOGICAL SCIENCES : PROCEEDINGS OF THE ACADEMY OF SCIENCES OF THE USSR, BIOLOGICAL SCIENCES SECTIONS 2020; 491:57-59. [PMID: 32483710 DOI: 10.1134/s0012496620020106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 12/04/2019] [Accepted: 12/04/2019] [Indexed: 11/23/2022]
Abstract
We used 183 F1 CBA×C57Bl hybrid mice to study the delayed effects of low-power long-term γ-irradiation at a dose of 12.6 Gy (10 mGy/min) 8 and 10 months after the treatment. Eight months after the treatment we found the increased expression of the transcription factor NFκB and its target genes iNOS and G-SCF in the bone marrow (BM). Ten months after the treatment malignant lymphomas were revealed in 14 of 94 mice in the liver, abdominal cavity, and subcutaneously. In the BM of these mice, the transcription of the PTEN, NFκB, and iNOS genes was inhibited and the contents of long non-coding RNAs (lncRNAs) lnc p21, NEAT1, and microRNA miR-125b were decreased. The expression of the NFκB(p65) gene and miR-125b was inhibited in the BM of irradiated mice without tumors ten months after the treatment. These data show the deregulation of the P53 system supporting the genome stability in the BM of irradiated mice. These indices will be studied as potential markers of risk of development of irradiation-induced tumors.
Collapse
Affiliation(s)
- D V Saleeva
- Burnazyan Federal Medical Biophysical Center, Federal Biomedical Agency of the Russian Federation, 123098, Moscow, Russia.
| | - V F Mikhailov
- Burnazyan Federal Medical Biophysical Center, Federal Biomedical Agency of the Russian Federation, 123098, Moscow, Russia
| | - L M Rozhdestvenskii
- Burnazyan Federal Medical Biophysical Center, Federal Biomedical Agency of the Russian Federation, 123098, Moscow, Russia
| | - L V Shulenina
- Burnazyan Federal Medical Biophysical Center, Federal Biomedical Agency of the Russian Federation, 123098, Moscow, Russia
| | - N F Raeva
- Burnazyan Federal Medical Biophysical Center, Federal Biomedical Agency of the Russian Federation, 123098, Moscow, Russia
| | - G D Zasukhina
- Burnazyan Federal Medical Biophysical Center, Federal Biomedical Agency of the Russian Federation, 123098, Moscow, Russia.,Vavilov Institute of General Genetics, Russian Academy of Sciences, 117971, Moscow, Russia
| |
Collapse
|
|
15
|
Helm JS, Rudel RA. Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast. Arch Toxicol 2020; 94:1511-1549. [PMID: 32399610 PMCID: PMC7261741 DOI: 10.1007/s00204-020-02752-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 04/16/2020] [Indexed: 12/15/2022]
Abstract
Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-response relationship. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events to the adverse outcome through intermediate key events, creating a qualitative AOP. We identified key events based on review articles, searched PubMed for recent literature on key events and IR, and identified additional papers using references. We manually curated publications and evaluated data quality. Ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS). RONS lead to DNA damage and epigenetic changes leading to mutations and genomic instability (GI). Proliferation amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS and DNA damage also increase inflammation. Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and breast cancer through pro-carcinogenic effects on cells and tissue. For example, gene expression changes alter inflammatory mediators, resulting in improved survival and growth of cancer cells and a more hospitable tissue environment. All of these events overlap at multiple points with events characteristic of "background" induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce that these biological activities are important characteristics of carcinogens. Agents that increase these biological processes should be considered potential breast carcinogens, and predictive methods are needed to identify chemicals that increase these processes. Techniques are available to measure RONS, DNA damage and mutation, cell proliferation, and some inflammatory proteins or processes. Improved assays are needed to measure GI and chronic inflammation, as well as the interaction with hormonally driven development and proliferation. Several methods measure diverse epigenetic changes, but it is not clear which changes are relevant to breast cancer. In addition, most toxicological assays are not conducted in mammary tissue, and so it is a priority to evaluate if results from other tissues are generalizable to breast, or to conduct assays in breast tissue. Developing and applying these assays to identify exposures of concern will facilitate efforts to reduce subsequent breast cancer risk.
Collapse
Affiliation(s)
- Jessica S Helm
- Silent Spring Institute, 320 Nevada Street, Suite 302, Newton, MA, 02460, USA
| | - Ruthann A Rudel
- Silent Spring Institute, 320 Nevada Street, Suite 302, Newton, MA, 02460, USA.
| |
Collapse
|
|
16
|
Sykes PJ. Until There Is a Resolution of the Pro-LNT/Anti-LNT Debate, We Should Head Toward a More Sensible Graded Approach for Protection From Low-Dose Ionizing Radiation. Dose Response 2020; 18:1559325820921651. [PMID: 32425725 PMCID: PMC7218310 DOI: 10.1177/1559325820921651] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 01/19/2023] Open
Abstract
Current regulation of ionizing radiation is based on the linear no-threshold (LNT) model where any radiation dose increases cancer risk and is independent of dose rate, resulting in large amounts of time and money being spent protecting from extremely small radiation exposures and hence extremely small risk. There are animal studies which demonstrate that LNT is incorrect at low doses, supporting a threshold or hormesis model and thus indicating that there is no need to protect from very low doses. This has led to a sometimes bitter debate between pro-LNT and anti-LNT camps, and the debate has been at a stalemate for some time. This commentary is not aimed at taking either side of the debate. It is likely that the public, workers, and the environment are adequately protected under current regulation, which is the most important outcome. Until those on one side of the debate can convince the other, it would be sensible to move forward toward a graded (risk-based) approach to regulation, where the stringency of control is commensurate with the risk, resulting hopefully in more sensible practical thresholds. This approach is gradually being put forward by international radiation protection advisory bodies.
Collapse
Affiliation(s)
- Pamela J Sykes
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University. Adelaide, South Australia, Australia
| |
Collapse
|
|
17
|
Kojima S, Cuttler JM, Inoguchi K, Yorozu K, Horii T, Shimura N, Koga H, Murata A. Radon Therapy Is Very Promising as a Primary or an Adjuvant Treatment for Different Types of Cancers: 4 Case Reports. Dose Response 2019; 17:1559325819853163. [PMID: 31210758 PMCID: PMC6552369 DOI: 10.1177/1559325819853163] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 04/25/2019] [Accepted: 04/30/2019] [Indexed: 12/14/2022] Open
Abstract
We report on the application of radon inhalation therapy to patients with 4 types of cancer: colon, uterine, lung, and liver cell. The radon treatments were given to improve the efficacy of chemotherapy and were potent in all 4 cases. Marker values decreased and disease symptoms were alleviated. We include a lengthy discussion on the mechanism that may be responsible for the observed results. While employing the radon generator to treat the patient with hepatocellular carcinoma, we discovered that a concentration of 6 MBq/m3 was very effective, while 1 MBq/m3 was marginal. This implies different, and rather high, radon concentration thresholds for the treatment of different types of cancer. The evidence from these 4 cases suggests that radon inhalation may be beneficial against various cancer types as an important adjuvant therapy to conventional chemotherapy and for local high-dose radiotherapy, which would address the problem of distant metastasis. A previous case report on 2 patients with advanced breast cancer, who refused chemotherapy or radiotherapy, indicates that radon may be effective as a primary therapy for cancer. Clinical trials should be carried out to determine the best radon concentrations for treatment of other types of cancer, at different stages of progression.
Collapse
Affiliation(s)
- Shuji Kojima
- Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science (TUS), Noda-city, Chiba, Japan
| | | | | | | | | | - Noriko Shimura
- Faculty of Pharmaceutical Sciences, Ohu University, Koriyama, Japan
| | - Hironobu Koga
- Lead and Company Co., Ltd., Minami-ku, Yokohama, Japan
| | | |
Collapse
|
|
18
|
The LNT model for cancer induction is not supported by radiobiological data. Chem Biol Interact 2019; 301:34-53. [PMID: 30763552 DOI: 10.1016/j.cbi.2019.01.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 01/07/2019] [Accepted: 01/09/2019] [Indexed: 12/18/2022]
Abstract
The hallmarks of cancer have been the focus of much research and have influenced the development of risk models for radiation-induced cancer. However, natural defenses against cancer, which constitute the hallmarks of cancer prevention, have largely been neglected in developing cancer risk models. These natural defenses are enhanced by low doses and dose rates of ionizing radiation, which has aided in the continuation of human life over many generations. Our natural defenses operate at the molecular, cellular, tissue, and whole-body levels and include epigenetically regulated (epiregulated) DNA damage repair and antioxidant production, selective p53-independent apoptosis of aberrant cells (e.g. neoplastically transformed and tumor cells), suppression of cancer-promoting inflammation, and anticancer immunity (both innate and adaptive components). This publication reviews the scientific bases for the indicated cancer-preventing natural defenses and evaluates their implication for assessing cancer risk after exposure to low radiation doses and dose rates. Based on the extensive radiobiological evidence reviewed, it is concluded that the linear-no-threshold (LNT) model (which ignores natural defenses against cancer), as it relates to cancer risk from ionizing radiation, is highly implausible. Plausible models include dose-threshold and hormetic models. More research is needed to establish when a given model (threshold, hormetic, or other) applies to a given low-dose-radiation exposure scenario.
Collapse
|
|
19
|
Premkumar K, Nair J, Shankar BS. Differential radio-adaptive responses in BALB/c and C57BL/6 mice: pivotal role of calcium and nitric oxide signalling. Int J Radiat Biol 2019; 95:655-666. [PMID: 30676176 DOI: 10.1080/09553002.2019.1571647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Purpose: Our earlier studies demonstrated that transient radio-adaptive responses (RAR) in BALB/c mice were due to MAPK hyperactivation. The objective of this study was to determine the time duration of this low dose induced MAPK activation in BALB/c mice and to find out if similar adaptive responses are observed in C57BL/6 mice. Materials and methods: Mice were irradiated with 0.1 Gy priming dose (PD), 2 Gy challenge dose (CD) with an interval of 4 h (P + CD) and radiation induced immunosuppression in splenic lymphocytes was monitored as the endpoint for RAR. Results: Time kinetics following 0.1 Gy demonstrated persistence of MAPK hyperactivation till 48 h. Similar experiments in C57BL/6 mice indicated absence of RAR at 24 h following CD, in spite of MAPK activation which was also confirmed by time kinetics. Therefore, upstream activators of MAPK, viz., reactive oxygen and nitrogen species (ROS, RNS) and calcium levels were estimated. There was increased intracellular calcium (Ca2+) and nitric oxide (NO) in BALB/c and an increase in intracellular ROS in C57BL/6 mice 24 h after PD. Inhibition of NO and calcium chelation abrogated RAR in BALB/c mice. In vitro treatment of spleen cells with combination of NO donor and Ca2+ ionophore mimicked the effect of PD and induced adaptive response after 2 Gy not only in BALB/c but also in C57BL/6 mice confirming their crucial role in RAR. Conclusions: These results suggest that low dose induced differential induction of Ca2+ and NO signaling along with MAPK was responsible for contrasting RAR with respect to immune system of BALB/c and C57BL/6 mice. Abbreviations [3H]-TdR: 3H-methyl-thymidine; BAPTA: 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; CD: Challenge Dose; CFSE: Carboxy Fluorescein Succinamidyl Ester; on A: Concanavalin A; DAF-FM: 4-amino-5-methylamino-2',7'-difluorescein; DCF-DA: 2',7'-dichlorofluorescein diacetate; DSB: Double Strand Break; ELISA: Enzyme Linked ImmunoSorbent Assay; ERK: Extracellular signal-Regulated protein Kinase; FBS: Fetal Bovine Serum; HIF-1A: Hypoxia-Inducible Factor 1-alpha; LDR: Low Dose Radiation; MAPK: Mitogen Activated Protein Kinase; MAPKK/MKK: MAPK Kinase; MAPKKK: MAPK Kinase Kinase; NO: Nitric Oxide; NOS: Nitric Oxide Synthase; P + CD: Priming + Challenge dose; PBS: Phosphate Buffered Saline; PBST: Phosphate Buffered Saline-Tween 20; PD: Priming Dose; PI3K: Phosphatidyl Inositol 3-Kinase; PKC: Protein Kinase C; RAR: Radio Adaptive Response; RNS: Reactive Nitrogen Species; ROS: Reactive Oxygen Species; RPMI-1640: Roswell Park Memorial Institute-1640 medium; SAPK/JNK: Stress-Activated Protein Kinase/ c-Jun NH2-terminal Kinase; SEM: Standard Error of Mean; SNAP: S-nitro amino penicillamine; TP53: Tumor Protein 53; γ-H2AX: Gamma- H2A histone family member X; Th1: Type 1 helper T cell responses; Th2: Type 2 helper T cell responses.
Collapse
Affiliation(s)
- Kavitha Premkumar
- a Immunology Section, Radiation Biology & Health Sciences Division , Bio-Science Group, Bhabha Atomic Research Centre , Mumbai , India
| | - Jisha Nair
- a Immunology Section, Radiation Biology & Health Sciences Division , Bio-Science Group, Bhabha Atomic Research Centre , Mumbai , India
| | - Bhavani S Shankar
- a Immunology Section, Radiation Biology & Health Sciences Division , Bio-Science Group, Bhabha Atomic Research Centre , Mumbai , India
| |
Collapse
|
|
20
|
Fuma S, Soeda H, Ihara S, Matsui K, Kawaguchi I, Ishikawa T, Kubota Y, Watanabe Y, Aono T. Effects of chronic γ-irradiation on growth and sexual maturation of the Tohoku hynobiid salamander, Hynobius lichenatus. JOURNAL OF ENVIRONMENTAL RADIOACTIVITY 2019; 196:98-103. [PMID: 30423483 DOI: 10.1016/j.jenvrad.2018.10.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/18/2018] [Accepted: 10/31/2018] [Indexed: 06/09/2023]
Abstract
There are still considerable gaps in knowledge regarding the biological effects of chronic ionising radiation exposure in amphibians. To fill these gaps, Tohoku hynobiid salamanders, Hynobius lichenatus (Amphibia, Caudata), were chronically irradiated with 137Cs γ-rays from embryonic to adult stages over 1954 days, and the effects on their growth and sexual maturation were examined under laboratory conditions. Irradiation at a dose rate of 33 μGy h-1 had some stimulatory effects on growth (body weight increase) of H. lichenatus, while growth was temporarily or permanently suppressed at 150 or 510 μGy h-1, respectively. On day 1802, secondary sexual characteristics (a tubercle at the anterior angle of the cloacal vent for males and ovisac development for females) were observed in 91% of the salamanders irradiated at 33 μGy h-1, and in a similar percentage of non-irradiated controls. At 150 and 510 μGy h-1, secondary sexual characteristics were not observed in any individuals. These results suggest that the derived consideration reference level (DCRL) of the International Commission on Radiological Protection (ICRP) for Reference Frog, i.e. 40-400 μGy h-1, is applicable for the protection of H. lichenatus, and that growth and sexual maturation of this salamander may not have been adversely affected even in the most severely contaminated area in Fukushima, where the highest dose rate to salamanders was estimated to be 50 μGy h-1. However, observations in the contaminated area are required to confirm this conclusion, considering the possible confounding factors which may make this salamander more sensitive to radiation in the natural environment than under laboratory conditions.
Collapse
Affiliation(s)
- Shoichi Fuma
- Fukushima Project Headquarters, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan.
| | - Haruhi Soeda
- Fukushima Project Headquarters, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Sadao Ihara
- Hokkaido University of Education Kushiro Campus, 1-15-55 Shiroyama, Kushiro, Hokkaido, 085-8580, Japan
| | - Kumi Matsui
- Laboratory of Veterinary Physiology 1, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Sagamihara, Kanagawa, 252-5201, Japan
| | - Isao Kawaguchi
- Center for Radiation Protection Knowledge, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Takahiro Ishikawa
- Department of Accelerator and Medical Physics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Yoshihisa Kubota
- Fukushima Project Headquarters, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Yoshito Watanabe
- Fukushima Project Headquarters, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Tatsuo Aono
- Fukushima Project Headquarters, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| |
Collapse
|
|
21
|
Nakashima M, Sugie C, Wang Z, Kondo T, Manabe Y, Murai T, Shibamoto Y. Biological Effects of Continuous Low-Dose-Rate Irradiation in Silkworms and Mice: Growth Promotion and Tumor Transplantability. Dose Response 2018; 16:1559325818811753. [PMID: 30479589 PMCID: PMC6247495 DOI: 10.1177/1559325818811753] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/01/2018] [Accepted: 10/10/2018] [Indexed: 11/17/2022] Open
Abstract
A previous study showed that continuous low-dose-rate irradiation promoted the growth of silkworm larvae. This study aimed to confirm that finding, determine the optimal dose rate for growth promotion, and compare low- and high-dose-rate irradiation in silkworms, while also investigating the effects of the radiation-emitting sheet on growth and tumor transplantability in mice. Silkworm eggs were placed on low-dose-emitting sheets with 4 different dose rates (γ-ray rate: 1.7 -22.4 μSv/hour) or on control sheets. The other groups of silkworm larvae received single whole-body X-irradiation (0.1-50 Gy), and subsequent body weight changes were monitored. Starting at 3 weeks old, Balb/c mice were bred on the same sheets, and body weight change was measured. Seven weeks later, the mice were used to investigate the transplantability of EMT6 tumor cells cultured in vitro. The silkworms bred on the 13.4- and 22.4-μSv/hour sheets became larger than the control. Single 50-Gy irradiation suppressed the growth of silkworms. An increase in the time to EMT6 tumor development was observed in low-dose-rate-irradiated mice. This study confirmed growth promotion of silkworms by continuous low-dose radiation and demonstrated growth suppression at a high dose rate. Growth promotion was not observed in mice; further studies using higher dose-rate sheets may be warranted.
Collapse
Affiliation(s)
- Masahiro Nakashima
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Chikao Sugie
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Zhen Wang
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takuhito Kondo
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshihiko Manabe
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Taro Murai
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yuta Shibamoto
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| |
Collapse
|
|
22
|
Shibamoto Y, Nakamura H. Overview of Biological, Epidemiological, and Clinical Evidence of Radiation Hormesis. Int J Mol Sci 2018; 19:E2387. [PMID: 30104556 PMCID: PMC6121451 DOI: 10.3390/ijms19082387] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 08/06/2018] [Accepted: 08/09/2018] [Indexed: 12/19/2022] Open
Abstract
The effects of low-dose radiation are being increasingly investigated in biological, epidemiological, and clinical studies. Many recent studies have indicated the beneficial effects of low doses of radiation, whereas some studies have suggested harmful effects even at low doses. This review article introduces various studies reporting both the beneficial and harmful effects of low-dose radiation, with a critique on the extent to which respective studies are reliable. Epidemiological studies are inherently associated with large biases, and it should be evaluated whether the observed differences are due to radiation or other confounding factors. On the other hand, well-controlled laboratory studies may be more appropriate to evaluate the effects of low-dose radiation. Since the number of such laboratory studies is steadily increasing, it will be concluded in the near future whether low-dose radiation is harmful or beneficial and whether the linear-no-threshold (LNT) theory is appropriate. Many recent biological studies have suggested the induction of biopositive responses such as increases in immunity and antioxidants by low-dose radiation. Based on recent as well as classical studies, the LNT theory may be out of date, and low-dose radiation may have beneficial effects depending on the conditions; otherwise, it may have no effects.
Collapse
Affiliation(s)
- Yuta Shibamoto
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
| | - Hironobu Nakamura
- Department of Radiology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
- Department of Radiology, Saito Yukokai Hospital, Osaka 567-0085, Japan.
| |
Collapse
|
|
23
|
Paraswani N, Thoh M, Bhilwade HN, Ghosh A. Early antioxidant responses via the concerted activation of NF-κB and Nrf2 characterize the gamma-radiation-induced adaptive response in quiescent human peripheral blood mononuclear cells. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2018; 831:50-61. [PMID: 29875077 DOI: 10.1016/j.mrgentox.2018.04.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 04/25/2018] [Accepted: 04/26/2018] [Indexed: 11/16/2022]
Abstract
The radiation-induced adaptive response (RI-AR) is a non-targeted effect which is outside the scope of the classical Linear-No-Threshold (LNT) dose-response paradigm. However, the mechanisms of the RI-AR are not well understood. We have studied the RI-AR in quiescent human peripheral blood mononuclear cells (PBMCs). PBMCs in G0 phase were 'primed' with a low dose (100 mGy gamma radiation) and then, after an 'adaptive window' of 4 h, 'challenged' with a high dose (2 Gy). A small (5.7%) increase in viability and a decrease in DNA strand breaks were seen in primed cells, compared to non-primed cells. This was consistent with lower levels of reactive oxygen species, higher mitochondrial membrane potential, and increased activity of antioxidant enzymes such as catalase, superoxide dismutase, thioredoxin reductase, and glutathione peroxidase, in the primed cells. Reduced oxidative stress in primed PBMCs correlated with greater nuclear translocation of the redox-sensitive transcription factors Nuclear factor kappa B (NF-κB) and Nuclear factor E2-related factor 2 (Nrf2). Distinct differences in responses were seen in PBMCs irradiated with low dose (100 mGy) and high dose (2 Gy). These findings provide insight into the mechanisms of radioadaptation in human cells.
Collapse
Affiliation(s)
- Neha Paraswani
- Radiation Signaling Group, Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India
| | - Maikho Thoh
- Free Radical Biology Section, Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
| | - Hari N Bhilwade
- Free Radical Biology Section, Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
| | - Anu Ghosh
- Radiation Signaling Group, Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India.
| |
Collapse
|
|
24
|
Lemon JA, Phan N, Boreham DR. Multiple CT Scans Extend Lifespan by Delaying Cancer Progression in Cancer-Prone Mice. Radiat Res 2017; 188:495-504. [DOI: 10.1667/rr14575.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Jennifer A. Lemon
- Medical Sciences, Northern Ontario School of Medicine, Sudbury, Canada, P3E 2C6
| | - Nghi Phan
- Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Canada, L8S 4K1
| | - Douglas R. Boreham
- Medical Sciences, Northern Ontario School of Medicine, Sudbury, Canada, P3E 2C6
| |
Collapse
|
|
25
|
Lemon JA, Phan N, Boreham DR. Single CT Scan Prolongs Survival by Extending Cancer Latency inTrp53Heterozygous Mice. Radiat Res 2017; 188:505-511. [DOI: 10.1667/rr14576.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Jennifer A. Lemon
- Medical Sciences Division, Northern Ontario School of Medicine, Sudbury, Canada, P3E 2C6
| | - Nghi Phan
- Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Canada, L8S 4K1
| | - Douglas R. Boreham
- Medical Sciences Division, Northern Ontario School of Medicine, Sudbury, Canada, P3E 2C6
| |
Collapse
|
|
26
|
Shibamoto Y, Kamei Y, Kamei K, Tsuchiya T, Aoyama N. Continuous Low-Dose-Rate Irradiation Promotes Growth of Silkworms. Dose Response 2017; 15:1559325817735252. [PMID: 29051717 PMCID: PMC5639971 DOI: 10.1177/1559325817735252] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 08/18/2017] [Accepted: 08/29/2017] [Indexed: 11/03/2022] Open
Abstract
To investigate the influence of low-dose-rate irradiation on the growth of silkworms, Bombyx mori, eggs of silkworms were randomly divided into 2 groups and were grown on either low-dose-radiation-emitting sheets or control sheets. On the radiation-emitting sheets, the dose rate was measured as 66.0 (4.3) μSv/h (mean [standard deviation]) by a Geiger-Müller counter for α, β, and γ rays and 3.8 (0.3) μSv/h by a survey meter for γ rays. The silkworms became larger when bred on the radiation-emitting sheets, and their body weight was about 25% to 37% heavier on day 42 to 49 after starting the experiment. Continuous low-dose-rate irradiation promoted the growth of silkworms. It should be further investigated whether this phenomenon could be utilized by the silk industry.
Collapse
Affiliation(s)
- Yuta Shibamoto
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya , Japan
| | - Yoshiaki Kamei
- Japan Regional Promotion Organization, Yasutomi-cho, Himeji , Japan
| | - Koichi Kamei
- Japan Regional Promotion Organization, Yasutomi-cho, Himeji , Japan
| | - Takahiro Tsuchiya
- Radiology Center, Nagoya City University Hospital, Mizuho-ku, Nagoya, Japan
| | | |
Collapse
|
|
27
|
Jiang B, Zhang Y, Zhao J, She C, Zhou X, Dong Q, Wang P. Effects of Localized X-Ray Irradiation on Peripheral Nerve Regeneration in Transected Sciatic Nerve in Rats. Radiat Res 2017; 188:455-462. [PMID: 28796579 DOI: 10.1667/rr14799.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Low-dose radiation has been used in clinical and experimental models for the prevention of scarring and for fracture healing. There is evidence that low-dose radiation improves the hormesis of various cell types but little is known about its effects on peripheral nerve tissue. In this study, we investigated the beneficial effects of low-dose radiation on the regeneration of transectional peripheral nerve injury in an experimental rat model. Seventy-two male Sprague-Dawley rats received transection injury to the left sciatic nerves, and the nerves were subsequently sutured by epineurium end-to-end anastomosis to restore continuity. Animals were randomly assigned to one of two treatment groups (n = 36/group): 1 Gy X-ray irradiation or control (sham irradiation). Gait analysis, electrophysiological examination and morphological investigations were performed. In addition, Western blot and qRT-PCR were performed to determine the level of vascular endothelial growth factor (VEGF) and growth-associated protein-43 (GAP-43). Content of VEGF and GAP-43 in the regenerated sciatic nerve of the irradiated group was higher than the control group. At 4 to 12 weeks after surgery, the irradiated animals exhibited a significantly improved functional recovery relative to controls. At 12 weeks after surgery, amplitude and conduction velocity of the irradiated group were higher than the control group (P < 0.05). The number of nerve fibers, diameter of axons and morphological structure of the myelin sheath in the irradiated group were superior to those of the control group. These results suggest that low-dose radiation contributed to regeneration and functional recovery after transverse peripheral nerve injury by inducing increased production of VEGF and GAP-43, which promote the axonal regeneration and myelination.
Collapse
Affiliation(s)
- Bo Jiang
- a Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P. R. China
| | - Yong Zhang
- a Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P. R. China
| | - Jiaju Zhao
- a Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P. R. China
| | - Chang She
- b Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P. R. China
| | - Xiaozhong Zhou
- b Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P. R. China
| | - Qirong Dong
- b Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P. R. China
| | - Peiji Wang
- a Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P. R. China
| |
Collapse
|
|
28
|
Yim JH, Yun JM, Kim JY, Nam SY, Kim CS. Estimation of low-dose radiation-responsive proteins in the absence of genomic instability in normal human fibroblast cells. Int J Radiat Biol 2017; 93:1197-1206. [DOI: 10.1080/09553002.2017.1350302] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Ji-Hye Yim
- Department of Low-Dose Radiation Research Team, KHNP Radiation Health Institute, Seoul, Korea
| | - Jung Mi Yun
- Department of Low-Dose Radiation Research Team, KHNP Radiation Health Institute, Seoul, Korea
| | - Ji Young Kim
- Department of Low-Dose Radiation Research Team, KHNP Radiation Health Institute, Seoul, Korea
| | - Seon Young Nam
- Department of Low-Dose Radiation Research Team, KHNP Radiation Health Institute, Seoul, Korea
| | - Cha Soon Kim
- Department of Molecular Biology Radiation Epidemiology Team, KHNP Radiation Health Institute, Seongnam-si, Gyeonggi-do, Korea
| |
Collapse
|
|
29
|
Janiak MK, Wincenciak M, Cheda A, Nowosielska EM, Calabrese EJ. Cancer immunotherapy: how low-level ionizing radiation can play a key role. Cancer Immunol Immunother 2017; 66:819-832. [PMID: 28361232 PMCID: PMC5489643 DOI: 10.1007/s00262-017-1993-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 03/22/2017] [Indexed: 12/17/2022]
Abstract
The cancer immunoediting hypothesis assumes that the immune system guards the host against the incipient cancer, but also "edits" the immunogenicity of surviving neoplastic cells and supports remodeling of tumor microenvironment towards an immunosuppressive and pro-neoplastic state. Local irradiation of tumors during standard radiotherapy, by killing neoplastic cells and generating inflammation, stimulates anti-cancer immunity and/or partially reverses cancer-promoting immunosuppression. These effects are induced by moderate (0.1-2.0 Gy) or high (>2 Gy) doses of ionizing radiation which can also harm normal tissues, impede immune functions, and increase the risk of secondary neoplasms. In contrast, such complications do not occur with exposures to low doses (≤0.1 Gy for acute irradiation or ≤0.1 mGy/min dose rate for chronic exposures) of low-LET ionizing radiation. Furthermore, considerable evidence indicates that such low-level radiation (LLR) exposures retard the development of neoplasms in humans and experimental animals. Here, we review immunosuppressive mechanisms induced by growing tumors as well as immunomodulatory effects of LLR evidently or likely associated with cancer-inhibiting outcomes of such exposures. We also offer suggestions how LLR may restore and/or stimulate effective anti-tumor immunity during the more advanced stages of carcinogenesis. We postulate that, based on epidemiological and experimental data amassed over the last few decades, whole- or half-body irradiations with LLR should be systematically examined for its potential to be a viable immunotherapeutic treatment option for patients with systemic cancer.
Collapse
Affiliation(s)
- Marek K Janiak
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland.
| | - Marta Wincenciak
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland
| | - Aneta Cheda
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland
| | - Ewa M Nowosielska
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland
| | - Edward J Calabrese
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA, 01003, USA
| |
Collapse
|
|
30
|
Brooks AL. The legacy of William Morgan: The PNNL years. Mutat Res 2017; 806:81-87. [PMID: 28347483 DOI: 10.1016/j.mrfmmm.2017.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 03/06/2017] [Indexed: 10/19/2022]
Affiliation(s)
- Antone L Brooks
- Washington State University, 6802 West 13th Kennewick, WA 99338, United States.
| |
Collapse
|
|
31
|
Morel KL, Ormsby RJ, Bezak E, Sweeney CJ, Sykes PJ. Parthenolide Selectively Sensitizes Prostate Tumor Tissue to Radiotherapy while Protecting Healthy Tissues In Vivo. Radiat Res 2017; 187:501-512. [PMID: 28398879 DOI: 10.1667/rr14710.1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Radiotherapy is widely used in cancer treatment, however the benefits can be limited by radiation-induced damage to neighboring normal tissues. Parthenolide (PTL) exhibits anti-inflammatory and anti-tumor properties and selectively induces radiosensitivity in prostate cancer cell lines, while protecting primary prostate epithelial cell lines from radiation-induced damage. Low doses of radiation have also been shown to protect from subsequent high-dose-radiation-induced apoptosis as well as DNA damage. These properties of PTL and low-dose radiation could be used to improve radiotherapy by killing more tumor cells and less normal cells. Sixteen-week-old male Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) and C57BL/6J mice were treated with PTL (40 mg/kg), dimethylaminoparthenolide (DMAPT, a PTL analogue with increased bioavailability) (100 mg/kg), or vehicle control three times over one week prior to combinations of low (10 mGy) and high (6 Gy) doses of whole-body X-irradiation. Tissues were analyzed for apoptosis at a range of time points up to 72 h postirradiation. Both PTL and DMAPT protected normal tissues, but not prostate tumor tissues, from a significant proportion of high-dose-radiation-induced apoptosis. DMAPT provided superior protection compared to PTL in normal dorsolateral prostate (71.7% reduction, P = 0.026), spleen (48.2% reduction, P = 0.0001) and colorectal tissue (38.0% reduction, P = 0.0002), and doubled radiation-induced apoptosis in TRAMP prostate tumor tissue (101.3% increase, P = 0.039). Both drugs induced the greatest radiosensitivity in TRAMP prostate tissue in areas with higher grade prostatic intraepithelial neoplasia (PIN) lesions. A 10 mGy dose delivered 3 h prior to a 6 Gy dose induced a radioadaptive apoptosis response in normal C57Bl/6J prostate (28.4% reduction, P = 0.045) and normal TRAMP spleen (13.6% reduction, P = 0.047), however the low-dose-adaptive radioprotection did not significantly add to the PTL/DMAPT-induced protection in normal tissues, nor did it affect tumor kill. These results support the use of the more bioavailable DMAPT and low-dose radiation, alone or in combination as useful radioprotectors of normal tissues to alleviate radiotherapy-induced side-effects in patients. The enhanced radiosensitisation in prostate tissues displaying high-grade PIN suggests that DMAPT also holds promise for targeted therapy of advanced prostate cancer, which may go on to become metastatic. The redox mechanisms involved in the differential radioprotection observed here suggest that increased radiotherapy efficacy by DMAPT is more broadly applicable to a range of cancer types.
Collapse
Affiliation(s)
- Katherine L Morel
- a Molecular Medicine and Pathology, Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Bedford Park, Adelaide, South Australia
| | - Rebecca J Ormsby
- a Molecular Medicine and Pathology, Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Bedford Park, Adelaide, South Australia
| | - Eva Bezak
- b Medical Radiation, School of Health Sciences, University of South Australia, Adelaide, South Australia
| | | | - Pamela J Sykes
- a Molecular Medicine and Pathology, Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Bedford Park, Adelaide, South Australia
| |
Collapse
|
|
32
|
Tang FR, Loke WK, Khoo BC. Low-dose or low-dose-rate ionizing radiation-induced bioeffects in animal models. JOURNAL OF RADIATION RESEARCH 2017; 58:165-182. [PMID: 28077626 PMCID: PMC5439383 DOI: 10.1093/jrr/rrw120] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/22/2016] [Indexed: 05/13/2023]
Abstract
Animal experimental studies indicate that acute or chronic low-dose ionizing radiation (LDIR) (≤100 mSv) or low-dose-rate ionizing radiation (LDRIR) (<6 mSv/h) exposures may be harmful. It induces genetic and epigenetic changes and is associated with a range of physiological disturbances that includes altered immune system, abnormal brain development with resultant cognitive impairment, cataractogenesis, abnormal embryonic development, circulatory diseases, weight gain, premature menopause in female animals, tumorigenesis and shortened lifespan. Paternal or prenatal LDIR/LDRIR exposure is associated with reduced fertility and number of live fetuses, and transgenerational genomic aberrations. On the other hand, in some experimental studies, LDIR/LDRIR exposure has also been reported to bring about beneficial effects such as reduction in tumorigenesis, prolonged lifespan and enhanced fertility. The differences in reported effects of LDIR/LDRIR exposure are dependent on animal genetic background (susceptibility), age (prenatal or postnatal days), sex, nature of radiation exposure (i.e. acute, fractionated or chronic radiation exposure), type of radiation, combination of radiation with other toxic agents (such as smoking, pesticides or other chemical toxins) or animal experimental designs. In this review paper, we aimed to update radiation researchers and radiologists on the current progress achieved in understanding the LDIR/LDRIR-induced bionegative and biopositive effects reported in the various animal models. The roles played by a variety of molecules that are implicated in LDIR/LDRIR-induced health effects will be elaborated. The review will help in future investigations of LDIR/LDRIR-induced health effects by providing clues for designing improved animal research models in order to clarify the current controversial/contradictory findings from existing studies.
Collapse
Affiliation(s)
- Feng Ru Tang
- Singapore Nuclear Research and Safety Initiative (SNRSI), National University of Singapore, 1 CREATE Way #04-01, CREATE Tower, 138602, Singapore
| | - Weng Keong Loke
- Temasek Laboratories, National University of Singapore, 5A, Engineering Drive 1, 117411,Singapore
| | - Boo Cheong Khoo
- DSO National Laboratories,Defence Medical and Environmental Research Institute, 11 Stockport Road,117605,Singapore
| |
Collapse
|
|
33
|
Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin 2017; 67:65-85. [PMID: 27570942 DOI: 10.3322/caac.21358] [Citation(s) in RCA: 352] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Approximately one-half of patients with newly diagnosed cancer and many patients with persistent or recurrent tumors receive radiotherapy (RT), with the explicit goal of eliminating tumors through direct killing. The current RT dose and schedule regimens have been empirically developed. Although early clinical studies revealed that RT could provoke important responses not only at the site of treatment but also on remote, nonirradiated tumor deposits-the so-called "abscopal effect"- the underlying mechanisms were poorly understood and were not therapeutically exploited. Recent work has elucidated the immune mechanisms underlying these effects and has paved the way for developing combinations of RT with immune therapy. In the wake of recent therapeutic breakthroughs in the field of immunotherapy, rational combinations of immunotherapy with RT could profoundly change the standard of care for many tumor types in the next decade. Thus, a deep understanding of the immunologic effects of RT is urgently needed to design the next generation of therapeutic combinations. Here, the authors review the immune mechanisms of tumor radiation and summarize the preclinical and clinical evidence on immunotherapy-RT combinations. Furthermore, a framework is provided for the practicing clinician and the clinician investigator to guide the development of novel combinations to more rapidly advance this important field. CA Cancer J Clin 2017;67:65-85. © 2016 American Cancer Society.
Collapse
Affiliation(s)
- Fernanda G Herrera
- Radiation Oncologist, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
- Instructor, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
| | - Jean Bourhis
- Professor, Chief of Radiation Oncology Service, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
| | - George Coukos
- Professor, Director, Department of Oncology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
- Director, Ludwig Institute for Cancer Research, University of Lausanne Branch, Lausanne, Switzerland
| |
Collapse
|
|
34
|
Yang G, Li W, Jiang H, Liang X, Zhao Y, Yu D, Zhou L, Wang G, Tian H, Han F, Cai L, Cui J. Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics. Int J Cancer 2016; 139:2157-2168. [PMID: 27299986 DOI: 10.1002/ijc.30235] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 05/01/2016] [Accepted: 06/06/2016] [Indexed: 12/26/2022]
Abstract
It has been generally accepted that both natural and man-made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low-dose radiation (LDR) are different from those of high-dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti-cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application.
Collapse
Affiliation(s)
- Guozi Yang
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
- Department of Radiation-Oncology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Wei Li
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Hongyu Jiang
- Health Examination Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Xinyue Liang
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yuguang Zhao
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Dehai Yu
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Lei Zhou
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Guanjun Wang
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Huimin Tian
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Fujun Han
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Lu Cai
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China.
- Kosair Children's Hospital Research Institute, Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology of the University of Louisville, Louisville, KY, 40202.
| | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China.
| |
Collapse
|
|
35
|
Sykes PJ. The ups and downs of low dose ionising radiobiology research. AUSTRALASIAN PHYSICAL & ENGINEERING SCIENCES IN MEDICINE 2016; 39:807-811. [PMID: 27658668 DOI: 10.1007/s13246-016-0486-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Pamela J Sykes
- Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, SA, Australia.
| |
Collapse
|
|
36
|
Bannister LA, Mantha RR, Devantier Y, Petoukhov ES, Brideau CLA, Serran ML, Klokov DY. Dose and Radioadaptive Response Analysis of Micronucleus Induction in Mouse Bone Marrow. Int J Mol Sci 2016; 17:ijms17091548. [PMID: 27649149 PMCID: PMC5037821 DOI: 10.3390/ijms17091548] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 09/01/2016] [Accepted: 09/05/2016] [Indexed: 12/12/2022] Open
Abstract
Enhanced cellular DNA repair efficiency and suppression of genomic instability have been proposed as mechanisms underlying radio-adaptive responses following low-dose radiation exposures. We previously showed that low-dose γ irradiation does not generate radio-adaptation by lowering radiation-induced cytogenetic damage in mouse spleen. Since radiation may exert tissue-specific effects, we extended these results here by examining the effects of γ radiation on cytogenetic damage and proliferative index in bone marrow erythrocytes of C57BL/6 and BALB/c mice. In C57BL/6 mice, the induction of micronuclei in polychromatic erythrocytes (MN-PCE) was observed at radiation doses of 100 mGy and greater, and suppression of erythroblast maturation occurred at doses of >500 mGy. A linear dose-response relationship for MN-PCE frequencies in C57BL/6 mice was established for radiation doses between 100 mGy and 1 Gy, with departure from linearity at doses of >1 Gy. BALB/c mice exhibited increased MN-PCE frequencies above baseline following a 20 mGy radiation exposure but did not exhibit radio-sensitivity relative to C57BL/6 mice following 2 Gy exposure. Radio-adaptation of bone marrow erythrocytes was not observed in either strain of mice exposed to low-dose priming γ irradiation (single doses of 20 mGy or 100 mGy or multiple 20 mGy doses) administered at various times prior to acute 2 Gy irradiation, confirming the lack of radio-adaptive response for induction of cytogenetic damage or suppression or erythrocyte proliferation/maturation in bone marrow of these mouse strains.
Collapse
Affiliation(s)
- Laura A Bannister
- Canadian Nuclear Laboratories, Radiobiology and Health, Chalk River, ON K0J1J0, Canada.
| | - Rebecca R Mantha
- Canadian Nuclear Laboratories, Radiobiology and Health, Chalk River, ON K0J1J0, Canada.
| | - Yvonne Devantier
- Canadian Nuclear Laboratories, Radiobiology and Health, Chalk River, ON K0J1J0, Canada.
| | - Eugenia S Petoukhov
- Canadian Nuclear Laboratories, Radiobiology and Health, Chalk River, ON K0J1J0, Canada.
| | - Chantal L A Brideau
- Canadian Nuclear Laboratories, Radiobiology and Health, Chalk River, ON K0J1J0, Canada.
| | - Mandy L Serran
- Canadian Nuclear Laboratories, Radiobiology and Health, Chalk River, ON K0J1J0, Canada.
| | - Dmitry Y Klokov
- Canadian Nuclear Laboratories, Radiobiology and Health, Chalk River, ON K0J1J0, Canada.
| |
Collapse
|
|
37
|
Stuart M, Festarini A, Schleicher K, Tan E, Kim SB, Wen K, Gawlik J, Ulsh B. Biological effects of tritium on fish cells in the concentration range of international drinking water standards. Int J Radiat Biol 2016; 92:563-71. [DOI: 10.1080/09553002.2016.1222090] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
| | - Amy Festarini
- Canadian Nuclear Laboratories (CNL), Chalk River, Canada
| | | | | | - Sang Bog Kim
- Canadian Nuclear Laboratories (CNL), Chalk River, Canada
| | - Kendall Wen
- Deep River Science Academy, Chalk River, Canada
| | | | - Brant Ulsh
- M. H. Chew & Associates, Inc., Cincinnati, OH, USA
| |
Collapse
|
|
38
|
Abdel-Rafei MK, Amin MM, Hasan HF. Novel effect of Daflon and low-dose γ-radiation in modulation of thioacetamide-induced hepatic encephalopathy in male albino rats. Hum Exp Toxicol 2016; 36:62-81. [PMID: 26987350 DOI: 10.1177/0960327116637657] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
This study was designed to evaluate the hepato and neuroprotective activity of Daflon and low-dose γ radiation on thioacetamide (TAA)-induced liver damage and hepatic encephalopathy (HE) in rats. Effect of daily Daflon treatment (100 mg/kg body weight, Per OS (p.o.) for consecutive 3 days) and/or fractionated low-dose γ-radiation (LDR; 0.25 Gy, twice the total dose of 0.5 Gy at the 1st and 3rd day, respectively) was evaluated against TAA (300 mg/kg, intraperitoneal × 3) induced liver damage and HE in rats. Serum aspartate transaminase, alanine transaminase, γ-glutamyltransferase, total bilirubin, ammonia, and manganese were estimated to evaluate liver function. In addition, malondialdehyde (MDA) as well as reduced glutathione (GSH), glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) were determined to assess antioxidant capacity in liver tissue. Moreover, hepatic apoptotic markers (cysteine-dependent aspartate-directed proteases 3, 8 (caspase-3, 8) and cytochrome C) were estimated to indicate hepatic apoptosis. HE was evaluated through the determination of whole brain ammonia, manganese, MDA, GSH, GPX, SOD, CAT, and caspase-3. The cognitive and locomotor deficits were assessed via step through passive avoidance test, activity cage (actophotometer), γ-aminobutyric acid, and N-methyl-d-aspartate/adenosine triphosphate-neuronal nitric oxide synthase/nitric oxide-cyclic guanosine monophosphate axis in rats' cerebella and hippocampi. The involvement of hypoxia inducible factor-1α, aquaporine-4, and matrix metalloproteinase 9 in association with the brain water content (%) in the whole brain as an index for brain edema was also evaluated. The obtained results showed a marked amelioration of the aforementioned biochemical parameters and behavioral tasks which is supported by histopathological and immunohistochemical examination. It could be concluded that Daflon and LDR afforded hepatoprotection and neuroprotection against TAA-induced acute liver damage and HE.
Collapse
Affiliation(s)
- MKh Abdel-Rafei
- 1 Department of Radiation Biology, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, Nasr city, Cairo, Egypt
| | - M M Amin
- 2 Department of Pharmacology, Medical Division, National Research Centre, Dokki, Giza, Egypt
| | - H F Hasan
- 1 Department of Radiation Biology, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, Nasr city, Cairo, Egypt
| |
Collapse
|
|
39
|
Sutou S. [Tremendous Human, Social, and Economic Losses Caused by Obstinate Application of the Failed Linear No-threshold Model]. YAKUGAKU ZASSHI 2016; 135:1197-211. [PMID: 26521869 DOI: 10.1248/yakushi.15-00188] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The linear no-threshold model (LNT) was recommended in 1956, with abandonment of the traditional threshold dose-response for genetic risk assessment. Adoption of LNT by the International Commission on Radiological Protection (ICRP) became the standard for radiation regulation worldwide. The ICRP recommends a dose limit of 1 mSv/year for the public, which is too low and which terrorizes innocent people. Indeed, LNT arose mainly from the lifespan survivor study (LSS) of atomic bomb survivors. The LSS, which asserts linear dose-response and no threshold, is challenged mainly on three points. 1) Radiation doses were underestimated by half because of disregard for major residual radiation, resulting in cancer risk overestimation. 2) The dose and dose-rate effectiveness factor (DDREF) of 2 is used, but the actual DDREF is estimated as 16, resulting in cancer risk overestimation by several times. 3) Adaptive response (hormesis) is observed in leukemia and solid cancer cases, consistently contradicting the linearity of LNT. Drastic reduction of cancer risk moves the dose-response curve close to the control line, allowing the setting of a threshold. Living organisms have been evolving for 3.8 billion years under radiation exposure, naturally acquiring various defense mechanisms such as DNA repair mechanisms, apoptosis, and immune response. The failure of LNT lies in the neglect of carcinogenesis and these biological mechanisms. Obstinate application of LNT continues to cause tremendous human, social, and economic losses. The 60-year-old LNT must be rejected to establish a new scientific knowledge-based system.
Collapse
Affiliation(s)
- Shizuyo Sutou
- Laboratory of Functional Genomics, School of Pharmacy, Shujitsu University
| |
Collapse
|
|
40
|
Premkumar K, Shankar BS. Involvement of MAPK signalling in radioadaptive response in BALB/c mice exposed to low dose ionizing radiation. Int J Radiat Biol 2016; 92:249-62. [DOI: 10.3109/09553002.2016.1146829] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
|
|
41
|
Hellweg CE. The Nuclear Factor κB pathway: A link to the immune system in the radiation response. Cancer Lett 2015; 368:275-89. [DOI: 10.1016/j.canlet.2015.02.019] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 02/08/2015] [Accepted: 02/10/2015] [Indexed: 01/01/2023]
|
|
42
|
Bannister LA, Serran ML, Mantha RR. Low-Dose Gamma Radiation Does Not Induce an Adaptive Response for Micronucleus Induction in Mouse Splenocytes. Radiat Res 2015; 184:533-44. [DOI: 10.1667/rr14102.1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
|
|
43
|
Manesh SS, Sangsuwan T, Wojcik A, Haghdoost S. Studies of adaptive response and mutation induction in MCF-10A cells following exposure to chronic or acute ionizing radiation. Mutat Res 2015; 780:55-59. [PMID: 26295444 DOI: 10.1016/j.mrfmmm.2015.07.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 06/24/2015] [Accepted: 07/23/2015] [Indexed: 06/04/2023]
Abstract
A phenomenon in which exposure to a low adapting dose of radiation makes cells more resistant to the effects of a subsequent high dose exposure is termed radio-adaptive response. Adaptive response could hypothetically reduce the risk of late adverse effects of chronic or acute radiation exposures in humans. Understanding the underlying mechanisms of such responses is of relevance for radiation protection as well as for the clinical applications of radiation in medicine. However, due to the variability of responses depending on the model system and radiation condition, there is a need to further study under what conditions adaptive response can be induced. In this study, we analyzed if there is a dose rate dependence for the adapting dose, assuming that the adapting dose induces DNA response/repair pathways that are dose rate dependent. MCF-10A cells were exposed to a 50mGy adapting dose administered acutely (0.40Gy/min) or chronically (1.4mGy/h or 4.1mGy/h) and then irradiated by high acute challenging doses. The endpoints of study include clonogenic cell survival and mutation frequency at X-linked hprt locus. In another series of experiment, cells were exposed to 100mGy and 1Gy at different dose rates (acutely and chronically) and then the mutation frequencies were studied. Adaptive response was absent at the level of clonogenic survival. The mutation frequencies were significantly decreased in the cells pre-exposed to 50mGy at 1.4mGy/h followed by 1Gy acute exposure as challenging dose. Importantly, at single dose exposures (1 Gy or 100mGy), no differences at the level of mutation were found comparing different dose rates.
Collapse
Affiliation(s)
- Sara Shakeri Manesh
- Centre for Radiation Protection Research, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
| | - Traimate Sangsuwan
- Centre for Radiation Protection Research, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
| | - Andrzej Wojcik
- Centre for Radiation Protection Research, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
| | - Siamak Haghdoost
- Centre for Radiation Protection Research, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden.
| |
Collapse
|
|
44
|
Partial kilovoltage cone beam computed tomography, complete kilovoltage cone beam computed tomography, and electronic portal images for breast radiation therapy: A dose-comparison study. Pract Radiat Oncol 2015; 5:e521-e529. [DOI: 10.1016/j.prro.2015.02.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Revised: 01/28/2015] [Accepted: 02/15/2015] [Indexed: 12/30/2022]
|
|
45
|
Yang G, Kong Q, Wang G, Jin H, Zhou L, Yu D, Niu C, Han W, Li W, Cui J. Low-dose ionizing radiation induces direct activation of natural killer cells and provides a novel approach for adoptive cellular immunotherapy. Cancer Biother Radiopharm 2015; 29:428-34. [PMID: 25402754 DOI: 10.1089/cbr.2014.1702] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Recent evidence indicates that limited availability and cytotoxicity have restricted the development of natural killer (NK) cells in adoptive cellular immunotherapy (ACI). While it has been reported that low-dose ionizing radiation (LDIR) could enhance the immune response in animal studies, the influence of LDIR at the cellular level has been less well defined. In this study, the authors aim to investigate the direct effects of LDIR on NK cells and the potential mechanism, and explore the application of activation and expansion of NK cells by LDIR in ACI. The authors found that expansion and cytotoxicity of NK cells were markedly augmented by LDIR. The levels of IFN-γ and TNF-α in the supernatants of cultured NK cells were significantly increased after LDIR. Additionally, the effect of the P38 inhibitor (SB203580) significantly decreased the expanded NK cell cytotoxicity, cytokine levels, and expression levels of FasL and perforin. These findings indicate that LDIR induces a direct expansion and activation of NK cells through possibly the P38-MAPK pathway, which provides a potential mechanism for stimulation of NK cells by LDIR and a novel but simplified approach for ACI.
Collapse
Affiliation(s)
- Guozi Yang
- Cancer Center, the First Hospital of Jilin University , Changchun, China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Kim CS, Seong KM, Lee BS, Lee IK, Yang KH, Kim JY, Nam SY. Chronic low-dose γ-irradiation of Drosophila melanogaster larvae induces gene expression changes and enhances locomotive behavior. JOURNAL OF RADIATION RESEARCH 2015; 56:475-484. [PMID: 25792464 PMCID: PMC4426922 DOI: 10.1093/jrr/rru128] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 12/15/2014] [Accepted: 12/27/2014] [Indexed: 06/04/2023]
Abstract
Although radiation effects have been extensively studied, the biological effects of low-dose radiation (LDR) are controversial. This study investigates LDR-induced alterations in locomotive behavior and gene expression profiles of Drosophila melanogaster. We measured locomotive behavior using larval pupation height and the rapid iterative negative geotaxis (RING) assay after exposure to 0.1 Gy γ-radiation (dose rate of 16.7 mGy/h). We also observed chronic LDR effects on development (pupation and eclosion rates) and longevity (life span). To identify chronic LDR effects on gene expression, we performed whole-genome expression analysis using gene-expression microarrays, and confirmed the results using quantitative real-time PCR. The pupation height of the LDR-treated group at the first larval instar was significantly higher (∼2-fold increase in PHI value, P < 0.05). The locomotive behavior of LDR-treated male flies (∼3 - 5 weeks of age) was significantly increased by 7.7%, 29% and 138%, respectively (P < 0.01), but pupation and eclosion rates and life spans were not significantly altered. Genome-wide expression analysis identified 344 genes that were differentially expressed in irradiated larvae compared with in control larvae. We identified several genes belonging to larval behavior functional groups such as locomotion (1.1%), oxidation reduction (8.0%), and genes involved in conventional functional groups modulated by irradiation such as defense response (4.9%), and sensory and perception (2.5%). Four candidate genes were confirmed as differentially expressed genes in irradiated larvae using qRT-PCR (>2-fold change). These data suggest that LDR stimulates locomotion-related genes, and these genes can be used as potential markers for LDR.
Collapse
Affiliation(s)
- Cha Soon Kim
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro and Nuclear Power Co. Ltd, Seoul 132-703, Korea
| | - Ki Moon Seong
- National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul 139-736, Korea
| | - Byung Sub Lee
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro and Nuclear Power Co. Ltd, Seoul 132-703, Korea
| | - In Kyung Lee
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro and Nuclear Power Co. Ltd, Seoul 132-703, Korea
| | - Kwang Hee Yang
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro and Nuclear Power Co. Ltd, Seoul 132-703, Korea
| | - Ji-Young Kim
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro and Nuclear Power Co. Ltd, Seoul 132-703, Korea
| | - Seon Young Nam
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro and Nuclear Power Co. Ltd, Seoul 132-703, Korea
| |
Collapse
|
|
47
|
Nenoi M, Wang B, Vares G. In vivo radioadaptive response: a review of studies relevant to radiation-induced cancer risk. Hum Exp Toxicol 2015; 34:272-83. [PMID: 24925363 PMCID: PMC4442823 DOI: 10.1177/0960327114537537] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Radioadaptive response (RAR) describes phenomena where small conditioning doses of ionizing radiation (IR) reduce detrimental effects of subsequent higher IR doses. Current radiation protection regulations do not include RAR because of the large variability in expression among individuals and uncertainties of the mechanism. However, RAR should be regarded as an indispensable factor for estimation and control of individual IR sensitivity. In this article, RAR studies relevant to individual cancer risk are reviewed. Using various stains of mice, carcinogenic RAR has been demonstrated. Consistently much in vivo evidence for RAR with end points of DNA and chromosome damage is reported. Most in vivo RAR studies revealed efficient induction of RAR by chronic or repeated low-dose priming irradiation. Chronic IR-induced RAR was observed also in human individuals after environmental, occupational, and nuclear accident radiation exposure. These observations may be associated with an intrinsically distinct feature of in vivo experimental systems that mainly consist of nonproliferating mature cells. Alternatively, induction of RAR by gap junction-mediated bystander effects suggests that multicellular systems comprising densely communicating cells may be capable of responding to long-lasting low-dose-rate priming irradiation. Regulation by endocrine factors is also a plausible mechanism for RAR at an individual level. Emerging evidence suggests that glucocorticoids, known as stress hormones, participate in in vivo RAR induction following long-term low-dose-rate exposure to IR.
Collapse
Affiliation(s)
- M Nenoi
- Research Center for Radiation Protection, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan
| | - B Wang
- Research Center for Radiation Protection, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan
| | - G Vares
- Research Center for Radiation Protection, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan
| |
Collapse
|
|
48
|
Calabrese EJ, O'Connor MK. Estimating Risk of Low Radiation Doses – A Critical Review of the BEIR VII Report and its Use of the Linear No-Threshold (LNT) Hypothesis. Radiat Res 2014; 182:463-74. [DOI: 10.1667/rr13829.1] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
|
|
49
|
Tanaka K, Satoh K, Kohda A. Dose and dose-rate response of lymphocyte chromosome aberrations in mice chronically irradiated within a low-dose-rate range after age adjustment. RADIATION PROTECTION DOSIMETRY 2014; 159:38-45. [PMID: 24870362 DOI: 10.1093/rpd/ncu173] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
The incidences of chromosome aberrations were analysed in splenic lymphocytes from mice that were continuously exposed to (137)Cs gamma rays within the low-dose-rate (LDR) range to evaluate the dose-response and dose-rate effects. Chromosome aberrations were detected by fluorescence in situ hybridisation method, and these were found to increase in frequency up to 8000 mGy at 20 mGy for 22 h d(-1) and to 700 mGy at 1 mGy for 22 h d(-1). Translocations increased in a linear quadratic manner with age in non-exposed mice. The dose-response relationship for the frequency of translocations at each dose rate (20 and 1 mGy for 22 h d(-1)) was obtained using age-adjusted multiple linear regression analysis. Values of the linear term, shown as the slope, decreased as the dose rate was reduced from 20 to 1 mGy for 22 h d(-1), indicating a positive dose-rate effect in the LDR range. These results will be useful for estimating the risk of LDR radiation exposure and radiation protection.
Collapse
Affiliation(s)
- K Tanaka
- Department of Radiobiology, Institute for Environmental Sciences, 2-121 Hachazawa, Takahoko, Rokkasho, Kamikita, Aomori 039-3213, Japan
| | - K Satoh
- Department of Environmetrics and Biometrics, Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Hiroshima 734-8551, Japan
| | - A Kohda
- Department of Radiobiology, Institute for Environmental Sciences, 2-121 Hachazawa, Takahoko, Rokkasho, Kamikita, Aomori 039-3213, Japan
| |
Collapse
|
|
50
|
Taylor K, Lemon JA, Phan N, Boreham DR. Low-dose radiation from 18F-FDG PET does not increase cancer frequency or shorten latency but reduces kidney disease in cancer-prone Trp53+/- mice. Mutagenesis 2014; 29:289-94. [PMID: 24870563 DOI: 10.1093/mutage/geu017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
There is considerable interest in the health effects associated with low-level radiation exposure from medical imaging procedures. Concerns in the medical community that increased radiation exposure from imaging procedures may increase cancer risk among patients are confounded by research showing that low-dose radiation exposure can extend lifespan by increasing the latency period of some types of cancer. The most commonly used radiopharmaceutical for positron emission tomography (PET) scans is 2-[(18)F] fluoro-2-deoxy-d-glucose ((18)F-FDG), which exposes tissue to a low-dose, mixed radiation quality: 634 keV β+ and 511 keV γ-rays. The goal of this research was to investigate how modification of cancer risk associated with exposure to low-dose ionising radiation in cancer-prone Trp53+/- mice is influenced by radiation quality from PET. At 7-8 weeks of age, Trp53+/- female mice were exposed to one of five treatments: 0 Gy, 10 mGy γ-rays, 10 mGy (18)F-FDG, 4 Gy γ-rays, 10 mGy (18)F-FDG + 4 Gy γ-rays (n > 185 per group). The large 4-Gy radiation dose significantly reduced the lifespan by shortening the latency period of cancer and significantly increasing the number of mice with malignancies, compared with unirradiated controls. The 10 mGy γ-rays and 10 mGy PET doses did not significantly modify the frequency or latency period of cancer relative to unirradiated mice. Similarly, the PET scan administered prior to a large 4-Gy dose did not significantly modify the latency or frequency of cancer relative to mice receiving a dose of only 4 Gy. The relative biological effectiveness of radiation quality from (18)F-FDG, with respect to malignancy, is approximately 1. However; when non-cancer endpoints were studied, it was found that the 10-mGy PET group had a significant reduction in kidney lesions (P < 0.021), indicating that a higher absorbed dose (20 ± 0.13 mGy), relative to the whole-body average, which occurs in specific tissues, may not be detrimental.
Collapse
Affiliation(s)
- Kristina Taylor
- Department of Medical Physics and Applied Radiation Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada and Department of Nuclear Medicine, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada
| | - Jennifer A Lemon
- Department of Medical Physics and Applied Radiation Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada and
| | - Nghi Phan
- Department of Medical Physics and Applied Radiation Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada and
| | - Douglas R Boreham
- Department of Medical Physics and Applied Radiation Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada and
| |
Collapse
|