Radiation research最新文献

Survivors of the hematopoietic acute radiation syndrome (H-ARS) face delayed effects of acute radiation exposure (DEARE), including chronic immune suppression and thymic involution, for which no effective countermeasures exist. We previously demonstrated that 16,16-dimethyl prostaglandin E2 (dmPGE2) enhances H-ARS survival when administered prior to irradiation. Here, we investigated its long-term radiation protective effects on immune reconstitution at 6 and 12 months after exposure in a lethal total-body irradiation (TBI) mouse model. C57BL/6J mice received dmPGE2 30 min prior to TBI (PGE-pre-irradiation), 24 h after TBI [prostaglandin E (PGE)-postirradiation], or vehicle (Veh), with non-irradiated mice included as controls. Surviving mice treated with Veh prior to TBI exhibited persistent thymic involution, decreased thymocyte subsets, and diminished splenic T and B cells, alongside elevated bone marrow (BM) and serum IL-6, KC, MCP-1, and G-CSF levels with reduced MIP-1β, reflecting systemic immune dysregulation. Treatment of mice with dmPGE2 pre-irradiation significantly prevented these effects with mice exhibiting enhanced thymocyte maturation, increased splenic lymphocytes, preservation of the thymic cortex/medulla ratio, attenuated BM/serum cytokine disturbance, and generation of functional lymphocytes in vitro. Administration of dmPGE2 at 24 h postirradiation had minimal effect. Competitive BM transplantation and in vitro co-culture studies in mice receiving dmPGE2 pre-irradiation revealed that dmPGE2 enhanced BM lymphoid progenitor cell differentiation and function. RNA sequencing of phenotypically defined hematopoietic stem cells (HSC) at 24 h after TBI from mice treated with dmPGE2 30 min prior to TBI showed upregulation of genes associated with lymphopoiesis, notably Flt3, involved in hematopoietic cell proliferation and survival, and Dntt, involved in the development of T and B cells. These findings demonstrate that dmPGE2 can prevent radiation-induced long-term immune suppression by protecting lymphoid progenitors, suggesting its potential as a radioprotectant for radiation accident victims and radiotherapy patients.

High-energy neutron radiation (HENR) induces severe cellular and tissue damage, yet effective prophylactic agents remain limited. In this study, the TLR2/NOD2 co-agonist CL429 was evaluated for its radioprotective potential against 14.1 MeV neutron exposure. A murine HENR model was established, and absorbed doses were calculated using the specific kinetic energy method. Pretreatment with CL429 significantly improved survival outcomes, with survival rates reaching 90% and prolonged survival times observed. CL429 administration markedly increased the organ indices of the spleen, thymus, and testis, reduced splenocyte apoptosis to near-normal levels, and restored leukocyte and platelet counts in the early postirradiation phase. Flow cytometry and Western blot analyses indicated that CL429 upregulated TLR2 and NOD2 expression, accompanied by activation of downstream signaling pathways. These findings suggest that CL429 confers significant protection against neutron radiation-induced injury, potentially through the dual activation of TLR2/NOD2-mediated protective mechanisms.

Inflammation is the initial immune response activated to protect an organism's integrity after cell or tissue damage caused by infectious agents or physical trauma, such as exposure to ionizing radiation. The mechanisms behind ionizing radiation-induced inflammation are not fully understood in untransformed human cells, especially at high dose exposures that can also cause cell death. Radiation-induced genotoxic stress triggers the cellular DNA damage response, and interactions between this pathway and inflammation may be crucial in determining the fate of irradiated cells. We studied how primary human vascular endothelial cells, telomerase-immortalized foreskin microvascular cells, blood mononuclear cells, and primary skin fibroblasts respond to radiation doses from 2 to 10 Gy for up to 24 h after exposure, prior to cell death. In endothelial cells, exposure to 10 Gy, but not lower doses, caused a temporary increase in the transcription of genes coding for inflammatory factors before the activation of DNA damage response genes. This early inflammatory reaction depends on ATM activity, which coordinates the DNA damage response, and is not observed in blood cells or fibroblasts. Additionally, we saw an increase in cytokine production and adhesion molecule expression in endothelial cells. This inflammatory response may contribute to changes in the immune microenvironment of irradiated cells.

Contralateral breast (CB) cancer is the most common subsequent cancer among breast cancer survivors, and radiotherapy has been linked to CB cancer risk. The purpose of this work was to evaluate doses to subregions of the contralateral breast from historical breast cancer treatments carried out in the United States between 1990 and 2012. We extracted treatment data from radiation therapy summaries for 2,442 radiotherapy patients during that period. We estimated CB doses for five breast regions: the upper inner quadrant (UIQ), lower inner quadrant, upper outer quadrant, lower outer quadrant (LOQ), and nipple, using extracted data and out-of-beam CB dose measurements. The mean treatment dose was approximately 5,000 cGy for tangential fields, which comprised 84% of the photon fields, and this remained constant throughout our study period. Most of the dose to the contralateral breast was from the tangential fields, and it varied by contralateral breast region. The UIQ of the contralateral breast received the highest median dose which decreased by 23% from 185 cGy in 1990-1994 to 143 cGy in 2005 and later (P < 0.0001). The LOQ dose received the lowest dose, which also decreased by 24% from 74 to 56 cGy (P < 0.0001). This decrease was due to the reduction in the utilization of physical wedges and an increase in the field-in-field technique, particularly after 2005. We observed a significant reduction in CB doses from breast radiotherapy in the United States between 1990 and 2010, which can be attributed to the impact of advanced radiotherapy techniques.

An evaluation is presented of differences in radiation-related solid cancer mortality risk for early versus contemporary sub-groups of radiation workers in both of the two constituent Million Person Study (MPS) cohorts. The two previously analyzed MPS cohorts are 123,401 industrial radiographers monitored from 1939-2011 and followed through 2019 and 135,193 nuclear power plant workers monitored from 1957-1984 and followed through 2011. The rationale behind this extended new analysis is to investigate if these two MPS cohorts support recently published increased risks for contemporary workers in a different cohort, The International Nuclear Workers Study (INWORKS) with pooled U.S., French and UK nuclear worker data, particularly for the U.S. component. The US-INWORKS contributed about one-third of the workers to the full-INWORKS study based on 309,932 workers. For all solid cancer mortality, the US-INWORKS study reported a low and non-significant excess relative risk (ERR) per Sv cumulative equivalent dose for the whole cohort of 0.19 (95% CI: -0.10; 0.52), whereas for contemporary workers the ERR per Sv was 2.23 (95% CI: 1.13, 3.49), approximately 10 times higher than the entire US-INWORKS cohort. The risk for the full INWORKS cohort was 0.52 (90% CI: 0.27; 0.77) per Gy colon dose whereas, for contemporary workers, the risk was 1.44 (90% CI: 0.65, 2.32), nearly 3 times higher. These risks for contemporary workers are both larger than risks informing radiation protection and much higher (7.0 and 4.5 times) than the Japanese A-bomb survivor's risk for males exposed acutely between the ages of 20 and 60 years of 0.32 (95% CI: 0.01; 0.50). Limitations include missing information on organ doses from radionuclide intake, neutrons and the absence of adjustment for non-radiation risk factors (notably asbestos exposure). The analysis of the MPS cohorts addresses these dosimetric- and asbestos-related limitations. For all solid cancer mortality, industrial radiographers showed equal Poisson ERRs per 100 mGy colon dose for early and contemporary workers: 0.06 (95% CI: 0.00; 0.12) and 0.07 (95% CI: 0.01; 0.13), respectively. The results for nuclear power plant workers were 0.10 (95% CI: -0.09; 0.29) and 0.02 (95% CI: -0.02; 0.06), respectively. It appears premature to conclude that there is generally a difference in excess risk between early and contemporary workers from radiation exposures.

Conventional radiotherapy based on X rays is used to treat more than 50% of cancers. Although effective, radiotherapy can damage healthy tissues around the tumor due to the X-ray dose deposition profile, as well as the safety margin needed to compensate for dose uncertainties. A notable side effect is cellular senescence, characterized by the cessation of cell division while maintaining metabolic activity and promoting the secretion of various components, called the senescence-associated secretory phenotype. To minimize toxicity in healthy tissues, proton therapy holds great promise as it enables tumors to be targeted more precisely while sparing healthy tissues beyond the tumor site. Another innovative method is ultra-high dose rate irradiation, which seems to induce less damage to healthy tissues while generating an anti-tumor response similar to standard dose rate irradiation. In this work, we aimed to compare the effects of X rays and protons at conventional dose rate (2 Gy/min) and ultra-high dose rate (454 Gy/s), on the induction of senescence in primary normal human dermal fibroblasts by analyzing several senescence biomarkers. Irradiation with ultra-high dose rate protons caused more pronounced cellular and nuclear morphological changes in normal human dermal fibroblasts than irradiation with conventional protons or X-rays. For other biomarkers, all three types of irradiations induced an increase in the proportion of senescence-associated beta-gal-positive cells, an irreversible cell cycle arrest and an accumulation of unrepaired DNA damage, but did not affect senescence-associated secretory phenotype.

High radon levels in the environment can lead to adverse biological effects such as DNA damage, thereby increasing cancer risk, especially lung cancer. This study focused on Tande-Tande sub-village in Mamuju, West Sulawesi, Indonesia, an area known for naturally high indoor radon concentrations, where inhabitants have been chronically exposed to radon throughout their lives. Blood samples from 38 subjects in Tande-Tande sub-village and the control area, Topoyo village, were examined. We then evaluated the DNA damage by assessing γ-H2AX for double-strand breaks and 8-hydroxydeoxyguanosine (8-OHdG) for oxidative damage. Additionally, we measured key molecules of the thioredoxin (Trx) system, Trx and thioredoxin reductase (TrxR), to gauge antioxidant levels and thus, oxidative stress response status. The C-reactive protein (CRP) to albumin ratio was analyzed to assess inflammatory status. Comparison of 8-OHdG, Trx, TrxR concentrations, and CRP/Albumin between the exposed and control groups were assessed by unpaired Student's t-test or Mann-Whitney test, depending on the normality of the data distribution. Correlations between concentration of 8-OHdG, Trx, TrxR or CRP/Albumin and indoor radon concentrations were investigated using either the Pearson or Spearman correlation tests, based on the distribution characteristics of the data. Our analyses of DNA damage markers (γ-H2AX and 8-OHdG), Trx, TrxR, and CRP/albumin ratio showed no significant increase in DNA damage markers in Tande-Tande sub-village residents compared to controls. Levels of 8-OHdG, Trx, and TrxR were significantly lower in Tande-Tande sub-village inhabitants when compared to the control area (P < 0.0001, P = 0.002, and P = 0.003, respectively), whereas CRP/albumin ratio did not differ significantly between these groups (P = 0.844). The present study did not find significant evidence of increased DNA damage, antioxidant system activity, or inflammatory status in inhabitants exposed to high radon levels. There is a possibility that the excessive ROS production existed in the early life period and subsequently manifested as a radio-adaptive response (RAR) during the adulthood of this population. These findings also support our previous assumptions that the excessive ROS production disrupts redox signaling and leads to a reduction in antioxidant levels.

Space radiation represents a significant health risk for deep-space exploration, yet its long-term effects on cardiovascular function remain poorly understood. While our previous studies have highlighted persistent transcriptional changes in left ventricular (LV) and right ventricular (RV) tissues after a single whole-body irradiation in mice, a systems-level understanding of pathway activity deregulation is lacking. To address this gap, we applied the Pathway Signal Flow (PSF) algorithm to analyze long-term pathway activity alterations in LV and RV tissues of C57Bl/6J mice exposed to gamma radiation (100 cGy 137Cs) or the simplified Galactic Cosmic Ray simulation (simGCRsim, 50 cGy 500 MeV/n) composition of ion beams. RNA sequencing data were analyzed to assess pathway activity changes, sex-specific effects, and ventricular differences 440 days post-irradiation. We observed marked sex- and ventricle-specific differences in pathway deregulation. Left ventricular tissues in females exhibited broad signaling pathway alterations after simGCRsim exposure, particularly in immune response, cytoskeletal remodeling, and survival-related pathways (e.g., NF-κB, VEGF, and MAPK). In contrast, male RV tissues demonstrated higher pathway deregulation than LV, particularly in PPAR, NF-κB, and HIF-1 pathways, implicating metabolic disruption and survival adaptations. Furthermore, simGCRsim exposure induced greater long-term pathway perturbations than gamma rays. Our findings suggest that sex-dependent and ventricle-specific signaling alterations contribute to long-term cardiovascular risks following space irradiation. Notably, VEGF and NF-κB signaling emerge as key regulators of cardiac adaptation in females. Future studies in larger cohorts, incorporating early-stage molecular responses and broader pathway analyses, are needed to refine cardiovascular risk assessments for space travel.

The issue of determining likely outcomes after low dose exposure to radiation is complex and controversial. Currently, the linear no-threshold (LNT) model is used to justify the linear extrapolation of (adverse) outcomes from high doses, where effects are clearly seen, to low doses, where effects are very difficult to detect and even more difficult to ascribe to the measured radiation exposure. Among the factors hindering the development of a more precise system are the lack of reliable predictors of system health. While biomarkers indicating the health of individual cells or organisms exist, they fail at low doses due to the complexity of cause-effect relationships and the multiple factors contributing "stress" to the system as a whole (whether "whole" is a whole organism, a population or an ecosystem). Approaches to capture this complexity include adverse outcome pathway (AOP) analysis, which looks at multiple levels of organization from gene to ecosystem. In this commentary, we discuss the role of non-targeted effects (NTE) such as genomic instability and bystander effects. These mechanisms involve transmission of information between different levels of organization. In the case of BE, signals from exposed to unexposed cells or organisms coordinate response at higher levels of organization, permitting population responses to radiation to be identified and, potentially, mitigated. Genomic instability is more complex as it involves not only signaling but also trans-generational transmission of genetic or epigenetic changes and may lead to long-term adaptive evolution. GI may also be involved in memory or legacy effects, which contribute a further component to the dose effect measured in legacy sites. Our recent analysis of the contributions of memory and legacy effects to the total effect using data sets from Chernobyl and Fukushima (voles, birds and butterflies) suggests this type of analysis may help reduce uncertainties over laboratory-to-field extrapolations. A focus on novel but widespread NTE mechanistic pathways may open the way to successful prophylaxis and development of new biomarkers for better risk assessment after low dose exposures.

Radiation-induced brain injury (RBI) adversely affects the quality of life and prognosis of patients with brain tumors who undergo radiation therapy. Although rehabilitation strategies are recommended for mitigating RBI, the underlying mechanisms remain poorly understood. Here, we focused on RBI after fractionated whole-brain irradiation (WBI) in adult mice and examined the effects of voluntary exercise (VE) on cognitive function, growth factors, neurogenesis, and synaptic plasticity. Male C57BL/6J mice, aged 10-12 weeks, were divided into four groups: cham control (Ctl), WBI, Ctl + VE, and WBI + VE. The WBI total dose was 8 Gy (4 Gy × 2 fractions). Voluntary exercise was provided for three weeks using a voluntary running wheel that was accessible 24 h a day. The effects of RBI and VE were analyzed using behavioral, biochemical, immunohistological, and electrophysiological evaluations. WBI significantly impaired cognitive functions including spatial working memory, reference memory, and cognitive flexibility. Additionally, WBI led to reduced plasma mature brain-derived neurotrophic factor (mBDNF) levels, neurogenic differentiation 1 (NeuroD1)-positive cell density in the dentate gyrus, and long-term potentiation in the hippocampal cornu ammonis 1 region. Conversely, VE intervention ameliorated these cognitive deficits and increased mBDNF levels, enhanced NeuroD1-positive cell density, and strengthened long-term potentiation. Our findings suggest that VE intervention mitigates the effects of RBI in adult mice by promoting neurogenesis and enhancing synaptic plasticity via growth factor upregulation. These results underscore the importance of physical activity in rehabilitation and suggest that VE is a noninvasive strategy for improving cognitive function in patients affected by RBI.