Radiation research最新文献

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.

The thymus is critical for the development and selection of T cells with a diverse range of non-self-reactive antigen receptors. Both the thymus and circulating T cells can be damaged by acute exposure to ionizing radiation, leading to dose-dependent lymphopenia, a temporarily increased risk of infection that can be life-threatening, and long-term disruptions in T cell homeostasis and function. Currently, there are no biomedical countermeasures available to prevent radiation-induced T cell lymphopenia or other T cell defects caused by radiation. Therefore, preclinical models of radiation-induced thymic injury are necessary for testing countermeasures. Adult mice and non-human primates (NHP) that are subjected to whole-body or thorax irradiation are suitable models for this purpose. However, findings from these models may not directly apply to juveniles, given the significant changes in thymus size and function during childhood. To address this, we characterized the effects of 10 Gy whole-thorax irradiation on the thymus of pediatric rhesus macaque NHPs. Computed tomography (CT) assessments of thymic density and volume were used as in vivo indicators of thymic injury, but they did not correlate with the changes in thymic weight observed 19 weeks after irradiation. Histopathological staining revealed that whole-thorax irradiation caused disruption of thymic architecture, evident four months post-irradiation in some animals. Molecular analyses showed that radiation led to a decrease in thymic output, reduced diversity of T cell antigen receptors, and an over-representation of certain receptor sequences indicative of extensive clonal expansion. Overall, this work demonstrates the usefulness of the NHP whole-thorax irradiation model-commonly employed in lung radiobiology research-in studying radiation-induced thymic injury in children and in developing medical countermeasures.

Delayed effects of acute radiation exposure (DEARE) and radiation late effects are a suite of conditions that become apparent months to years after initial exposure to radiation in both humans and non-human primates. Many of these disorders, including cardiac complications, insulin resistance, bone loss, hypertension, and others, are also more common among aging cohorts independent of radiation exposure. This study characterized disease incidence, age of onset, and multimorbidity for 20 common, chronic diseases in 226 irradiated and 51 control rhesus macaques (Macaca mulatta) from the Wake Forest Non-Human Primate Radiation Late Effects Cohort (RLEC) to identify the excess risk of chronic disease caused by radiation-induced tissue damage. Irradiated animals were exposed to 4.0-8.5 Gy of ionizing radiation (mean 6.17 ± 1.29 Gy) one year on average prior to joining the cohort. In addition to the acute impact of early-life irradiation, these animals have been aging postirradiation for up to 15 years (mean 5.2 ± 3.0 years). Lifespan is an average of 5.1 years shorter in irradiated animals and radiation is associated with significantly increased rates of periodontitis, cataracts, testicular atrophy, tumors, diabetes, and brain lesions. While most of these chronic diseases occur in non-irradiated macaques, irradiated animals have significantly earlier age of onset for periodontitis, cataracts, bone loss, being overweight, and arthritis. This accelerated onset leads to 2.9 ± 1.9 comorbid conditions among irradiated animals compared to 1.9 ± 1.2 diagnoses among controls by young adulthood (age 8) and 5.2 ± 2.4 compared to 3.4 ± 1.8 conditions by middle age (15 years). Subsets of these comorbid conditions cluster among animals with fibrosis-related disorders (diabetes, lung injury, liver disease, kidney disease, heart disease, and tumors) commonly diagnosed together independent of prevalence. A second cluster of comorbidities centers around bone loss and is associated with being underweight and female reproductive problems. While there are significant differences in disease burden between irradiated and control animals, there was no dose effect of radiation on lifespan, age to first diagnosis, or comorbidities and substantial heterogeneity across each of these measures. This underlying heterogeneity in response to radiation suggests the existence of a yet unidentified determinant of resilience.

National security concerns regarding radiological incidents, accidental or intentional in nature, have increased substantially over the past few years. A primary area of intense planning is the assessment of exposed individuals and timely medical management. However, exposed individuals who receive survivable radiation doses may develop delayed effects of acute radiation exposure many months or years later. Therefore, it is necessary to identify such individuals and determine whether their symptoms may have been initiated by radiation and require complex medical interventions. We previously developed early response metabolomic biosignatures in biofluids from non-human primates exposed to a total body gamma radiation dose of 4 Gy (up to 60 days). A follow-up of these animals has been ongoing with samples consistently collected every few months for up to 2 years after exposure, providing a unique cohort to determine if a radiation signal persists longer than 2 months. Metabolic fingerprinting in urine and serum determined that exposed animals remain metabolically different from pre-exposure levels and from age-matched controls, and the pre-determined biosignature maintains high sensitivity and specificity. Significant perturbations in tricarboxylic acid intermediates, cofactors and nucleotide metabolism were noted, signifying energetic changes that could be attributed to or perpetuate altered mitochondrial dynamics. Importantly, these animals have begun developing diseases such as hypertension much earlier than their age-matched controls, further emphasizing that radiation exposure may lead to accelerated aging. This NHP cohort provides important information and highlights the potential of metabolomics in determining persistent changes and a radiation-specific signature that can be correlated to phenotype.

In the event of a nuclear accident or attack, thousands of people could receive high doses of total-body irradiation (TBI). Although retrospective analyses of atomic bomb and nuclear disaster survivors have been conducted, the long-term outcomes on the brain and cognitive function are conflicting. Radiation-induced brain injury (RIBI) is characterized by inflammation, vascular injury, deficits in neuronal function, and white matter (WM) injury, but the molecular mechanisms by which this occurs remain unknown. Animal models are crucial for evaluating radiation effects on the brain and have provided significant insight into the pathogenesis of RIBI. Rodents are the most commonly utilized animal models in radiation research, and much has been gleaned from these animals. Non-human primates (NHPs) are the closest genetically, anatomically, and physiologically to humans and therefore represent a valuable resource in translational neuroscience. NHPs have been utilized in radiation studies for several decades and continue to be important models of RIBI, yet few studies have evaluated the long-term impact of radiation on neurocognitive function. The Radiation Late Effects Cohort (RLEC) is a group of rhesus macaques dedicated to evaluating the long-term effects of TBI on multiple systems, including the nervous system. Studies have demonstrated that animals within the RLEC manifest shared patterns of injury between macaques and humans after fractionated whole-brain irradiation (WBI), including vascular injury, neuroinflammation, and WM injury. While pathological outcomes in late-delayed RIBI have been well characterized, studies evaluating the functional outcomes in NHPs are scarce, highlighting the need for future studies. Correlating relevant structural and functional outcomes are critical for identifying targets involved in the pathogenesis of injury. Much information has been gleaned from animal studies of RIBI, and NHPs, particularly those in the RLEC will continue to be valuable models in translational neuroscience.

Total-body irradiation has long-term effects and may cause joint damage, especially in individuals with diabetes. Lowered bone mineral density and arthropathy related to radiation can contribute to the development of osteoarthritis. Monitoring these conditions in humans is challenging, but non-human primate models allow for longitudinal tracking of metabolic and degenerative changes. This study investigated the effect of radiation on joint health in non-human primates, including bone mineral density, and examined how diabetes influences the development of osteoarthritis. We hypothesized that joint health would be worse in diabetic and irradiated primates. Our group evaluated 163 irradiated rhesus macaques and 38 unexposed controls (total n = 201). Diabetes was present in 24 animals. Osteoarthritis was assessed in the knees, hips, shoulders, and spine, with overall osteoarthritis defined as osteoarthritis in at least one joint. Two sub-cohorts of 134 irradiated and 32 nonirradiated animals, and nine diabetic and 77 non-diabetic animals, were selected to analyze proximal humeral length and bone mineralization. The prevalence of diabetes was similar between irradiated and control groups. No link was observed between radiation exposure and overall osteoarthritis, but osteoarthritis was significantly more common in nonirradiated animals across the knee, hip, shoulder, and spine. Diabetic animals showed higher rates of osteoarthritis in all joints and overall. Irradiated non-human primates had reduced cortical volume, lower cortical and trabecular bone mineral densities, and shorter humeral length. Diabetic primates exhibited higher cortical volume and bone mineral density, while trabecular bone mineral density and humeral length remained similar. Osteoarthritis in all joints was more prevalent among diabetic and obese non-human primates. Radiation exposure decreased cortical volume and mineralization, whereas diabetes increased both cortical volume and mineralization. Overall, diabetes appears to contribute to joint degeneration and increased bone mineralization, while radiation decreases bone mineralization without increasing osteoarthritis. These findings lay the groundwork for future studies to investigate the pathways that may contribute to these conditions.

In the event of a large-scale radiological emergency, delivering timely medical aid to individuals receiving potentially lethal doses of radiation will result in improved survival and decreased severity of injuries. While it may be possible to reconstruct a dose estimate based on a location during the event and/or early symptoms presenting after the event, limitations with readily available information and inaccuracy of that estimate may not provide enough certainty for successful medical triage. Thus, individual biodosimetry assessments would assist medical professionals in providing prompt care to those who would benefit the most. In this study, a variety of accessible biospecimens (blood, plasma, serum, feces, saliva, and urine) from eight rhesus macaques irradiated with a single total body sublethal dose of 4 Gy of 60Co γ rays were collected before and up to 60 days after exposure for distribution to 10 different investigators' work sites for site-specific analyses. Results showing statistically significant changes in hematology parameters as well as gene, protein, and metabolite expression have since been published. Here, these results are combined and integrated with new data from microRNA (miRNA) expression in plasma samples as well as 16S rRNA sequencing and metabolomics data from fecal samples. A total of 40 unique miRNAs were significantly expressed on days 3, 6, 30, or 60. Metabolomic analysis of fecal samples found changes in multiple pathways, including steroid hormones, C18 (sex) hormones, and bile acid synthesis. Temporal changes were found in the gut microbiome for microbial abundance and richness. Finally, a retrospective view of the collective results demonstrated common overlapping pathways that were enriched from significantly altered biomarkers. This large, collaborative study from a single irradiated cohort demonstrates the utility of multiple timepoints, biospecimen types, and omics technologies that collectively identified 61 common biomarkers across 4 omics platforms that were enriched for pathways relevant to an acute radiation injury to the hematopoietic system that may aid future radiation biodosimetry efforts.

Increased incidence of diabetes has been reported after whole-body irradiation in cancer survivors and in the years after exposure in research studies of nonhuman primates. Type 2 diabetes presents in the absence of obesity and suggests that skeletal muscle, the predominant organ responsible for minute-to-minute glucose disposal, is persistently dysfunctional. We evaluated skeletal muscle (SkM) from control (CTL, n = 8) and irradiated (IRRAD, n = 16) male rhesus macaques (Macaca mulatta) that had been exposed to an average whole-body dose of 6.5 Gy after an average of 4 years of follow-up. Irradiated animals had deficient SkM basal and insulin-stimulated receptor activation that was unrelated to histologically assessed fiber size, extracellular matrix and endothelial components. Protein extracted from irradiated muscle showed that Akt2, downstream of insulin receptor activation, was sulfenyl-modified and thus a target for radiation-related glycemic dysregulation. Shotgun proteomics identified upregulation of many mitochondrial and peroxisome-associated proteins, and increases were confirmed by immunoblotting of select protein targets. Proteomic pathway enrichment mapping showed distinct protein clustering between CTL and IRRAD groups. Mitochondrial proteins were surveyed and confirm that mitochondrial turnover may be increased after irradiation with higher fission and fusion markers. The results indicate that irradiated muscle is persistently insulin resistant, with evidence of intracellular protein oxidation and shifts in mitochondrial dynamics and function.

The Wake Forest Radiation Late Effects Cohort (RLEC), formerly known as the Radiation Survivors Cohort, of rhesus (Macaca mulatta) non-human primates (NHPs) is a unique colony of long-term survivors of total-body irradiation (TBI). The cohort includes 212 live animals, with 17% being unirradiated controls, and 104 deceased animals, including 15% controls. This cohort has been monitored for over 16 years, with an average observation period of 5 years. Irradiated NHPs were exposed to single TBI doses ranging from 1.14 to 8.5 Gy (average = 6.1 Gy). One animal received 10 Gy partial-body irradiation with approximately 5% bone marrow sparing. In this paper, we present the postmortem findings from 104 deceased members of the RLEC. Animals underwent a comprehensive, standardized necropsy, which included a complete gross and histopathologic examination of 36 organs and tissues. For this study, necropsy reports of 104 deceased animals (87 irradiated and 17 controls) were reviewed by two board-certified veterinary pathologists (GWS and JMC), and all diagnoses were cataloged. A total of 2,790 diagnoses were recorded across all organ systems and analyzed for statistical differences between irradiated and control animals using Fisher's exact test. Deceased control animals ranged in age from 9.9 to 21.4 years (mean = 16 years), whereas irradiated animals were younger, with ages from 2.7 to 23.1 years (mean = 11.6 years, P = 0.0001). The time from irradiation to death ranged from 0.3 to 14.4 years (average = 6.4 years). Radiation doses for these deceased animals ranged from 3.5 to 8.5 Gy (average = 6.6 Gy). The prevalence of most lesions was not statistically different from controls. Common findings among the irradiated animals included multi-organ fibrosis and chronic inflammation. Additionally, there was an increased occurrence of neoplasia in the irradiated animals. These data represent comprehensive, systemic, long-term pathology assessments conducted on a large group of NHPs years after total-body irradiation in the molecular era. They provide a solid foundation for molecular and translational studies of radiation late effects. The fact that many of the same lesions appeared in both the irradiated and unirradiated control animals, despite the significant age difference, suggests an accelerated-aging phenotype in the survivors.