Radiation research最新文献

Susceptibility to radiation-induced lung disease differs among people and among inbred strains of mice; C3H/HeJ mice develop early onset distress from pneumonitis and C57BL/6J mice present later onset pneumonitis with fibrosis. Previous studies revealed C3H/HeJ alleles at a 28 Mb locus on chromosome 2 to be linked to early onset distress and at an 18 Mb locus on chromosome 17 (called Radpf1 for radiation-induced pulmonary fibrosis-1) to decrease fibrosis in whole-thorax irradiated mice. To potentially reduce these genomic intervals, parental chr17-subcongenic mice with 0.71 Mb of C3H/HeJ alleles, and chr 2-congenic mice with region-spanning C3H/HeJ alleles from 95 to 123 Mb, and four lines of subcongenic mice received 16 Gy whole thorax irradiation and were assessed for onset of respiratory distress and histological lung disease at distress. One hundred percent of irradiated C3H/HeJ and C57BL/6J mice exhibited respiratory distress from pneumonitis and pneumonitis with fibrosis (6.8% of lung), respectively, while 18/19 chr17-subcongenic mice survived to 25 weeks post-treatment without symptoms of distress and with significantly decreased radiation-induced pulmonary fibrosis (0.3% of lung, P = 0.002). Of the chr2-subcongenics, mice of one line, which we refer to as Pneum1 (pneumonitis one), succumbed at an average of 20.2 ± 1.1 weeks postirradiation in females and 26.3 ± 1.2 weeks in males (P > 0.22 vs. congenic mice), reducing this locus to 5.6 Mb. Bioinformatic analyses revealed 114 candidate genes within these reduced intervals, with effects on pathways including on immune pathways. Mapping refined genetic susceptibility to radiation-induced lung disease in mice.

Recent advances in dose-delivery techniques have led to a reduction in normal tissue complications in radiotherapy patients. However, significant early and late cardiovascular (CV) effects may result when the heart is included in the radiation field and exposed to doses commonly used to treat several types of malignancies, or during total-body irradiation (TBI) prior to hematopoietic stem cell transplantation. Moreover, a radiological or nuclear (RAD/NUC) incident in which thousands of people are exposed to potentially lethal doses of ionizing radiation could result in the development of delayed effects of acute radiation exposure (DEARE) in survivors; several life-threatening cardiac DEARE-related pathologies would be observed months to years after TBI doses that trigger the hematopoietic acute radiation syndrome (H-ARS). While mitigators are available to treat acute symptoms in individuals that received radiation doses high enough to trigger the H-ARS, there are no drugs or strategies for mitigating early or late cardiovascular effects in radiotherapy patients, or late cardiac pathologies that would subsequently manifest in H-ARS survivors; while some drugs have shown promise, toxicity, limited efficacy or logistical issues regarding administration precludes their clinical use. Thus, there is great interest in the development of mitigators of cardiovascular dysfunction. We previously identified a novel non-pharmacological strategy that is effective in mitigating the lethal effects of TBI in mice when administered after exposure. Our approach involved the creation of a small subcutaneous (SC) incision postirradiation. We found that subcutaneous wounding several minutes after a high-dose TBI greatly protected against lethality, and that mitigation of the resulting H-ARS was likely mediated by enhanced recovery of hematopoiesis. We refer to this approach as "protective wounding." We now show that a subcutaneous cut preserves cardiac function, specifically, pumping capacity as measured by the Langendorff technique, in mice when assessed 30 days after a single dose or fractionated TBI. For example, left ventricular developed pressure (LVDP) at end diastolic pressure (EDP) 30-39 was 22.5% greater in mice that received a cut after a TBI dose of 6.5 Gy, compared to sham-cut mice. We propose that "protective wounding" may be used as a novel model for interrogating the proteins and pathways involved in reducing cardiotoxicity after irradiation and ultimately guiding development of pharmacological mitigators of cardiotoxicity in radiotherapy patients or victims of RAD/NUC incidents.

Ionizing radiation causes various types of DNA damage in mammalian cells, leading to tissue reactions and stochastic effects. Different cultured cell lines have been used to study DNA alterations at the molecular level; however, most previous studies have used diploid cells, making it difficult to accurately analyze structural variations (SVs), such as insertions and deletions (indels), in autosomal chromosomes. Here, we report the development of a unique experimental system using HAP1 cells, a human haploid cell line derived from the chronic myeloid leukemia (CML) cell line KBM-7. To compare their biological properties with normal human diploid fibroblasts (NHDFs), we measured radiation sensitivity, protein expression, and DNA damage response. The results showed that HAP1 cells exhibit properties similar to NHDFs. We also demonstrated their usefulness in next-generation sequencing analysis to identify SVs in autosomes caused by ionizing radiation. Therefore, HAP1 cells serve as an ideal model system for investigating molecular radiation signatures.

Ionizing radiation induces cytokine expression, affecting apoptosis through pro- and anti-apoptotic signals. Although some innate immune pathways regulating radiation-induced germ cell apoptosis have been identified in Caenorhabditis elegans, the precise mechanisms remain unclear. To clarify how innate immune genes regulate germ cell apoptosis, we first combined transcriptome sequencing and WormExp enrichment analysis to explore early gene expression changes in C. elegans after irradiation. The results showed that radiation triggers innate immunity genes similarly to pathogen responses. Subsequently, we employed mutants of innate immune pathways to investigate the underlying regulatory mechanisms. Germ cell apoptosis was reduced in pmk-1(km25), mpk-1(n2521), dbl-1(wk70), and daf-2(e1370) innate immunity related-mutants compared to N2 worms after irradiation. RNA-seq analysis revealed that the innate immune gene expression was downregulated in the mutant pmk-1(km25), while upregulated in mpk-1(n2521), dbl-1(wk70), kgb-1(um3), and daf-2(e1370). Pro-apoptotic genes egl-1 and ced-13 were significantly upregulated in wild-type worms and these mutants postirradiation. Further RNA-seq enrichment analysis using Gene Set Enrichment Analysis (GSEA) indicated distinct biological processes in these mutants after irradiation. Genes upregulated in wild-type but downregulated in mutants were involved in innate immunity, and RNAi of dod-21 significantly inhibited germ cell apoptosis. This suggests that reduced apoptosis in mutants is partly due to decreased expression of innate immunity genes.

This paper investigates cosmic ray exposure among Antarctic expeditioners through detailed case analyses of individuals undertaking diverse polar missions, encompassing both summer campaigns and extended winter-overs. The first case profiles a glaciologist with a longitudinal dataset spanning over three decades (1988-2025) and 31 high-altitude missions at key stations such as Vostok and Concordia. The second case examines an astronomer, referred to as Stella, whose exposure history includes multiple summer deployments and two overwintering periods between 2001 and 2025. The third case presents a comprehensive evaluation of overwintering personnel at Concordia, incorporating mission frequency, duration, and cumulative dose assessments over several years, with some subjects completing up to four winter stays within a seven-year timeframe. Exposure assessments, leveraging sophisticated modeling tools alongside empirical measurements, reveal annual effective doses generally below one mSv for summer expeditions. Overwintering expeditioners exhibit higher cumulative doses, occasionally approaching or exceeding the lower value of the ICRP's recommended reference level range for existing exposure situations (1-20 mSv per year) when averaged over five years. These results underscore the significance of mission duration, solar activity, and repeated exposure, and support the value of continued dosimetric monitoring. They also suggest that tailored radiological considerations may be beneficial for long-term expeditioners in polar environments.

Space radiation, primarily originating from galactic cosmic rays, is mainly composed of protons. Given NASA's plans for manned lunar and Mars missions, it is critical to assess the risk of proton radiation in disrupting tissue homeostasis, including in the intestine, which is a highly radiosensitive organ that harbors trillions of bacteria on the luminal surface. One-carbon metabolism encompasses the folate and methionine cycle and plays a crucial role in maintaining tissue homeostasis by regulating methylation, reductive metabolism, and nucleotide synthesis. However, the effects of proton radiation on intestinal one-carbon metabolism and the luminal microbiome profile are unknown. To address this, 6-month-old male C57BL/6J mice were exposed to a single dose of 0.5 Gy or 1.0 Gy of protons (150 MeV/n; dose rate = 35-55 cGy/min). Nine months after irradiation, significant shifts in the one-carbon metabolism pathway were detected in the mouse proximal jejunum and colon. These changes were exhibited as a loss of intra-intestinal methionine, s-adenosylmethionine, and glutathione tissue concentrations, with more pronounced effects being observed in the proximal jejunum compared to the colon. This resulted in the loss of DNA methylation within long-interspersed nucleotide element-1 (LINE-1), indicative of a global hypomethylative phenotype. Molecular changes were characterized by substantial dysregulation of gene expression in the proximal jejunum, where the most pronounced changes were associated with the dramatic loss of Nos2 expression and reactivation of Casp14, suggesting potential shifts in amino acid utilization and restoration of epithelial barriers in the gut. Furthermore, claudins Cldn5, Cldn6, and Cldn10 were substantially modulated in the proximal jejunum of exposed mice. Gross shifts in the microbiota profiles were exhibited as increases in both overall richness and diversity, however, at the expense of commensal bacterial species, like Akkermansia. The extent of the observed alterations was not congruent with the relatively low doses used in the study, the late time-point, and the overall lack of histomorphological alterations. Altogether, our findings demonstrate that exposure to space-relevant proton radiation causes substantial and persistent changes in the mouse gut. The degree and nature of the observed effects suggest the potential for negative health consequences after exposure to proton radiation during deep space exploration.

Radiation-induced brain injury (RIBI) continues to pose a significant clinical problem linked to neuroinflammation, oxidative stress, and neuronal death. This research evaluates the neuroprotective efficacy of oxytetracycline (OTC) in mitigating RIBI, examining its effects on behavioral, histological, biochemical, and metabolic characteristics. Female Wistar albino rats were categorized into three groups: a control group, a group subjected to brain irradiation with saline, and a group subjected to brain irradiation with oxytetracycline therapy at a dosage of 30 mg/kg/day for 15 days. Behavioral results were assessed through daily sociability, open-field, and passive avoidance learning tests. Biochemical studies included the quantification of inflammatory and oxidative stress indicators, including TNF-α, malondialdehyde (MDA), and superoxide dismutase (SOD). Histopathological assessments focused on neuronal integrity and astrocytic activity in hippocampus (CA1 and CA3 areas) and cerebellar tissues. Magnetic resonance (MR) spectroscopy was used to evaluate metabolic alterations, including lactate, N-acetylaspartate (NAA), and creatine (Cr) concentrations. oxytetracycline therapy markedly decreased oxidative stress indicators, including malondialdehyde (MDA), and restored antioxidant enzyme activity (SOD). Inflammatory markers such as TNF-α, Iba-1, and TLR-4 were reduced, however levels of neurotrophic factors (NGF and NRG-1) remained constant. Improvements in behavior were seen in friendliness, memory retention, and inquisitive behaviors. Histopathological analysis indicated maintained neuronal integrity and diminished GFAP immunostaining in the hippocampus and cerebellum. MR spectroscopy revealed reduced lactate levels and normalized NAA and Cr levels, indicating metabolic stability. Thus, oxytetracycline has neuroprotective properties that act via mitigation of inflammation, decreasing oxidative stress, and maintaining neuronal integrity. Furthermore, its capacity to alleviate metabolic dysfunction enhances its prospective use in safeguarding cognitive and neurological processes. These findings underscore the therapeutic efficacy of oxytetracycline in mitigating radiation-induced cerebral damage.

This study aims to elucidate the processes involved in radiation-induced liver injury and subsequent hepatocyte proliferation, and to identify novel metabolic profiles associated with progression of liver injury and hepatocyte proliferation. Six-week-old male Sprague-Dawley rats were exposed to a single 25 Gy dose of radiation to the whole liver to induce a model of radiation-induced liver injury and subsequent hepatocyte proliferation. Liver injury and hepatocyte proliferation were assessed using a range of techniques, including Masson's trichrome staining, liver histopathology, ELISA, immunohistochemistry, and Western blotting. Dynamic changes in metabolic profiles and biomarker concentrations in liver tissue were investigated using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry. After radiation exposure, acute radiation-induced liver dysfunction occurs, but then there is gradual recovery over time, concomitant with the onset of hepatocyte proliferation. Metabolomic analysis of liver tissues at different time points, specifically day 1, day 8, day 15, and day 30 postirradiation, revealed notable differences in all 22 metabolites, with a predominance of lipid metabolites. Among them, 9 metabolites showed more than a twofold change on days 15 and 30. We validated the correlation between these 9 metabolites with injury scores and Ki-67 positive cells (%). Notably, there was a strong negative correlation between glycerylphosphorylethanolamine (GPE) and the injury score (correlation coefficient: -0.701) and between 1-hexadecanoyl-2-(5-hydroxy-8-oxo-6E-octenoyl)-sn-glycero-3-phosphoserine (PHOOA-PS) and the Ki-67 positive cells (%) (correlation coefficient: -0.824). Additionally, GPE has significant value in differentiating the degree of injury [area under the curve (AUC) = 0.958]. This study successfully established a rat model of radiation-induced hepatic injury and subsequent hepatocyte proliferation, shedding light on dynamic metabolic changes at different times.

The variation of the oxygen enhancement ratio (OER) across linear energy transfer (LET) currently lacks a comprehensive mechanistic interpretation and a mechanistic model. Our earlier research revealed a significant correlation between the distribution of double-strand breaks (DSBs) within 3D genome and radiation-induced cell death, which offers valuable insights into the oxygen effect. We propose a model where the reaction of oxygen is represented as the probability of inducing DNA strand breaks. Then it is integrated into a track-structure Monte Carlo simulation to investigate the impact of oxygen on the distribution of DSBs within 3D genome. Using the parameters from our previous study, we calculate the OER values related to cell survival. Results show that the incidence ratios of clustered DSBs within a single topologically associating domain (TAD) (case 2) and within frequently interacting TADs (case 3) under aerobic and hypoxic conditions align with the trend in the OER of cell survival across LET. Our OER curves exhibit good correspondence with experimental data. This study provides a potentially mechanistic explanation for changes in OER across LET. High-LET irradiation leads to dense ionization events, resulting in an overabundance of lesions that readily induce case 2 and case 3, which have substantially higher probabilities of cell killing than other damage patterns. This may contribute to the main mechanism governing the variation of OER for high LET. Our study further underscores the importance of the DSB distribution within 3D genome in the context of radiation-induced cell death.