Consumption of Apigenin Prevents Radiation-induced Gut Dysbiosis in Male C57BL/6J Mice Exposed to Silicon Ions.

The search for medical treatments to prevent radiation-induced damage to gastrointestinal tissue is crucial as such injuries can be fatal. This study aimed to investigate the effects of apigenin (AP) on the gut microbiome of irradiated mice, as it is a promising radiation countermeasure. Male C57BL/6J mice were divided into four groups, with six mice in each group. Two groups were given food with apigenin (20 mg/kg body weight or AP 20) before and after exposure to 0 or 50 cGy of silicon (28Si) ions, while another two groups of mice received regular diet without apigenin (0 mg/kg body weight or AP 0) before and after irradiation. The duodenum, the primary site for oral AP absorption, was collected from each mouse seven days after radiation exposure. Using 16S rRNA amplicon sequencing, we found significant differences in microbial diversity among groups. Firmicutes and Bacteroidetes were the major phyla for all groups, while actinobacterial and proteobacterial sequences represented only a small percentage. Mice not given dietary apigenin had a higher Firmicutes and Bacteroidetes (F/B) ratio and an imbalanced duodenal microbiota after exposure to radiation, while irradiated mice given apigenin had maintained homeostasis of the microbiota. Additionally, irradiated mice not given apigenin had decreased probiotic bacteria abundance and increased inflammation, while apigenin-supplemented mice had reduced inflammation and restored normal histological structure. In conclusion, our results demonstrate the potential of dietary apigenin as a countermeasure against radiation-induced gut injuries due to its anti-inflammatory activity, reduction of gut microbiota dysbiosis, and increase in probiotic bacteria (e.g., Lachnospiraceae, Muribaculaceae and Bifidobacteriaceae).

Exposición a sílice de mineros en altitud. Dosis inhalada, método de evaluación en condición de hipobariaV / Silica exposure among miners at high altitude. Inhaled dose and evaluation methods in hypobaric environments

Objetivo: Evaluar la exposición a sílice de mineros chilenos en altitud usando diferentes metodologías, con el propósito de determinar el método más seguro para controlar la ex-posición. Métodos: Los 46 mineros que conforman la muestra trabajan a 3000 metros sobre el nivel del mar con sistema de turnos no convencionales, en jornadas de 12 horas diarias por 4 días consecutivos, después de los cuales se descansa por otros 4 días. Se tomaron mues-tras de sílice en cada uno de los puestos de trabajo de estos 46 mineros en altitud. Los re-sultados de las concentraciones se presentan en (mg/m3). La exposición se evaluó usando el Threshold Limit Value y otras dos metodologías que incorporan parámetros respiratorios. Se determinó el grupo de mineros en riesgo con cada uno de estos métodos y se comparó la proporción de mineros expuestos en cada caso.Resultados: evaluando con el Threshold Limit Value (método 1) se obtuvo un 43,48% de mi-neros en riesgo. Con los métodos que incluyen parámetros respiratorios se obtuvo una pro-porción de mineros sobre-expuestos del 82,61% con el método 2, y 73,91% con el método 3.Conclusiones: de los tres métodos analizados, el que considera el parámetro respiratorio volumen minuto, a través de la estimación de la dosis inhalada, es el más seguro para defi-nir el grupo de mineros en riesgo por exposición a sílice a gran altura (AU)

Objective: To evaluate silica exposure among Chilean miners at high altitude, using dif-ferent methodological approaches, for the purpose of determining the safest method to control exposures. Methods: The 46 miners in the sample worked at 3000 meters above sea level in nonstan-dard work shifts, consisting of four consecutive 12-hour days, followed by four consecutive days off. Silica samples were obtained in each of the jobs positions of these 46 high-altitude miners. The results of the concentrations are presented in mg/m3. Exposures were evalu-ated in compatison to the Threshold Limit Value (Method 1) and using two other methodol-ogies that incorporate respiratory parameters (Methods 2 and 3). The proportion of miners at risk was determined with each of these methods and compared.Results: Based on the Threshold Limit Value (Method 1), 43.48% of miners were classified as being at risk. With the other two methods that incorporate respiratory parameters, the proportion of overexposed miners was 82.61% with Method 2, and 73.91% with Method 3.Conclusions: Of the three methods analyzed, the one that considers the respiratory param-eter minute volume, through the estimation of the inhaled dose, is the safest to define the group of miners at risk due to exposure to silica at high altitude (AU)

[Autoimmune/inflammatory syndrome induced by aduvants].

For decades, breast implants have been available for breast reconstructions and breast augmentations to improve the patients' health-related quality of life. Silicone implants (SI) have been used since the middle of the last century for breast reconstruction, for example after breast cancer, for birth defects, gender confirmation procedures, or for breast augmentation. Every year, several hundred SI are performed in Iceland for these purposes, but no central register is maintained. It can be estimated that at least 1000 - 3000 women have SI in Iceland and that around 300 Icelandic patients get SI every year. This informal review article discusses the so-called ASIA syndrome, the immunological effects of silicone and the possible relationship of SI to autoimmune diseases, symptoms, and diagnosis. In the methodology, this paper does not rely on the strict conditions of systematic reviews, but the authors relied only on peer-reviewed sources through PubMed, UpToDate and Scopus. The keywords used are silicon, silicon implant, silicon particles, immune response, autoimmunity, autoinflammation, Autoimmune/inflammatory syndrome induced by aduvants, ASIA, ASIA syndrome, breast implant illness. The paper reviews known facts about the disease, its characteristics, and statistical aspects.

Associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation.

The space radiation environment consists of multiple species of charged particles, including 28Si ions, that may impact brain function during and following missions. To develop biomarkers of the space radiation response, BALB/c and C3H female and male mice and their F2 hybrid progeny were irradiated with 28Si ions (350 MeV/n, 0.2 Gy) and tested for behavioral and cognitive performance 1, 6, and 12 months following irradiation. The plasma of the mice was collected for analysis of miRNA levels. Select pertinent brain regions were dissected for lipidomic analyses and analyses of levels of select biomarkers shown to be sensitive to effects of space radiation in previous studies. There were associations between lipids in select brain regions, plasma miRNA, and cognitive measures and behavioral following 28Si ion irradiation. Different but overlapping sets of miRNAs in plasma were found to be associated with cognitive measures and behavioral in sham and irradiated mice at the three time points. The radiation condition revealed pathways involved in neurodegenerative conditions and cancers. Levels of the dendritic marker MAP2 in the cortex were higher in irradiated than sham-irradiated mice at middle age, which might be part of a compensatory response. Relationships were also revealed with CD68 in miRNAs in an anatomical distinct fashion, suggesting that distinct miRNAs modulate neuroinflammation in different brain regions. The associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation could be used for the development of biomarker of the space radiation response.

Recording site placement on planar silicon-based probes affects signal quality in acute neuronal recordings.

Multisite, silicon-based probes are widely used tools to record the electrical activity of neuronal populations. Several physical features of these devices are designed to improve their recording performance. Here, our goal was to investigate whether the position of recording sites on the silicon shank might affect the quality of the recorded neural signal in acute experiments. Neural recordings obtained with five different types of high-density, single-shank, planar silicon probes from anesthetized rats were analyzed. Wideband data were filtered to extract spiking activity, then the amplitude distribution of samples and quantitative properties of the recorded brain activity (single unit yield, spike amplitude and isolation distance) were compared between sites located at different positions of the silicon shank, focusing particularly on edge and center sites. Edge sites outperformed center sites: for all five probe types there was a significant difference in the signal power computed from the amplitude distributions, and edge sites recorded significantly more large amplitude samples both in the positive and negative range. Although the single unit yield was similar between site positions, the difference in spike amplitudes was noticeable in the range corresponding to high-amplitude spikes. Furthermore, the advantage of edge sites slightly decreased with decreasing shank width. Our results might aid the design of novel neural implants in enhancing their recording performance by identifying more efficient recording site placements.

The cadmium tolerance development of poplar callus is influenced by silicon.

Cadmium-tolerant plants were studied for their possible usage in phytoremediation techniques. However, their response to cadmium cations at a cellular level has not been properly studied. Silicon is a beneficial element that seems to change the plant's response to the Cd2+ presence. The aim of the present study was to investigate the Cd2+ tolerance patterns of poplar callus cells exposed to Cd+2 and/or Si over short and long cultivation periods. We determined the growth parameters of the callus, the growth dynamics, cell vitality, photosynthetic pigment concentrations and the activity of antioxidant enzymes. The effects were studied over short (21 days) and long (63 days) cultivation periods. The most important result proved that the poplar callus tissue is able to build up a tolerance to Cd2+ after a longer cultivation period. On the 63rd day of the cultivation, Cd2+ stressed calli showed improvement in studied parameters and the callus cells accumulated Cd2+ more efficiently than on the 21st day. Supplementation with Si in higher concentrations (2.5 mM and 5 mM) heightened the Cd-tolerance potential of the tissue. The treatment of Cd2+, and Si in a 2.5 mM concentration was the most efficient variant for Cd2+ removal from medium. The activity of antioxidant enzymes showed that poplar callus cells effectively develop tolerance against Cd2+ after a longer cultivation period.

Protons and High-Linear Energy Transfer Radiation Induce Genetically Similar Lymphomas With High Penetrance in a Mouse Model of the Aging Human Hematopoietic System.

PURPOSE: Humans are exposed to charged particles in different scenarios. The use of protons and high-linear energy transfer (LET) in cancer treatment is steadily growing. In outer space, astronauts will be exposed to a mixed radiation field composed of both protons and heavy ions, in particularly the long-term space missions outside of earth's magnetosphere. Thus, understanding the radiobiology and transforming potential of these types of ionizing radiation are of paramount importance. METHODS AND MATERIALS: We examined the effect of 10 or 100 cGy of whole-body doses of protons or 28Si ions on the hematopoietic system of a genetic model of aging based on recent studies that showed selective loss of the MLH1 protein in human hematopoietic stems with age. RESULTS: We found that Mlh1 deficient animals are highly prone to develop lymphomas when exposed to either low doses of protons or 28Si ions. The lymphomas that develop are genetically indistinguishable, in spite of different types of damage elicited by low- and high-LET radiation. RNA sequencing analyses reveal similar gene expression patterns, similar numbers of altered genes, similar numbers of single nucleotide variants and insertions and deletions, and similar activation of known leukemogenic loci. CONCLUSIONS: Although the incidence of malignancy is related to radiation quality, and increased due to loss of Mlh1, the phenotype of the tumors is independent of LET.

Comparison of silicon and metallic bifurcated stents in patients with malignant airway lesions.

INTRODUCTION AND OBJECTIVE: Silicon and metallic are two types of stents in use. In this study, we compared complications and long-term survival among patients who received silicon or fully covered, bifurcated self-expandable metallic stents (SEMS) for a malignant tracheobronchial obstruction and/or tracheo/bronchial oesophageal fistulas. METHODS: Patients in whom Y-shaped stents were used from January 2013 to June 2017 in our interventional pulmonology unit were evaluated retrospectively from patient files. RESULTS: Of the 47 patients, 30 (23 males, 76.7%) were in the silicon stent group and 17 (14 males, 82.4%) were in the covered SEMS group. No differences between the groups were detected in ECOG status, pathological properties of the disease, radiotherapy or chemotherapy history before the procedure, symptoms at presentation, or comorbidities. The most common symptom was dyspnoea (96.7% and 100%), and the most common comorbidity was chronic obstructive pulmonary disease (26.7% and 23.5%). A total of 20 complications (42.6%) were seen, with no significant difference between the groups (silicon, 40%; SEMS, 47.1%; P = . 62). Mean survival was 164.51 ± 38.83 days for the silicon stent group and 254.45 ± 103.32 days for the SEMS group (P = .588). No differences were observed in 30-, 90- or 180-day mortality between the two groups (P = .966, .846 and .534, respectively). CONCLUSIONS: No significant differences in symptom palliation, insertion safety, complication rate or survival were detected between the two types of stent.

Reactive hyperemia and baseline pulse amplitude among smelter workers exposed to fine and ultrafine particles.

OBJECTIVE: Ambient exposure to fine particles is associated with increased cardiovascular morbidity and mortality. Associations between occupational particulate matter (PM) exposure and cardiovascular disease have been studied less. The objective of this study was to examine associations between PM exposure and endothelial function among workers in Norwegian smelters. METHODS: We examined endothelial function with Endo-PAT equipment after a working day (WD) and on a day off (DO) in 59 furnace workers recruited from three metal smelters in Norway. The difference in baseline pulse amplitude (BPA) and reactive hyperemia index (RHI) between the 2 days was analysed in relation to individual exposure to PM < 250 nm (PM250) or the respirable aerosol fraction of particles, and adjusted for relevant covariates. RESULTS: The exposure to PM250 ranged from 0.004 to 5.7 mg/m3. The mean BPA was significantly higher on WD relative to DO (772 vs. 535, p = 0.001). This difference was associated with PM concentrations among participants ≥ 34 years, but not among the younger workers. Reactive hyperemia was significantly lower on workdays relative to days off (1.70 vs. 1.84, p = 0.05). This difference was observed only among participants above the age 34. No associations with PM exposure were observed. CONCLUSIONS: PM exposure was associated with higher BPA among participants older than 34 years. BPA reflects microvessel pulsatility. Our results may indicate an age-dependent cardiovascular susceptibility to PM exposure. Endothelial function measured by RHI was reduced on WD among participants 34 years and older, but we found no associations between PM exposure and RHI.

Complications of silicone Y stents placed due to malignant airway stenosis.

INTRODUCTION: Malignant central airway obstruction around the main carina often requires placement of Y­shaped stents. In this study, we aimed to determine the safety of silicone Y stents placed around the main carina in the malignant airway obstruction by examining the long term complications, emergence times and treatment approaches of complications. MATERIALS AND METHODS: Between May 2012 and July 2015, 47 silicone Y stents were placed in 46 patients with malignant external compression or mixed type stenosis around the main carina. Patient stents were placed via rigid bronchoscopy under total intravenous anesthesia in operating room conditions. RESULT: In the half of the patients (23/46), stents were placed under urgent conditions due to acute respiratory failure. Stents were deployed successfully in all the patients. No procedure related deaths were observed. The median time of survival following stent insertion was 157 days. The total long-term complication rate of silicone Y stents was 28.3%. Mucostasis (8.7%) and migration (2.2%) were observed within the first month after placement of the silicone Y stents (median 18 days), stent-edge granulation tissue development (13.0%) was observed at the earliest one month (median 64, range 34-386 days) and stent-edge tumor tissue development (4.3%) were observed at the earliest 3 months (median 151, range 85-217 days). A total of 7 (15.2%) stents were removed, 2 of which were due to mucostasis and 5 of which were due to granulation tissue development. One patient's stent was replaced with a longer silicone Y stent due to stent-edge tumor tissue development. CONCLUSIONS: The best palliative treatment of malignant tumor stenosis around the main carina is still silicone Y stent placement, but the long-term complication rate can be high. For this group of patients, bronchoscopy to be performed at the first and third months after silicone Y stent placement may provide early detection of stent-edge tissue development.

Nonsurgical Clinical Management of Periapical Lesions Using Calcium Hydroxide-Iodoform-Silicon-Oil Paste.

BACKGROUND: The study aim is to avoid tooth extraction by nonsurgical treatment of periapical lesion. It assesses healing progress in response to calcium hydroxide-iodoform-silicon oil paste (CHISP). Numeric Pain Rating Scale was used to validate the approach. Furthermore, CHISP was used to treat cystic lesions secondary to posttraumatic avulsion of permanent teeth. MATERIALS AND METHODS: Over 200 patients with radicular cysts were treated with CHISP through the root canal. Radiographs were used to verify lesion size and position, ensure correct delivery to the site, and monitor the progress of bone healing in the lesion area. Ten males and 10 females were randomly selected for statistical assessment. RESULTS: No severe pain, complications, or failure in cyst healing was reported. Complete healing was achieved in an average of 75 days. Furthermore, healing of radicular cyst secondary to posttraumatic tooth avulsion was successful. CONCLUSION: CHISP indicated an antiseptic effect, which enhanced and shortened healing time of periapical lesions. The less invasive procedure avoids tooth extraction and reduces bone resorption. Cyst management with CHISP can remedy failed root canal treatments. The results show a bone regenerative capacity of CHISP suggested in first rapid phase and a second slow phase.

Dynamic analysis of the interactions between Si/SiO2 quantum dots and biomolecules for improving applications based on nano-bio interfaces.

Due to their outstanding properties, quantum dots (QDs) received a growing interest in the biomedical field, but it is of major importance to investigate and to understand their interaction with the biomolecules. We examined the stability of silicon QDs and the time evolution of QDs - protein corona formation in various biological media (bovine serum albumin, cell culture medium without or supplemented with 10% fetal bovine serum-FBS). Changes in the secondary structure of BSA were also investigated over time. Hydrodynamic size and zeta potential measurements showed an evolution in time indicating the nanoparticle-protein interaction. The protein corona formation was also dependent on time, albumin adsorption reaching the peak level after 1 hour. The silicon QDs adsorbed an important amount of FBS proteins from the first 5 minutes of incubation that was maintained for the next 8 hours, and diminished afterwards. Under protein-free conditions the QDs induced cell membrane damage in a time-dependent manner, however the presence of serum proteins attenuated their hemolytic activity and maintained the integrity of phosphatidylcholine layer. This study provides useful insights regarding the dynamics of BSA adsorption and interaction of silicon QDs with proteins and lipids, in order to understand the role of QDs biocorona.

Impaired Attentional Set-Shifting Performance after Exposure to 5 cGy of 600 MeV/n 28Si Particles.

Astronauts on deep space missions will be required to work more autonomously than on previous missions, and thus their ability to perform executive functions could be critical to mission success. One of the most common measures of executive function in humans is the ability to perform attentional set shifting, which requires contributions from working memory, discrimination, reversal learning, attentional set shifting and attention. Rodent attentional set shifting assays require rats to form an association between the presence of the food reward and an associative cue, which is either the digging media or the scent that is placed in the bowl; by altering the combination of scent and digging media, progressively more complex cognitive processes can be tested. In this study, we have determined the effect that exposure to 5-20 cGy of 600 MeV/n 28Si particles has on the ability of male retired breeder Wistar rats to perform attentional set shifting at three months postirradiation. All doses of Si resulted in a significant impairment in the ability of the rats to perform the first and most simple step of the ATSET assay, the simple discrimination (SD) task. If astronauts were to experience HZE-induced SD impairments, they would be unable to identify key factors to successfully resolve a situation. Performance in at least one other component of the ATSET test was impaired at all doses studied, however, these varied according to the dose. Compared with our previous studies using 1 GeV/n 56Fe and 48Ti particles, 600 MeV/n 28Si ions impaired attentional set-shifting performance at lower doses than the heavier ions. However, when the effect of isofluences of the three HZE ions were compared, there were no significant differences in the severity of the impaired performance; there were, however, ion-specific decrements in the ability of rats to perform within the various stages of the test. This study further supports the notion that "mission-relevant" doses of HZE particles (<20 cGy) can impair certain aspects of attentional set-shifting performance in retired breeder rats, but there may be some ion-specific changes in the specific cognitive domains impaired.

Occupational exposure to photocopiers and their toners cause genotoxicity.

Photocopier machines are inevitable office equipment, but they are also sources of air pollution. Millions of people across the world are involved in the operation and maintenance of photocopiers. We aimed to evaluate the potential genotoxic effects of exposure to photocopiers in photocopier operators and maintenance personnel by Comet assay. This study involved 50 photocopier operators, 61 maintenance personnel and 52 controls. Both the photocopier exposed groups exhibited significantly increased DNA damage when compared to controls. Cumulative exposure to photocopiers was the most significant contributor for genotoxicity ( p < 0.001). Genotoxicity among photocopier maintenance personnel may be due to the presence of carbon black, iron, silicon, magnetite and the high levels of other elements in the photocopier toners. Genotoxicity among photocopier operators might be due to exposure to high levels of particulate matter and volatile organic compounds emitted by photocopiers during operation. Research is essential to improve toner manufacturing processes and chemical composition of toners to reduce genotoxicity. Clean technologies are the need of the day to cut down on particulate matter and volatile organic compound emissions from photocopiers.

Safety, acceptability and tolerability of uncoated and excipient-coated high density silicon micro-projection array patches in human subjects.

Most vaccinations are performed by intramuscular injection with a needle and syringe. However, this method is not ideal due to limitations, such as the risk of needle-stick injury, the requirement for trained personnel to give injections and the need to reconstitute lyophilized vaccines. Therefore, we tested an alternative delivery technology that overcomes the problems with needle and syringe. The Nanopatch™ is an array of 10,000 silicon micro-projections per cm2 that can be dry-coated with vaccine for skin delivery. The high number and density of micro-projections means that high velocity application is required to achieve consistent skin penetration. Before clinically testing a vaccine Nanopatch, this study tests the safety, tolerability and acceptability/utility of uncoated and excipient-coated Nanopatches in healthy adults. Nanopatches were applied to skin of the upper arm and volar forearm and left in contact with the skin for two minutes before removal. The application sites were assessed for local skin response over 28 days. Acceptability interviews were also performed. No unexpected adverse events directly related to the Nanopatch application were reported. All applications of the Nanopatch resulted in an expected erythema response which faded between days 3 and 7. In some subjects, some skin discolouration was visible for several days or up to 3 weeks after application. The majority (83%) of subjects reported a preference for the Nanopatch compared to the needle and syringe and found the application process to be simple and acceptable. On a pain scale from 0 to 10, 78% of applications were scored "0" (no pain) with the average scores for less than 1. The results from this study demonstrate the feasibility of the Nanopatch to improve vaccination by showing that application of the product without vaccine to human skin is safe, tolerable and preferred to needle and syringe administration. Clinical trial registry ID: ACTRN1261500083549.

Neurobiochemical changes in the vicinity of a nanostructured neural implant.

Neural interface technologies including recording and stimulation electrodes are currently in the early phase of clinical trials aiming to help patients with spinal cord injuries, degenerative disorders, strokes interrupting descending motor pathways, or limb amputations. Their lifetime is of key importance; however, it is limited by the foreign body response of the tissue causing the loss of neurons and a reactive astrogliosis around the implant surface. Improving the biocompatibility of implant surfaces, especially promoting neuronal attachment and regeneration is therefore essential. In our work, bioactive properties of implanted black polySi nanostructured surfaces (520-800 nm long nanopillars with a diameter of 150-200 nm) were investigated and compared to microstructured Si surfaces in eight-week-long in vivo experiments. Glial encapsulation and local neuronal cell loss were characterised using GFAP and NeuN immunostaining respectively, followed by systematic image analysis. Regarding the severity of gliosis, no significant difference was observed in the vicinity of the different implant surfaces, however, the number of surviving neurons close to the nanostructured surface was higher than that of the microstructured ones. Our results imply that the functionality of implanted microelectrodes covered by Si nanopillars may lead to improved long-term recordings.

Ultrapure laser-synthesized Si-based nanomaterials for biomedical applications: in vivo assessment of safety and biodistribution.

Si/SiOx nanoparticles (NPs) produced by laser ablation in deionized water or aqueous biocompatible solutions present a novel extremely promising object for biomedical applications, but the interaction of these NPs with biological systems has not yet been systematically examined. Here, we present the first comprehensive study of biodistribution, biodegradability and toxicity of laser-synthesized Si-SiOx nanoparticles using a small animal model. Despite a relatively high dose of Si-NPs (20 mg/kg) administered intravenously in mice, all controlled parameters (serum, enzymatic, histological etc.) were found to be within safe limits 3 h, 24 h, 48 h and 7 days after the administration. We also determined that the nanoparticles are rapidly sequestered by the liver and spleen, then further biodegraded and directly eliminated in urine without any toxicity effects. Finally, we found that intracellular accumulation of Si-NPs does not induce any oxidative stress damage. Our results evidence a huge potential in using these safe and biodegradable NPs in biomedical applications, in particular as vectors, contrast agents and sensitizers in cancer therapy and diagnostics (theranostics).

Silicon Injection Granulomata: 67Ga Citrate Findings in Free Silicon Buttock Augmentation.

Ga citrate is frequently used in the workup of fever of unknown origin. Here, we report a case of avid Ga-citrate in bilateral gluteal regions of a patient with a history of free silicon injection buttock augmentation referred for suspected diagnosis of sarcoidosis. CT findings were equivocal for inflammation/infection in the buttock region, and nuclear scintigraphy allowed for more definitive diagnosis.

Relative Biological Effectiveness of Energetic Heavy Ions for Intestinal Tumorigenesis Shows Male Preponderance and Radiation Type and Energy Dependence in APC(1638N/+) Mice.

PURPOSE: There are uncertainties associated with the prediction of colorectal cancer (CRC) risk from highly energetic heavy ion (HZE) radiation. We undertook a comprehensive assessment of intestinal and colonic tumorigenesis induced after exposure to high linear energy transfer (high-LET) HZE radiation spanning a range of doses and LET in a CRC mouse model and compared the results with the effects of low-LET γ radiation. METHODS AND MATERIALS: Male and female APC(1638N/+) mice (n=20 mice per group) were whole-body exposed to sham-radiation, γ rays, (12)C, (28)Si, or (56)Fe radiation. For the >1 Gy HZE dose, we used γ-ray equitoxic doses calculated using relative biological effectiveness (RBE) determined previously. The mice were euthanized 150 days after irradiation, and intestinal and colon tumor frequency was scored. RESULTS: The highest number of tumors was observed after (28)Si, followed by (56)Fe and (12)C radiation, and tumorigenesis showed a male preponderance, especially after (28)Si. Analysis showed greater tumorigenesis per unit of radiation (per cGy) at lower doses, suggesting either radiation-induced elimination of target cells or tumorigenesis reaching a saturation point at higher doses. Calculation of RBE for intestinal and colon tumorigenesis showed the highest value with (28)Si, and lower doses showed greater RBE relative to higher doses. CONCLUSIONS: We have demonstrated that the RBE of heavy ion radiation-induced intestinal and colon tumorigenesis is related to ion energy, LET, gender, and peak RBE is observed at an LET of 69 keV/µm. Our study has implications for understanding risk to astronauts undertaking long duration space missions.

Late-occurring chromosome aberrations and global DNA methylation in hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon ((28)Si) ions.

Although myeloid leukemia (ML) is one of the major health concerns from exposure to space radiation, the risk prediction for developing ML is unsatisfactory. To increase the reliability of predicting ML risk, a much improved understanding of space radiation-induced changes in the target cells, i.e. hematopoietic stem/progenitor cells (HSPCs), is important. We focused on the in vivo induction of late-occurring damage in HSPCs of mice exposed to (28)Si ions since such damage is associated with radiation-induced genomic instability (a key event of carcinogenesis). We gave adult male CBA/CaJ mice, known to be sensitive to radiation-induced ML, a whole-body exposure (2 fractionated exposures, 15 days apart, that totaled each selected dose, delivered at the dose-rate of 1 cGy/min) to various doses of 300 MeV/n (28)Si ions, i.e. 0 (sham controls), 0.1, 0.25, or 0.5 Gy. At 6 months post-irradiation, we collected bone marrow cells from each mouse (five mice per treatment-group) for obtaining the myeloid-lineage of HSPC-derived clones for analyses. We measured the frequencies of late-occurring chromosome aberrations (CAs), using the genome-wide multicolor fluorescence in situ hybridization method. The measurement of CAs was coupled with the characterization of the global DNA methylation patterns, i.e. 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5 hmC). A dose-dependent increase in the frequencies of CAs was detected (Analysis of Variance or ANOVA, p<0.01), indicating the induction of genomic instability after exposure of mice to 300 MeV/n (28)Si ions. Slight increases in the levels of 5 mC were observed in all treatment groups, as compared to the sham-control level. In contrast, there was a significant reduction in levels of 5 hmC (ANOVA, p<0.01). Since these endpoints were evaluated in the same mouse, our data suggested for the first time a link between a reduction in 5 hmC and genomic instability in HSPC-derived myeloid colonies of CBA/CaJ mice exposed to 300 MeV/n (28)Si ions.