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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 559 records · Page 31
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Gadolinium chloride ameliorates acute lung injury associated with severe acute pancreatitis in rats by regulating CYLD/NF-κB signaling

The present study was embarked on an investigation of the mechanisms behind the effects of Gadolinium chloride (GdCl{sub 3}) on lung injury associated with severe acute pancreatitis (SAP) in rats. Rats were randomly distributed into three groups: sham operation group (SO), SAP group and SAP treated with GdCl{sub 3} group (SAP + GdCl{sub 3}). Retrograde injection of 5% sodium taurocholate into the biliopancreatic duct was adopted to induce SAP. Lung tissue specimens were harvested for histological study, wet-to-dry weight ratio calculation and myeloperoxidase examination. Meanwhile, bronchoalveolar lavage fluid was analyzed for TNF-α and IL-1β activity and proteins content. Then the apoptosis ratio of alveolar macrophages (AMs) was detected. NF-κB activation and cylindromatosis (CYLD) expression in AMs were measured respectively. Results showed that GdCl{sub 3} treatment notably ameliorated lung injury induced by SAP, and simultaneously, the apoptosis ratio of AMs was significantly promoted. The NF-κB activation was obviously inhibited when CYLD expression was markedly up-regulated in AMs of SAP + GdCl{sub 3}. Negative correlation was analyzed between CYLD and NF-κB in both SAP and SAP + GdCl{sub 3}. These data demonstrate that GdCl{sub 3} ameliorates lung injury secondary to SAP in rats mainly by up-regulating CYLD expression and inhibiting NF-κB activation in AMs, which may play a vital role in lung injury. - Highlights: • GdCl{sub 3} ameliorates lung injury associated with SAP by inducing the apoptosis of AMs. • NF-kB activation can inhibit the apoptosis of AMs. • CYLD negatively regulates NF-kB activation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Recombinant human GLP-1(rhGLP-1) alleviating renal tubulointestitial injury in diabetic STZ-induced rats

Highlights: • Establishment diabetic nephropathy of STZ-induced rats model. • The treatment effect of Recombinant human GLP-1(rhGLP-1) on diabetic nephropathy caused tubulointerstitial inflammation. • Inhibition of Recombinant human GLP-1(rhGLP-1) for various inflammatory cytokines. GLP-1-based treatment improves glycemia through stimulation of insulin secretion and inhibition of glucagon secretion. Recently, more and more findings showed that GLP-1 could also protect kidney from diabetic nephropathy. Most of these studies focused on glomeruli, but the effect of GLP-1 on tubulointerstitial and tubule is not clear yet. In this study, we examined the renoprotective effect of recombinant human GLP-1 (rhGLP-1), and investigated the influence of GLP-1 on inflammation and tubulointerstitial injury using diabetic nephropathy rats model of STZ-induced. The results showed that rhGLP-1 reduced urinary albumin without influencing the body weight and food intake. rhGLP-1 could increased the serum C-peptide slightly but not lower fasting blood glucose significantly. In diabetic nephropathy rats, beside glomerular sclerosis, tubulointerstitial fibrosis was very serious. These lesions could be alleviated by rhGLP-1. rhGLP-1 decreased the expression of profibrotic factors collagen I, α-SMA, fibronectin, and inflammation factors MCP-1 and TNFα in tubular tissue and human proximal tubular cells (HK-2 cells). Furthermore, rhGLP-1 significantly inhibited the phosphorylation of NF-κB, MAPK in both diabetic tubular tissue and HK-2 cells. The inhibition of the expression of TNFα, MCP-1, collagen I and α-SMA in HK-2 cells by GLP-1 could be mimicked by blocking NF-κB or MAPK. These results indicate that rhGLP-1 exhibit renoprotective effect by alleviation of tubulointerstitial injury via inhibiting phosphorylation of MAPK and NF-κB. Therefore, rhGLP-1 may be a potential drug for treatment of diabetic nephropathy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LOX-related collagen crosslink changes act as an initiator of bone fragility in a ZDF rats model

Highlights: • Bone mechanical loss in type 2 diabetes is mainly restricted to the post-yield behavior. • Loss of insoluble collagen in the matrix phase is the initial cause of bone mechanical loss in type 2 diabetes. • The insoluble collagen amount in bone tissue is the positive regressor of bone post-yield behavior. • The expression of Lox and lox-like family are downregulated in bone tissue in type 2 diabetes. Diabetes mellitus type 2 (DM2) results in bone abnormalities that manifest as increased bone fragility. Bone consists of two phases, the mineral phase and the matrix phase, and disorders in both are seen in DM2. However, the phase in which DM2 mediated bone fragility is initiated is still unknown. In this study, a male Zucker diabetic fatty (fa/fa) (ZDF) rat model was used to investigate the underlying mechanism initiating DM2 mediated bone fragility. The fracture surface morphology, pre- and post-yield bone mechanical behavior, insoluble collagen volume, lysyl oxidase family (LOX) enzyme levels and correlation analysis was performed to determine the relationship between insoluble collagen and post-yield behavior. Four weeks after the induction of diabetes, insoluble collagen was decreased in only the matrix phase in diabetic rats. Consistently, mechanical testing of the bone showed changes only in post-yield behavior. Diabetic rats also had decreased levels of enzymes involved in insoluble collagen formation (LOX and LOXL1 families). Correlation analysis demonstrated that insoluble collagen was a positive regressor of post-yield displacement (R = 0.894, P P < 0.001). Together, these findings suggest that bone fragility in DM2 is initiated in the matrix phase and that the LOX family may play a critical part in the pathogenesis of DM2 mediated bone fragility.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons

Highlights: • ROS from nNOS are involved in MPP{sup +}-induced cytotoxicity in nNOS-expressing PC12 cells and rat cerebellar granule neurons. • 8-Nitro-cGMP, a downstream molecule in the NO/ROS redox signaling pathway, is involved in MPP{sup +}-induced neurotoxicity. • Involvement of H-Ras/ERK signaling activated by 8-Nitro-cGMP was also demonstrated in MPP{sup +}-induced neurotoxicity. To investigate the role of nitric oxide (NO)/reactive oxygen species (ROS) redox signaling in Parkinson's disease-like neurotoxicity, we used 1-methyl-4-phenylpyridinium (MPP{sup +}) treatment (a model of Parkinson's disease). We show that MPP{sup +}-induced neurotoxicity was dependent on ROS from neuronal NO synthase (nNOS) in nNOS-expressing PC12 cells (NPC12 cells) and rat cerebellar granule neurons (CGNs). Following MPP{sup +} treatment, we found production of 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP), a second messenger in the NO/ROS redox signaling pathway, in NPC12 cells and rat CGNs, that subsequently induced S-guanylation and activation of H-Ras. Additionally, following MPP{sup +} treatment, extracellular signal-related kinase (ERK) phosphorylation was enhanced. Treatment with a mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor attenuated MPP{sup +}-induced ERK phosphorylation and neurotoxicity. In conclusion, we demonstrate for the first time that NO/ROS redox signaling via 8-nitro-cGMP is involved in MPP{sup +}-induced neurotoxicity and that 8-nitro-cGMP activates H-Ras/ERK signaling. Our results indicate a novel mechanism underlying MPP{sup +}-induced neurotoxicity, and therefore contribute novel insights to the mechanisms underlying Parkinson's disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Differential effects of voluntary wheel running and toy rotation on the mRNA expression of neurotrophic factors and FKBP5 in a post-traumatic stress disorder rat model with the shuttle-box task

Highlights: • Running wheel or toy rotation produces almost the same behavioral effects. • The running wheel might alter PTSD-like behaviors via neurotrophic factors. • Toy rotation might alter PTSD-like behaviors via the HPA system. Life-threatening experiences can result in the development of post-traumatic stress disorder. We have developed an animal model for post-traumatic stress disorder (PTSD) using a shuttle box in rats. In this paradigm, the rats were exposed to inescapable foot-shock stress (IS) in a shuttle box, and then an avoidance/escape task was performed in the same box 2 weeks after IS. A previous study using this paradigm revealed that environmental enrichment (EE) ameliorated avoidance/numbing-like behaviors, but not hyperarousal-like behaviors, and EE also elevated hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the differential effects of EE components, i.e., running wheel (RW) or toy rotation, on PTSD-like behaviors has remained unclear. In this experiment, we demonstrated that RW, toy rotation, and EE (containing RW and toy rotation) ameliorated avoidance/numbing-like behaviors, induced learning of avoidance responses, and improved depressive-like behaviors in traumatized rats. The RW increased the hippocampal mRNA expression of neurotrophic factors, especially BDNF and glial-cell derived neurotrophic factor. Toy rotation influenced FK506 binding protein 5 mRNA expression, which is believed to be a regulator of the hypothalamic-pituitary-adrenal (HPA)-axis system, in the hippocampus and amygdala. This is the first report to elucidate the differential mechanistic effects of RW and toy rotation. The former appears to exert its effects via neurotrophic factors, while the latter exerts its effects via the HPA axis. Further studies will lead to a better understanding of the influence of environmental factors on PTSD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Reno-protective effects of TAK-242 on acute kidney injury in a rat model

Highlights: • Acute kidney inschemia/reperfusion (I/R) injury is characterized by an abrupt loss of kidney function. • TAK-242 is a selective inhibitor of the Toll-like receptor 4, which may cause kidney damage via aldosterone-induced pathway. • Administration of TAK-242 may act as a reno-protective agent in reducing overall kidney damage following ischemia/reperfusion injury. • IL-18, MDA and NGAL are useful biomarkers of kidney damage following ischemia/reperfusion injury . Acute kidney inschemia/reperfusion (I/R) injury is characterized by an abrupt loss of kidney function, resulting in the retention of urea and other nitrogenous waste products and in the dysregulation of extracellular volume and electrolytes. Despite the advances in therapeutic techniques, the mortality and morbidity of patients remain high and have not appreciably improved. This study aims to evaluate the potential protective effect of TAK-242 on renal ischemia/reperfusion injury using an animal model. Thirty-five adult male Sprague-dawely rats (weighing 200–300), were assigned randomly into the following experimental groups (n = 7 in each group), Control (I/R), Sham (negative control), TAK-242 (5 mg/kg body weight), TAK-242 (10 mg/kg body weight) and Vehicle (DMSO). Rats were exposed to a 30 min of ischemia then 3 h of reperfusion. At the end of reperfusion phase, rats were sacrificed then plasma, serum and tissue samples were obtained to measure markers of kidney oxidative stress and inflammation. Plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), and tissue levels of interleukin-18 (IL-18) and malondialdehyde (MDA) were significantly lower in TAK-242 pretreated groups than the vehicle group and the control group (p < 0.05). Furthermore; serum levels of urea and creatinine were significantly lower in the TAK-242 pretreated groups as compared to the control group (p < 0.05). We conclude that administration of TAK-242 can be useful preventive method in attenuating the degree of acute kidney injury during ischemic reperfusion process as shown by a significant reduction of urinary inflammatory markers as well as significant reduction of urea and creatinine levels.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Necrostatin-1 ameliorates adjuvant arthritis rat articular chondrocyte injury via inhibiting ASIC1a-mediated necroptosis

Necroptosis, a necrotic cell death pathway regulated by receptor interacting protein (RIP) 1 and 3, plays a key role in pathophysiological processes, including rheumatoid arthritis (RA). However, whether necroptosis is involved in RA articular cartilage damage processes remain unclear. The aim of present study was to investigate the dynamic changes in arthritic chondrocyte necroptosis and the effect of RIP1 inhibitor necrostatin-1 (Nec-1) and acid-sensing ion channels (ASICs) inhibitor amiloride on arthritic cartilage injury and acid-induced chondrocyte necroptosis. Our results demonstrated that the expression of RIP1, RIP3 and mixed lineage kinase domain-like protein phosphorylation (p-MLKL) were increased in adjuvant arthritis (AA) rat articular cartilage in vivo and acid-induced chondrocytes in vitro. High co-expression of ASIC1a and RIP1 showed in AA rat articular cartilage. Moreover, Nec-1 and amiloride could reduce articular cartilage damage and necroinflammation in AA rats. In addition, acid-induced increase in necroptosis markers RIP1/RIP3 were inhibited by Nec-1, ASIC1a-specific blocker psalmotoxin-1 (PcTx-1) or ASIC1a-short hairpin RNA respectively, which revealed that necroptosis is triggered in acid-induced chondrocytes and mediated by ASIC1a. These findings indicated that blocking ASIC1a-mediated chondrocyte necroptosis may provide potential therapeutic strategies for RA treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Assessment of the subcutaneous degradation process of insoluble hyaluronic acid in rats

Highlights: • Assessment of the subcutaneous degradation process of insoluble hyaluronic acid. • The speed of degradation of in vivo insoluble hyaluronic acid membranes varies depending on their swelling rate. • The process of degradation of insoluble hyaluronic acid in the subcutaneous over time was elucidated. Insoluble hyaluronic acid (IHA) may prevent adhesions by forming a physical barrier during the period when postoperative adhesions form. This study was performed to verify the changes that a solid IHA membrane undergoes as it is degraded in vivo, and to ascertain the swelling rate of IHA required for it to function as a physical barrier during the postoperative adhesion formation period. Nine female WI rats weighing 300–400 g were used. Discs 8 mm in diameter were cut out of dry IHA membranes made of IHA with a swelling rate (wet weight/dry weight) of either 2.47 (high-swelling IHA) or 1.94 (low-swelling IHA). They were placed in saline to swell and then washed with saline before subcutaneous implantation in four pockets in each rat. The high-swelling IHA started to degrade more rapidly than the low-swelling IHA. There was no evidence of degradation of the low-swelling IHA until day 7, but once it had started, the speed of degradation tended to be similar to that of the high-swelling IHA. The present results showed that, when IHA is implanted subcutaneously in rats, it is degraded over time in a phased process. The swelling rate required for the use of IHA as a postoperative adhesion barrier was also suggested.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Microcapsule of sweet orange essential oil changes gut microbiota in diet-induced obese rats

Highlights: • Sweet orange essential oil (SOEO) microcapsules had weight loss effect on obese SD rats induced by high-fat diet. • SOEO microcapsules increased the relative abundance of Bifidobacterium (genus-level) in gut microbiota. • SOEO microcapsules protected gut barrier and decreased gut endotoxin levels by increasing the content of Bifidobacterium. Obesity is associated with the changes in gut microbiota. The aim of present study was to investigate the effects of sweet orange essential oil (SOEO) microcapsules on body weight and gut microbiota in obese rats induced by high-fat diet. By analyzing the body weight, fat rate and the sequence of cloned microbial small-subunit ribosomal RNA genes (16S rDNA) in rats fecal samples, we found that SOEO microcapsules decreased the body weight and increased the relative abundance of Bifidobacterium (genus-level) in gut microbiota. The analysis of endotoxin content proved that SOEO microcapsules protected gut barrier and decreased gut endotoxin levels by increasing the content of Bifidobacterium, then ameliorated low-grade inflammation, achieving the goal of losing weight. This might be the mechanism of SOEO microcapsules to lose body weight and provided a novel anti-obesity dietary supplement.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Rats use memory confidence to guide decisions

Memory enables access to past experiences to guide future behavior. Humans can determine which memories to trust (high confidence) and which to doubt (low confidence). How memory retrieval, memory confidence, and memory-guided decisions are related, however, is not understood. In particular, how confidence in memories is used in decision making is unknown. We developed a spatial memory task in which rats were incentivized to gamble their time: betting more following a correct choice yielded greater reward. Rat behavior reflected memory confidence, with higher temporal bets following correct choices. We applied machine learning to identify a memory decision variable and built a generative model of memories evolving over time that accurately predicted both choices and confidence reports. Our results reveal in rats an ability thought to exist exclusively in primates and introduce a unified model of memory dynamics, retrieval, choice, and confidence.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Bisphenol A, bisphenol F and bisphenol S affect differently 5α-reductase expression and dopamine–serotonin systems in the prefrontal cortex of juvenile female rats

Background: Early-life exposure to the endocrine disruptor bisphenol A (BPA) affects brain function and behavior, which might be attributed to its interference with hormonal steroid signaling and/or neurotransmitter systems. Alternatively, the use of structural analogs of BPA, mainly bisphenol F (BPF) and bisphenol S (BPS), has increased recently. However, limited in vivo toxicity data exist. Objectives: We investigated the effects of BPA, BPF and BPS on 5α-reductase (5α-R), a key enzyme involved in neurosteroidogenesis, as well as on dopamine (DA)- and serotonin (5-HT)-related genes, in the prefrontal cortex (PFC) of juvenile female rats. Methods: Gestating Wistar rats were treated with either vehicle or 10 μg/kg/day of BPA, BPF or BPS from gestational day 12 to parturition. Then, female pups were exposed from postnatal day 1 through day 21 (PND21), when they were euthanized and RT-PCR, western blot and quantitative PCR-array experiments were performed. Results: BPA decreased 5α-R2 and 5α-R3 mRNA and protein levels, while both BPF and BPS decreased 5α-R3 mRNA levels in PFC at PND21. Further, BPA, BPF and BPS significantly altered, respectively, the transcription of 25, 56 and 24 genes out of the 84 DA and 5-HT-related genes assayed. Of particular interest was the strong induction by all these bisphenols of Cyp2d4, implicated in corticosteroids synthesis. Conclusions: Our results demonstrate for the first time that BPA, BPF and BPS differentially affect 5α-R and genes related to DA/5-HT systems in the female PFC. In vivo evidence of the potential adverse effects of BPF and BPS in the brain of mammals is provided in this work, raising questions about the safety of these chemicals as substitutes for BPA. - Highlights: • Juvenile prefrontal cortex of female rats exposed to bisphenol A, F or S was analyzed. • We provide the first in vivo data of BPF and BPS effects in mammal brain. • BPA, BPF and BPS differently affected dopamine and serotonin-related genes. • 5α-reductase was found as a potential target for BPA action in juvenile female brain.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Neurotransmitter changes in rat brain regions following glyphosate exposure

Highlights: • Glyphosate oral exposure caused neurotoxicity in rats. • Brain regions were susceptible to changes in CNS monoamine levels. • Glyphosate reduced 5-HT, DA, NE levels in a brain regional- and dose-related manner. • Glyphosate altered the serotoninergic, dopaminergic and noradrenergic systems. The effects of glyphosate oral exposure (35, 75, 150 and 800 mg/kg bw, 6 days) on brain region monoamine levels of male Wistar rats were examined. Glyphosate-treated rats (35, 75, 150 and 800 mg/kg bw, 6 days), had no visible injury, i.e., no clinical signs of dysfunction were observed. After last dose of glyphosate, serotonin (5-HT), dopamine (DA) and norepinephrine (NE) and its metabolites levels were determined in the brain regions striatum, hippocampus, prefrontal, cortex, hypothalamus and midbrain, by HPLC. Glyphosate caused statistically significant changes in the 5-HT and its metabolite 5-hydroxy-3-indolacetic acid (5-HIAA), DA and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and NE and its metabolite 3-metoxy-4-hydroxyphenylethyleneglycol (MHPG) levels in a brain regional- and dose-related manner. Moreover, glyphosate, dose-dependent, evoked a statistically significant increase in 5-HT turnover in striatum and hypothalamus and in DA turnover in prefrontal cortex and hippocampus, and a statistically significant decrease in NE turnover in prefrontal cortex and hypothalamus. The present findings indicate that glyphosate significantly altered central nervous system (CNS) monoaminergic neurotransmitters in a brain regional- and dose-related manner, effects that may contribute to the overall spectrum of neurotoxicity caused by this herbicide.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Report of final results regarding brain and heart tumors in Sprague-Dawley rats exposed from prenatal life until natural death to mobile phone radiofrequency field representative of a 1.8 GHz GSM base station environmental emission

Highlights: • Carcinogenic effects of exposure to RFR generated by base stations of mobile phone on rats. • Increased incidence of tumors of the brain and heart in RFR-exposed rats. • Call for the re-evaluation of IARC conclusions on the carcinogenic potential of RFR in humans. In 2011, IARC classified radiofrequency radiation (RFR) as possible human carcinogen (Group 2B). According to IARC, animals studies, as well as epidemiological ones, showed limited evidence of carcinogenicity. In 2016, the NTP published the first results of its long-term bioassays on near field RFR, reporting increased incidence of malignant glial tumors of the brain and heart Schwannoma in rats exposed to GSM – and CDMA – modulated cell phone RFR. The tumors observed in the NTP study are of the type similar to the ones observed in some epidemiological studies of cell phone users.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2018

Results of lifespan exposure to continuous and intermittent extremely low frequency electromagnetic fields (ELFEMF) administered alone to Sprague Dawley rats

Highlights: • Carcinogenic effects of ELFEMF whole-body chronic exposure were evaluated on rats. • Exposure to ELFEMF alone does not represent risk factor for neoplastic development. • ELFEMF might act as a cancer enhancer if co-administered to other known carcinogens. Up to now, experimental studies on rodents have failed to provide definitive confirmation of the carcinogenicity of extremely low frequency electromagnetic fields (ELFEMF). Two recent studies performed in our laboratory on Sprague-Dawley rats reported a statistically significant increase in malignant tumors of different sites (mammary gland, C-cells carcinoma, hemolymphoreticular neoplasia, and malignant heart Schwannoma) when ELFEMF exposure was associated with exposure to formaldehyde (50 mg/l) or acute low dose of γ-radiation (0.1 Gy) (Soffritti et al., 2016a) (Soffritti et al., 2016b). The same doses of known carcinogenic agents (50 mg/l formaldehyde, or acute 0.1 Gy γ-radiation), when administered alone, previously failed to induce any statistically significant increase in the incidence of total and specific malignant tumors in rats of the same colony.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2013

Influence of Age on the Relative Biological Effectiveness of Carbon Ion Radiation for Induction of Rat Mammary Carcinoma

Purpose: The risk of developing secondary cancer after radiotherapy, especially after treatment of childhood cancers, remains a matter of concern. The high biological effects of carbon-ion radiation have enabled powerful radiotherapy, yet the approach is commonly restricted to the treatment of adults. Susceptibility of the fetus to particle radiation–induced cancer is also unclear. The present study is aimed to investigate the effect of carbon-ion irradiation in childhood on breast carcinogenesis. Methods and Materials: We irradiated female Sprague-Dawley rats of various ages (embryonic days 3, 13, and 17 and 1, 3, 7, and 15 weeks after birth) with {sup 137}Cs γ rays or a 290-MeV/u monoenergetic carbonion beam (linear energy transfer, 13 keV/μm). All animals were screened weekly for mammary carcinoma by palpation until they were 90 weeks old. Results: Irradiation of fetal and mature (15-week-old) rats with either radiation source at a dose of 0.2 or 1 Gy did not substantially increase the hazard ratio compared with the nonirradiated group. Dose responses (0.2-2.0 Gy) to γ rays were similar among the groups of rats irradiated 1, 3, and 7 weeks after birth. The effect of carbon ions increased along with the age at the time of irradiation, indicating relative biological effectiveness values of 0.2 (−0.3, 0.7), 1.3 (1.0, 1.6), and 2.8 (1.8, 3.9) (mean and 95% confidence interval) for animals that were 1, 3, and 7 weeks of age, respectively. Conclusions: Our findings imply that carbonion therapy may be associated with a risk of secondary breast cancer in humans, the extent of which may depend on the age of the patient at the time of irradiation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects

Purpose: Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed the dose-limiting toxicity. Methods and Materials: A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects. Results: Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD. Conclusions: In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation

Purpose: In pediatric cancer survivors treated with whole-brain irradiation (WBI), long-term cognitive deficits and morbidity develop that are poorly understood and for which there is no treatment. We describe similar cognitive defects in juvenile WBI rats and correlate them with alterations in diffusion tensor imaging and magnetic resonance spectroscopy (MRS) during brain development. Methods and Materials: Juvenile Fischer rats received clinically relevant fractionated doses of WBI or a high-dose exposure. Diffusion tensor imaging and MRS were performed at the time of WBI and during the subacute (3-month) and late (6-month) phases, before behavioral testing. Results: Fractional anisotropy in the splenium of the corpus callosum increased steadily over the study period, reflecting brain development. WBI did not alter the subacute response, but thereafter there was no further increase in fractional anisotropy, especially in the high-dose group. Similarly, the ratios of various MRS metabolites to creatine increased over the study period, and in general, the most significant changes after WBI were during the late phase and with the higher dose. The most dramatic changes observed were in glutamine-creatine ratios that failed to increase normally between 3 and 6 months after either radiation dose. WBI did not affect the ambulatory response to novel open field testing in the subacute phase, but locomotor habituation was impaired and anxiety-like behaviors increased. As for cognitive measures, the most dramatic impairments were in novel object recognition late after either dose of WBI. Conclusions: The developing brains of juvenile rats given clinically relevant fractionated doses of WBI show few abnormalities in the subacute phase but marked late cognitive alterations that may be linked with perturbed MRS signals measured in the corpus callosum. This pathomimetic phenotype of clinically relevant cranial irradiation effects may be useful for modeling, mechanistic evaluations, and testing of mitigation approaches.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2024

Non-DNA radiosensitive targets that initiate persistent behavioral deficits in rats exposed to space radiation

Predicting future CNS risks for astronauts during deep-space missions will rely substantially on ground-based rodent data with space-relevant ions and behaviors. For rats, the accumulated evidence indicates that less densely ionizing radiation, such as 4 He and 12 C ions, induce behavior deficits at lower doses than densely ionizing ions, such as 48 Ti and 56 Fe. However, this observation conflicts with standard somatic radiobiology, in which densely ionizing ions are generally more effective than less densely ionizing ions, and where the DNA/nucleus is the accepted target for radiation-induced tumorigenesis, cytogenetic aberrations, genetic mutations, and reproductive cell death. To gain deeper insight into the subcellular nature of the radiation targets for behavior risks, we compared the effects of dose, fluence, and linear energy transfer (LET) of 4 He and 56 Fe particles using existing datasets for four distinct behavioral outcomes in rats: elevated plus maze (EPM-anxiety), novel object recognition (NOR-memory), operant responding (OR-response to environmental stimuli), and attentional set-shifting (ATSET-cognitive flexibility). We confirmed that less densely ionizing particles (except protons) showed ~100-fold lower threshold doses than densely ionizing particles for behavioral deficits (0.1–1 cGy for 4 He vs. 15–100 cGy for 56 Fe). However, when analyzed by fluence the behavioral responses converged, indicating that 4 He and 56 Fe were equally effective on a per-track basis. When analyzed by LET, there were ~100-fold differences in the LET for maximum effectiveness for behavioral deficits and DNA endpoints (~1 vs ~100 keV/μm, respectively). These unique features of radiation-induced behavioral deficits (high sensitivity to particles in the 1-keV/μm range, insensitivity to protons in the 0.2 keV/μm range, and isofluence dependence for particles with LET>1 keV/μm) provide evidence in support of a new hypothesis of sub-micron sized radiosensitive targets for behavioral effects consistent with the thickness of plasma membranes and/or small subcellular structures, smaller than a whole synapse. Like our behavior findings, mouse immature oocyte killing which is known to have a plasma membrane target was also better explained by fluence, rather than dose. In contrast, fluence analyses for DNA/nuclear endpoints in somatic cells (e.g., tumor induction, chromosome aberrations) showed opposite results, suggesting that behavior targets are not DNA. Our findings raise questions regarding the identity of subcellular targets and the multi-cellular functional unit for behavior risks, low-dose susceptibility, and generalizability from rat to other species and astronauts.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗