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At least 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
NASA NTRS1994

An initiation-promotion model of tumour prevalence from high-charge and energy radiations

A repair/misrepair kinetic model for multiple radiation-induced lesions (mutation inactivation) is coupled to a two-mutation model of initiation-promotion in tissue to provide a parametric description of tumour prevalence in the mouse Harderian gland from high-energy and charge radiations. Track-structure effects are considered using an action-cross section model. Dose-response curves are described for gamma rays and relativistic ions, and good agreement with experiment is found. The effects of nuclear fragmentation are also considered for high-energy proton and alpha-particle exposures. The model described provides a parametric description of age-dependent cancer induction for a wide range of radiation fields. Radiosensitivity parameters found in the model for an initiation mutation (sigma 0 = 7.6 x 10(-10) cm2 and D0 = 148.0 Gy) are somewhat different than previously observed for neoplastic transformation of C3H10T1/2 cell cultures (sigma 0 = 0.7 x 10(-10) cm2 and D0 = 117.0 Gy). We consider the two hypotheses that radiation acts solely as an initiator or as both initiator and promoter and make model calculations for fractionation exposures from gamma rays and relativistic Fe ions. For fractionated Fe exposures, an inverse-dose-rate effect is provided by a promotion hypothesis with an increase of 30% or more, dependent on the dose level and fractionation schedule, using a mutation rate for promotion similar to that of single-gene mutations.

NASA Discipline Radiation Health↗
NASA NTRS1995

Association of particulate air pollution and acute mortality: involvement of ultrafine particles?

Recent epidemiological studies show an association between particulate air pollution and acute mortality and morbidity down to ambient particle concentrations below 100 micrograms/m3. Whether this association also implies a causality between acute health effects and particle exposure at these low levels is unclear at this time; no mechanism is known that would explain such dramatic effects of low ambient particle concentrations. Based on results of our past and most recent inhalation studies with ultrafine particles in rats, we propose that such particles, that is, particles below approximately 50 nm in diameter, may contribute to the observed increased mortality and morbidity In the past we demonstrated that inhalation of highly insoluble particles of low intrinsic toxicity, such as TiO2, results in significantly increased pulmonary inflammatory responses when their size is in the ultrafine particle range, approximately 20 nm in diameter. However, these effects were not of an acute nature and occurred only after prolonged inhalation exposure of the aggregated ultrafine particles at concentrations in the milligrams per cubic meter range. In contrast, in the course of our most recent studies with thermodegradation products of polytetrafluoroethylene (PTFE) we found that freshly generated PTFE fumes containing singlet ultrafine particles (median diameter 26 nm) were highly toxic to rats at inhaled concentrations of 0.7-1.0 x 10(6) particles/cm3, resulting in acute hemorrhagic pulmonary inflammation and death after 10-30 min of exposure. We also found that work performance of the rats in a running wheel was severely affected by PTFE fume exposure. These results confirm reports from other laboratories of the highly toxic nature of PTFE fumes, which cannot be attributed to gas-phase components of these fumes such as HF, carbonylfluoride, or perfluoroisobutylene, or to reactive radicals. The calculated mass concentration of the inhaled ultrafine PTFE particles in our studies was less than 60 micrograms/m3, a very low value to cause mortality in healthy rats. Aging of the fumes with concomitant aggregation of the ultrafine particles significantly decreases their toxicity. Since ultrafine particles are always present in the urban atmosphere, we suggest that they play a role in causing acute lung injury in sensitive parts of the population.

NASA Discipline Environmental Health↗
NASA NTRS1985

SEM visualization of glycosylated surface molecules using lectin-coated microspheres

There are several techniques currently used to localize glycosylated surface molecules by scanning electron microscopy (Grinnell, 1980; Molday, 1976; Linthicum and Sell, 1975; Nicolson, 1974; Lo Buglio, et al, 1972). A simple and rapid method, using a modification of Grinnell's technique is reported here. Essentially, microspheres coated with Concavalin A are used to bind to glycosylated regions of the palatal shelf epithelium and are visualized in the scanning electron microscope (SEM).

Non-NASA Center↗
NASA NTRS1988

Core temperature is regulated, although at a lower temperature, in rats exposed to hypergravic fields

1. In rats acclimated to 23 degrees C (RT rats) or 5 degrees C (CA rats), core temperature (Tc), tail temperature (Tt) and oxygen consumption (VO2) were measured during exposure to a hypergravic field. 2. Rats were exposed for 5.5 h to a 3 g field while ambient temperature (Ta) was varied. For the first 2 h, Ta was 25 degrees C; then Ta was raised to 34 degrees C for 1.5 h. During this period of warm exposure, Tc increased 4 degrees C in both RT and CA rats. Finally, Ta was returned to 25 degrees C for 2 h, and Tc decreased toward the levels measured prior to warm exposure. 3. In a second experiment at 3 g, RT and CA rats were exposed to cold (12 degrees C) after two hours at 25 degrees C. During the one hour cold exposure, Tc fell 1.5 degrees C in RT and 0.5 degree C in CA rats. After cold exposure, when ambient temperature was again 25 degrees C, Tc of RT and CA rats returned toward the levels measured prior to the thermal disturbance. 4. Rats appear to regulate their temperature, albeit at a lower level, in a 3 g field.

NASA Discipline Number 40-30↗
NASA NTRS1988

Micronucleation in the lens epithelium following in vivo exposure to physical and chemical mutagens

Rats were exposed to cataractogenic doses of known physical and chemical genotoxic agents in order to study the efficacy of using micronuclei to monitor mutagenicity in the lens epithelium. The total numbers of micronuclei were counted in lens epithelia from rats exposed to graded doses of either 250 kVp X-rays or the anti-leukemic drug, 1,4 dimethanesulfonoxybutane (Myleran (R)). The results indicate a dose-dependent incidence of micronucleation in the lens epithelium following exposure. The findings are consistent with the hypothesis that the cataractogenicity of certain agents may be related to their effect on the genome of lens epithelial cells.

NASA Discipline Number 22-70↗
NASA NTRS1991

Effects of murine leukemia virus env gene proteins on macrophage-mediated cytotoxicity in vitro

F5b Tumor cells were incubated with concentrated culture supernatants taken from cells resistant (F5m) or sensitive (F5b) to contact-dependent macrophage cytotoxicity. Macrophage cell line B6MP102 and murine peritoneal macrophages killed targets incubated with supernatants taken from sensitive cells but poorly killed cells incubated in supernatants isolated from resistant cells. Membranes from cells resistant to macrophage killing, F5m, were fused into F5b cells. The fused F5b cells were killed significantly less than F5b cells fused with F5b cell membranes or untreated F5b cells. The decreased killing of F5b cells corresponded to increased concentrations of gp70(a) molecules on F5b cells. Affinity purified gp70(a) was added to cytotoxicity assays but failed to inhibit macrophage cytotoxicity. P15E molecules were detectable on both F5b and F5m cells. In addition, a synthetic peptide found to exhibit the inhibitory properties of p15E was added to cytotoxicity assays. P15E synthetic peptide also did not inhibit macrophage cytotoxicity. Therefore, env gene proteins of murine leukemia virus do not appear responsible for inducing tumor cell resistance to activated macrophage contact-dependent cytotoxicity.

NASA Program NSCORT↗
NASA NTRS1994

Acute, 2-week, and 13-week inhalation toxicity studies on dimethylethoxysilane vapor in Fischer 344 rats

Dimethylethoxysilane (DMES), a volatile liquid, is used by NASA to waterproof the heat-protective silica tiles and blankets on the Space Shuttle. Acute, 2-wk, and 13-wk inhalation exposures to DMES vapor were conducted in male and female Fischer 344 rats. In the acute study, rats were exposed to 4000, 2000, 1000, 500, or 0 (control) ppm DMES for 4 h and observed for 14 days. There were no deaths. Narcosis and ataxia were observed in rats of the two highest concentrations only. These signs disappeared within 1 h following exposure. There were no DMES-related gross or microscopic tissue lesions in rats of all exposure groups. In the 2-wk study, rats were exposed for 6 h/day, 5 days/wk to 3000, 1000, 300, 100, or 0 ppm DMES. During exposure, narcosis was observed in rats of the 3000 and 1000 ppm groups. There was a mild decrease in body weight gain in rats of the 3000 ppm group. A decrease in platelet count, an increase in bile acids, and reduced weights of the thymus, testis, and liver were observed in rats of the 3000 ppm group. Microscopically, hypospermatogenesis and spermatid giant cells were observed in the seminiferous tubules of the testes of rats exposed to 3000 ppm DMES. In the 13-wk study, rats were exposed 6 h/day, 5 days/wk to 2000, 600, 160, 40, or 0 ppm DMES. During exposure, rats of the 2000 ppm group exhibited mild narcosis and loss of startle reflex. Recovery from these central nervous system signs was rapid. Body weights were mildly decreased for rats of the 2000 ppm group. There were no exposure-related effects in hematology, serum chemistry, or urinalysis. Female rats of the 2000 ppm group had delayed estrous cycles (6 days compared to 5 days in control rats). Noteworthy organ weight changes in rats of the 2000 ppm group included decreases in thymus, liver, and testicular weights; however, pathologic lesions were observed in the testes only. Sperm motility, epididymal sperm count, and testicular spermatid count were dramatically reduced. Microscopic lesions included degeneration of the seminiferous tubular cells, pyknosis or absence of germ cells, and hypospermia in the epididymis. Rats of the 600 ppm group had a slight decrease in thymic weight and a transient decrease in body weight. Results of the acute, 2-wk, and 13-wk inhalation studies indicate DMES concentrations of 1000 ppm and higher produce narcosis that rapidly disappears following exposure. Repeated exposure of rats to DMES at either 3000 ppm for 2 wk or 2000 ppm for 13 wk caused testicular atrophy and hypospermia in male rats. Female rats exposed to 2000 ppm for 13 wk had delayed estrous cycles. Toxicological effects in rats of the 600 ppm group were minimal and equivocal. The 160 ppm concentration was a no-observable-effect level (NOEL) for 13 wk of exposure to DMES.

NASA Discipline Number 04-10↗
NASA NTRS2002

Transforming growth factor-beta1 mediates cellular response to DNA damage in situ

Transforming growth factor (TGF)-beta1 is rapidly activated after ionizing radiation, but its specific role in cellular responses to DNA damage is not known. Here we use Tgfbeta1 knockout mice to show that radiation-induced apoptotic response is TGF-beta1 dependent in the mammary epithelium, and that both apoptosis and inhibition of proliferation in response to DNA damage decrease as a function of TGF-beta1 gene dose in embryonic epithelial tissues. Because apoptosis in these tissues has been shown previously to be p53 dependent, we then examined p53 protein activation. TGF-beta1 depletion, by either gene knockout or by using TGF-beta neutralizing antibodies, resulted in decreased p53 Ser-18 phosphorylation in irradiated mammary gland. These data indicate that TGF-beta1 is essential for rapid p53-mediated cellular responses that mediate cell fate decisions in situ.

Non-NASA Center↗
NASA NTRS2001

Dose and dose rate effects of whole-body gamma-irradiation: II. Hematological variables and cytokines

The goal of part II of this study was to evaluate the effects of gamma-radiation on circulating blood cells, functional characteristics of splenocytes, and cytokine expression after whole-body irradiation at varying total doses and at low- and high-dose-rates (LDR, HDR). Young adult C57BL/6 mice (n = 75) were irradiated with either 1 cGy/min or 80 cGy/min photons from a 60Co source to cumulative doses of 0.5, 1.5, and 3.0 Gy. The animals were euthanized at 4 days post-exposure for in vitro assays. Significant dose- (but not dose-rate-) dependent decreases were observed in erythrocyte and blood leukocyte counts, hemoglobin, hematocrit, lipopolysaccharide (LPS)-induced 3H-thymidine incorporation, and interleukin-2 (IL-2) secretion by activated spleen cells when compared to sham-irradiated controls (p < 0.05). Basal proliferation of leukocytes in the blood and spleen increased significantly with increasing dose (p < 0.05). Significant dose rate effects were observed only in thrombocyte counts. Plasma levels of transforming growth factor-beta 1 (TGF-beta 1) and splenocyte secretion of tumor necrosis factor-alpha (TNF-alpha) were not affected by either the dose or dose rate of radiation. The data demonstrate that the responses of blood and spleen were largely dependent upon the total dose of radiation employed and that an 80-fold difference in the dose rate was not a significant factor in the great majority of measurements.

NASA Discipline Radiation Health↗
NASA NTRS2001

Dose and dose rate effects of whole-body gamma-irradiation: I. Lymphocytes and lymphoid organs

The major goal of part I of this study was to compare varying doses and dose rates of whole-body gamma-radiation on lymphoid cells and organs. C57BL/6 mice (n = 75) were exposed to 0, 0.5, 1.5, and 3.0 Gy gamma-rays (60Co) at 1 cGy/min (low-dose rate, LDR) and 80 cGy/min (high-dose rate, HDR) and euthanized 4 days later. A significant dose-dependent loss of spleen mass was observed with both LDR and HDR irradiation; for the thymus this was true only with HDR. Decreasing leukocyte and lymphocyte numbers occurred with increasing dose in blood and spleen at both dose rates. The numbers (not percentages) of CD3+ T lymphocytes decreased in the blood in a dose-dependent manner at both HDR and LDR. Splenic T cell counts decreased with dose only in HDR groups; percentages increased with dose at both dose rates. Dose-dependent decreases occurred in CD4+ T helper and CD8+ T cytotoxic cell counts at HDR and LDR. In the blood the percentages of CD4+ cells increased with increasing dose at both dose rates, whereas in the spleen the counts decreased only in the HDR groups. The percentages of the CD8+ population remained stable in both blood and spleen. CD19+ B cell counts and percentages in both compartments declined markedly with increasing HDR and LDR radiation. NK1.1+ natural killer cell numbers and proportions remained relatively stable. Overall, these data indicate that the observed changes were highly dependent on the dose, but not dose rate, and that cells in the spleen are more affected by dose rate than those in blood. The results also suggest that the response of lymphocytes in different body compartments may be variable.

NASA Discipline Radiation Health↗
NASA NTRS2001

Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice

Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm(+/+) mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.

Non-NASA Center↗
NASA NTRS2001

Time course changes in [Ca2+]i, force, and protein content in hindlimb-suspended mouse soleus muscles

BACKGROUND: Exposure to reduced gravitational forces during spaceflight is associated with significant reductions in skeletal muscle mass and strength. The purpose of this study was to test the hypothesis that increases in resting cytosolic free calcium concentration ([Ca2+]i) would precede reductions in protein content and maximal isometric tetanic force (Po) in mouse soleus muscle after initiation of hindlimb suspension. METHODS: Female ICR mice (n = 42) were hindlimb suspended for 1, 2, 3, 5, or 7 d; weight-matched mice were used as controls. Following the hindlimb suspension, the left soleus muscle was used to determine Po in vitro and the right soleus muscle was used to determine protein content and [Ca2+]i via confocal laser scanning microscopy. RESULTS: Compared with controls, [Ca2+]i was elevated by 38% at 2 d, and 117% at 7 d. Compared with controls, soleus muscle total and myofibrillar protein contents were reduced 27-29% and 30-34%, respectively, at 5-7 d after initiation of hindlimb suspension. Compared with controls, soleus muscle Po was decreased by 24% at 3 d, and 38% at 7 d. CONCLUSION: It appears that resting cytosolic Ca2+ homeostasis is disturbed soon after the initiation of hindlimb suspension, and these elevations in [Ca2+]i may play a role in initiating soleus muscle atrophy.

Non-NASA Center↗
NASA NTRS2001

Intracranial distribution of the sympathetic system in mice: DiI tracing and immunocytochemical labeling

The intracranial distribution of the cephalic branches of the superior cervical ganglion (scg) was studied in mice using indocarbocyanine dye (DiI) anterograde tracing. Two main branches were traced from the scg. The first branch joined the nerve of the pterygoid canal (the vidian nerve), npc, from which several intracranial sympathetic branches passed to the branches of the trigeminal nerve (tgn), abducent nerve (abn), trochlear nerve (trn), and oculomotor nerve (ocn). Most of the second branch joined the abn, from which sympathetic fibers dispersed in the distal region of the trigeminal ganglion (tgg) to form a plexus close to the ganglion's branches. Branches from this plexus joined the branches of the tgn, trn, and ocn. Several minor branches arising from the second branch of the scg were also observed. One formed a sympathetic plexus around the internal carotid artery (ica); a second formed a sympathetic plexus in the proximal region of tgg, close to its root; and a third branch coursed laterally to reach the ear by passing along the greater petrosal nerve (gpn). All of the intracranial trajectories traced from scg were found to be catecholaminergic, and likely sympathetic, using tyrosine hydroxylase (TH) immunocytochemistry.

Non-NASA Center↗
NASA NTRS2001

Differential global gene expression in red and white skeletal muscle

The differences in gene expression among the fiber types of skeletal muscle have long fascinated scientists, but for the most part, previous experiments have only reported differences of one or two genes at a time. The evolving technology of global mRNA expression analysis was employed to determine the potential differential expression of approximately 3,000 mRNAs between the white quad (white muscle) and the red soleus muscle (mixed red muscle) of female ICR mice (30-35 g). Microarray analysis identified 49 mRNA sequences that were differentially expressed between white and mixed red skeletal muscle, including newly identified differential expressions between muscle types. For example, the current findings increase the number of known, differentially expressed mRNAs for transcription factors/coregulators by nine and signaling proteins by three. The expanding knowledge of the diversity of mRNA expression between white and mixed red muscle suggests that there could be quite a complex regulation of phenotype between muscles of different fiber types.

Non-NASA Center↗
NASA NTRS2000

Hematological and TGF-beta variations after whole-body proton irradiation

The acute effects of proton whole-body irradiation on five bone-marrow-derived cell types and transforming growth factor-beta 1 (TGF-beta 1) were examined and compared to the effects of photons (60Co). C57BL/6 mice were exposed to 3 Gy (0.4 Gy/min) protons at spread-out Bragg peak (SOBP), protons at entry (E), or 60Co and euthanized on days 0.5-17 thereafter. 60Co-irradiated animals had decreased erythrocytes, hemoglobin and hematocrit at 12 hours post-exposure; depression was not noted in proton (SOBP or E)-irradiated groups until day 4. Significantly decreased leukocyte counts were observed at this same time in all irradiated groups, with lymphocyte loss being greater than that of monocytes, and the depression was generally maintained. In contrast, the levels of neutrophils and thrombocytes fluctuated, especially during the first week; significant differences were noted among irradiated groups in neutrophil levels. Plasma TGF-beta 1 was elevated on day 7 in the 60Co, but not proton, irradiated mice. Collectively, the data show that dramatic and persistent changes occurred in all irradiated groups. However, few differences in assay results were seen between animals exposed to protons (SOBP or E) or photons, as well as between the groups irradiated with either of the two regions of the proton Bragg curve.

Non-NASA Center↗
NASA NTRS2000

Impact of p53 status on heavy-ion radiation-induced micronuclei in circulating erythrocytes

Transgenic mice that differed in their p53 genetic status were exposed to an acute dose of highly charged and energetic (HZE) iron particle radiation. Micronuclei (MN) in two distinct populations of circulating peripheral blood erythrocytes, the immature reticulocytes (RETs) and the mature normochromatic erythrocytes (NCEs), were measured using a simple and efficient flow cytometric procedure. Our results show significant elevation in the frequency of micronucleated RETs (%MN-RETs) at 2 and 3 days post-radiation. At 3 days post-irradiation, the magnitude of the radiation-induced MN-RET was 2.3-fold higher in the irradiated p53 wild-type animals compared to the unirradiated controls, 2.5-fold higher in the p53 hemizygotes and 4.3-fold higher in the p53 nullizygotes. The persistence of this radiation-induced elevation of MN-RETs is dependent on the p53 genetic background of the animal. In the p53 wild-type and p53 hemizygotes, %MN-RETs returned to control levels by 9 days post-radiation. However, elevated levels of %MN-RETs in p53 nullizygous mice persisted beyond 56 days post-radiation. We also observed elevated MN-NCEs in the peripheral circulation after radiation, but the changes in radiation-induced levels of MN-NCEs appear dampened compared to those of the MN-RETs for all three strains of animals. These results suggest that the lack of p53 gene function may play a role in the iron particle radiation-induced genomic instability in stem cell populations in the hematopoietic system.

NASA Discipline Radiation Health↗
NASA NTRS2001

Hippocampal place-cell firing during movement in three-dimensional space

"Place" cells of the rat hippocampus are coupled to "head direction" cells of the thalamus and limbic cortex. Head direction cells are sensitive to head direction in the horizontal plane only, which leads to the question of whether place cells similarly encode locations in the horizontal plane only, ignoring the z axis, or whether they encode locations in three dimensions. This question was addressed by recording from ensembles of CA1 pyramidal cells while rats traversed a rectangular track that could be tilted and rotated to different three-dimensional orientations. Cells were analyzed to determine whether their firing was bound to the external, three-dimensional cues of the environment, to the two-dimensional rectangular surface, or to some combination of these cues. Tilting the track 45 degrees generally provoked a partial remapping of the rectangular surface in that some cells maintained their place fields, whereas other cells either gained new place fields, lost existing fields, or changed their firing locations arbitrarily. When the tilted track was rotated relative to the distal landmarks, most place fields remapped, but a number of cells maintained the same place field relative to the x-y coordinate frame of the laboratory, ignoring the z axis. No more cells were bound to the local reference frame of the recording apparatus than would be predicted by chance. The partial remapping demonstrated that the place cell system was sensitive to the three-dimensional manipulations of the recording apparatus. Nonetheless the results were not consistent with an explicit three-dimensional tuning of individual hippocampal neurons nor were they consistent with a model in which different sets of cells are tightly coupled to different sets of environmental cues. The results are most consistent with the statement that hippocampal neurons can change their "tuning functions" in arbitrary ways when features of the sensory input or behavioral context are altered. Understanding the rules that govern the remapping phenomenon holds promise for deciphering the neural circuitry underlying hippocampal function.

Non-NASA Center↗
NASA NTRS2001

p53 deficiency alters the yield and spectrum of radiation-induced lacZ mutants in the brain of transgenic mice

Exposure to heavy particle radiation in the galacto-cosmic environment poses a significant risk in space exploration and the evaluation of radiation-induced genetic damage in tissues, especially in the central nervous system, is an important consideration in long-term manned space missions. We used a plasmid-based transgenic mouse model system, with the pUR288 lacZ transgene integrated in the genome of every cell of C57Bl/6(lacZ) mice, to evaluate the genetic damage induced by iron particle radiation. In order to examine the importance of genetic background on the radiation sensitivity of individuals, we cross-bred p53 wild-type lacZ transgenic mice with p53 nullizygous mice, producing lacZ transgenic mice that were either hemizygous or nullizygous for the p53 tumor suppressor gene. Animals were exposed to an acute dose of 1 Gy of iron particles and the lacZ mutation frequency (MF) in the brain was measured at time intervals from 1 to 16 weeks post-irradiation. Our results suggest that iron particles induced an increase in lacZ MF (2.4-fold increase in p53+/+ mice, 1.3-fold increase in p53+/- mice and 2.1-fold increase in p53-/- mice) and that this induction is both temporally regulated and p53 genotype dependent. Characterization of mutants based on their restriction patterns showed that the majority of the mutants arising spontaneously are derived from point mutations or small deletions in all three genotypes. Radiation induced alterations in the spectrum of deletion mutants and reorganization of the genome, as evidenced by the selection of mutants containing mouse genomic DNA. These observations are unique in that mutations in brain tissue after particle radiation exposure have never before been reported owing to technical limitations in most other mutation assays.

Non-NASA Center↗