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At least 1,387 records · Page 77
All sourcesNASA NTRSDOE OSTI
NASA NTRS2005

Diet as a factor in behavioral radiation protection following exposure to heavy particles

Major risks associated with radiation exposures on deep space missions include carcinogenesis due to heavy-particle exposure of cancer-prone tissues and performance decrements due to neurological damage produced by heavy particles. Because exposure to heavy particles can cause oxidative stress, it is possible that antioxidants can be used to mitigate these risks (and possibly some health risks of microgravity). To assess the capacity of antioxidant diets to mitigate the effects of exposure to heavy particles, rats were maintained on antioxidant diets containing 2% blueberry or strawberry extract or a control diet for 8 weeks prior to exposure to 1.5 or 2.0 Gy of accelerated iron particles at Brookhaven National Laboratory. Following irradiation rats were tested on a series of behavioral tasks: amphetamine-induced taste aversion learning, operant responding and spatial learning and memory. The results indicated that the performance of the irradiated rats maintained on the antioxidant diets was, in general, significantly better than that of the control animals, although the effectiveness of the diets ameliorating the radiation-induced deterioration in performance varied as a function of both the specific diet and the specific endpoint. In addition, animals fed antioxidant diets prior to exposure showed reduced heavy particle-induced tumorigenesis one year after exposure compared to the animals fed the control diet. These results suggest that antioxidant diets have the potential to serve as part of a system designed to provide protection to astronauts against the effects of heavy particles on exploratory missions outside the magnetic field of the earth.

Non-NASA Center↗
DOE OSTI2021

Repetitive diacetyl vapor exposure promotes ubiquitin proteasome stress and precedes bronchiolitis obliterans pathology

Bronchiolitis obliterans (BO) is a devastating lung disease seen commonly after lung transplant but also seen following severe respiratory tract infection or chemical inhalation exposure. Diacetyl (DA; 2,3-butanedione), highly reactive alpha-diketone is known to cause BO when inhaled, however, the mechanisms of how inhalation exposure leads to BO development remains poorly understood. In the current work, we combined two clinically relevant models for studying the pathogenesis of DA-induced BO: (1) an in vivo rat model of repetitive DA vapor exposures with recovery and (2) an in vitro model of primary human airway epithelial cells exposed to pure DA vapors. Rats exposed to 5 consecutive days 200 parts-per-million DA 6 hrs per day had worsening survival, persistent hypoxemia, poor weight gain, and histologic evidence of BO 14 days after DA exposure cessation. At the end of exposure, increased expression of the ubiquitin stress protein, ubiquitin-C, accumulated within DA-exposed rat lung homogenates, localized primarily to the airway epithelium, the primary site of BO development, and did not occur in air-exposed controls. Lung proteasome activity increased concurrently after DA exposure. In primary human airway cultures, global proteomics analysis identified 519 significantly modified proteins in DA-exposed samples relative to controls with the ubiquitin proteasome system, endosomal reticulum transport, and the response to unfolded protein pathways being upregulated while cell-cell adhesion and oxidation-reduction pathways being downregulated in DA-exposed samples. Altogether, repetitive DA vapor exposure resulted in abundant protein damage, accumulation of polyubiquinated proteins, and ubiquitin proteasome stress prior to the development of chemical-induced BO pathology.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

New Approach Methodology for Assessing Inhalation Risks of a Contact Respiratory Cytotoxicant: Computational Fluid Dynamics-Based Aerosol Dosimetry Modeling for Cross-Species and In Vitro Comparisons

Regulatory agencies are considering alternative approaches to assessing inhalation toxicity that utilizes in vitro studies with human cells and in silico modeling in lieu of additional animal studies. In support of this goal, computational fluid-particle dynamics models were developed to estimate site-specific deposition of inhaled aerosols containing the fungicide, chlorothalonil, in the rat and human for comparisons to prior rat inhalation studies and new human in vitro studies. Under bioassay conditions, the deposition was predicted to be greatest at the front of the rat nose followed by the anterior transitional epithelium and larynx corresponding to regions most sensitive to local contact irritation and cytotoxicity. For humans, simulations of aerosol deposition covering potential occupational or residential exposures (1–50 µm diameter) were conducted using nasal and oral breathing. Aerosols in the 1–5 µm range readily penetrated the deep region of the human lung following both oral and nasal breathing. Under actual use conditions (aerosol formulations >10 µm), the majority of deposited doses were in the upper conducting airways. Beyond the nose or mouth, the greatest deposition in the pharynx, larynx, trachea, and bronchi was predicted for aerosols in the 10–20 µm size range. Only small amounts of aerosols >20 µm penetrated past the pharyngeal region. Using the ICRP clearance model, local retained tissue dose metrics including maximal concentrations and areas under the curve were calculated for each airway region following repeated occupational exposures. These results are directly comparable with benchmark doses from in vitro toxicity studies in human cells leading to estimated human equivalent concentrations that reduce the reliance on animals for risk assessments.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2024

Lipid droplet-associated proteins in alcohol-associated fatty liver disease: A proteomic approach

The earliest manifestation of alcohol-associated liver disease (ALD) is steatosis characterized by deposition of fat in specialized organelles called lipid droplets (LDs). While alcohol administration causes a rise in LD numbers in the hepatocytes, little is known regarding their characteristics that allow their accumulation and size to increase. The aim of the present study is to gain insights into underlying pathophysiological mechanisms by investigating the ethanol-induced changes in hepatic LD proteome as a function of LD size. Adult male Wistar rats (180–200 g BW) were fed with ethanol liquid diet for 6 weeks. At sacrifice, large-, medium-, and small-sized hepatic LD subpopulations (LD1, LD2, and LD3, respectively) were isolated and subjected to morphological and proteomic analyses. Morphological analysis of LD1-LD3 fractions of ethanol-fed rats clearly demonstrated that LD1 contained larger LDs compared with LD2 and LD3 fractions. Our preliminary results from principal component analysis showed that the proteome of different-sized hepatic LD fractions was distinctly different. Proteomic data analysis identified over 2000 proteins in each LD fraction with significant alterations in protein abundance among the three LD fractions. Among the altered proteins, several were related to fat metabolism, including synthesis, incorporation of fatty acid, and lipolysis. Ingenuity pathway analysis revealed increased fatty acid synthesis, fatty acid incorporation, LD fusion, and reduced lipolysis in LD1 compared to LD3. Overall, the proteomic findings indicate that the increased level of protein that facilitates fusion of LDs combined with an increased association of negative regulators of lipolysis dictates the generation of large-sized LDs during the development of alcohol-associated hepatic steatosis. Several significantly altered proteins were identified in different-sized LDs isolated from livers of ethanol-fed rats. Ethanol-induced increases in specific proteins that hinder LD lipid metabolism led to the accumulation and persistence of large-sized LDs in the liver.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1971

Continuous exposure of animals to methylisobutylketone

Continuous exposure of dogs, monkeys, mice, and rats to MIBK for two weeks and all animals except mice for 90 days resulted in measurable adverse effects only in the case of rats. Rat kidney weights and kidney to body weight ratios were significantly elevated after exposure to 410 mg/cu m for two weeks, and kidney and liver organ weights and organ to body weight ratios were elevated after exposure to 820 mg/cu m for two weeks and to 410 mg/cu m for 90 days.

Vernot, E. H.↗
NASA NTRS1973

Contraction kinetics of ventricular muscle from hibernating and nonhibernating mammals.

Temperature-dependent studies of excitability and tension-production kinetics were made on isolated trabecular strips from hibernating hamsters (HH), nonhibernating hamsters (CH), and from rats (R). The strips were electrically driven and isometric tension along with its first time derivative (dP/dt) were recorded. Excitabilities of both hamster tissues were greater than that of rat tissue from 5 to 38 C with HH greater than CH. Peak tension production followed the order of HH greater than CH greater than R at all temperatures below 24 C. Rat preparations showed an optimum peak tension production at about 31 C while HH and CH showed optima between 17 and 24 C. Times to maximal rates of tension rise showed significant variation. In this respect, the order of sensitivity to decreasing temperature was HH greater than CH greater than R.

South, F. E.↗
NASA NTRS1974

Alteration of pituitary-adrenal dynamics induced by a water deprivation regimen

Experiments are described which were designed to assess the degree of adaptation that occurs in rats chronically exposed to the stress of a water-deprivation regimen and to determine if that adaptation represents a normalization of the hypothalamic-pituitary-adrenal axis. There were no significant differences in mean corticosterone concentrations among control nondeprived rats 1, 4, and 8 weeks after the start of the experiment. The water-deprived rats, however, had significantly elevated plasma steroids 1 and 4 weeks after the onset of deprivation as compared to controls, but not after 8 weeks. Thus, there was a significant decrease in mean plasma corticosterone levels during water deprivation from 1 week to 8 weeks.

Sakellaris, P. C.↗
NASA NTRS1974

Continued investigation of kinetic aspects of bone mineral metabolism

The total body calcium in humans was determined by measuring expired Ar-37 after neutron irradiation. The excretion of Ar-37 from humans was found to be much slower than the excretion from rats and dogs, and to be related to the age of a person. A study of the uniformity of the Ar-37 production throughout the thickness of the body was studied using phantoms. The results indicate that it should be possible to obtain a uniformity within plus or minus 3% for the production of Ar-37 per unit of calcium by using a bilateral irradiation. New low background, large volume proportional counters were developed and constructed, for more sensitive measurement of Ar-37 in the expired air from patients. A new irradiation enclosure was developed for measuring total body calcium in rats by the Ar-37 method. With this enclosure the Ar-37 production per gram of calcium is constant with a standard deviation of plus or minus 2.8% for any size rat between 100 and 500 grams. The use of Na-22 as measure of bone replacement in the fractured femur of a dog was not successful.

Palmer, H. E.↗
NASA NTRS1975

Selection of artificial gravity by animals during suborbital rocket flights

White rats selected preferred artificial gravity levels by locomotion in centrifuges consisting of two runways mounted in the nose of sounding rockets. Roll rate of the Aerobee 150A rocket was designed to produce an angular velocity of 45 rpm during 5 min of free-fall, providing a gravity range from 0.3 to 1.5 G depending on a subject's runway position. One animal was released at the high and one at the low gravity position in each flight. Animal positions were continuously recorded. Locomotion patterns during these flights were similar. All four animals explored the entire available G-range. One rat settled at 0.4 G after 2 min; the others crossed the 1-G location in progressively narrower excursions and were near earth gravity at the end of the test period. Tentatively, the data suggest that normal earth-reared rats select earth gravity when available magnitudes include values above and below 1 G. Modification of gravity preference by prolonged exposure to higher or lower levels remains a possibility.

Lange, K. O.↗
NASA NTRS1978

Inhibition of bone formation during space flight

Parameters of bone formation and resorption were measured in rats orbited for 19.5 days aboard the Soviet Cosmos 782 biological satellite. The most striking effects were on bone formation. During flight, rats formed significantly less periosteal bone than did control rats on the ground. An arrest line at both the periosteum and the endosteum of flight animals suggests that a complete cecessation of bone growth occurred. During a 26-day postflight period, the defect in bone formation was corrected. No significant changes in bone resorption were observed.

Morey, E. R.↗
NASA NTRS1979

The joint US-USSR biological satellite program

The joint US-USSR biological satellite missions carried out in 1975 and 1977 using Cosmos 782 and Cosmos 936 spacecraft, respectively, is reviewed. The experimental equipment and the biological specimens aboard the aircraft are considered, and it is noted that Cosmos 782, unlike Cosmos 936, carried no centrifuges for rats, although it did contain a centrifuge where a variety of biological specimens, including carrot tissue and fruit flies, were subjected to artificial gravity during space flight. The ground control groups, designed for biological experiments under simulated space-conditions, are taken into account. The U.S. experiments aboard the aircraft are described, with attention given to the experiments with rats, fish embryos, plants, and insects. Results of the experiments are noted, including the finding that space flight factors, especially weightlessness, have a measurable effect on the erythropoietic and musculoskeletal systems of rats

Souza, K. A.↗
NASA NTRS1979

Mechanism of disorder of plastic processes in tissue during prolonged hypokinesia

The subcellular structures of the myocardium, skeletal muscles, liver and kidneys of adult rats subjected to hypokinesia (in immobilization chambers) for 15, 30, and 45 days were studied. An anabolyser (retabolil) and vitamin D (a Ca metabolism regulator) were administered to two groups of rats. On the second week of hypokinesia, inhibition of synthesis processes was observed. Administration of retabolil increased protein synthesis both in the normal and hypokinesia-subjected rats; however, in the latter group, synthesis did not completely normalize, especially in the myocardium. Administration of vitamin D also stimulated protein synthesis, apparently by normalizing Ca tissue metabolism. The combined action of both preparations was the most effective in normalizing protein synthesis intensity. It was concluded that inhibition of synthesis is related to weakening of hormone synthesis induction and disorder of Ca metabolism.

Makarov, G. A.↗
NASA NTRS1980

Femur-bending properties as influenced by gravity. IV - Limits after high and low weight-bearing

Gravity enhances femur growth as measured in terms of strength, but shows little or even a growth-retarding effect in terms of relative brittleness, defined as the inverse of ultimate or tolerable strain. Chronic weightlessness was simulated by harness suspension or by extrapolation of results from 3-g centrifugation. Experimental results from 45 male, white rats (34-520 d old) were compared to 72 control or baseline rats (28-520 d old) with correction for age and size differences. After suspension, the youngest rats showed subnormal tolerable strains. Combined results, however, although predicting 19 + or 1% below normal strength, after a week of weightlessness, predicted less effect (1 + or - 4%) for the tolerable strain.

Wunder, C. C.↗
NASA NTRS1981

US plant and radiation dosimetry experiments flown on the Soviet satellite Cosmos 1129

Experiments included: 30 young male Wistar SPF rats used for wide range physiological studies; experiments with plants, fungi, insects, and mammalian tissue cultures; radiation physics experiments; a heat convection study; a rat embryology experiment in which an attempt was made to breed 2 male and 5 female rats during the flight; and fertile quail eggs used to determine the effects of spaceflight on avian embryogenesis. Specimens for US experiments were initially prepared at the recovery site or in Moscow and transferred to US laboratories for complete analyses. An overview of the mission focusing on preflight, on orbit, and postflight activities pertinent to the fourteen US experiments aboard Cosmos 1129 is presented.

Heinrich, M. R.↗
NASA NTRS1982

Effect of space flight on bone strength

To test the possibility that spaceflight has a deleterious effect on bone mechanical properties, femur breaking strength by torsional loading in rats that had been flown for 19 days aboard Cosmos 936 was determined. The results showed that femurs from flight rats were less stiff than the flight controls, and failed under torsion at a lower torque and energy of absorption. The defect was corrected following space flight and could be prevented during space flight by centrifuging the rats at 1 x g. Altered bone geometry due to inhibition of bone formation at the periosteal surface provides the most likely explanation for the decrease in bone strength during spaceflight.

Spengler, D. M.↗
NASA NTRS1982

Animal models for simulating weightlessness

NASA has developed a rat model to simulate on earth some aspects of the weightlessness alterations experienced in space, i.e., unloading and fluid shifts. Comparison of data collected from space flight and from the head-down rat suspension model suggests that this model system reproduces many of the physiological alterations induced by space flight. Data from various versions of the rat model are virtually identical for the same parameters; thus, modifications of the model for acute, chronic, or metabolic studies do not alter the results as long as the critical components of the model are maintained, i.e., a cephalad shift of fluids and/or unloading of the rear limbs.

Morey-Holton, E.↗
NASA NTRS1983

Alterations in calcium homeostasis and bone during actual and simulated space flight

Skeletal alteration in experimental animals induced by actual and simulated spaceflight are discussed, noting that the main factor contributing to bone loss in growing rats placed in orbit aboard Soviet Cosmos biosatellites appears to be diminished bone formation. Mechanical unloading is seen as the most obvious cause of bone loss in a state of weightlessness. Reference is made to a study by Roberts et al. (1981), which showed that osteoblast differentiation in the periodontal ligament of the maxilla was suppressed in rats flown in space. Since the maxilla lacks a weight-bearing function, this finding indicates that the skeletal alterations associated with orbital flight may be systemic rather than confined to weight-bearing bones. In addition, the skeletal response to simulated weightlessness may also be systemic (wronski and Morey, 1982). In suspended rats, the hindlimbs lost all weight-bearing functions, while the forelimbs maintained contact with the floor of the hypokinetic model. On this basis, it was to be expected that there would be different responses at the two skeletal sites if the observed abnormalities were due to mechanical unloading alone. The changes induced by simulated weightlessness in the proximal tibia and humerus, however, were generally comparable. This evidence for systemic skeletal responses has drawn attention to endocrine factors.

Wronski, T. J.↗
NASA NTRS1982

Modulation of the cytosolic androgen receptor in striated muscle by sex steroids

The influence of orchiectomy (GDX) and steroid administration on the level of the cytosolic androgen receptor in the rat levator ani muscle and in rat skeletal muscles (tibialis anterior and extensor digitorum longus) was studied. Androgen receptor binding to muscle cytosol was measured using H-3 methyltrienolone (R1881) as ligand, 100 fold molar excess unlabeled R1881 to assess nonspecific binding, and 500 fold molar excess of triamcinolone acetonide to prevent binding to glucocorticoid and progestin receptors. Results demonstrate that modification of the levels of sex steroids can alter the content of androgen receptors of rat striated muscle. Data suggest that: (1) cytosolic androgen receptor levels increase after orchiectomy in both levator ani muscle and skeletal muscle; (2) the acute increase in receptor levels is blocked by an inhibitor of protein synthesis; and (3) administration of estradiol-17 beta to castrated animals increases receptor binding in levator ani muscle but not in skeletal muscle.

Rance, N. E.↗