Characterizing low dose and dose rate effects in rodent and human neural stem cells exposed to proton and gamma irradiation
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Bertrand P. Tseng↗
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RNAseq Analysis of Rodent Spaceflight Experiments Is Confounded by Sample Collection Techniques
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San-Huei Lai Polo↗
The Combined Effects of Pulsed Magnetic Radiation (Diapulse) and Chemotherapy on Tumor Bearing Mice. The Measurement of Rodent Palatal Explants as a Device for Measurement of the Biologic Effects of Nonionic Radiation (EMR)
Simultaneous treatment utilizing pulsed radiowave and cancer chemotherapy significantly extended the life span of mice with Lewis lung transplanted carcinoma. In comparison with nontreated controls, the combination of hydroxyurea and whole body nonionizing EM radiation (at 27.12 MHz) produced differential enhancement of longevity depending on hydroxyurea combined with highest power output achieved by pulsing the radiation 600 times per second; at a 3.9% duty cycle, peak watts = 975 produced the mean extension of life 67% greater than that of the group treated with hydroxyurea alone.
Regelson, W.↗
Risk estimates for CO exposure in man based on behavioral and physiological responses in rodents
An examination of animal response to CO is studied along with potential models for extrapolating animal test data to humans. The best models for extrapolating data were found to be the Probit and Weibull models.
Gross, M. K.↗
Knee-ligament loading properties as influenced by gravity. I - Junction with bone of 3-G rodents
The effect of 3-G conditions on the bone-to-ligament junctions of the knee is studied in rats. Results following chronic 3-G centrifugation of rats show that their bone-to-ligament junctions exhibited a force-sustaining capacity (F) which was 95 + or - 12% of the value for the control group. However, F was actually 29 + or - 5% greater for centrifuged rats than for control rats of comparable size, as the experimental animals grew to smaller body mass. It is concluded that gravity determines part of the magnitude of F, and therefore this value will probably be weaker after development in a weightless environment.
Wunder, C. C.↗
Timing of neuron development in the rodent vestibular system
The timing of cell generation (onset and duration) in the developing rat vestibular and proprioceptive systems is investigated. The results clearly indicate a defined time-span for generation of all neurons in the central nervous system nuclei studied. This cytogenetic period in both vestibular and proprioceptive sensory nuclei is determined to occur during and immediately after placentation, a potentially critical period for spaceflight exposure due to alterations in maternal physiology.
Keefe, J. R.↗
Rodent CNS neuron development: Timing of cell birth and death
Data obtained from a staged series of single paired injections of tritiated thymidine to pregnant Wistar rats or C57B16/j mice on selected embryonic days and several postnatal times are reported. All injected specimens were allowed to come to term, each litter culled to six pups and specimens were sacrificed on PN28, with fixation and embedding for paraffin and plastic embedding. The results are derived from serial paraffin sections of PN28 animals exposed to autoradiographic processing and plotted with respect to heavily labelled cell nuclei present in the selected brain stem nuclei and sensory ganglia. Counts from each time sample/structure are totalled and the percentage of cells in the total labelled population/structure represented by each injection time interval plotted.
Keefe, J. R.↗
Morphometric studies of heavy ion damage in the brains of rodents
The relative biological effectiveness (RBE) of different heavy ions for the mammalian brain was determined in mice irradiated at 100 days of age with He-4, C-12, Ne-20, Fe-56, Ar-40, or Co-60 gamma photons (with the primary particle LET values ranging from 2 to 650). Brain preparations were examined 16 months later for volume changes in the external plexiform layer (P-zone) of the olfactory bulb and an internal region (G-zone), which consists of the granule cells, the internal plexiform layer, and the mitral cell layer. The result indicate that the volume changes did occur in the olfactory bulb, not only in absolute terms but also when expressed as the ratio of the structures to each other and to the bulb as a whole. While the observed increased neuronal loss in mice receiving 700 cGy of Co-60 support the earlier data from irradiated rabbits, the increases observed in bulbar volumes and in the volume ratios of the P and the G zones measured in the mice given lower doses (320 or 160 cGy of He or C), were not expected.
Kraft, L. M.↗
Experiment K-6-10. Effects of zero gravity on myofibril protein content and isomyosin distribution in rodent skeletal muscle
The purpose of this experiment was to investigate the effects of 12 days of zero gravity (0G) exposure (Cosmos 1887 Biosputnik) on the enzymatic properties, protein content, and isomyosin distribution of the myofibril fraction of the slow-twitch vastus intermedius (VI) and the fast-twitch vastus lateralis (VL) muscles of adult male rats. Measurements were obtained on three experimental groups (n=5 each group) designated as flight-group (FG), vivarium-control (VC), and synchronous-control (SC). Body weight of the FG was significantly lower than the two control groups (p less than 0.05). Compared to the two control groups, VI weight was lower by 23 percent (p less than 0.10); whereas no such reduction was observed for the VL muscle. Myofibril yields (mg protein/g of muscle) in the VI were 35 percent lower in the FG compared to the controls (p less than 0.05); whereas, no such pattern was apparent for the VL muscle. When myofibril yields were expressed on a muscle basis (mg/g x muscle weight), the loss of myofibril protein was more exaggerated and suggests that myofibril protein degradation is an early event in the muscle atrophy response to 0G. Analysis of myosin isoforms indicated that slow-myosin was the primary isoform lost in the calculated degradation of total myosin. No evidence of loss of the fast isomyosins was apparent for either muscle following space flight. Myofibril ATPase activity of the VI was increased in the FG compared to controls, which is consistent with the observation of preferential slow-myosin degradation. These data suggest that muscles containing a high percent of slow-twitch fibers undergo greater degrees of myofibril protein degradation than do muscles containing predominantly fast-twitch fibers in response to a relatively short period of 0G exposure, and the primary target appears to be the slow-myosin molecule.
Baldwin, K.↗
Physiological Anatomical Rodent Experiment (PARE) .04 Feasibility Test 1
The objective of this feasibility study was to investigate the environmental/treatment stresses in the proposed PARE.04 experiments in a ground based study to determine if these stresses were of sufficient magnitude to compromise the planned shuttle experiments. Eighty pregnant Sprague-Dawley rats were received on day 2 (day l equals day of vaginal plug) of gestation (G2) and on G7 60 were laparotomized to determine the condition of pregnancy and allow assignment to test groups. The five test groups (N equals 10 each group) were as follows: Group 1, nominal flight; Group 2, laparotomy control; Group 3, hysterectomy control; Group 4, vivarium control; Group 5, caesarean delivery. On G17, groups 1, 2, and 5 were subjected to unilateral hysterectomy to obtain fetuses for evaluation. There was no difference in fetal crown-rump length, fetal weight, or placental weight in any of the test groups subjected to unilateral hysterectomy at G17. Animals were allowed to go to term and animals in each group delivered between the morning of G22 and the afternoon of G23. Rats assigned to Group 5 began delivering vaginally prior to the designated time for caesarean section, thus only 2 animals in this group were delivered by caesarean section. After delivery, a blood sample was taken from the dam, and they were euthanized and the thymus and adrenal glands weighed. Pups from experimental dams were tattooed for identification, the anogenital distance of male pups was photographed for later measurement, and all pups placed with foster dams and litter sizes were standardized to 10. On day 7, all pups were euthanized, and pup adrenal glands and thymus weighed. Laparotomy at G7 with or without unilateral hysterectomy at G17, had no effect on pregnancy maintenance or vaginal delivery. There was no difference in maternal adrenal or thymus weights or plasma levels of catecholamines, estradiol, progesterone, or corticosterone. Likewise, there was no difference in the anogenital distance (index of fetal stress) of neonatal male pups, between any of the experimental groups. From days 0-7, weight gain from dams in all experimental groups was similar. Lastly, there was no difference in weights of thymus and adrenal glands in pups euthanized at day 7. Collectively, these data indicate that treatment stresses inherent in the proposed PARE.04 experimental design should not compromise the planned shuttle experiments.
Burden, Hubert W.↗
Physiological Anatomical Rodent Experiment (PARE) .04 feasibility test 2
The objective of this feasibility study was to subject pregnant rats of the same age, strain, and size that will be utilized in a shuttle flight experiment to all flight conditions except the unique microgravity of space flight and determine the feasibility of the proposed experimental design to meet the experimental objectives. The study utilized facilities at NASA, Ames Research Center, Moffett Field, CA to subject the rats to the gravitational stresses of a simulated shuttle launch and simulated shuttle landing. One hundred pregnant rats were received on gestation day (G) 2 (day 1 = day of vaginal sperm) and on G7, eighty rats were laparotomized to determine the condition of pregnancy and allow assignment to test groups. The five test groups (N=10 each group) were as follows: Group 1, Nominal Flight; Group 2, Laparotomy Control; Group 3, Hysterectomy Control; Group 4, Vivarium Control; Group 5, Delayed Recovery. On G9, animals in groups 1,2,3, and 5 were subjected to a shuttle launch simulation. On G18, groups 1,2, and 3 were subjected to a shuttle landing simulation and on this same day groups 1 and 2 were subjected to unilateral hysterectomy to obtain fetuses and placentas for evaluation. Fetal crown-rump length and fetal weight of the Nominal Flight group was significantly less than the Laparotomy Control group, but placentas were similar. On G20, group 5 was subjected to a shuttle landing simulation and on this day this group received a unilateral hysterectomy and fetuses and placentas were weighed. Animals in all groups were allowed to go to term and all animals delivered between 06:00 hours G22 and 18:00 hours G23. After delivery, a blood sample was taken from each experimental dam, and they were euthanized and the thymus and adrenal glands weighed. The thymus weight from all experimental group dams was decreased relative to the Vivarium Control group but adrenal glands and hormone values in dam plasma was similar in all groups. Pups from experimental groups were tattooed for identification, the anogenital distance of male pups was measured, and all pups placed with foster dams and litter sizes were standardized to 10. There was no difference in anogenital distances between male pups from different test groups. Pups delivered from Delayed Recovery animals were smaller than pups delivered from Nominal Flight animals. On neonatal day 7, all pups were euthanized and pup adrenal glands and thymus weighed. There was no difference in weights of thymus and adrenal glands in pups euthanized at neonatal day 7. Collectively, these data confirm the feasibility of the experimental design to meet objectives of the studies proposed for shuttle flight.
Burden, Hubert W.↗
Functional and cellular adaptations of rodent skeletal muscle to weightlessness
This paper describes the affects of microgravity upon three key cellular levels (functional, protein, and mRNA) that are linked to one another. It is clear that at each of these levels, microgravity produces rapid and substantial alterations. One of the key challenges facing the life science community is the development of effective countermeasures that prevent the loss of muscle function as described in this paper. The development of optimal countermeasures, however, awaits a clearer understanding of events occurring at the levels of transcription, translation, and degradation.
Caiozzo, Vincent J.↗
Effects of Centrifuge Diameter and Operation on Rodent Adaptation to Chronic Centrifugation
This study examined the responses of rats to centrifugation in a constant acceleration field (1.5 G). Centrifuge diameter (1.8m, 2.5m or 6.0m) and schedule of operation (Daily or weekly stop) varied between groups. Body mass, food consumption, water consumption and neurovestibular function were measured weekly. Body temperature and activity were continuously monitored using telemetry. A subset of subjects were videotaped (50 minutes per day) to allow for movement analysis. Exposure to a hyperdynamic field of this magnitude did cause the expected depression in the physiological variables monitored. Recovery was accomplished within a relatively rapid time frame; all variables returned to precentrifugation levels. In general, the magnitudes of the changes and the rate of recovery were similar at different centrifuge diameters and stopping frequency. There were cases, however, in which the magnitude of the response and/or the rate of recovery to a new steady-state were altered as a result of centrifuge diameter. In summary, these results indicate that stopping frequency has little, if any, effect on adaptation to chronic centrifugation. However, the angular velocity (omega), and therefore centrifuge diameter is an important consideration in the adaptation of an organism to chronic centrifugation.
Fuller, Charles A.↗
Effects of Centrifuge Diameter and Operation on Rodent Adaptation to Chronic Centrifugation
This study examined the responses of rats to centrifugation in a constant acceleration field (1.5 G). Centrifuge diameter (1.8m, 2.5m or 6.0m) and schedule of operation (Daily or weekly stop) varied between groups. Body mass, food consumption, water consumption and neurovestibular function were measured weekly. Body temperature and activity were continuously monitored using telemetry. A subset of subjects were videotaped (50 minutes per day) to allow for movement analysis. Exposure to a hyperdynamic field of this magnitude did cause the expected depression in the physiological variables monitored. Recovery was accomplished within a relatively rapid time frame; all variables returned to precentrifugation levels. In general, the magnitudes of the changes and the rate of recovery were similar at different centrifuge diameters and stopping frequency. There were cases, however, in which the magnitude of the response and/or the rate of recovery to a new steady-state were altered as a result of centrifuge diameter. In summary, these results indicate that stopping frequency has little, if any, effect on adaptation to chronic centrifugation. However, the angular velocity (omega), and therefore centrifuge diameter is an important consideration in the adaptation of an organism to chronic centrifugation.
Fuller, Charles A.↗
Effects of Space Flight on Rodent Tissues
As the inevitable expression of mankind's search for knowledge continues into space, the potential acute and long-term effects of space flight on human health must be fully appreciated. Despite its critical role relatively little is known regarding the effects of the space environment on the ocular system. Our proposed studies were aimed at determining whether or not space flight causes discernible disruption of the genomic integrity, cell kinetics, cytoarchitecture and other cytological parameters in the eye. Because of its defined and singular biology our main focus was on the lens and possible changes associated with its primary pathology, cataract. We also hoped to explore the possible effect of space flight on the preferred orientation of dividing cells in the perilimbal region of conjunctiva and cornea.
Worgul, Basil V.↗
Physiological Anatomical Rodent Experiment (PARE): 04 Flight Support
Rats were shipped to Kennedy Space Center (KSC), Florida, on day 2 of gestation [(G2) (day 1 = morning on which spermatozoa are present in the vagina)] and laparotomized on G7 to determine the number of implantation sites in each uterine horn. On G8, ten pregnant rats meeting flight criteria (at least five implantation sites each horn) were placed into NASA flight cages (animal enclosure modules, AEMS, five rats per cage), loaded onto the mid-deck of the space shuttle Atlantis, and on G9 (November 3, 1994) they were launched into orbit. On gestation day 20, (November 14, 1994) the shuttle returned to Edwards Air Force Base, California and the flight animals were recovered from the shuttle and subjected to unilateral hysterectomy to provide fetal material from one horn to investigators identified by NASA to study selected fetal parameters. After unilateral hysterectomy, the animals were allowed to recover and deliver vaginally. There were three groups (n = 10 each group) of control animals housed at KSC in the study. A synchronous control group, delayed 24 hours with reference to the flight group, received the same surgeries and was housed five rats per AEM and exposed to all flight conditions (identical temperatures, lighting and humidity) except microgravity. Vivarium control group I did not receive any surgery and was housed in the vivarium in clear polycarbonate cages. Vivarium control group 2 received only a unilateral hysterectomy on day 20 of gestation but otherwise was housed like the vivarium control group 1. Control groups were allowed to complete their pregnancy and deliver fetuses from the remaining horn (Synchronous control and vivarium control group 2) or horns (Vivarium control group 1). After surgery, the dams were euthanized and tissues recovered, and the neonates were assigned to foster dams.
Burden, Hubert W.↗
Rodent Studies of Cardiovascular Deconditioning
Changes in blood pressure can occur for two reasons: 1) A decrease in cardiac output resulting from the altered contractility of the heart or through changes in venous filling pressure via the Frank Starling mechanism or; 2) A change in systemic vascular resistance. The observed changes in cardiac output and blood pressure after long term space flight cannot be entirely explained through changes in contractility or heart rate alone. Therefore, alterations in filling pressure mediated through changes in systemic venous capacitance and arterial resistance function may be important determinants of cardiac output and blood pressure after long term space flight. Our laboratory and previous studies have shown the importance of veno-constriction mediated by the carotid sinus baroreceptor reflex system on overall circulatory homeostasis and in the regulation of cardiac output. Our proposed experiments test the overall hypothesis that alterations in venous capacitance function and arterial resistance by the carotid sinus baroreceptor reflex system are an important determinant of the cardiac output and blood pressure response seen in astronauts after returning to earth from long term exposure to microgravity. This hypothesis is important to our overall understanding of circulatory adjustments made during long term space flight. It also provides a framework for investigating counter measures to reduce the incidence of orthostatic hypotension caused by an attenuation of cardiac output. We continue to use hind limb unweighted (HLU) rat model to simulate the patho physiological effects as they relate to cardiovascular deconditioning in microgravity. We have used this model to address the hypothesis that microgravity induced cardiovascular deconditioning results in impaired vascular responses and that these impaired vascular responses result from abnormal alpha-1 AR signaling. The impaired vascular reactivity results in attenuated blood pressure and cardiac output responses to an orthostatic challenge. We have used in vitro vascular reactivity assays to explore abnormalities in vascular responses in vessels from HLU animals and, cardiac output (CO), blood pressure (BP) and heart rate (HR) measurements to characterize changes in hemodynamics following HLU.
Shoukas, Artin A.↗
National Institutes of Health, Rodent 4 (NIH.R4); Calcium Metabolism and Vascular Function After Spaceflight: A Collaborative Series with NASA and NIH
The NIH.R4 payload was a collaborative experiment conducted by NASA's Ames Research Center in conjunction with the National Institutes of Health (NIH). This middeck payload was the fourth in a series of experiments focusing on developmental biology and the effects of microgravity on mammalian systems. The NIH.R4 payload was flown onboard STS-80, which launched November 19, 1996, and landed at Kennedy Space Center on December 7, 1996, and was the longest shuttle mission to date. Fourteen male Spontaneously Hypertensive rats (SHR) were flown; seven in each of two Animal Enclosure Modules (AEM) in the shuttle middeck. The flight animals were exposed to 18 days of microgravity. Two synchronous control groups were utilized for this study in addition to an asynchronous post-flight AEM control study conducted at the PI lab. The animals were fed two different calcium diets in the NASA food bar (2.0% and 0.2%) three weeks prior to launch and insight. Blood pressures were taken at pre-determined intervals and were the basis for flight selection. Upon recovery Dwight animals blood pressure was measured and a variety of tissues were collected. Project testing and data will be presented.
Reiss-Bubenheim, Debra↗