Effect Of Whole-body Irradiation Research Articles

Prophylactic strategies to minimize the effect of whole body irradiation on hematopoietic, gastrointestinal and respiratory system leading to morbidity/mortality in animals

Increase in radionuclide application has gone far and wide in the last many decades; though its usage has benefited the society at large, however occasional unplanned exposure to radiation (terrorist/accidental) has also troubled human life. Exposure of humankind to nuclear disaster, accidental and natural background radiation exposure, has created the need to develop complete understanding of the subject and preparedness for having safe countermeasures. In whole-body radiation exposure scenario, all the three organs are responsible for leading the animal to its death; however, hematopoietic (HP) organ is the first to collapse followed by gastrointestinal (GI) and respiratory systems. Radiation-induced basic damage in these organs follows more or less similar pattern. Derangement starts with radiation-induced reactive oxygen species causing damage to DNA, lipids, and proteins and disturbing their regulatory pathways. However, damage in HP and GI is more rapid and severe due to the presence of highly radiosensitive multipotent stem cells essential to meet the need of high cell turnover rate in these organs. To overcome radiation-induced damage to these vital organs, serious efforts are continued globally to find safe remedial measure.

Salivary biochemical markers as potential acute toxicity parameters for acute radiation injury: A study on small experimental animals.

Researchers have been evaluating several biodosimetric/screening approaches to assess acute radiation injury, related to mass causality. Keeping in mind this background, we hypothesized that effect of whole-body irradiation in single fraction in graded doses can affect the secretion of various salivary components that could be used as acute radiation injury/toxicity marker, which can be used in screening of large population at the time of nuclear accidents/disaster. Thirty Sprague Dawley rats treated with whole-body cobalt-60 gamma irradiation of dose 1-5 Gy (dose rate: 0.95 Gy/min) were included in this study. Whole mixed saliva was collected from all animals before and after radiation up to 72 h postradiation. Saliva was analyzed for electrolytes, total protein, urea, and amylase. Intragroup comparison of salivary parameters at different radiation doses showed significant differences. Potassium was significantly increased as the dose increased from 1 Gy to 5 Gy (p < 0.01) with effect size of difference (r > 0.5). Sodium was significantly altered after 3-5 Gy (p < 0.01, r > 0.5), except 1 and 2 Gy, whereas changes in sodium level were nonsignificant (p > 0.5). Urea, total protein, and amylase levels were also significantly increased as the radiation dose increased (p < 0.01) with large effect size of difference (r > 0.5). This study suggests that salivary parameters were sensitive toward radiation even at low radiation dose which can be used as a predictor of radiation injury.

Lens crystallin response to whole body irradiation with single and fractionated doses of gamma radiation

Purpose: This study was aimed at determining the effect of whole body irradiation with single and fractionated low doses of γ-radiation on the structure of normal rats lens crystallin with the concept of correlating this with the changes in its molecular weight. Materials and methods: Three groups of Wistar albino rats were involved in this study; the first group is the control (n = 10) and the second group (n = 10) treated with a single dose of 4.0 Gy administered in one application from Cesium-137. The third group (n = 60) was treated for 8 weeks with fractionated dose rate of 0.5 Gy/week. Lens crystallin was analysed for protein content measurements and column chromatography. Results: Measurements of total soluble lens protein indicated pronounced decreases after exposure to single and fractionated doses of γ-radiation. The molecular weights and the protein content for the βH (with high molecular weight), βL (with low molecular weight) and γ-crystallin fractions revealed generalized alteration for all groups. Conclusion: Single and fractionated doses of γ-radiations induced lens crystallin changes that might lead to development of cataract due to induction of cross-linking and aggregation. βH-crystallin was the most stable against radiation induced damage, and the molecular weight of γ-crystallin was the most sensitive to gamma radiation.

Enhancement of tumor radioresponse by docetaxel: Involvement of immune system.

Docetaxel, a potent chemotherapeutic drug and a strong enhancer of tumor radioresponse, possesses immunomodulating properties. We previously reported that 40% of murine tumors responding to docetaxel by growth delay showed heavy infiltration with macrophages or lymphocytes. The present study explored the effect of whole body irradiation on antitumor action of docetaxel alone or docetaxel plus tumor irradiation. Mice bearing 8-mm MCa-K mammary carcinoma in the leg received 33 mg/kg docetaxel i.v., 5 to 65 Gy tumor irradiation, or both (radiation given 24 h after docetaxel). Docetaxel delayed tumor growth and enhanced the efficacy of radiation: it dramatically reduced TCD50 (radiation dose yielding 50% tumor cure) from the control value of 38.6 Gy to 11.8 Gy, for an enhancement factor of 3.27. In addition to enhancing tumor radioresponse, docetaxel decreased the lung metastatic rate in mice with local tumor control from 26% in mice receiving radiation alone to 11% in mice receiving docetaxel plus radiation. Docetaxel induced heavy infiltration of tumors with lymphocytes, determined 2-4 days after treatment: the percentage of lymphocytes increased from the control value of <2% to 27% in mice that received docetaxel 3 days earlier. This increase was due to the influx of helper/inducer T-lymphocytes and natural killer cells. Immunosuppression of tumor-bearing mice with 6 Gy whole-body irradiation prior to tumor isotransplantation reduced docetaxel-induced lymphocyte infiltration of tumors, antitumor and anti-metastatic action of docetaxel, and docetaxel-induced enhancement of tumor radioresponse. Thus, our results showed that docetaxel stimulates tumor infiltration with immune cells, which then participate in antitumor action of docetaxel alone or when combined with radiotherapy.

Exposure to ionizing radiation modifies circulating gastrin levels and gastrointestinal endocrine cell densities in the rat

Purpose: Gastrointestinal functions, controlled partly by gut peptides, are disturbed by ionizing radiation exposure. The effect of whole-body irradiation on circulating gastrin levels, densities of gastrointestinal endocrine cells and gastric acid secretion was investigated. Materials and methods: Rats were exposed to 2 or 6 Gy gamma -radiation. They were killed 3 or 7 days later and compared with shams. Plasma gastrin and basal acid output were measured. Endocrine cells were identified by argyrophilia or immunohistochemistry and their densities estimated. Results: Radiation exposure significantly increased gastrinaemia and gastric acid output at the times studied (p 0.05- p 0.001). Endocrine cells displayed different sensitivities to irradiation. In the gastric mucosa, a 6 Gy dose induced a decrease in fundic argyrophil cell, antral gastrin and somatostatin cell densities, always accentuated 7 days after irradiation, while in the intestinal mucosa it induced an increase, with highest values often at 7 days post-irradiation (p 0.01- p 0.001). This was true for neurotensin cells in the jejunum and ileum, substance P cells in ileum and enteroglucagon cells in the descending colon. Conclusions: Whole-body irradiation in rats significantly alters plasma gastrin levels, and several gut endocrine cell densities. This has repercussions on hormonal function, such as that exerted on acid secretion, and may explain gastrointestinal dysfunction observed following radiation exposure.

The Effect of Whole-Body Irradiation of Nude Mice on the Tumor Transplantability and Control Probability of a Human Soft Tissue Sarcoma Xenograft

This study has evaluated the impact of the suppression and recovery of the residual immunity in NCr/Sed nude (nu/nu) mice after whole-body irradiation using xenotransplantability and tumor control probability as the end points. For this investigation the xenograft was a human soft tissue sarcoma (HSTS26T). Two assays, the TD50 (the number of tumor cells required to induce a tumor in 50% of the recipients) and the TCD50 (the radiation dose required to control 50% of tumors) were used. For TD50 assays, tumor cells were injected subcutaneously (sc) into the legs of control and whole-body- irradiated nude mice at 1 day or 4, 8 or 12 weeks after irradiation. For TCD50 assays, tumors were transplanted sc into the legs of nude mice which had not been irradiated or which had been given whole-body irradiation at 1 day or 12 weeks prior to transplantation. The tumors were given single-dose irradiation when they reached 6 mm mean diameter under clamp-hypoxic conditions. The results show that the TD50's of mice receiving the injection 1 day and 4 and 8 weeks after whole-body irradiation were 3.6 to >100 times lower than that of unirradiated mice. Two groups which showed a statistically significant difference in TD50 's were those which received the injection 1 day and 8 weeks after whole-body irradiation (P < 0.01 and P < 0.05, respectively). No difference was found in TD50 values between mice that received injection 12 weeks after whole-body irradiation and those which were not irradiated. The TCD50 values of tumors in nonirradiated mice and in mice which had received whole-body irradiation 1 day and 12 weeks prior to to transplantation were 26.8, 44.1 and 33.9 Gy, respectively. Significantly lower TCD50 values were found in groups of nonirradiated mice or mice which received whole-body irradiation 12 weeks prior to transplantation in comparison with the group of mice that received whole-body irradiation on day 1 (both P < 0.05). No significant difference was found between the TCD50 values of the group of mice that received whole-body irradiation 12 weeks prior to transplantation and those for nonirradiated controls. Our conclusion is that the whole-body irradiation can enhance the transplantability of the HSTS26T tumor in nude mice significantly; this enhancing effect will decrease to the pre-irradiation level by 12 weeks after whole-body irradiation. Also, the suppression and recovery of residual immunity after whole-body irradiation can influence the TCD50 values of the same tumor xenografts in nude mice significantly. The changes in TD50 and TCD50 values correlate with the depletion and recovery of the total splenic lymphoid cell number, and especially in natural killer cell activity. We recommend that further immunosuppression in nude mice is necessary when using this model system for studies of human tumors.

Enhancement of concanavalin A-induced proliferation of spleno-lymphocytes by low-dose-irradiated macrophages.

The effect of whole-body irradiation with low doses of gamma-rays was investigated for the Con A-induced proliferation of splenocytes. Proliferation was enhanced by 0.02 Gy irradiation, but was inhibited by 0.2 Gy. The enhanced proliferation produced by low-dose irradiation also was studied using co-cultures of spleno-lymphocytes and peritoneal macrophages (M phi s) instead of spleno-M phi s. The proliferative response of spleno-lymphocytes was not affected by low doses of gamma-ray irradiation; whereas, the responses of unirradiated spleno-lymphocytes cultured with the peritoneal M phi s that had been irradiated at 0.02 and 0.04 Gy respectively were about 120 and 145% of the control. Proliferative enhancement was found when peritoneal M phi s collected 4 h after whole-body irradiation were used, but not with those collected at 1 and 12 h. No enhancement took place when in vitro irradiation was used. These results suggest that the enhancement in Con A-induced proliferation of splenocytes by low-dose irradiation was caused not by the activation of spleno-lymphocytes, but by activation of spleno-M phi s, and that the M phi s were activated indirectly.

Effect of Whole-Body Irradiation by Fast Neutrons on Mouse Tissues; Part II: Activity of Acid Phosphatase and Succinic Dehydrogenase in Testicular Tissues

Male Swiss albino mico were exposed to whole-body irradiation by fast neutrons of 14 MeV average energy. Two single doses of 7 or 14 rem were used, corresponding to a fluence of 1.27×108 and 2.54×108n/cm2, respectively. Two enzymes were assessed in testicular tissue, acid phosphatase activity to measure the changes in lysosomal function and succinic dehydrogenase activity to test mitochondrial functions and energy production. Lysosomal affection was revealed by statistically significant increase of ACP activity in all cell types of testicular tissue with either of the two doses used. Although SDH was characterised by relatively low activity in most of the testicular tissues, decrease in enzyme activity was clear. Complete absence of activity was sometimes noted. The magnitude of response was dose dependent and there was a tendency to return to pre-irradiation levels of both enzymes with time.

Effect of Whole-Body Irradiation by Fast Neutrons on Mouse Tissues; Part 1: Activity of Acid Phosphatase and Succinic Dehydrogenase in Kidney, Lung and Liver

Groups of male Swiss albino mice were irradiated by single doses of either 7 rem or 14 rem of fast neutrons with 14 MeV average energy, corresponding to fluences of 1.27×108 n/cm2 and 2.54×108 n/cm2, respectively. The activities of acid phosphatase (ACP) and succinic dehydrogenase (SDH) in kidney, lung and liver were determined at different time point up to seven days after irradiation. Lysosomal affection was respresented by statistically significant increase of ACP activity in all cell types of the three tested organs immediately after irradiation with either of the doses used. The effect of SDH was represented by reduction in activity in all three organs. The activities of both enzymes showed tendencies to return to pre-irradiation levels with time in most cell types especially after the 7 rem dose.

Effect of whole-body irradiation on precursor frequency of autoantibody-secreting cells and plaque-forming cells specific for bromelain-modified erythrocytes.

Murine spleen cells and peritoneal cells were assayed for autoantibody production against bromelain-modified mouse erythrocytes (mouse brom-RBC) after whole-body irradiation at a dose of 5 Gy. Spleens were taken directly from mice 3 days after irradiation, or cultured for 3 days 24 h after irradiation, and assayed. Cells taken directly from irradiated mice had a higher number of plaque-forming cells (PFC) against mouse brom-RBC, compared with unirradiated mice, when the data were expressed as PFC/10(6) viable cells. This apparent increase can be accounted for by the reduced number of cells in the spleens from irradiated mice. In both spleen cells and peritoneal cells cultured in high cell densities, no difference was observed in the number of PFC in cells from irradiated or unirradiated mice. The detected precursor frequency of autoimmune B cells in both cell populations cultured in limiting dilution was found to be lower in cells from irradiated mice. In contrast to other published data, it was concluded from these investigations that whole-body irradiation, at a dose of 5 Gy, does not augment autoantibody production against mouse brom-RBC. It is proposed that the reason for this is the presence of a regulatory cell that is relatively radioresistant and, hence, not removed after whole-body irradiation at a dose of 5 Gy.

Suppression of Delayed-Type Hypersensitivity to Oxazolone in Whole-Body-Irradiated Mice and Protection by WR-2721

The effect of whole-body irradiation on cellular immunity, as measured in vivo by delayed-type hypersensitivity (DTH) to oxazolone (4- ethoxymethylene -2-phenyl- oxazol -5-one), was determined in CD2F1 mice. DTH, determined by changes in ear swelling after challenge with oxazolone, was significantly depressed in irradiated mice (500-900 rad of 60Co) in a dose-dependent fashion when animals were irradiated after sensitization and before challenge with oxazolone. Administration of WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] 30 min before irradiation (2 days after sensitization) resulted in protection against suppression of DTH, which was dependent on drug and radiation dose. An effective dose of WR-2721 (200 mg/kg body wt) provided an approximate dose-modifying factor of 1.3. The data suggest that WR-2721 interacts with cells involved in that DTH response (lymphocytes and/or macrophages) and that WR-2721 may be useful in protecting against radiation-induced decrements in cell-mediated immunity.

Effect of whole-body irradiation on phagocytic activity of rat alveolar macrophages.

The phagocytic activity of rat alveolar macrophages was studied in vitro for up to six weeks after whole-body gamma irradiation (7.5 Gy). Ingestion of fluorescent latex microspheres was evaluated using both microscopic examination and flow cytometric quantitation. After a transient decrease on first day post-irradiation, a slight increase in the phagocytic ability was observed from day 14 to day 28, with a maximum on day 21. From day 35 onwards, phagocytic capacities returned approximately to those of the controls. The percentage of phagocytic cells (cells having ingested one microsphere or more) increased by 75 per cent on day 21 after irradiation and the phagocytic index (percentage of phagocytic cells X the average number of ingested microspheres per cell) increased by 250 per cent while at the same time, the number of recovered alveolar cells decreased by 37 per cent. The augmentation of phagocytic capacities after irradiation was particularly characterized by an increase in the percentage of cells ingesting more than five microspheres. Flow cytometric studies showed a significant increase in mean cell size on day 21 post-irradiation. The augmentation of the phagocytic activity was not found when macrophages from control rats were incubated with serum or alveolar lavage fluid from an irradiated donor. Augmentation of phagocytic capacity was also observed after 8.5 Gy but no effect could be observed after 6.5 Gy.

Effects of whole body irradiation in mice treated with C. parvum

We have investigated the effect of whole body irradiation (WBI) upon the survival of Corynebacterium parvum ( C. parvum)-treated CBA mice. Applied to mice 7 days after C. parvum WBI with 350–950 rad of X-ray killed more C. parvum-treated than -untreated mice. The number of endogenous hematopoietic colonies determined either at 9 days of irradiation or at the time of death of mice was greater in C. parvum-treated mice than in mice irradiated only. Using the exogenous spleen colony assay, it was found that CFUs from the spleen of mice treated with C. parvum were more sensitive to irradiation than the CFUs from the spleen of normal mice, Leucopenia caused by irradiation was equally severe in both groups of mice. However, a decrease in the number of erythrocytes was more pronounced in mice treated with C parvum and irradiation than in those given irradiation alone. Possible reasons for the increased radiosensitivity of C. parvum-treated mice as well as the relevance of these findings to tumor immunotherapy are discussed.

Effect of whole-body irradiation on Michaelis-Menten constants of microsomal enzyme systems of rat liver

FEBS LettersVolume 98, Issue 2 p. 260-262 Full-length articleFree Access Effect of whole-body irradiation on Michaelis-Menten constants of microsomal enzyme systems of rat liver Pierre Bernard, Pierre Bernard Division de Radiochimie, CRSSA, 1 bis, rue du Lt. R. Batany, F-92141 Clamart, FranceSearch for more papers by this authorGuy Rocquet, Guy Rocquet Division de Radiochimie, CRSSA, 1 bis, rue du Lt. R. Batany, F-92141 Clamart, FranceSearch for more papers by this author Pierre Bernard, Pierre Bernard Division de Radiochimie, CRSSA, 1 bis, rue du Lt. R. Batany, F-92141 Clamart, FranceSearch for more papers by this authorGuy Rocquet, Guy Rocquet Division de Radiochimie, CRSSA, 1 bis, rue du Lt. R. Batany, F-92141 Clamart, FranceSearch for more papers by this author First published: February 15, 1979 https://doi.org/10.1016/0014-5793(79)80195-7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 R.W. Estabrook, B. Cohen, J.R. Gillette Microsomes and Drug Oxidation (1969), Academic Press New York 95– 109. 2 V. Nair, Chicago Med. Sch. Quart., 28, (1969), 9– 25. 3 T. Nakazawa, O. Yukawa, S. Ushijima, S. Fujimori, Rad. Res., 66, (1976), 373– 383. 4 J. McTaggart, E.D. Wills, Rad. Res., 72, (1977), 122– 133. 5 A. Szysko, S. Bitny-Szlachto, Acta. Pol. Pharm., 34, (1977), 673– 677. 6 J.C.A. Knott, E.E. Wills, Rad. Res., 53, (1973), 65– 76. 7 Bernard P., Neveux, Y., Rocquet, G. and Drouet, J. (1979) in preparation. 8 A.P. Casarett, Radiation Biology (1968), Prentice Hall Inc Englewood Cliffs NJ 220– 225. 9 D. Dallner, Acta Pathol. Microbiol. Scand. Supp., 166, (1963), 1– 94. 10 A.G. Gornall, C.J. Bardawill, M.M. David, J. Biol. Chem., 177, (1949), 751– 766. 11 A. Hildebrandt, R.W. Estabrook, Arch. Biochem. Biophys., 143, (1971), 66– 79. 12 T. Nash, Biochem. J., 55, (1953), 416– 421. 13 J.G. Parkes, W. Thompson, Biochim. Biophys. Acta, 196, (1970), 162– 169. 14 D.J. Lowry, J.A. Lopez, J. Biol. Chem., 162, (1946), 421– 428. Volume98, Issue2February 15, 1979Pages 260-262 ReferencesRelatedInformation

Effect of whole body irradiation on different tissues. Experiments with 14C leucine in the rat.

The uptake and elimination of 14C leucine were analysed in controls and in rats irradiated 2 h before injection with 8 Gy whole-body irradiation. Plasma, small intestine, kidney and skin were assayed after homogenization for TCA soluble activity curves. In highly differentiated tissues with poor proliferative activity and low protein turnover, the uptake and elimination of the tracer did not appear to be affected by irradiation. In the small intestine differences between control and irradiated animals seemed significant.

Ribonucleic Acid Synthesis in Regenerating Liver of Irradiated Adrenalectomized Rats

The effect of whole-body irradiation on RNA synthesis in regenerating and non-growing livers was studied in intact and adrenalectomized rats. The animals were divided into four sub-groups: (1) control; (2) irradiation only; (3) partially-hepatectomized; and (4) irradiated partially-hepatectomized. Newly-synthesized RNA was determined by 30 or 40 min uptake of (6-14C) orotic acid. Both nuclear and polyribosomal RNA synthesis in regenerating livers of adrenalectomized rats were depressed below their control levels, regardless of whether irradiation was 2 hours before or 2 hours after partial hepatectomy. Specific radioactivity values of regenerating livers of adrenal intact and adrenalectomized rats were elevated above those of the non-growing livers from irradiated and unirradiated rats.

Effect of whole-body irradiation on transcription in the rat thymus.

Studies were carried out to elucidate the mechanism underlying the impairment in RNA synthesis in the rat thymus after whole-body exposure to X-rays (1000 rad). The ability of thymus nuclei to catalyse RNA polymerization in vitro was adversely affected in irradiated rats. Further experiments showed that whole-body irradiation caused a considerable decrease in both the activity of RNA polymerase and the template efficiency of chromatin but not in that of DNA isolated from chromatin. These radiation-induced changes in transcription seem to arise partly from the direct effect of radiation on the thymus itself and partly from the abscopal mechanism(s).

The Effect of Whole-Body Irradiation on the Metabolism of 5-Fluorouracil-2- 14 C in the Rat

The effect of whole-body irradiation on the metabolism of the anticancer drug 5-fluorouracil (FU) was determined in male rats by quantitating labeled urinary metabolites and14 CO2 after the14 C-labeled drug was administered. Treated animals received 445 to 461 R of60 Co irradiation followed in 24 hr by an intraperitoneal injection of 50 mg FU/kg containing approximately 24 μCi. Control animals received labeled drug but no irradiation. During the 24-hr experiments animals were housed in controlled-ventilation glass metabolism cages from which14 CO2 and urine samples were collected. Urinary metabolites were separated by thin-layer chromatography and quantitated by internal liquid scintillation counting. Irradiation produced an overall increase in the catabolism of FU although the magnitude of this effect was small and is not likely to be of significant clinical importance.

Effect of Whole-Body Irradiation and Puromycin on Hydrolytic Enzyme Activation in Regenerating Rat Liver

The effects of whole-body gamma irradiation, which blocks DNA synthesis, and puromycin, a protein synthesis inhibitor, on total organ activities of three acid hydrolases of regenerating, radiosensitive rat liver, were studied. Doses of 1000 or 10,000 rads, given immediately or 6 hours after subtotal hepatectomy, failed to prevent the twofold increase in total organ activities normally elicited by partial hepatectomy. Puromycin, injected every 3 hours in amounts large enough to inhibit protein synthesis, was also not effective. The observed rise of total organ hydrolase activities in regenerating liver may be due to selective removal of natural inhibitors of the enzymes, or to some form of enzyme activation. The process is not sensitive to gamma irradiation or protein synthesis arrest.

Appearance of an Early “Primed State” in Mice following the Concomitant Injections of Antigen and Specific Antiserum

Abstract Injection of mice with immune complexes formed with bovine serum albumin (BSA) and rabbit anti-BSA in antigen excess produced an enhanced anti-BSA response. An enhanced antibody response was also obtained when immune complexes prepared at equivalence were injected intravenously and a second antigen injection was made within 4 days. The results suggest that immune complexes elicit within a few days a “primed state” which is identical to the primed state observed weeks after a single antigen injection; that is, the kinetics of the appearance of antibody and the effect of whole-body irradiation upon the antibody response following the second antigen injection were similar to those observed in mice primed with antigen alone. The role of antibody and antigen-antibody complexes in eliciting a primed state is discussed.