Begell House Inc.
Journal of Environmental Pathology, Toxicology and Oncology
JEP(T)
0731-8898
23
2
2004
Alterations in Colonic Barrier Function Caused By a Low Sodium Diet or Ionizing Radiation
20
10.1615/JEnvPathToxOncol.v23.i2.10
Richard
Naftalin
King's College London, Physiology Division, Guys Campus, London, UK
This article reviews how cytokines and radiation-induced apoptosis affect the barrier function of the colonic pericryptal sheath and thereby colonic crypt fluid absorption. A layer of myofibroblasts forming a pericryptal sheath surrounds the colonic crypt epithelial cells. The colonic pericryptal hypertonicity (250—350 mM NaCl) resulting from Na+ pumping into the space between the crypt epithelial cells and the myofibroblasts provides the driving force required to produce the suction tension (5—10 atmospheres) that dehydrates feces. [Na+] in the pericryptal space and crypt lumen is monitored in vivo with a Na+ ion-sensitive fluorescent dye, Sodium Red. Dietary Na+ restriction increases this hypertonicity. The rate of dextran—labeled with fluorescein isothiocyanate (FITC)—accumulation in the crypt lumen monitors fluid absorption by the crypt lumen. The rate of leakage of FITC dextran (10 kDa) across the crypt wall reflects its permeability. With low Na+ intake, there is decreased crypt luminal dextran permeability. This decrease in crypt permeability is due to increased systemic and local release of angiotensin II and TGF-β and is accompanied by pericryptal growth stimulation with consequent increased expression of myofibroblast proteins, smooth muscle actin, collagen 4, and OB cadherin. Inhibition of cytokine formation by the angiotensin-converting enzyme inhibitor (ACEI) captopril prevents these trophic effects. Colonic fluid absorption is inhibited 4 days after whole-body exposure to ionizing radiation of >8 Gy. Concurrently, there is loss of the pericryptal myofibroblasts resulting from apoptosis, with consequent loss of the barrier function of the pericryptal sheath. These effects cause increased rates of dextran leakage across the crypt wall and loss of myofibroblast markers. Normal colonic function returns after 10 days accompanied by repair of the pericryptal sheath. The caspase inhibitor, Z-VAD Fmk, reduces sheath apoptosis. Longer term irradiation of >8 Gy produces overgrowth of the myofibroblasts and fibrosis, which is inhibited by captopril.
Radiation and Cardiovascular Diseases
8
10.1615/JEnvPathToxOncol.v23.i2.20
Akhilesh
Trivedi
Radiation Protection Bureau, Health Canada, Ottawa; and Radiation Biology and Health Physics Branch, Atomic Energy of Canada Limited, Chalk River, Ontario, Canada (Posthumous)
Mohammed A.
Hannan
Division of Radiation Research, Environment Health Science Bureau, Health Canada, Ottawa, Ontario, Canada
Both epidemiological and experimental evidence emphasize the connection between radiation exposure and cancer. Little effort has been directed toward finding an association between radiation and cardiovascular diseases. Lately, studies on the A-bomb survivors and Chernobyl accident victims have indicated that radiation doses as low as 0.05-1.0 Gy could be responsible for an increase in the incidence of cardiovascular diseases. Exposures to high doses of radiation (~10-40 Gy) have also been reported to induce atherosclerotic lesions in cancer patients undergoing radiotherapy. Earlier studies in experimental animals have shown that radiation, mostly at high doses (>5 Gy), could accelerate the formation of atherosclerotic lesions. This article provides an up-to-date review of the literature connecting cardiovascular diseases to radiation exposures, particularly at low doses, and the potential implications of this connection in radiation risk assessment.
Cellular Inactivation and Chromosomal Aberrations: Initial Damage
10
10.1615/JEnvPathToxOncol.v23.i2.30
Arnaud
Boissiere
Groupe de Physique des Solides, Universites Paris 6 et Paris 7, Paris, France
Anne
Eschenbrenner
Groupe de Physique des Solides, Universites Paris 6 et Paris 7, Paris, France
Francois
Gobert
Groupe de Physique des Solides, Universites Paris 6 et Paris 7, Paris, France
Marie-Anne Herve
du Penhoat
Groupe de Physique des Solides, Universites Paris 6 et Paris 7, Paris, France
Francois
Abel
Groupe de Physique des Solides, Universites Paris 6 et Paris 7, Paris, France
Michele
Lamoureux
Groupe de Physique des Solides, Universites Paris 6 et Paris 7, Paris, France
Luis
Martins
Laboratoire de Radiobiologie et Oncologie, Fontenay aux Roses, France
Marie-Francoise
Politis
Groupe de Physique des Solides, Universites Paris 6 et Paris 7, Paris, France
Michele
Ricoul
Laboratoire de Radiobiologie et Oncologie, Fontenay aux Roses, France
Alain
Touati
Groupe de Physique des Solides, Universites Paris 6 et Paris 7, Paris, France
Evelyne
Sage
Laboratoire de Genotoxicite et Modulation de l'Expression Genique, Institut Curie Recherche, Orsay, France
Laure
Sabatier
Laboratoire de Radiobiologie et Oncologie, Fontenay aux Roses, France
Annie
Chetioui
Groupe de Physique des Solides, Universites Paris 6 et Paris 7, Paris, France
It has been proposed that unrepaired or misrepaired complex lesions of DNA are responsible for cell inactivation and chromosomal aberrations. The detailed features of the critical damage and the nature of initiating physical events are actively investigated. We studied the role of inner-shell (core) ionizations in DNA atoms is studied. Ultrasoft X-rays from LURE synchrotron radiation have been used to mimic core events induced by ionizing radiations. For biological matter, inner-shell photoionization is indeed the main interaction channel of these radiations. Moreover, by tuning the X-ray energy below and above the carbon K-threshold, it is possible to achieve a two-fold increase in the number of core-ionizations in DNA for a same dose. Cell survival and chromosome aberrations have thus been studied at three iso-attenuated energies: 250,350, and 810 eV. Relative biological efficiencies (RBEs) for cell inactivation and chromosome aberrations were found to be strongly correlated with the yields of core events in DNA.
Modification of Thymocytes Membrane Radiooxidative Damage and Apoptosis by Eugenol
6
10.1615/JEnvPathToxOncol.v23.i2.40
Badri Narain
Pandey
Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India
Kaushala Prasad
Mishra
Department of Life Sciences, University of Mumbai, Mumbai, India; Nehru Gram Bharati University, Allahabad, UP, India; Foundation for Education and Research, Mumbai, India; BM International Research Centre, Mumbai, India
Radiation-induced membrane oxidative damage, generation of reactive oxygen species (ROS), and cellular apoptosis, as well as their modification by a natural antioxidant from plant source, eugenol, have been investigated in mouse thymocytes.Thymocyte suspension was irradiated by γ-rays, and the malondialdehyde (MDA) formation was measured with the thiobarbituric acid reactive species (TBARS) method. The results showed an increase in MDA in irradiated (2 Gy) thymocytes, which was inhibited in samples treated with increasing concentrations of eugenol (10—200 μ;M) prior to irradiation. The concentration of eugenol required to inhibit half of the MDA formation (IC50) in irradiated thymocytes was 100 μ;M. A dose-dependent increase in the generation of ROS was observed in irradiated thymocytes (0.5—200 cGy) as measured by 2,7-dichlorodihydro fluorescein diacetate (DCH-FDA), which was, however, inhibited by eugenol administered before irradiation. Furthermore, experiments showed a significant decrease in thymocytes apoptosis by antioxidant as measured by annexin-V labeling protocol. The inhibition of apoptosis by membrane-localized antioxidants such as eugenol, isoeugenol, and α-tocopherol acetate was more effective than a cytosolic antioxidant such as ascorbic acid. The results suggest an effective prevention of membrane and cellular damage in irradiated thymocytes by eugenol. It is inferred that damage to membrane played a significant role in radiation-induced cellular apoptotic death, which was markedly modified by membrane-specific antioxidants.
Induction of Apoptosis in Thymocytes by Hippophae rhamnoides: Implications in Radioprotection
16
10.1615/JEnvPathToxOncol.v23.i2.50
Harish Chandra
Goel
Department of Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
Premkumar
Indraghanti
Department of Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
Namita
Samanta
Department of Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
Suresh V. S.
Rana
Department of Zoology, Ch. Charan Singh University, Meerut, India
Hippophae rhamnoides (RH-3), which has been recently reported to elicit dose-dependent pro- and antioxidant properties in vitro, induced apoptosis in murine thymocytes. In a concentration-dependent manner, RH-3 induced apoptosis in thymocytes in ex vivo conditions. The maximum effect was observed with 100 μ;g/mL of RH-3. Beyond this dose, the induction of apoptosis was inhibited, as seen on the ladder formation. However, apoptotic body formation, another indicator of apoptosis, was not manifested when various doses of RH-3 (20—200 μ;g/mL) were administered. RH-3 (>100 μ;g/mL) compacted chromatin in the form of densely stained masses, and subsequent treatment with proteinase-K loosened them and developed a halo around each mass. RH-3 treatment of cells that had already undergone apoptosis induced chromatin compaction, which made the ladder invisible. During in vivo experiments in mice, the radioprotective dose of RH-3 (30 mg/kg b.w.) induced significant DNA fragmentation in thymocytes studied spectrofluorimetrically. RH-3 treatment before irradiation in vivo enhanced radiation-induced apoptosis. These results were confirmed by hypodiploid population studied flow-cytometrically and also by ladder formation. RH-3 treatment was prooxidative in nature because it depleted thiols and enhanced lipids peroxidation after 8 hours of treatment. The paradox between the prooxidant and the antioxidant effects of RH-3 in the context of its overall radioprotective efficacy has been explained.
Radioprotective Effect of Podophyllotoxin in Saccharomyces cerevisiae
6
10.1615/JEnvPathToxOncol.v23.i2.60
Harish Chandra
Goel
Department of Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
Madhu
Bala
Division of Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India
Recent reports showed that whole extract of Podophyllum hexandrum was radioprotective in mice. 1 Podophyllotoxin is one of the major constituents of the whole extract of Podophyllum. In this study we report on the radioprotective action of podophyllotoxin in Saccharomyces cerevisiae yeast. Proliferating yeast cells pretreated with podophyllotoxin (2.5-5.0 μ;g/mL) for ≥3 hours showed a higher surviving fraction after 60Co-γ-irradiation (200-600 Gy) than did the irradiated cells not pretreated with podophyllotoxin. The maximum increase (2.0 times) in surviving fraction was observed in cells treated with 2.5 μ;g/mL podophyllotoxin, 5 hours before 60Co-γ-irradiation (400 Gy). Podophyllotoxin was not mutagenic or recombinogenic at radioprotective doses (2.5 μ;g/mL). A post-irradiation decrease in revertants and gene convertants was observed in cells treated with podophyllotoxin (2.5 μ;g/mL podophyllotoxin, -5 hours, 400 Gy). This study indicates that podophyllotoxin is radioprotective in yeast, and its radioprotective effects in higher eukaryotes would be worth investigating.
Evaluation of Radioprotective Action of Compounds Using Saccharomyces cerevisiae
8
10.1615/JEnvPathToxOncol.v23.i2.70
Purva
Nemavarkar
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India
Bishnavath K.
Chourasia
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India
Karpagam
Pasupathy
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India
The yeast Saccharomyces cerevisiae serves as a model eukaryotic system to screen radioprotectors that can be used primarily in radiotherapy as well as in occupational workers in nuclear and allied industries. A number of antioxidants are suggested to be radioprotectors by virtue of their ability to quench reactive oxygen species, but their radioprotective action has not been investigated so far. In this study, a number of antioxidants were tested for their efficacy in radioprotection using yeast cells. Sulfhydryl compounds (disulfiram at 100 and 200 μ;M) and reduced glutathione (10 and 100 mM), purified compounds of plant origin, such as curcumin (1 mM, 10 mM, and 100 mM), quercetin (100 and 500 μ;M), rutin (100 and 200 μ;M), ellagic acid (100,200, and 500 μ;M) and gallic acid (100 and 500 μ;M)—were studied. The results revealed that all compounds, except gallic acid, specifically protected normal yeast cells from γ-radiation damage. Using rad 52 mutants, which lack recombinational DNA repair pathway, it has been found that protection was solely brought about by reducing DNA damage rather than by interfering with DNA repair. Results with DNA repair polymerase further substantiated this contention. We conclude that simple eukaryotic yeast cells can serve as a test system not only for rapid screening of radiomodifiers but also to study their mode of action.
Relevance of Radioprotectors in Radiotherapy: Studies with Tocopherol Monoglucoside
8
10.1615/JEnvPathToxOncol.v23.i2.80
Cherupally Krishnan Krishnan
Nair
Mar Athanasious College for Advanced Studies, Tiruvalla, Tiruvalla, Kerala, India; St.Gregorios Dental College & Research Centre, Kothamangalam, Kerala, India
Veena
Salvi
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Center, Mumbai, India
Tsutomu V.
Kagiya
Health Research Foundation, Kinki Invention Center, Kyoto, Japan
Rema
Rajagopalan
Radiation Biology Division, Bhabha Atomic Research Centre, Bombay, India
Radioprotective compounds are of importance in clinical radiation therapy, because normal tissues should be protected against radiation injury while using higher doses of radiation to obtain better cancer control. We investigated the radioprotection of cellular DNA in cancer and in various cells and tissues, in a murine system following exposure to γ-radiation and tocopherol monoglucoside (TMG) administration. We used single-cell gel electrophoresis (comet assay) and studied the progression of murine fibrosarcoma following radiation exposure and administration of TMG. The administration of TMG to tumor-bearing mice protected the cellular DNA against radiation-induced strand breaks as shown by the decrease in comet tail length, tail moment, and percentage of DNA in the tails of the cells of normal tissues. The same parameters were not altered in the cells of fibrosarcoma. Our results showed that the administration of TMG immediately after exposure to γ-radiation can protect normal tissues against radiation damages in tumor-bearing mice. Local γ-radiation exposure (5 Gy) of the tumor retarded the tumor growth. Administration of TMG did not protect cancer cells from radiation damage because the growth curves of cancer cells treated with radiation alone and those treated with TMG after irradiation were not significantly different.