This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Narayanan, P. K. Articles by Lehnert, B. E. Search for Related Content PubMed PubMed Citation Articles by Narayanan, P. K. Articles by Lehnert, B. E.

Particles Initiate Biological Production of Superoxide Anions and Hydrogen Peroxide in Human Cells¹

Cell and Molecular Biology Group, LS-4, Life Sciences Division, MS M888. Los Alamos National Laboratory, Los Alamos, New Mexico 87545

The mechanism(s) by which high-linear energy transfer particles, like those emitted by inhaled radon and radon daughters, cause lung cancer has not been elucidated. Conceivably, DNA damage that is induced by particles may be mediated by the metabolic generation of reactive oxygen species (ROS), in addition to direct particle-DNA interactions and hydroxyl radical-DNA interactions. Using normal human lung fibroblasts, we investigated the hypothesis that densely ionizing particles may induce the intracellular generation of superoxide (O₂·^-) and hydrogen peroxide (H₂O₂). Ethidium bromide and 2',7'-dichlorofluorescein, fluorescent products of the membrane-permeable dyes hydroethidine and 2',7'-dichlorofluorescin diacetate, respectively, were used to monitor the intracellular production of O₂·^- and H₂O₂, respectively, by flow cytometry. Compared to sham-irradiated cells, fibroblasts that were exposed to particles (0.4–19 cGy) had significant increases in intracellular O₂·^- production, along with concomitant increases in H₂O₂ production. Further analyses suggest that the plasma membrane-bound NADPH-oxidase is primarily responsible for this increased intracellular generation of ROS and that the ROS response does not require direct nuclear or cellular "hits" by the particles. In this latter regard, we additionally report that unirradiated cells also show the ROS response when they are incubated with serum-containing culture medium that has been exposed to particles or when they are incubated with supernatants from -irradiated cells. Our overall results support the possibility that particles, at least in part, may mediate their DNA-damaging effects indirectly via a ROS-related mechanism.

¹ This investigation was supported by United States Department of Energy-funded project entitled "Low Dose Ionizing Radiations, Reactive Oxygen Species, and Genomic Instability."

² To whom requests for reprints should be addressed. Phone: (505) 667-2753; Fax: (505) 665-3024.

Received 4/ 4/97. Accepted 7/18/97.

This article has been cited by other articles:

				D. Xiao, A. A. Powolny, and S. V. Singh Benzyl Isothiocyanate Targets Mitochondrial Respiratory Chain to Trigger Reactive Oxygen Species-dependent Apoptosis in Human Breast Cancer Cells J. Biol. Chem., October 31, 2008; 283(44): 30151 - 30163. [Abstract] [Full Text] [PDF]

				H. Hu, H.-J. Lee, C. Jiang, J. Zhang, L. Wang, Y. Zhao, Q. Xiang, E.-O. Lee, S.-H. Kim, and J. Lu Penta-1,2,3,4,6-O-galloyl-{beta}-D-glucose induces p53 and inhibits STAT3 in prostate cancer cells in vitro and suppresses prostate xenograft tumor growth in vivo Mol. Cancer Ther., September 1, 2008; 7(9): 2681 - 2691. [Abstract] [Full Text] [PDF]

				H. Zhou, V. N. Ivanov, Y.-C. Lien, M. Davidson, and T. K. Hei Mitochondrial Function and Nuclear Factor-{kappa}B-Mediated Signaling in Radiation-Induced Bystander Effects Cancer Res., April 1, 2008; 68(7): 2233 - 2240. [Abstract] [Full Text] [PDF]

				G. Sgouros, S. J. Knox, M. C. Joiner, W. F. Morgan, and A. I. Kassis MIRD Continuing Education: Bystander and Low Dose-Rate Effects: Are These Relevant to Radionuclide Therapy? J. Nucl. Med., October 1, 2007; 48(10): 1683 - 1691. [Abstract] [Full Text] [PDF]

				W Han, L Wu, B Hu, L Zhang, S Chen, L Bao, Y Zhao, A Xu, and Z Yu The early and initiation processes of radiation-induced bystander effects involved in the induction of DNA double strand breaks in non-irradiated cultures Br. J. Radiol., September 1, 2007; 80(Special_Issue_1): S7 - S12. [Abstract] [Full Text] [PDF]

				M Natarajan, C F Gibbons, S Mohan, S Moore, and M A Kadhim Oxidative stress signalling: a potential mediator of tumour necrosis factor {alpha}-induced genomic instability in primary vascular endothelial cells Br. J. Radiol., September 1, 2007; 80(Special_Issue_1): S13 - S22. [Abstract] [Full Text] [PDF]

				L. Tartier, S. Gilchrist, S. Burdak-Rothkamm, M. Folkard, and K. M. Prise Cytoplasmic Irradiation Induces Mitochondrial-Dependent 53BP1 Protein Relocalization in Irradiated and Bystander Cells Cancer Res., June 15, 2007; 67(12): 5872 - 5879. [Abstract] [Full Text] [PDF]

				Y. Y. Tyurina, L. V. Basova, N. V. Konduru, V. A. Tyurin, A. I. Potapovich, P. Cai, H. Bayir, D. Stoyanovsky, B. R. Pitt, A. A. Shvedova, et al. Nitrosative Stress Inhibits the Aminophospholipid Translocase Resulting in Phosphatidylserine Externalization and Macrophage Engulfment: IMPLICATIONS FOR THE RESOLUTION OF INFLAMMATION J. Biol. Chem., March 16, 2007; 282(11): 8498 - 8509. [Abstract] [Full Text] [PDF]

				B.-H. Liu, T.-S. Wu, F.-Y. Yu, and C.-C. Su Induction of Oxidative Stress Response by the Mycotoxin Patulin in Mammalian Cells Toxicol. Sci., February 1, 2007; 95(2): 340 - 347. [Abstract] [Full Text] [PDF]

				K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]

				D. Xiao, V. Vogel, and S. V. Singh Benzyl isothiocyanate-induced apoptosis in human breast cancer cells is initiated by reactive oxygen species and regulated by Bax and Bak. Mol. Cancer Ther., November 1, 2006; 5(11): 2931 - 2945. [Abstract] [Full Text] [PDF]

				D. Xiao, K. L. Lew, Y. Zeng, H. Xiao, S. W. Marynowski, R. Dhir, and S. V. Singh Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential Carcinogenesis, November 1, 2006; 27(11): 2223 - 2234. [Abstract] [Full Text] [PDF]

				M. Boyd, S. C. Ross, J. Dorrens, N. E. Fullerton, K. W. Tan, M. R. Zalutsky, and R. J. Mairs Radiation-Induced Biologic Bystander Effect Elicited In Vitro by Targeted Radiopharmaceuticals Labeled with {alpha}-, {beta}-, and Auger Electron-Emitting Radionuclides J. Nucl. Med., June 1, 2006; 47(6): 1007 - 1015. [Abstract] [Full Text] [PDF]

				J. Antosiewicz, A. Herman-Antosiewicz, S. W. Marynowski, and S. V. Singh c-Jun NH2-Terminal Kinase Signaling Axis Regulates Diallyl Trisulfide-Induced Generation of Reactive Oxygen Species and Cell Cycle Arrest in Human Prostate Cancer Cells. Cancer Res., May 15, 2006; 66(10): 5379 - 5386. [Abstract] [Full Text] [PDF]

				B. Hu, L. Wu, W. Han, L. Zhang, S. Chen, A. Xu, T. K. Hei, and Z. Yu The time and spatial effects of bystander response in mammalian cells induced by low dose radiation Carcinogenesis, February 1, 2006; 27(2): 245 - 251. [Abstract] [Full Text] [PDF]

				H. Zhou, V. N. Ivanov, J. Gillespie, C. R. Geard, S. A. Amundson, D. J. Brenner, Z. Yu, H. B. Lieberman, and T. K. Hei Mechanism of radiation-induced bystander effect: Role of the cyclooxygenase-2 signaling pathway PNAS, October 11, 2005; 102(41): 14641 - 14646. [Abstract] [Full Text] [PDF]

				S. V. Singh, S. K. Srivastava, S. Choi, K. L. Lew, J. Antosiewicz, D. Xiao, Y. Zeng, S. C. Watkins, C. S. Johnson, D. L. Trump, et al. Sulforaphane-induced Cell Death in Human Prostate Cancer Cells Is Initiated by Reactive Oxygen Species J. Biol. Chem., May 20, 2005; 280(20): 19911 - 19924. [Abstract] [Full Text] [PDF]

				C. Shao, M. Folkard, B. D. Michael, and K. M. Prise Targeted cytoplasmic irradiation induces bystander responses PNAS, September 14, 2004; 101(37): 13495 - 13500. [Abstract] [Full Text] [PDF]

				E. I Azzam and J. B Little The radiation-induced bystander effect: evidence and significance Human and Experimental Toxicology, February 1, 2004; 23(2): 61 - 65. [Abstract] [PDF]

				R. Mikkelsen Redox signaling mechanisms and radiationinduced bystander effects Human and Experimental Toxicology, February 1, 2004; 23(2): 75 - 79. [PDF]

				E. G Wright Commentary on radiation-induced bystander effects Human and Experimental Toxicology, February 1, 2004; 23(2): 91 - 94. [Abstract] [PDF]

				C. Shao, V. Stewart, M. Folkard, B. D. Michael, and K. M. Prise Nitric Oxide-Mediated Signaling in the Bystander Response of Individually Targeted Glioma Cells Cancer Res., December 1, 2003; 63(23): 8437 - 8442. [Abstract] [Full Text] [PDF]

				S. Falt, K. Holmberg, B. Lambert, and A. Wennborg Long-term global gene expression patterns in irradiated human lymphocytes Carcinogenesis, November 1, 2003; 24(11): 1837 - 1845. [Abstract] [Full Text] [PDF]

				C. SHAO, Y. FURUSAWA, Y. KOBAYASHI, T. FUNAYAMA, and S. WADA Bystander effect induced by counted high-LET particles in confluent human fibroblasts: a mechanistic study FASEB J, August 1, 2003; 17(11): 1422 - 1427. [Abstract] [Full Text] [PDF]

				T. Shibata, T. Yamada, T. Ishii, S. Kumazawa, H. Nakamura, H. Masutani, J. Yodoi, and K. Uchida Thioredoxin as a Molecular Target of Cyclopentenone Prostaglandins J. Biol. Chem., July 3, 2003; 278(28): 26046 - 26054. [Abstract] [Full Text] [PDF]

				M. Pollycove and L. E Feinendegen Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage Human and Experimental Toxicology, June 1, 2003; 22(6): 290 - 306. [Abstract] [PDF]

				E. I. Azzam, S. M. de Toledo, D. R. Spitz, and J. B. Little Oxidative Metabolism Modulates Signal Transduction and Micronucleus Formation in Bystander Cells from {alpha}-Particle-irradiated Normal Human Fibroblast Cultures Cancer Res., October 1, 2002; 62(19): 5436 - 5442. [Abstract] [Full Text] [PDF]

				M. Lluria-Prevatt, J. Morreale, J. Gregus, D. S. Alberts, F. Kaper, A. Giaccia, and M. B. Powell Effects of Perillyl Alcohol on Melanoma in the TPras Mouse Model Cancer Epidemiol. Biomarkers Prev., June 1, 2002; 11(6): 573 - 579. [Abstract] [Full Text] [PDF]

				A. Deshpande, P. K. Narayanan, and B. E. Lehnert Silica-Induced Generation of Extracellular Factor(s) Increases Reactive Oxygen Species in Human Bronchial Epithelial Cells Toxicol. Sci., June 1, 2002; 67(2): 275 - 283. [Abstract] [Full Text] [PDF]

				J. K. Leach, S. M. Black, R. K. Schmidt-Ullrich, and R. B. Mikkelsen Activation of Constitutive Nitric-oxide Synthase Activity Is an Early Signaling Event Induced by Ionizing Radiation J. Biol. Chem., May 3, 2002; 277(18): 15400 - 15406. [Abstract] [Full Text] [PDF]

				H. Nagasawa, A. Cremesti, R. Kolesnick, Z. Fuks, and J. B. Little Involvement of Membrane Signaling in the Bystander Effect in Irradiated Cells Cancer Res., May 1, 2002; 62(9): 2531 - 2534. [Abstract] [Full Text] [PDF]

				V. Anantharam, M. Kitazawa, J. Wagner, S. Kaul, and A. G. Kanthasamy Caspase-3-Dependent Proteolytic Cleavage of Protein Kinase Cdelta Is Essential for Oxidative Stress-Mediated Dopaminergic Cell Death after Exposure to Methylcyclopentadienyl Manganese Tricarbonyl J. Neurosci., March 1, 2002; 22(5): 1738 - 1751. [Abstract] [Full Text] [PDF]

				B E Lehnert and R Iyer Exposure to low-level chemicals and ionizing radiation: reactive oxygen species and cellular pathways Human and Experimental Toxicology, February 1, 2002; 21(2): 65 - 69. [Abstract] [PDF]

				H. Zhou, M. Suzuki, G. Randers-Pehrson, D. Vannais, G. Chen, J. E. Trosko, C. A. Waldren, and T. K. Hei Radiation risk to low fluences of alpha particles may be greater than we thought PNAS, December 4, 2001; 98(25): 14410 - 14415. [Abstract] [Full Text] [PDF]

				N.G. Oliveira, M. Castro, A.S. Rodrigues, I.C. Goncalves, R. Cassapo, A.P. Fernandes, T. Chaveca, J.M. Toscano-Rico, and J. Rueff Evaluation of the genotoxic effects of the boron neutron capture reaction in human melanoma cells using the cytokinesis block micronucleus assay Mutagenesis, September 1, 2001; 16(5): 369 - 375. [Abstract] [Full Text] [PDF]

				J. K. Leach, G. Van Tuyle, P.-S. Lin, R. Schmidt-Ullrich, and R. B. Mikkelsen Ionizing Radiation-induced, Mitochondria-dependent Generation of Reactive Oxygen/Nitrogen Cancer Res., May 1, 2001; 61(10): 3894 - 3901. [Abstract] [Full Text]

				K. REZNIKOV, L. KOLESNIKOVA, A. PRAMANIK, K. TAN-NO, I. GILEVA, T. YAKOVLEVA, R. RIGLER, L. TERENIUS, and G. BAKALKIN Clustering of apoptotic cells via bystander killing by peroxides FASEB J, September 1, 2000; 14(12): 1754 - 1764. [Abstract] [Full Text]

				E. I. Azzam, S. M. de Toledo, A. J. Waker, and J. B. Little High and Low Fluences of {{alpha}}-Particles Induce a G1 Checkpoint in Human Diploid Fibroblasts Cancer Res., May 1, 2000; 60(10): 2623 - 2631. [Abstract] [Full Text]

				J. B. Little Radiation carcinogenesis Carcinogenesis, March 1, 2000; 21(3): 397 - 404. [Abstract] [Full Text] [PDF]

				R. Iyer and B. E. Lehnert Factors Underlying the Cell Growth-related Bystander Responses to {{alpha}} Particles Cancer Res., March 1, 2000; 60(5): 1290 - 1298. [Abstract] [Full Text]

				K. S. Iwamoto, S. Fujii, A. Kurata, M. Suzuki, T. Hayashi, Y. Ohtsuki, Y. Okada, M. Narita, M. Takahashi, S. Hosobe, et al. p53 mutations in tumor and non-tumor tissues of Thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver Carcinogenesis, July 1, 1999; 20(7): 1283 - 1291. [Abstract] [Full Text] [PDF]

				A. J. Grosovsky Radiation-induced mutations in unirradiated DNA PNAS, May 11, 1999; 96(10): 5346 - 5347. [Full Text] [PDF]

				L.-J. Wu, G. Randers-Pehrson, A. Xu, C. A. Waldren, C. R. Geard, Z. Yu, and T. K. Hei Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells PNAS, April 27, 1999; 96(9): 4959 - 4964. [Abstract] [Full Text] [PDF]

				M. Kondo, T. Oya-Ito, T. Kumagai, T. Osawa, and K. Uchida Cyclopentenone Prostaglandins as Potential Inducers of Intracellular Oxidative Stress J. Biol. Chem., April 6, 2001; 276(15): 12076 - 12083. [Abstract] [Full Text] [PDF]

				E. I. Azzam, S. M. de Toledo, and J. B. Little Direct evidence for the participation of gap junction-mediated intercellular communication in the transmission of damage signals from alpha -particle irradiated to nonirradiated cells PNAS, January 16, 2001; 98(2): 473 - 478. [Abstract] [Full Text] [PDF]

				H. Zhou, G. Randers-Pehrson, C. A. Waldren, D. Vannais, E. J. Hall, and T. K. Hei Induction of a bystander mutagenic effect of alpha particles in mammalian cells PNAS, February 29, 2000; 97(5): 2099 - 2104. [Abstract] [Full Text] [PDF]