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"THE EFFECT OF RADIATION QUALITY AND DOSE IN THE PERSISTENCE OF STRESSFUL EFFECTS IN PROGENY OF IRRADIATED NORMAL HUMAN CELLS AND NEIGHBORING BYSTANDERS:
THE ROLE OF OXIDATIVE METABOLISM AND GAP JUNCTION INTERCELLULAR COMMUNICATION"

by
Manuela Buonanno
Interdisciplinary Biomedical Sciences Program
B.Sc. 2004, Univ. Federico II, Naples, Italy



Thesis Advisor: Edouard I. Azzam, Ph.D.
Professor
Department of Radiology, Division of Radiation Research

Monday, July 18, 2011
1:00 P.M., NJMS UH Cancer Center, Conference Room, G-level


Abstract

The health risks to humans from the increasing frequency of exposure to low dose/low fluence ionizing radiation is of immense scientific, regulatory and public concern. The need to establish risk assessment standards based on the mechanisms underlying low level radiation exposure has been considered critical to adequately protect people and to make the most effective use of national resources.
In addition to damage resulting from the direct deposition of radiation energy in targeted cells, widespread evidence indicates that deleterious effects may manifest also in non-irradiated cells in the exposed population. We tested the hypotheses that the linear energy transfer (LET) and dose of the radiation determine the nature and the extent of persistent biological effects induced in irradiated normal mammalian cells, their neighboring bystanders and their progeny, and that radiation-induced non-targeted effects, including genomic instability, bystander effects and adaptive responses, involve redox-regulated processes that greatly depend on intercellular communication.
Several population doublings after exposure to low or high doses of high LET 3.2 MeV  particles (LET ~ 122 keV/m) or 1 GeV/u iron ions (LET ~ 151 keV/m), the progeny of irradiated AG1522 normal human fibroblasts exhibited reduced proliferative capacity and harbored higher levels of micronuclei and reactive oxygen species (ROS) than control. In contrast, the progeny of cells exposed to low LET  rays (LET ~ 0.9 keV/m) or 1 GeV protons (LET ~ 0.2 keV/m), at low or high doses, had similar cloning efficiency and harbored similar levels of micronuclei and ROS as control. However, the duration of their traverse from G1 to S phase of the cell cycle increased as a function of increasing cell generations, and was further amplified following a new challenge dose of γ rays.
Similar to progeny of high-LET-irradiated cells, stressful effects persisted also in the progeny of bystander cells with which they had been in contiguous co-culture. Progeny of bystander cells that were co-cultured with cells exposed to low/moderate fluences of 1 GeV/u iron or 0.6 GeV/u silicon ions (LET ~ 51 keV/μm) harbored higher levels of micronuclei, protein oxidation, and lipid peroxidation than respective control. This correlated with decreased activity of antioxidant enzymes, inactivation of the redox-sensitive metabolic enzyme aconitase, and altered expression of proteins encoded by mitochondrial DNA. A significant increase in the spontaneous neoplastic transformation frequency in the progeny of bystander cells was also observed when C3H 10T mouse embryo fibroblasts were used. The increase, which greatly depended on events communicated through gap junction channels linking irradiated cells with bystander cells, was not observed when irradiated cells were targeted with low LET protons. These results were consistent with the observation that bystander cells co-cultured with low dose proton-irradiated cells are protected from the clastogenic effects of a subsequent challenge dose from 1 GeV/u iron ions delivered during 24 h after co-culture.
Collectively, our data indicate that exposure of normal mammalian cell populations to ionizing radiations of different LET induces in the progeny of irradiated and bystander cells in the population differential effects that involve oxidative metabolism and intercellular communication through gap junctions. By multiple endpoints, high LET radiation was more effective than low LET radiation at inducing persistent oxidative stress in progeny cells, and the extent of the effects was dependent on the dose delivered to the irradiated cell population. These results may be relevant to radiotherapy and the setting of adequate radiation protection guidelines.


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