We recently described the effects of low-dose γ-radiation exposures on atherosclerosis in genetically susceptible (ApoE–/–) mice with normal p53 function. Doses as low as 25 mGy, given at either early or late stage disease, generally protected against atherosclerosis in a manner distinctly nonlinear with dose. We now report the influence of low doses (25–500 mGy) on atherosclerosis in ApoE–/– mice with reduced p53 function (Trp53+/–). Single exposures were given at either low or high dose rate (1 or 150 mGy/min) to female C57BL/6J ApoE–/– Trp53+/– mice. Mice were exposed at either early stage disease (2 months of age) and examined 3 or 6 months later, or at late stage disease (7 months of age) and examined 2 or 4 months later. In unirradiated mice, reduced p53 functionality elevated serum cholesterol and accelerated both aortic root lesion growth and severity in young mice. Radiation exposure to doses as low as 25 mGy at early stage disease, at either the high or the low dose rate, inhibited lesion growth, decreased lesion frequency and slowed the progression of lesion severity in the aortic root. In contrast, exposure at late stage disease produced generally detrimental effects. Both low-and high-dose-rate exposures accelerated lesion growth and high dose rate exposures also increased serum cholesterol levels. These results show that at early stage disease, reduced p53 function does not influence the protective effects against atherosclerosis of low doses given at low dose rate. In contrast, when exposed to the same doses at late stage disease, reduced p53 function produced detrimental effects, rather than the protective effects seen in Trp53 normal mice. As in the Trp53 normal mice, all effects were highly nonlinear with dose. These results indicate that variations in p53 functionality can dramatically alter the outcome of a low-dose exposure, and that the assumption of a linear response with dose for human populations is probably unwarranted.
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1 February 2013
REGULAR ARTICLES|
January 04 2013
Low-Dose Radiation Exposure and Protection Against Atherosclerosis in ApoE–/– Mice: The Influence of P53 Heterozygosity
R. E. J. Mitchel;
R. E. J. Mitchel
1
aRadiological Protection Research and Instrumentation Branch, Atomic Energy of Canada Limited, Chalk River, Ontario, Canada
1 Address for correspondence: Radiological Protection Research and Instrumentation Branch, Atomic Energy of Canada Limited, Chalk River, Ontario, Canada K0J 1J0; e-mail mitchelr@aecl.ca or mitchelr@magma.ca.
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M. Hasu;
M. Hasu
bDepartments of Pathology and Laboratory Medicine and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
cVascular Biology Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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M. Bugden;
M. Bugden
aRadiological Protection Research and Instrumentation Branch, Atomic Energy of Canada Limited, Chalk River, Ontario, Canada
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H. Wyatt;
H. Wyatt
aRadiological Protection Research and Instrumentation Branch, Atomic Energy of Canada Limited, Chalk River, Ontario, Canada
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G. Hildebrandt;
G. Hildebrandt
dDepartment of Radiotherapy, University Hospital, Rostock, Germany
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Y-X. Chen;
Y-X. Chen
cVascular Biology Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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N. D. Priest;
N. D. Priest
aRadiological Protection Research and Instrumentation Branch, Atomic Energy of Canada Limited, Chalk River, Ontario, Canada
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S. C. Whitman
S. C. Whitman
2
bDepartments of Pathology and Laboratory Medicine and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
cVascular Biology Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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Radiat Res (2013) 179 (2): 190–199.
Article history
Received:
July 30 2012
Accepted:
September 26 2012
Citation
R. E. J. Mitchel, M. Hasu, M. Bugden, H. Wyatt, G. Hildebrandt, Y-X. Chen, N. D. Priest, S. C. Whitman; Low-Dose Radiation Exposure and Protection Against Atherosclerosis in ApoE–/– Mice: The Influence of P53 Heterozygosity. Radiat Res 1 February 2013; 179 (2): 190–199. doi: https://doi.org/10.1667/RR3140.1
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