Low-Dose Radiation Exposure and Atherosclerosis in ApoE−/− Mice

Abstract The hypothesis that single low-dose exposures (0.025–0.5 Gy) to low-LET radiation given at either high (about 150 mGy/min) or low (1 mGy/min) dose rate would promote aortic atherosclerosis was tested in female C57BL/6J mice genetically predisposed to this disease (ApoE−/−). Mice were exposed either at an early stage of disease (2 months of age) and examined 3 or 6 months later or at a late stage of disease (8 months of age) and examined 2 or 4 months later. Changes in aortic lesion frequency, size and severity as well as total serum cholesterol levels and the uptake of lesion lipids by lesion-associated macrophages were assessed. Statistically significant changes in each of these measures were observed, depending on dose, dose rate and disease stage. In all cases, the results were distinctly non-linear with dose, with maximum effects tending to occur at 25 or 50 mGy. In general, low doses given at low dose rate during either early- or late-stage disease were protective, slowing the progression of the disease by one or more of these measures. Most effects appeared and persisted for months after the single exposures, but some were ultimately transitory. In contrast to exposure at low dose rate, high-dose-rate exposure during early-stage disease produced both protective and detrimental effects, suggesting that low doses may influence this disease by more than one mechanism and that dose rate is an important parameter. These results contrast with the known, generally detrimental effects of high doses on the progression of this disease in the same mice and in humans, suggesting that a linear extrapolation of the known increased risk from high doses to low doses is not appropriate.

[1]  H. Sugiyama,et al.  Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950-2003 , 2010, BMJ : British Medical Journal.

[2]  Ioanna Tzoulaki,et al.  A Model of Cardiovascular Disease Giving a Plausible Mechanism for the Effect of Fractionated Low-Dose Ionizing Radiation Exposure , 2009, PLoS Comput. Biol..

[3]  Efrati Shai,et al.  Carotid atherosclerotic disease following childhood scalp irradiation. , 2009, Atherosclerosis.

[4]  F. Stewart,et al.  Single-dose and fractionated irradiation promote initiation and progression of atherosclerosis and induce an inflammatory plaque phenotype in ApoE(-/-) mice. , 2008, International journal of radiation oncology, biology, physics.

[5]  G. Gulis,et al.  Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15-Country Study of nuclear industry workers. , 2007, International journal of epidemiology.

[6]  F. Stewart,et al.  Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE-/- mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. , 2006, The American journal of pathology.

[7]  R. Sponsler,et al.  Nuclear shipyard worker study (1980-1988): a large cohort exposed to low-dose-rate gamma radiation , 2005 .

[8]  B. Modan,et al.  Long-Term Follow-up for Brain Tumor Development after Childhood Exposure to Ionizing Radiation for Tinea Capitis , 2005, Radiation research.

[9]  Sarah C. Darby,et al.  Low Doses of Ionizing Radiation and Circulatory Diseases: A Systematic Review of the Published Epidemiological Evidence , 2005, Radiation research.

[10]  C. Land,et al.  Coronary heart disease after radiotherapy for peptic ulcer disease. , 2005, International journal of radiation oncology, biology, physics.

[11]  Kumiko Naito,et al.  Prevalence of atherosclerosis in relation to atomic bomb radiation exposure: An RERF Adult Health Study , 2005, International journal of radiation biology.

[12]  G. Howe,et al.  Analysis of the Mortality Experience amongst U.S. Nuclear Power Industry Workers after Chronic Low-Dose Exposure to Ionizing Radiation , 2004, Radiation research.

[13]  M. Akahoshi,et al.  Noncancer Disease Incidence in Atomic Bomb Survivors, 1958–1998 , 2004, Radiation research.

[14]  A. Daugherty,et al.  Depletion of Natural Killer Cell Function Decreases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[15]  Charles Mw,et al.  Studies of mortality of atomic bomb survivors. Report 13: Solid cancer and noncancer disease mortality: 1950-1997. , 2003 .

[16]  Yukiko Shimizu,et al.  Studies of Mortality of Atomic Bomb Survivors. Report 13: Solid Cancer and Noncancer Disease Mortality: 1950–1997 , 2003, Radiation research.

[17]  R. Virmani,et al.  Radiation-induced atherosclerotic plaque progression in a hypercholesterolemic rabbit: a prospective vulnerable plaque model? , 2003, Cardiovascular radiation medicine.

[18]  A. Daugherty,et al.  IFN-gamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E-/- mice. , 2002, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[19]  A. Daugherty,et al.  Interleukin-18 Enhances Atherosclerosis in Apolipoprotein E−/− Mice Through Release of Interferon-&ggr; , 2002, Circulation research.

[20]  R. Virmani,et al.  Intravascular radiation accelerates atherosclerotic lesion formation of hypercholesteremic rabbits. , 2001, Cardiovascular radiation medicine.

[21]  L. Curtiss,et al.  Effect of &ggr;-Irradiation and Bone Marrow Transplantation on Atherosclerosis in LDL Receptor-Deficient Mice , 2001 .

[22]  A. Daugherty,et al.  Exogenous interferon-γ enhances atherosclerosis in apolipoprotein E-/- mice , 2000 .

[23]  D A Pierce,et al.  Studies of the mortality of atomic bomb survivors. Report 12, part II. Noncancer mortality: 1950-1990. , 1999, Radiation research.

[24]  E. Gong,et al.  Ionizing radiation accelerates aortic lesion formation in fat-fed mice via SOD-inhibitable processes. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[25]  T. V. van Berkel,et al.  Bone marrow transplantation in apolipoprotein E-deficient mice. Effect of ApoE gene dosage on serum lipid concentrations, (beta)VLDL catabolism, and atherosclerosis. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[26]  W D Wagner,et al.  A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[27]  W D Wagner,et al.  A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[28]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[29]  N. Maeda,et al.  Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[30]  B. Modan,et al.  Thyroid neoplasia following low-dose radiation in childhood. , 1989, Radiation research.

[31]  H. C. Stary,et al.  Macrophages, macrophage foam cells, and eccentric intimal thickening in the coronary arteries of young children. , 1987, Atherosclerosis.

[32]  I. Thierry-Chef,et al.  Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15-Country Study of nuclear industry workers , 2007 .

[33]  H. C. Stary.  Composition and classification of human atherosclerotic lesions , 2005, Virchows Archiv A.

[34]  Alan Daugherty,et al.  Quantification of atherosclerosis in mice. , 2003, Methods in molecular biology.

[35]  A. Daugherty,et al.  Interleukin-18 Enhances Atherosclerosis in Apolipoprotein E 2 / 2 Mice Through Release of Interferon-g , 2002 .

[36]  L. Curtiss,et al.  Effect of gamma-irradiation and bone marrow transplantation on atherosclerosis in LDL receptor-deficient mice. , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[37]  A. Daugherty,et al.  Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E-/- mice. , 2000, The American journal of pathology.

[38]  R. Ross,et al.  ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[39]  H. C. Stary,et al.  The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life. , 1990, European heart journal.