Low-dose radiation exposure and protection against atherosclerosis in ApoE(-/-) mice: the influence of P53 heterozygosity.

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.

Low-dose radiation exposure and atherosclerosis in ApoE⁻/⁻ mice.

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.