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.

FIG. 1

Disease progression with increasing age in unexposed ApoE^−/− mice. Panel A: Aortic root lesion frequency. Panel B: Average lesion cross-sectional area in the aortic root. Panel C: Average lesion severity stage. Panel D: Distribution of lesions by severity stage. The numbers on the histogram bars indicate the lesion severity stage (increasing severity 1–5) at the various mouse ages. Panel E: Total serum cholesterol. Closed diamonds, ApoE^−/− mice; open squares, ApoE^+/+ mice. n = 6–10. Panel F: The percentage of total lesion lipids contained within lesion-associated macrophages. Error bars indicate ± SE.

FIG. 2

Influence of low-dose-rate exposure at an early stage of disease (2 months of age). Panel A: Lesion frequency.*P < 0.01 at 5 months of age and P < 0.04 at 8 months of age. Panel B: Average lesion cross-sectional area. *P < 0.001. Open circles, examined at 5 months of age; solid squares, examined at 8 months of age. Error bars indicate ± SE.

FIG. 3

Influence of high-dose-rate exposure given at an early stage of disease (2 months of age). Panel A: Lesion frequency. Open circles. examined at 5 months of age; solid squares, examined at 8 months of age. *P < 0.05. Panel B: Average aortic root lesion cross-sectional area. Open circles, examined at 5 months of age; solid squares, examined at 8 months of age. *P ≤ 0.003. Panel C: Percentage of lesions at various stages of severity examined at 5 months of age. Solid diamonds, control, unexposed mice; open squares, mice that received 0.025 Gy. *P = 0.009. Panel D: Serum cholesterol. Open circles, examined at 5 months of age, P < 0.02 for all doses; solid squares, examined at 8 months of age, P < 0.05 for 0.025 and 0.5 Gy. Panel E: Percentage of lesion lipid within lesion associated macrophages. Open circles, examined at 5 months of age. *P < 0.03 at 0.050 Gy. Solid squares, examined at 8 months of age. *P = 0.005 at 0.05 Gy and P < 0.04 at 0.5 Gy. Error bars indicate ± SE.

FIG. 4

Influence of low-dose-rate exposure given at a late stage of disease (8 months of age). Panel A: Lesion frequency. Open circles, examined at 10 months of age, solid squares, examined at 12 months of age.*P ≤ 0.02. Panel B: Average lesion cross-sectional area. Open circles, examined at 10 months of age, solid squares, examined at 12 months of age; *P ≤ 0.007. Panel C: Total serum cholesterol. Examined at 10 months of age (open circles, p>0.05 for all doses) or at 12 months of age (solid squares, P ≤ 0.003 for doses 0.05–0.5 Gy). n = 11–17. Error bars indicate ± SE.

FIG. 5

Changes in lesion severity with increasing high- or low-dose-rate exposure given to mice at a late stage of disease (8 months of age) and examined at 10 months of age. The figure shows the change in the percentage of aortic lesions at each severity stage of the disease. Panel A: Low-dose-rate exposure *P ≤ 0.02. Panel B: High-dose-rate exposure; *P ≤ 0.01. Error bars indicate ± SE.