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. 2012 Aug;120(8):1130-6.
doi: 10.1289/ehp.1104294. Epub 2012 Apr 26.

Integrated molecular analysis indicates undetectable change in DNA damage in mice after continuous irradiation at ~ 400-fold natural background radiation

Werner Olipitz  1 , Dominika Wiktor-Brown, Joe Shuga, Bo Pang, Jose McFaline, Pallavi Lonkar, Aline Thomas, James T Mutamba, Joel S Greenberger, Leona D Samson, Peter C Dedon, Jacquelyn C Yanch, Bevin P Engelward
Affiliations

Integrated molecular analysis indicates undetectable change in DNA damage in mice after continuous irradiation at ~ 400-fold natural background radiation

Werner Olipitz et al. Environ Health Perspect. 2012 Aug.

Abstract

Background: In the event of a nuclear accident, people are exposed to elevated levels of continuous low dose-rate radiation. Nevertheless, most of the literature describes the biological effects of acute radiation.

Objectives: DNA damage and mutations are well established for their carcinogenic effects. We assessed several key markers of DNA damage and DNA damage responses in mice exposed to low dose-rate radiation to reveal potential genotoxic effects associated with low dose-rate radiation.

Methods: We studied low dose-rate radiation using a variable low dose-rate irradiator consisting of flood phantoms filled with 125Iodine-containing buffer. Mice were exposed to 0.0002 cGy/min (~ 400-fold background radiation) continuously over 5 weeks. We assessed base lesions, micronuclei, homologous recombination (HR; using fluorescent yellow direct repeat mice), and transcript levels for several radiation-sensitive genes.

Results: We did not observe any changes in the levels of the DNA nucleobase damage products hypoxanthine, 8-oxo-7,8-dihydroguanine, 1,N6-ethenoadenine, or 3,N4-ethenocytosine above background levels under low dose-rate conditions. The micronucleus assay revealed no evidence that low dose-rate radiation induced DNA fragmentation, and there was no evidence of double strand break-induced HR. Furthermore, low dose-rate radiation did not induce Cdkn1a, Gadd45a, Mdm2, Atm, or Dbd2. Importantly, the same total dose, when delivered acutely, induced micronuclei and transcriptional responses.

Conclusions: These results demonstrate in an in vivo animal model that lowering the dose-rate suppresses the potentially deleterious impact of radiation and calls attention to the need for a deeper understanding of the biological impact of low dose-rate radiation.

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Conflict of interest statement

The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
Exposure to 10.5 Gy acute (7.1 cGy/min) and chronic irradiation (0.0002 cGy/min) does not change steady-state base lesion levels. Effects of chronic, low dose-rate and acute irradiation on DNA base lesion levels of (A) 8-oxodG, (B) dI, (C) εdA, and (D) εdC were measured by LC-MS/MS in splenic DNA. Data represent mean ± SE for n = 6 and were analyzed by Student’s t-test.
Figure 2
Figure 2
Representative image of a PCE-containing micronuclei (MN-PCE; arrowheads) and of a normal RBC (arrow) isolated from bone marrow; bar = 20 µm (A). Low dose-rate (0.0002 cGy/min) irradiation (B) does not induce micronuclei in PCEs, whereas acute (7.1 cGy/min) irradiation (C) does. Data (mean ± SE ) are representative of two independent experiments; percent MN-PCE was calculated from > 2,000 scored PCE per sample. *p < 0.05 using unpaired two-tailed Student’s t-test.
Figure 3
Figure 3
FYDR mice carry a recombination substrate (A) that results in expression of Eyfp upon recombination repair. The Eyfp signal can be detected by in situ imaging. The frequency of Eyfp+ cells increases with age [(B) 4-week-old (young) mouse; (C) 24-week-old (old) mouse]. Chronic, low dose-rate (0.0002 cGy/min; D,F) and acute (7.1 cGy/min; E,G) irradiation do not affect HR frequency in the pancreas; +, positive. Chronic irradiation does not affect Eyfp expression in FYDR control mouse (H). Values are mean ± SE; statistical analysis was performed using two-tailed Mann–Whitney U test.
Figure 4
Figure 4
Effects of chronic, low dose-rate (0.0002 cGy/min; A,B) and acute (7.1 cGy/min; C,D) ionizing radiation on gene expression in WBCs. Gene expression changes were compared between control and treated groups after irradiation (A,C) and in irradiated animals before and after irradiation (B,D). Data (mean ± SE) are representative of two independent experiments. *p < 0.05 using unpaired two-tailed Student’s t-test (A,C) and paired two-tailed Student’s t-test (B,D).
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