The effect of genetic background and dose on non-targeted effects of radiation

Abstract

Purpose: This work investigates the hypothesis that genetic background plays a significant role in the signalling mechanisms underlying induction and perpetuation of genomic instability following radiation exposure. Materials and methods:Bone marrow from two strains of mice (CBA and C57), were exposed to a range of X-ray doses (0, 0.01, 0.1, 1 and 3 Gy). Different cellular signalling endpoints: apoptosis, cytokine levels and calcium flux, were evaluated at 2h, 24h and 7d post-irradiation to evaluate immediate and delayed effects.Results: In CBA (radio-sensitive) elevated apoptosis levels were observed at 24h post X-irradiation, transforming growth factor-β (TGF-β) levels were additionally shown to increase with time and dose. C57 showed a higher background level of apoptosis compared to CBA, which was sustained 7 days after radiation exposure. Levels of tumor necrosis factor-α (TNF-α) were also increased at day 7 for higher X-ray doses. TGF-β levels were higher in CBA, whilst C57 exhibited a greater TNF-α response.Calcium flux was induced in reporter cells on exposure to conditioned media from both strains. Conclusions:These results show genetic and dose specific differences in radiation-induced signalling in the initiation and perpetuation of the instability process, which have potential implications on evaluation of non-targeted effects in radiation risk assessment.3

Low-dose or low-dose-rate ionizing radiation–induced bioeffects in animal models

“…(2012) found statistically significant, low-dose-specific, changes to metabolic profiles 6 h post irradiation at 100 mGy [25]. Low-dose–low-LET X-ray irradiation induced delayed genomic instability in both CBA/H and C57BL/6J hemopoeitic stem cells [26]. …”

“…There are sex- and tissue-specific differences in p16(INKa) promoter methylation upon LDR exposure. In male liver tissue, p16(INKa) promoter methylation was more pronounced than in female tissue.[65]Decrease in histone H4-Lys20 trimethylation in the thymus, which was accompanied by a significant decrease in global DNA methylation as well as the accumulation of DNA damage.[68]pKZ1 mouseX-rays1 μGy–2 Gyanimal age: not mentioned3 days after irradiation>100 mGy or <0.01 mGy: induction of chromosomal inversions in spleen cells; 0.1–100 mGy: decrease of chromosomal inversions[19–21]C57BL/6J plasmid-based lacZ transgenic mouseProton radiation6–12-wk-old with100 mGy–4 Gy1 day to 16 weeks after irradiationIncreased mutant frequencies in brain tissue from 2 days to 8 weeks at 100 mGy[22]Female B6.129S2-Trp53tm1Tyj/1x129×1/SvJ mousePositron emission tomography (PET) scans7–9-wk-oldwith 18 F-FDG at 0–150 or γ-rays at 0–100 mGy24 and 43 h after irradiationIrradiation doses to the bone marrow corresponding to 33.43 mGy and above for internal 18 F-FDG exposure and to 25 mGy and above for external X-ray exposure induced significant increases in micronucleated reticulocyte formation in blood cells[23, 24]BALB/c and Spret/EiJ), and F1-backcross (F1Bx)X-rays100 mGy6 h after irradiationSignificant low-dose-specific metabolic profiles[25]Male CBA/H and C57BL/6 mouseX-rays10–12-wk-old mice at 10 mGy–3.0 Gy24 h after irradiationChromosomal instability, higher levels of TGF-β1 and TNF-α[26]…”

Time and Cell Type Dependency of Survival Responses in Co-cultured Tumor and Fibroblast Cells after Exposure to Modulated Radiation Fields

“…Genetic background, particularly p53 status, has been shown to have an important role in mediating RIBEs in vitro and in vivo (26)(27)(28)(29). The cell models used in this study are of different p53 backgrounds, specifically, DU-145 (p53 mutant), AG0-1522b (p53 wild-type) and H460 (p53 wildtype) (30-32), which we postulate is likely to affect out-offield response.…”

The Effect of Radiation on the Immune System in Pigs Affected by the Fukushima Daiichi Nuclear Power Plant Accident

“…The mechanisms behind LD/ LDR radiation-induced alterations differ depending on the animal species, strain, age, sex and organ. In an investigation on immunological effects, C57BL/6 mice exposed to 0.01-3.0 Gy of X-rays demonstrated a higher level of TNF-α at 24 h after irradiation, while the elevation of TGF-β expression was identified in CBA mice [20]. TGF-β expression was also highly increased at 3 days postirradiation in Balb/c mice irradiated with 0.1-5 Gy of γ-irradiation [21].…”