Spectrum of Complex DNA Damages Depends on the Incident Radiation

Biology Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA.
Radiation Research (Impact Factor: 2.91). 03/2006; 165(2):223-30. DOI: 10.1667/RR3498.1
Source: PubMed


Ionizing radiation induces bistranded clustered damages--two or more abasic sites, oxidized bases and strand breaks on opposite DNA strands within a few helical turns. Since clusters are refractory to repair and are potential sources of double-strand breaks (DSBs), they are potentially lethal and mutagenic. Although induction of single-strand breaks (SSBs) and isolated lesions has been studied extensively, little is known about the factors affecting induction of clusters other than DSBs. To determine whether the type of incident radiation could affect the yields or spectra of specific clusters, we irradiated genomic T7 DNA, a simple 40-kbp linear, blunt-ended molecule, with ion beams [iron (970 MeV/nucleon), carbon (293 MeV/nucleon), titanium (980 MeV/nucleon), silicon (586 MeV/nucleon), protons (1 GeV/nucleon)] or 100 kVp X rays and then quantified DSBs, Fpg-oxypurine clusters and Nfo-abasic clusters using gel electrophoresis, electronic imaging and number average length analysis. The yields (damages/Mbp Gy(-1)) of all damages decreased with increasing linear energy transfer (LET) of the radiation. The relative frequencies of DSBs compared to abasic and oxybase clusters were higher for the charged particles-including the high-energy, low-LET protons-than for the ionizing photons.

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    • "Over the years, it has become clear that the cellular and organismal response to low dose irradiation is different from the high dose response [Feinendegen et al., 2011a, b, c]. Further, it has been shown that the quality, or linear energy transfer (LET), of the radiation can alter the radiation response [Brooks et al., 2001; Hada and Sutherland, 2006; Antonovic et al., 2013]. Although the picture is far from complete, a growing body of literature is defining the epigenetic radiation response and has been well reviewed [Kovalchuk and Baulch 2008; Ma et al., 2010; Aypar et al., 2011; Merrifield and Kovalchuk, 2013]. "
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    ABSTRACT: DNA methylation is an epigenetic mechanism that drives phenotype and that can be altered by environmental exposures including radiation. The majority of human radiation exposures occur in a relatively low dose range; however, the biological response to low dose radiation is poorly understood. Based on previous observations, we hypothesized that in vivo changes in DNA methylation would be observed in mice following exposure to doses of high linear energy transfer (LET) (56) Fe ion radiation between 10 and 100 cGy. We evaluated the DNA methylation status of genes for which expression can be regulated by methylation and that play significant roles in radiation responses or carcinogenic processes including apoptosis, metastasis, cell cycle regulation, and DNA repair (DAPK1, EVL, 14.3.3, p16, MGMT, and IGFBP3). We also evaluated DNA methylation of repeat elements in the genome that are typically highly methylated. No changes in liver DNA methylation were observed. Although no change in DNA methylation was observed for the repeat elements in the lungs of these same mice, significant changes were observed for the genes of interest as a direct effect and a delayed effect of irradiation 1, 7, 30, and 120 days post exposure. At delayed times, differences in methylation profiles among genes were observed. DNA methylation profiles also significantly differed based on dose, with the lowest dose frequently affecting the largest change. The results of this study are the first to demonstrate in vivo high LET radiation-induced changes in DNA methylation that are tissue and locus specific, and dose and time dependent. Environ. Mol. Mutagen. 55:266-277, 2014. © 2013 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 04/2014; 55(3):266-77. DOI:10.1002/em.21832 · 2.63 Impact Factor
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    • "Meanwhile, we can find that X-rays could induce more 53BP1 foci than heavy ions do at 1 h after irradiation. It is probably because the foci induction is mainly concerned with particle frequency (Hada and Sutherland 2006). As HZE beams have much higher LET, so they have a less particle frequency when the dosage is same. "
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    ABSTRACT: Space exploration represents great challenge to astronauts’ health because of the uncertain risk of carcinogenesis caused by space radiation, in which high-charge and -energy (HZE) particles should be the most harmful components. Although there are a number of researches confirming that HZE particles have more severe biological effects including tumorigenesis than low-LET radiations, it is still very hard to accurately estimate the cancer risk of space HZE radiation due to the lack of suitable epidemiological data on exposures to low-dose HZE particle irradiation. Ground-based experiments on high-energy heavy ion accelerators might be appropriate complement for understanding the risk of space radiation. On the other hand, effective countermeasures to reduce the radiation damage are essential to manned space exploration. Up to now, shielding is still the most practical way to attenuate biological responses of space radiation. However, the knowledge on the biological effects of secondary particles produced by the interaction of HZE particles with shielding materials is required for space shielding design. This review will discuss the issues of space HZE particles and the biological effects of secondary particles produced by the interaction of space radiation and shielding materials.
    Rendiconti Lincei. Scienze Fisiche e Naturali 03/2014; 25(S1). DOI:10.1007/s12210-014-0288-y · 0.75 Impact Factor
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    • "While high-energy protons constitute a major part of sporadically occurring SPE, heavy ions such as 56Fe, 28Si, 16O, and 12C are the major contributors to the dose equivalent in GCR, which is ubiquitous in space [2]. Heavy ion radiation with its high linear energy transfer (high-LET) characteristics is known not only to cause dense ionization events along its primary tract but also to generate greater numbers of secondary ionization tracts (delta rays) in the traversed tissues relative to low-LET γ radiation [3]–[6]. During prolonged space missions such, as a mission to Mars, astronauts could receive a cumulative radiation dose that has the potential for long-term deleterious effects on human health [1], [7]. "
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    ABSTRACT: Tissue consequences of radiation exposure are dependent on radiation quality and high linear energy transfer (high-LET) radiation, such as heavy ions in space is known to deposit higher energy in tissues and cause greater damage than low-LET γ radiation. While radiation exposure has been linked to intestinal pathologies, there are very few studies on long-term effects of radiation, fewer involved a therapeutically relevant γ radiation dose, and none explored persistent tissue metabolomic alterations after heavy ion space radiation exposure. Using a metabolomics approach, we report long-term metabolomic markers of radiation injury and perturbation of signaling pathways linked to metabolic alterations in mice after heavy ion or γ radiation exposure. Intestinal tissues (C57BL/6J, female, 6 to 8 wks) were analyzed using ultra performance liquid chromatography coupled with electrospray quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) two months after 2 Gy γ radiation and results were compared to an equitoxic (56)Fe (1.6 Gy) radiation dose. The biological relevance of the metabolites was determined using Ingenuity Pathway Analysis, immunoblots, and immunohistochemistry. Metabolic profile analysis showed radiation-type-dependent spatial separation of the groups. Decreased adenine and guanosine and increased inosine and uridine suggested perturbed nucleotide metabolism. While both the radiation types affected amino acid metabolism, the (56)Fe radiation preferentially altered dipeptide metabolism. Furthermore, (56)Fe radiation caused upregulation of 'prostanoid biosynthesis' and 'eicosanoid signaling', which are interlinked events related to cellular inflammation and have implications for nutrient absorption and inflammatory bowel disease during space missions and after radiotherapy. In conclusion, our data showed for the first time that metabolomics can not only be used to distinguish between heavy ion and γ radiation exposures, but also as a radiation-risk assessment tool for intestinal pathologies through identification of biomarkers persisting long after exposure.
    PLoS ONE 01/2014; 9(1):e87079. DOI:10.1371/journal.pone.0087079 · 3.23 Impact Factor
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