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  • 1.
    Belyaev, I. Y.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Radiation-induced DNA repair foci: Spatio-temporal aspects of formation, application for assessment of radiosensitivity and biological dosimetry2010In: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 704, no 03-jan, p. 132-141Article in journal (Refereed)
    Abstract [en]

    Several proteins involved in DNA repair and DNA damage signaling have been shown to produce discrete foci in response to ionizing radiation. These foci are believed to co-localize to DSB and referred to as ionizing radiation-induced foci (IRIF) or DNA repair foci. Recent studies have revealed that some residual IRIF remain in cells for a relatively long time after irradiation, and have indicated a possible correlation between radiosensitivity of cells and residual IRIF. Remarkably, residual foci are significantly larger in size than the initial foci. Increase in the size of IRIF with time upon irradiation has been found in various cell types and has partially been correlated with dynamics and fusion of initial foci. Although it is admitted that the number of IRIF reflect that of DSB, several studies report a lack of correlation between kinetics for IRIF and DSB and a lack of co-localization between DSB repair proteins. These studies suggest that some proportion of residual IRIF that depend on cell type, dose, and postirradiation time may represent alternations in chromatin structure after DSB have been repaired or misrepaired. While precise functions of residual foci are presently unknown, their possible link to remaining chromatin alternations, nuclear matrix, apoptosis, delayed repair and misrejoining of DSB, activity of several kinases, phosphatases, and checkpoint signaling has been suggested. Another intriguing possibility is that some of DNA repair foci may mark break-points at chromosomal aberrations (CA). While this possibility has not been confirmed substantially, the residual foci seem to be useful for biological dosimetry and estimation of individual radiosensitivity in radiotherapy of cancer.

  • 2.
    Fred, Charlotta
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Grawé, Jan
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Hemoglobin adducts and micronuclei in rodents after treatment with isoprene monoxide or butadiene monoxide2005In: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 585, no 1-2, p. 21-32Article in journal (Refereed)
    Abstract [en]

    1,3-Butadiene and isoprene (2-methyl-1,3-butadiene) are chemically related substances that are carcinogenic to rodents. The overall aim of this work is to elucidate the role of the genotoxic action of diepoxide metabolites in the carcinogenesis of the dialkenes. In vivo doses of the diepoxide metabolites were measured through reaction products with hemoglobin (Hb adducts) in studies of induced micronuclei (MN) in rodents. In the reaction with N-terminal valine in Hb, diepoxybutane and isoprenediepoxide form ring-closed adducts, pyrrolidines [N,N-(2,3-dihydroxy-1,4-butadiyl)valine and N,N-(2,3-dihydroxy-2-methyl-1,4-butadiyl)valine, respectively]. The method applied for Hb-adduct measurement is based on tryptic degradation of the protein and liquid chromatography electrospray ionisation tandem mass spectrometry (LC–ESI-MS/MS) analysis. Mice were given single i.p. injections of the monoepoxides of butadiene and isoprene, 1,2-epoxy-3-butene or 1,2-epoxy-2-methyl-3-butene, respectively. Rats were treated in the same way with 1,2-epoxy-3-butene. In mice pyrrolidine adduct levels increased with increasing administered doses of the monoepoxides. The in vivo dose of diepoxybutane was on average twice as high (0.29 ± 0.059 mMh) as the in vivo dose of isoprenediepoxide (0.15 ± 0.053 mMh) per administered dose (mmol/kg body weight) of the monoepoxides. In mice the genotoxic effects of the two monoepoxides, measured as the increase in the frequencies of micronuclei (MN), were approximately linearly correlated to the in vivo doses of the diepoxides (except at the highest dose of diepoxybutane). In rats the pyrrolidine-adduct levels from diepoxybutane were below the limit of quantification at all administered doses of 1,2-epoxy-3-butene and no significant increase was observed in the frequency of MN. Measurement of the ring-closed adducts to N-termini in Hb by the applied method permits analysis of in vivo doses of diepoxybutane and isoprenediepoxide, which may be further used for the elucidation of the mechanisms of carcinogenesis of butadiene and isoprene.

  • 3. Hall, Janet
    et al.
    Jeggo, Penny A.
    West, Catharine
    Gomolka, Maria
    Quintens, Roel
    Badie, Christophe
    Laurent, Olivier
    Aerts, An
    Anastasov, Natasa
    Azimzadeh, Omid
    Azizova, Tamara
    Baatout, Sarah
    Baselet, Bjorn
    Benotmane, Mohammed A.
    Blanchardon, Eric
    Gueguen, Yann
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Harms-Ringhdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hess, Julia
    Kreuzer, Michaela
    Laurier, Dominique
    Macaeva, Ellina
    Manning, Grainne
    Pernot, Eileen
    Ravanat, Jean-Luc
    Sabatier, Laure
    Tack, Karine
    Tapio, Soile
    Zitzelsberger, Horst
    Cardis, Elisabeth
    Ionizing radiation biomarkers in epidemiological studies - An update2017In: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 771, p. 59-84Article, review/survey (Refereed)
    Abstract [en]

    Recent epidemiology studies highlighted the detrimental health effects of exposure to low dose and low dose rate ionizing radiation (IR): nuclear industry workers studies have shown increased leukaemia and solid tumour risks following cumulative doses of < 100 mSv and dose rates of < 10 mGy per year; paediatric patients studies have reported increased leukaemia and brain tumours risks after doses of 30-60 mGy from computed tomography scans. Questions arise, however, about the impact of even lower doses and dose rates where classical epidemiological studies have limited power but where subsets within the large cohorts are expected to have an increased risk. Further progress requires integration of biomarkers or bioassays of individual exposure, effects and susceptibility to IR. The European DoReMi (Low Dose Research towards Multidisciplinary Integration) consortium previously reviewed biomarkers for potential use in IR epidemiological studies. Given the increased mechanistic understanding of responses to low dose radiation the current review provides an update covering technical advances and recent studies. A key issue identified is deciding which biomarkers to progress. A roadmap is provided for biomarker development from discovery to implementation and used to summarise the current status of proposed biomarkers for epidemiological studies. Most potential biomarkers remain at the discovery stage and for some there is sufficient evidence that further development is not warranted. One biomarker identified in the final stages of development and as a priority for further research is radiation specific mRNA transcript profiles.

  • 4. Pernot, Eileen
    et al.
    Hall, Janet
    Baatout, Sarah
    Benotmane, Mohammed Abderrafi
    Blanchardon, Eric
    Bouffler, Simon
    El Saghire, Houssein
    Gomolka, Maria
    Guertler, Anne
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jeggo, Penny
    Kreuzer, Michaela
    Laurier, Dominique
    Lindholm, Carita
    Mkacher, Radhia
    Quintens, Roel
    Rothkamm, Kai
    Sabatier, Laure
    Tapio, Soile
    de Vathaire, Florent
    Cardis, Elisabeth
    Ionizing radiation biomarkers for potential use in epidemiological studies2012In: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 751, no 2, p. 258-286Article, review/survey (Refereed)
    Abstract [en]

    Ionizing radiation is a known human carcinogen that can induce a variety of biological effects depending on the physical nature, duration, doses and dose-rates of exposure. However, the magnitude of health risks at low doses and dose-rates (below 100 mSv and/or 0.1 mSv min(-1)) remains controversial due to a lack of direct human evidence. It is anticipated that significant insights will emerge from the integration of epidemiological and biological research, made possible by molecular epidemiology studies incorporating biomarkers and bioassays. A number of these have been used to investigate exposure, effects and susceptibility to ionizing radiation, albeit often at higher doses and dose rates, with each reflecting time-limited cellular or physiological alterations. This review summarises the multidisciplinary work undertaken in the framework of the European project DoReMi (Low Dose Research towards Multidisciplinary Integration) to identify the most appropriate biomarkers for use in population studies. In addition to logistical and ethical considerations for conducting large-scale epidemiological studies, we discuss the relevance of their use for assessing the effects of low dose ionizing radiation exposure at the cellular and physiological level. We also propose a temporal classification of biomarkers that may be relevant for molecular epidemiology studies which need to take into account the time elapsed since exposure. Finally, the integration of biology with epidemiology requires careful planning and enhanced discussions between the epidemiology, biology and dosimetry communities in order to determine the most important questions to be addressed in light of pragmatic considerations including the appropriate population to be investigated (occupationally, environmentally or medically exposed), and study design. The consideration of the logistics of biological sample collection, processing and storing and the choice of biomarker or bioassay, as well as awareness of potential confounding factors, are also essential.

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