RADIATION RESEARCH 180, 235–246 (2013) 0033-7587/13 $15.00 Ó2013 by Radiation Research Society. All rights of reproduction in any form reserved. DOI: 10.1667/RR3190.1 DNA Damage Caused by Chronic Transgenerational Exposure to Low Dose Gamma Radiation in Medaka Fish (Oryzias latipes) D. Grygoryev, a,d O. Moskalenko, b,d T. G. Hinton c and J. D. Zimbrick d,1 a Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, Oregon 97239; b High Performance Computing Center, University of Florida, Gainesville, Florida, 32611; c Institute of Radiation Protection and Nuclear Safety, Saint- Paul-lez-Durance Cedex, France; and d Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523 Grygoryev, D., Moskalenko, O., Hinton, T. G. and Zimbrick, J. D. DNA Damage Caused by Chronic Trans- generational Exposure to Low Dose Gamma Radiation in Medaka Fish (Oryzias latipes). Radiat. Res. 180, 235–246 (2013). The effect of transgenerational exposure to low dose rate (2.4 and 21 mGy/day) gamma irradiation on the yield of DNA double-strand breaks and oxidized guanine (8-hydroxygua- nine) has been studied in the muscle and liver tissue of a model organism, the Japanese medaka fish. We found the level of unrepaired 8-hydroxyguanine in muscle tissue increased nonlinearly over four generations and the pattern of this change depended on the radiation dose rate, suggesting that our treatment protocols initiated genomic instability and an adaptive response as the generations progressed. The yield of unrepaired double-strand breaks did not vary significantly among successive generations in muscle tissue in contrast to liver tissue in which it varied in a nonlinear manner. The 8- hydroxyguanine and DSB radiation yields were significantly higher at 2.4 mGy/day than at 21 mGy/day in both muscle and liver tissue in all generations. These data are consistent with the hypothesis of a threshold for radiation-induced activation of DNA repair systems below which tissue levels of DNA repair enzymes remain unchanged, leading to the accumulation of unrepaired damage at very low doses and dose rates. Ó 2013 by Radiation Research Society INTRODUCTION Low levels of ionizing radiation exist throughout our environment and originate from both natural sources and human activity. For example one of the most notable areas on the planet contaminated with radioactivity resulting from human activity is the Chernobyl site, north of Kiev, Ukraine, on which a nuclear reactor exploded and released large quantities of radioactivity to the environment that now chronically irradiate the biota living there. On a global scale, exposures to low levels of ionizing radiation are frequently chronic and are delivered at low-exposure rates. However, our knowledge about possible biological and health effects of low dose radiation are based largely on extrapolations from high dose/high dose-rate data after corrections are made by use of dose and dose-rate effectiveness factors. Although there are numerous published studies on the heritable effects of radiation, there are still gaps in our knowledge regarding whether chronic low doses of radiation delivered over several generations of offspring produce any heritable adverse health effects. The need for such information grows more urgent as the potential grows for human exposure to low dose/low dose-rate radiation from civilian and military uses of radiation, terrorist deployment of ‘‘dirty’’ bombs, increasing use of radiation in medical applications and long-term space travel including eventual colonization of other planets. The radiation-induced adaptive response, the bystander effect, low dose hypersensitivity and genomic instability are important effects observed after exposure to low dose/low dose-rate radiation (1). Radiation-induced genomic insta- bility is observed as an increased rate of genome alterations, which can be detected several generations after irradiation (2, 3). This phenomenon provides a striking departure from the traditional radiation effect paradigm, which has always assumed that any adverse effects in an irradiated cell were restricted to that cell. A number of reports in the literature provide evidence of radiation-induced genomic instability in rapidly dividing cells in culture (4, 5). Also several studies have reported radiation-induced genomic instability in animals and humans caused by both acute, relatively high- radiation doses and chronic, low-radiation doses (6–12). In most of these studies the instability is manifest as an increase in mutation rates at mini- and microsatellite loci, which can persist in unexposed offspring. For example, it has been shown that mutation rates at simple tandem repeat DNA loci in the nonexposed offspring of irradiated male mice are significantly increased in both the germ line (6) and somatic tissues (7). In addition, an elevated frequency 1 Address for correspondence: Department of Environmental and Radiological Health Sciences, 1681 Campus Delivery, Fort Collins, CO 80523; e-mail: zimbrick@colostate.edu. 235