Prevention of Gamma Radiation-Induced Mortality in Mice by the Isoflavone Genistein

There is a need to develop medical countermeasures to protect first-responders and remediation workers from the biomedical effects of ionizing radiation. Agents that can protect against ionizing radiation and that can be administered before radiation would permit rescue workers to perform needed operations. The ideal radioprotector would be nontoxic and would not degrade performance. Soy phytoestrogens have strong antioxidant activity and have been reported to have many beneficial health effects, including a reduction in bone loss and the incidence of some types of cancer. The most plentiful isoflavone from soybeans is genistein (4', 5, 7trihydroxy-flavone). In the present study, the radioprotective and behavioral effects of an acute administration of the isoflavone genistein were investigated in adult CD2F1 male mice. They were administered a single subcutaneous dose of genistein, either 24 hr or 1 hr before a lethal dose of gamma radiation (9.5 Gy cobalt-60 at 0.6 Gy/min). The mice received vehicle or genistein at 3.12, 6.25, 12.5, 25, 50, 100, 200, or 400 mg/kg. For mice treated 24 hr before irradiation, there was a significant increase in 30-day survival for animals receiving genistein doses of 25 to 400 mg/kg (p < 0.001) compared to the vehicle control group. In contrast, the 30day survival rates of mice treated with genistein 1 hr before irradiation were not significantly different from those of the vehicle control group. In a separate experiment, the toxicity of genistein was evaluated in nonirradiated male mice administered a single subcutaneous injection of vehicle, or genistein at 100, 200, or 400 mg/kg. Compared with controls at these genistein doses, there were no adverse effects on locomotor activity, grip strength, body weight, testes weight, or histopathology. The results demonstrate that a single subcutaneous administration of the flavonoid genistein at nontoxic doses provides protection against acute radiation injury. Future studies are planned to examine the mechanism for genistein’s radioprotective effects. These studies will use human ex vivo whole-blood and murine in vivo spleen models and evaluate the effects of genistein on signal transduction involving DNA repair, apoptosis, and cytokine targets. 1.0 INTRODUCTION Radioprotective agents are compounds that are administered before exposure to ionizing radiation to reduce its damaging effects, including radiation-induced lethality [Stone 2004]. They have applications in radiological terrorism, military scenarios, clinical oncology, space travel, radiation site cleanup [Johnson 2004, Mettler 2002, Nair 2001, Waselenko 2004]. Recently, the U.S. Office of Science and Technology Policy and the Paper presented at the Human Factors and Medicine Panel Research Task Group 099 “Radiation Bioeffects and Countermeasures” meeting, held in Bethesda, Maryland, USA, June 21-23, 2005, and published in AFRRI CD 05-2. NATO RTG-099 2005 17–1 Report Documentation Page Form Approved OMB No. 0704-0188 Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. 1. REPORT DATE 2005 2. REPORT TYPE 3. DATES COVERED 4. TITLE AND SUBTITLE Prevention of Gamma Radiation-Induced Mortality in Mice by the Isoflavone Genistein 5a. CONTRACT NUMBER