The radioactive heavy metal, depleted uranium (DU), an alpha-particle emitter, is used in U.S. military munitions. This use has resulted in a number of casualties among U.S. personnel injured by fragments from DU munitions. Additional soldiers may have been exposed via inhalation or ingestion of DU particles. Recently, an alloy of tungsten, nickel, and cobalt (WA) has also been used by the U.S. military. The Persian Gulf War and the Iraq War resulted in a number of casualties among U.S. and British personnel injured by fragments from DU munitions. It is unknown whether these embedded fragments will affect the long-term health of offspring conceived by these soldiers. Studies have demonstrated that paternal preconceptional exposure to radiation or heavy metals like cadmium can induce cancer in unexposed offspring. To address this question, we investigated the paternal transmission of genetic damage in offspring of male rodents carrying embedded DU or WA fragments using a transgenic mouse model. This system allows us to assess λlacIgene mutation frequency in multiple tissues obtained from progeny of exposed fathers by employing a λlacI shuttle vector carried by cells of a transgenic mouse (Big Blue: strain C57BL/6 hemizygous mice containing 40 copies of a λlacI shuttle vector per cell). Male rodents were internally exposed to DU or WA (high and low dose) and the mutation frequencies in testes and bone marrow were then measured. Offspring from exposed male parents were genotyped and those positive for the λlacI gene were assessed for transmission of genetic damage in bone marrow tissue. Data demonstrate that offspring from DU- and WA- exposed (high dose) male parents exhibited a significant increase in the mutation frequency of the λlacI gene in their bone marrow (9.4-fold elevation and 7.7-fold elevation, respectively. The λlacI mutation frequency in progeny from unimplanted fathers did not demonstrate an increase in bone marrow mutation frequency. The results from this study indicate the possibility of transmission of genomic instability from male parents carrying embedded DU and WA to the somatic cells of their offspring. Further studies are warranted to address these questions.

Supported by the Armed Forces Radiobiology Research Institute under work unit RAB5AA. Research was conducted according to the principles enumerated in the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council.



98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA