[Proc Amer Assoc Cancer Res, Volume 47, 2006]
Carcinogenesis 5: Environmental and Endogenous Carcinogens
Preconceptional paternal exposure to radiation or heavy metals like cadmium can induce cancer in unexposed offspring
Alexandra C. Miller,
Robert J. Merlot and
AFRRI, Bethesda, MD and University of Paris, Paris, France
The use of heavy metals like depleted uranium (DU) and tungsten alloy (WA) in military munitions could result in soldiers being wounded with heavy metal shrapnel. The long-term health effects, including carcinogenic and transgenerational effects of chronic exposure to internalized DU or WA, are not fully understood. Currently, no known birth defects have been observed in children from DU-injured fathers. However, 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 fragments using a transgenic mouse model. This system allows us to assess lacI gene mutation frequency in multiple tissues obtained from progeny of exposed fathers by employing a lacI shuttle vector carried by cells of a transgenic mouse (Big Blue: strain C57BL/6 hemizygous mice containing 40 copies of a lacI 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 lacI gene were assessed for transmission of genetic damage in bone marrow tissue. Data demonstrate that DU exposure (high and low dose) of fathers induced a significant increase in the lacI mutation frequency in both testes and bone marrow (10.2- and 6.5 fold elevation respectively).Similar elevations were observed in WA-exposed fathers (7.3- and 4.4 fold elevation). Offspring from DU-exposed (high dose) male parents also demonstrated a significant increase in the mutation frequency of the lacI gene in their bone marrow (9.4-fold elevation). Similarly, a 6.6 fold elevation was measured in offspring from WA-exposed fathers. The mutation frequencies in bone marrow from progeny of males exposed to a lower dose of internalized DU or WA were not significantly different from control (nonsurgical and Tantalum-implanted P1) progeny. The results from this study indicate the possibility of transmission of genomic instability from male parents carrying embedded DU or WA to the somatic cells of their offspring. Further studies are warranted to address these questions.
Copyright © 2006 by the American Association for Cancer Research.