Leukemic transformation of hematopoietic cells in mice internally exposed to depleted uranium
Depleted uranium (DU) is a dense heavy metal used in military applications. During military conflicts, US military personnel have been wounded by DU shrapnel. The health effects of embedded DU are unknown. Published data from our laboratory demonstrated that DU exposure in vitro can transform immortalized human osteoblast cells (HOS) to the tumorigenic phenotype. Results from our laboratory have also shown that DU is genotoxic and mutagenic in cultured human cells. Internalized DU could be a carcinogenic risk and concurrent alpha particle and heavy metal toxic effects complicate this potential risk. Anecdotal reports have suggested that DU can cause leukemia. To better assess this risk, we have developed an in vivo leukemogenesis model. This model involves using murine hematopoietic cells (FDC-P1) that are dependent on stimulation by granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin 3 (IL-3) and injected into mice to produce myeloid leukemia. Although immortalized, these cells are not tumorigenic on subcutaneous inoculation in mice. Intravenous injection of FDC-P1 cells into DU-implanted DBA/2 mice was followed by the development of leukemias in 76% of all mice implanted with DU pellets. In contrast, only 12% of control mice developed leukemia. Karyotypic analysis confirmed that the leukemias originated from FDC-P1 cells. The growth properties of leukemic cells from bone marrow, spleen, and lymph node were assessed and indicate that the FDC-P1 cells had become transformed in vivo. The kidney, spleen, bone marrow, muscle, and urine showed significant elevations in tissue uranium levels prior to induction of leukemia. These results demonstrated that a DU altered in vivo environment may be involved in the pathogenesis of DU induced leukemia in an animal model.
Key WordsDBA depleted uranium heavy-metals internal exposure leukemia mice
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- 2.Miller AC, Fuciarelli AF, Jackson WE, Ejnik EJ, Emond C, Strocko S, Hogan J, Page N, Pellmar T: Urinary and serum mutagenicity studies with rats implanted with depleted uranium or tantalum pellets. Mutagenesis 13: 101–106, 1998Google Scholar
- 3.Andrew SP, Caligiuri RD, Eiselstein LE: A review of penetration mechanisms and dynamic properties of tungsten and depleted uranium penetrators. In: A. Crowson, E.S. Chen (eds). Tungsten and Tungsten Alloys: Recent Advances, Plenum Press, NY, 1991Google Scholar
- 4.Miller AC, Whittaker T, Hogan J, McBride S, Benson K: Oncogenes as biomarkers for low dose radiation-induced health effects. Can Detect Prev 20: 235–236, 1996Google Scholar
- 9.Miller AC, Xu J, Stewart M, Brooks K, Hodge S, Shi L, Page N, McClain D: Observation of radiation specific damage in human cells exposed to depleted uranium: Dicentric frequency and neoplastic transformation as endpoints. Radiat Protect Dosim 99: 275–278, 2002Google Scholar
- 10.Miller AC, Brooks K, Smith J, Page N: Effect of militarily relevant heavy metals, depleted uranium and heavy metal tungsten alloy on gene expression in human liver carcinoma cells [HePG2]. Molec Cell Biochem 255: 247–256, 2004vadjustGoogle Scholar
- 11.Mould RF: Depleted uranium and radiation-induced lung cancer and leukemia. Br Radiol 74: 677–683, 2001Google Scholar
- 13.Duhrsen D, Metcalf D: Factors influencing the time and site of leukemic transformation of factor-dependent cells after injection into irradiated recipient mice. Int J Can 44: 1074–1081, 1989Google Scholar
- 14.Duhrsen D, Metcalf D. Effects of irradiation of recipient mice on the behavior and leukemogenic potential of factor-dependent hematopoietic cell lines. Blood 75: 190–197, 1990Google Scholar
- 18.National Research Council Committee on Biological Effects of Ionizing Radiation: Health Effects of Exposure to Radon – BEIR VI, National Academy Press, Washington, DC, 1999Google Scholar
- 21.Waalkes MP, Rehm S, Sass B, Ward JM: Induction of tumors of the hematopoietic system by cadmium in rats. IARC Sci Pub 118: 401–404, 1992Google Scholar