Leukemic transformation of hematopoietic cells in mice internally exposed to depleted uranium |
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Authors: | Alexandra C Miller Catherine Bonait-Pellie Robert F Merlot John Michel Michael Stewart Paul D Lison |
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Institution: | (1) Applied Cellular Radiobiology Department, Armed Forces Radiobiology Research, Institute, Bethesda, Maryland, USA;(2) Department of Occupational and Environmental Medicine, University of Paris, Paris, France;(3) Applied Cellular Radiobiology Department, AFRRI, 8901 Wisconsin Ave, Bethesda, MD 20889-5603, USA |
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Abstract: | 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. |
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Keywords: | DBA depleted uranium heavy-metals internal exposure leukemia mice |
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