Leukemic transformation of hemopoietic cells in mice internally exposed to depleted uranium: prevention by phenylacetate
Armed Forces Radiobiology Research Institute, Bethesda, MD, Paris
Depleted uranium (DU) is a dense heavy metal used primarily in military applications. Published data from our laboratory have demonstrated that DU exposure in vitro can transform immortalized human osteoblast cells (HOS) to the tumorigenic phenotype. Internalized DU could be a significant carcinogenic risk complicated by concurrent alpha particle and heavy metal toxic effects. To better assess this risk, we have developed an in vivo leukemogenesis model using murine hematopoietic cells (FDC-P1) that are dependent on stimulation by granulocyte-macrophage colony stimulating factor. Although immortalized, these cells are not tumorigenic on subcutaneous inoculation. Intravenous injection of FDC-P1 cells into syngeneic DBA/2 mice was followed by the development of leukemias in 68% of all mice implanted with DU pellets in their hind limbs. In contrast, only 14% 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 were characterized by classic leukemic cell growth. Since this leukemia induction was related to DU effects on the host environment and not direct DU effects on the hemopoietic cells, immune system effects are being examined. Preliminary data show that there was a significant decrease in the cellularity of the spleen, thymus, and peripheral lymph nodes. Furthermore, blood element counts showed a decrease in neutrophils, monocytes, and circulating NK cells. These are the first studies to demonstrate an effect of DU on hematological parameters and the structure of the immune system. Most importantly, these results demonstrated that a DU-altered environment may play a role in the pathogenesis of a DU-induced leukemia in an animal model.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 898 (Oncogenesis).