Leukemic transformation of hematopoietic cells in mice internally exposed to depleted uranium
Leukemic transformation of hematopoietic cells in mice internally exposed to depleted uranium
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DOI：
10.1007/s11010-005-8226-z
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发表时间：
2005-11-01
影响因子：
4.3
通讯作者：
Lison, PD
中科院分区：
文献类型：
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作者：
Miller, AC;Bonait-Pellie, C;Lison, PD
贫化铀(DU)是一种用于军事应用的高密度重金属。在军事冲突中，美国军事人员曾被杜弹片打伤。嵌入的DU对健康的影响尚不清楚。我们实验室公布的数据表明，体外DU暴露可以将永生化的人成骨细胞(HOS)转化为致瘤表型。我们实验室的结果还表明，DU对培养的人细胞具有遗传毒性和致突变性。DU内化可能是一种致癌风险，同时阿尔法粒子和重金属毒性效应使这一潜在风险复杂化。坊间报道表明，DU会导致白血病。为了更好地评估这种风险，我们开发了一个体内白血病发生模型。该模型使用依赖于粒细胞-巨噬细胞集落刺激因子(GM-CSF)或白介素3(IL-3)刺激的小鼠造血细胞(FDC-P1)，并将其注射到小鼠体内产生髓系白血病。尽管这些细胞是永生的，但在小鼠皮下接种时不会产生肿瘤。将FDC-P1细胞静脉注射到DU移植的DBA/2小鼠后，76%的DBA/2小鼠发生了白血病。相比之下，只有12%的对照组小鼠患上了白血病。核型分析证实该白血病来源于FDC-P1细胞。对来自骨髓、脾和淋巴结的白血病细胞的生长特性进行了评估，表明FDC-P1细胞在体内发生了转化。在诱发白血病之前，肾、脾、骨髓、肌肉和尿液的组织铀水平显著升高。这些结果表明，DU体内环境的改变可能参与了DU诱导的动物模型白血病的发病机制。
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.