Miller Alexandra C, Brooks Kia, Smith Jan, Page Natalie
Applied Cellular Radiobiology Department, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603, USA.
Mol Cell Biochem. 2004 Jan;255(1-2):247-56. doi: 10.1023/b:mcbi.0000007280.72510.96.
Depleted uranium (DU) and heavy-metal tungsten alloys (HMTAs) are dense heavy-metals used primarily in military applications. Chemically similar to natural uranium, but depleted of the higher activity 235U and 234U isotopes, DU is a low specific activity, high-density heavy metal. In contrast, the non-radioactive HMTAs are composed of a mixture of tungsten (91-93%), nickel (3-5%), and cobalt (2-4%) particles. The use of DU and HMTAs in military munitions could result in their internalization in humans. Limited data exist however, regarding the long-term health effects of internalized DU and HMTAs in humans. Both DU and HMTAs possess a tumorigenic transforming potential and are genotoxic and mutagenic in vitro. Using insoluble DU-UO2 and a reconstituted mixture of tungsten, nickel, cobalt (rWNiCo), we tested their ability to induce stress genes in thirteen different recombinant cell lines generated from human liver carcinoma cells (HepG2). The commercially available CAT-Tox (L) cellular assay consists of a panel of cell lines stably transfected with reporter genes consisting of a coding sequence for chloramphenicol acetyl transferase (CAT) under transcriptional control by mammalian stress gene regulatory sequences. DU, (5-50 microg/ml) produced a complex profile of activity demonstrating significant dose-dependent induction of the hMTIIA FOS, p53RE, Gadd153, Gadd45, NFkappaBRE, CRE, HSP70, RARE, and GRP78 promoters. The rWNiCo mixture (5-50 microg/ml) showed dose-related induction of the GSTYA, hMTIIA, p53RE, FOS, NFkappaBRE, HSP70, and CRE promoters. An examination of the pure metals, tungsten (W), nickel (Ni), and cobalt (Co), comprising the rWNiCo mixture, demonstrated that each metal exhibited a similar pattern of gene induction, but at a significantly decreased magnitude than that of the rWNiCo mixture. These data showed a synergistic activation of gene expression by the metals in the rWNiCo mixture. Our data show for the first time that DU and rWNiCo can activate gene expression through several signal transduction pathways that may be involved in the toxicity and tumorigenicity of both DU and HMTAs.
贫铀（DU）和重金属钨合金（HMTAs）是主要用于军事用途的高密度重金属。DU在化学性质上与天然铀相似，但贫化了高活性的235U和234U同位素，是一种低比活度、高密度的重金属。相比之下，非放射性的HMTAs由钨（91 - 93%）、镍（3 - 5%）和钴（2 - 4%）颗粒的混合物组成。在军事弹药中使用DU和HMTAs可能导致它们在人体内蓄积。然而，关于人体内蓄积的DU和HMTAs对健康的长期影响，现有数据有限。DU和HMTAs都具有致瘤转化潜能，并且在体外具有遗传毒性和致突变性。我们使用不溶性的DU - UO2以及钨、镍、钴的重组混合物（rWNiCo），测试了它们在由人肝癌细胞（HepG2）产生的13种不同重组细胞系中诱导应激基因的能力。市售的CAT - Tox (L)细胞检测法由一组稳定转染了报告基因的细胞系组成，这些报告基因包含在哺乳动物应激基因调控序列转录控制下的氯霉素乙酰转移酶（CAT）编码序列。DU（5 - 50微克/毫升）产生了复杂的活性图谱，显示出对hMTIIA、FOS、p53RE、Gadd153、Gadd45、NFkappaBRE、CRE、HSP70、RARE和GRP78启动子有显著的剂量依赖性诱导。rWNiCo混合物（5 - 50微克/毫升）显示出对GSTYA、hMTIIA、p53RE、FOS、NFkappaBRE、HSP70和CRE启动子的剂量相关诱导。对构成rWNiCo混合物的纯金属钨（W）、镍（Ni）和钴（Co）的检测表明，每种金属都表现出相似的基因诱导模式，但诱导程度明显低于rWNiCo混合物。这些数据表明rWNiCo混合物中的金属对基因表达有协同激活作用。我们的数据首次表明DU和rWNiCo可以通过几种信号转导途径激活基因表达，这些途径可能与DU和HMTAs的毒性和致瘤性有关。
