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.