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Bin Wan,^1,2 James T. Fleming,^1,3 Terry W. Schultz,^1,2,4 and Gary S. Sayler^1,2,3

¹Center for Environmental Biotechnology, ²Department of Ecology and Evolutionary Biology, ³Department of Microbiology, and ⁴Department of Comparative Medicine, University of Tennessee, Knoxville, Tennessee, USA

Abstract
Depleted uranium (DU) is a by-product of the uranium enrichment process and shares chemical properties with natural and enriched uranium. To investigate the toxic effects of environmental DU exposure on the immune system, we examined the influences of DU (in the form of uranyl nitrate) on viability and immune function as well as cytokine gene expression in murine peritoneal macrophages and splenic CD4⁺ T cells. Macrophages and CD4⁺ T cells were exposed to various concentrations of DU, and cell death via apoptosis and necrosis was analyzed using annexin-V/propidium iodide assay. DU cytotoxicity in both cell types was concentration dependent, with macrophage apoptosis and necrosis occurring within 24 hr at 100 µM DU exposure, whereas CD4⁺ T cells underwent cell death at 500 µM DU exposure. Noncytotoxic concentrations for macrophages and CD4⁺ T cells were determined as 50 and 100 µM, respectively. Lymphoproliferation analysis indicated that macrophage accessory cell function was altered with 200 µM DU after exposure times as short as 2 hr. Microarray and real-time reverse-transcriptase polymerase chain reaction analyses revealed that DU alters gene expression patterns in both cell types. The most differentially expressed genes were related to signal transduction, such as c-jun, NF- Bp65, neurotrophic factors (e.g., Mdk) , chemokine and chemokine receptors (e.g., TECK/CCL25) , and interleukins such as IL-10 and IL-5, indicating a possible involvement of DU in cancer development, autoimmune diseases, and T helper 2 polarization of T cells. The results are a first step in identifying molecular targets for the toxicity of DU and the elucidation of the molecular mechanisms for the immune modulation ability of DU. Key words: apoptosis, CD4⁺ T cell, cytokine gene expression, depleted uranium, macrophage function, necrosis. Environ Health Perspect 114:85-91 (2006) . doi:10.1289/ehp.8085 available via http://dx.doi.org/ [Online 17 August 2005]

Address correspondence to G.S. Sayler, Center for Environmental Biotechnology, University of Tennessee, Knoxville, 676 Dabney Hall, Knoxville, TN 37996-1605 USA. Telephone: (865) 974-8080. Fax: (865) 974-8086. E-mail: sayler@utk.edu

We acknowledge the assistance of H. Zaghouani, B. Rouse, U. Kumaraguru, J. Young, and personnel of the University of Tennessee animal facilities.

This work was supported by the Center for Environmental Biotechnology, Research Center of Excellence, by the Waste Management Research and Education Institute, and by the Office of the Vice Chancellor for Research, University of Tennessee. Partial support for this project was provided by National Science Foundation grant BES-0116610.

The authors declare they have no competing financial interests.

Received 2 March 2005 ; accepted 17 August 2005.