Abstract 3590: Depleted uranium-induced leukemia: Epigenetic and genetic changes.
Authors: Miller Alexandra C. , Clancy Hailey , Kluz Thomas , Cohen Stuart , Rivas Rafael , Miller Karvelisse , Costa Max 
Published: August 2014

Epigenetic and genetic changes are associated with leukemia development. Depleted uranium is used in military missions and U.S. military personnel have been wounded with DU shrapnel. In vivo studies have demonstrated that DU is leukemogenic. To further understand DU leukemogenic effects in vivo, we used a murine model to characterize and compare the DU-induced epigenetic and genetic changes in a variety of tissues including, spleen, hind limb muscle, thymus, and kidney. DU exposure (high and low dose) was evaluated in five groups of males and females: control group, DU-low dose, and DU-high dose. To determine the status of DNA methylation in female and male mice after DU exposure, the sensitive HpaII-based cytosine extension assay was used. The data from samples from DU-exposed animals demonstrated that low dose DU exposure for 3 months was associated with a 2.2- to 4.5- fold increase in the [3H]dCTP incorporation in female and male spleen, muscle, and thymus indicative of hypomethylation of DNA. Similarly data from high dose DU exposed mice indicated that DU was associated with a 4.6- to 11.5- fold increase in the [3H]dCTP incorporation in murine spleen, muscle, and bone marrow. These observations are important since the spleen and thymus are important components of hematopoietic and lymphatic systems and are significantly affected in lymphomas and leukemias. These data support the hypothesis that DNA hypomethylation is one possible mechanism involved in the development of DU-induced leukemia.

To assess gene expression changes associated with DU internalized exposure in vivo kidneys from three DU-exposed and three age-matched control mice were subject to RNA extraction and Affymetrix analysis with the MoGene-1_0-st-v1.na32.mm array. Data were analyzed with GeneSpring software.There was a clear distinction in kidney mRNA expression between DU-exposed and control mice. As compared to the control mice, the DU-exposed mice showed a decrease in expression of genes related to fatty acid metabolism and the Peroxisome proliferator-activated receptor (PPAR) pathway. From a subset of 49 genes involved in the metabolism of fatty acids, 86% of genes were down-regulated. Additionally, 45 different members of the solute carrier family of genes displayed differential expression, with 84% of the changes being down-regulation as compared to the controls. These results indicate that further gene expression studies are warranted to better understand the functional impact of these DU-effects.

Both these results support the hypothesis that DU exposure leads to genome destabilization and further studies are necessary to fully understand the epigenetic and genetic effects of DU exposure.

Citation Format: Alexandra C. Miller, Hailey Clancy, Thomas Kluz, Stuart Cohen, Rafael Rivas, Karvelisse Miller, Max Costa. Depleted uranium-induced leukemia: Epigenetic and genetic changes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3590. doi:10.1158/1538-7445.AM2013-3590