Toxicogenomic assessment of organ-specific responses following plutonium internal contamination

Abstract

• Gene expression analysis was used to study toxicity mechanisms of 238 Pu in mice. • Immune responses and lipid homeostasis are key biological functions affected by 238 Pu. • Organ-specific responses included arrested cell proliferation and DNA repair. • RT-qPCR was used to corroborate genome-wide analysis results. Plutonium is a radioactive element widely used as an energy source and further employed in military applications. Although global stockpiles of plutonium have increased with time, the toxicological profile of this metal has only been partially characterized. The vast majority of studies have focused on either the biodistribution of plutonium following internal contamination, or the identification of important proteins involved in plutonium uptake within the body. Thus, an enhanced knowledge of the metal biology may improve future therapeutic approaches to mitigate uncontrolled releases of plutonium. Herein, we have employed genome-wide toxicogenomics to assess the biological functions and response mechanisms disrupted by plutonium in vivo. Microarray gene expression was used to identify the differentially expressed genes in liver, kidneys and lungs after internal contamination of Swiss-Webster mice with plutonium. Functional analysis revealed that plutonium altered immune and inflammatory responses and lipid homeostasis, likely as a consequence of radiation-induced damage and the disruption of metal-regulated processes. Moreover, protein-protein interaction network analysis identified several key proteins associated with cellular responses to plutonium-induced damage, including ribosome biosynthesis, cell proliferation inhibition, DNA repair and glycolysis upregulation. Lastly, real-time quantitative polymerase chain reaction was used to corroborate microarray results and analyze the effects of plutonium dosing and time of exposure. This study provides substantial context for the further development of novel therapeutics and prophylactics targeting the effects of Pu isotopes by identifying the key genes and proteins that are important to specific biological functions and cellular mechanisms.