Date Published: April 3, 2007
Publisher: Public Library of Science
Author(s): Holly K Dressman, Garrett G Muramoto, Nelson J Chao, Sarah Meadows, Dawn Marshall, Geoffrey S Ginsburg, Joseph R Nevins, John P Chute, CHristopher Kemp
Abstract: BackgroundThe capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation.Methods and FindingsWe have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans.ConclusionsWe suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.
Partial Text: Environmental risks and individual genetic repertoires are considered to be the primary influences that dictate a person’s susceptibility to disease. However, for any given disease, accurate estimation of the contribution of either environmental influences or genotype to disease development can be difficult. Once an association between a given environmental exposure and a particular biological phenotype has been suggested, it is important, if possible, to prospectively determine whether the environmental exposure has a causative or predictive impact on the biological phenotype.
The ability to assess exposure to ionizing radiation, both to measure adverse effects that might result from low level exposure and to assess the extent of exposure following exposure to high-level radiation, could have a significant impact on subsequent clinical care. With this in mind, we have sought to develop gene expression signatures that could reflect radiation exposure and have the capacity to discriminate based on the exposure level. More broadly, these studies have the potential to identify specific genes and pathways involved in radiation-induced cellular damage and, therefore, targets for radioprotective intervention. An examination of the functional categories represented within the mouse radiation profiles revealed protein and cellular biosynthesis and immune response as highly represented gene predictor functions (Table S2). Additionally, individual genes involved in DNA repair (e.g., recombination activating gene 1 [Rag1])  as well as hematopoietic cell activation (membrane spanning 4-domains, subfamily A, member 1 [Ms4a1])  were identified. More generally, biological processes including apoptosis (e.g., Ei24) were highlighted. While it may be premature to consider how the biological processes represented by the radiation response genes we have identified may be exploited for therapeutic purposes, these results clearly provide clues to guide future studies focused on this goal.