The 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 Findings
We 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.
We 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.
John Chute and colleagues report that gene expression patterns in peripheral blood mononuclear cells from mice and humans reflect prior radiation exposure.
Everyone living on earth is constantly exposed to low levels of ionizing radiation—energy in the form of waves or particles that is powerful enough to strip electrons out of atoms and to break chemical bonds in important biomolecules. These low levels of ionizing radiation come from radioactive chemicals in the ground and cosmic rays, for example, and are relatively harmless. Occasionally, though, individuals are exposed to larger amounts of ionizing radiation, often as a result of medical tests and treatments but sometimes through the accidental or deliberate release of radioactive chemicals. These larger doses, which permanently damage or kill cells, can cause radiation sickness, a condition characterized by bone marrow failure, gut problems, susceptibility to bacterial infections, and other symptoms that develop days or months after exposure to ionizing radiation. Particularly large doses can be lethal but even moderate doses can increase an individual's risk of developing cancer later in life.
Why Was This Study Done?
Some of the effects of ionizing radiation can be reduced if suitable treatment is started immediately after exposure. Unfortunately, it takes several days to estimate the amount of ionizing radiation to which an individual has been exposed. It would be useful to measure personal exposures more quickly, especially in emergency situations where ideally doctors would be able to distinguish rapidly and accurately between the “worried well” and exposed individuals. As cells respond to irradiation by altering the expression of some genes, the researchers in this study investigated whether gene expression profiling (a molecular biology technique that catalogues all the genes expressed by a cell) can be used to define a set of gene expression changes—called a metagene—that differentiates between irradiated and non-irradiated cells.
What Did the Researchers Do and Find?
The researchers exposed mice to no ionizing radiation, a low dose that causes no medical problems, an intermediate dose that damages blood cells, or a lethal dose. Six hours later, they isolated blood cells from the mice, and catalogued which genes each sample expressed. Using this information, the researchers identified and validated metagenes that accurately distinguished between blood samples from non-irradiated and irradiated animals and between samples from animals exposed to different radiation doses. The researchers then developed a metagene for human radiation exposure using blood samples taken from patients before and after total body irradiation given as part of their medical treatment. This metagene correctly identified 18 of 20 pre-irradiation samples and 17 of 20 post-irradiation samples. Finally, the researchers tested whether the radiation metagenes developed in mice could distinguish between samples taken from irradiated and non-irradiated people. Although the high-dose mouse metagene correctly identified all of the samples from healthy donors as being non-irradiated, it correctly identified only two-thirds of the pre-irradiated samples from patients.
What Do These Findings Mean?
These findings indicate that metagenes can be generated that recognize different levels of radiation exposure in mice and people. In the mouse study a metagene was identified that correctly identified in all cases whether a sample came from a non-irradiated mouse or an animal exposed to the lowest dose of radiation. This result suggests that it might be possible to use a metagene to identify exposed individuals among thousands of “worried well” after a radiation emergency. First, however, the mouse and human metagenes identified here need to be refined to improve their accuracy and then validated in more people. The current high-dose mouse metagene may be bad at identifying non-irradiated patients, for example, because of gene expression changes that are a result of the patients' underlying disease or previous medical treatments. By studying additional patients, it might be possible to improve the accuracy of the metagene by taking these radiation-independent changes into account. Finally and more generally, these findings suggest that the metagene approach could be used to monitor people's exposure to other dangerous environmental agents.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040106.
US Environmental Protection Agency offers information on understanding radiation and factsheets on ionizing radiation
MedlinePlus provides links to information on radiation exposure and pages on radiation sickness
US Centers for Disease Control and Prevention has information on emergency preparedness and response to radiation emergencies
Wikipedia has pages on ionizing radiation, radiation poisoning, and expression profiling (note that Wikipedia is a free online encyclopedia that anyone can edit)