Identification of differentially expressed genes and pathways in mice exposed to mixed field neutron/photon radiation

Constantinos G Broustas,Andrew D Harken,Sally A Amundson,Guy Garty

doi:10.1186/s12864-018-4884-6

Constantinos G Broustas, Andrew D Harken + Show 2 more

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https://doi.org/10.1186/s12864-018-4884-6

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Abstract

BackgroundRadiation exposure due to the detonation of an improvised nuclear device remains a major security concern. Radiation from such a device involves a combination of photons and neutrons. Although photons will make the greater contribution to the total dose, neutrons will certainly have an impact on the severity of the exposure as they have high relative biological effectiveness.ResultsWe investigated the gene expression signatures in the blood of mice exposed to 3 Gy x-rays, 0.75 Gy of neutrons, or to mixed field photon/neutron with the neutron fraction contributing 5, 15%, or 25% of a total 3 Gy radiation dose. Gene ontology and pathway analysis revealed that genes involved in protein ubiquitination pathways were significantly overrepresented in all radiation doses and qualities. On the other hand, eukaryotic initiation factor 2 (EIF2) signaling pathway was identified as one of the top 10 ranked canonical pathways in neutron, but not pure x-ray, exposures. In addition, the related mTOR and regulation of EIF4/p70S6K pathways were also significantly underrepresented in the exposures with a neutron component, but not in x-ray radiation. The majority of the changed genes in these pathways belonged to the ribosome biogenesis and translation machinery and included several translation initiation factors (e.g. Eif2ak4, Eif3f), as well as 40S and 60S ribosomal subunits (e.g. Rsp19, Rpl19, Rpl27). Many of the differentially downregulated ribosomal genes (e.g. RPS19, RPS28) have been causally associated with human bone marrow failure syndromes and hematologic malignancies. We also observed downregulation of transfer RNA processes, in the neutron-only exposure (p < 0.005). Ingenuity Pathway Analysis (p < 0.05) of differentially expressed genes predicted significantly suppressed activity of the upstream regulators c-Myc and Mycn, transcription factors known to control ribosome biogenesis.ConclusionsWe describe the gene expression profile of mouse blood following exposure to mixed field neutron/photon irradiation. We have discovered that pathways related to protein translation are significantly underrepresented in the exposures containing a neutron component. Our results highlight the significance of neutron exposures that even the smallest percentage can have profound biological effects that will affect medical management and treatment decisions in case of a radiological emergency.

Highlights

Radiation exposure due to the detonation of an improvised nuclear device remains a major security concern
Microarray experiments We recently described the gene expression profiles of mouse blood cells following either x-ray or neutron irradiation and analyzed them 1 and 7 days post-irradiation
We investigated whether we can identify the neutron component after a mixed field x-ray/neutron exposure, by analyzing gene expression signatures

Summary

Introduction

Radiation exposure due to the detonation of an improvised nuclear device remains a major security concern. Radiation from such a device involves a combination of photons and neutrons. Radiation exposure due to the detonation of an improvised nuclear device poses a growing threat to human health. In such a scenario, large populations will be exposed to various doses of radiation. A small number of studies have focused on comparing gene expression profiles in various tissues between photon and heavy ions or α-particles, which could be relevant to a radiological dispersal device. Depending on the cell type, similar or distinct gene expression profiles have been described [7,8,9]

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