Comparison of gene expression response to neutron and x-ray irradiation using mouse blood

Abstract

BackgroundIn the event of an improvised nuclear device detonation, the prompt radiation exposure would consist of photons plus a neutron component that would contribute to the total dose. As neutrons cause more complex and difficult to repair damage to cells that would result in a more severe health burden to affected individuals, it is paramount to be able to estimate the contribution of neutrons to an estimated dose, to provide information for those making treatment decisions.ResultsMice exposed to either 0.25 or 1 Gy of neutron or 1 or 4 Gy x-ray radiation were sacrificed at 1 or 7 days after exposure. Whole genome microarray analysis identified 7285 and 5045 differentially expressed genes in the blood of mice exposed to neutron or x-ray radiation, respectively. Neutron exposure resulted in mostly downregulated genes, whereas x-rays showed both down- and up-regulated genes. A total of 34 differentially expressed genes were regulated in response to all ≥1 Gy exposures at both times. Of these, 25 genes were consistently downregulated at days 1 and 7, whereas 9 genes, including the transcription factor E2f2, showed bi-directional regulation; being downregulated at day 1, while upregulated at day 7. Gene ontology analysis revealed that genes involved in nucleic acid metabolism processes were persistently downregulated in neutron irradiated mice, whereas genes involved in lipid metabolism were upregulated in x-ray irradiated animals. Most biological processes significantly enriched at both timepoints were consistently represented by either under- or over-expressed genes. In contrast, cell cycle processes were significant among down-regulated genes at day 1, but among up-regulated genes at day 7 after exposure to either neutron or x-rays. Cell cycle genes downregulated at day 1 were mostly distinct from the cell cycle genes upregulated at day 7. However, five cell cycle genes, Fzr1, Ube2c, Ccna2, Nusap1, and Cdc25b, were both downregulated at day 1 and upregulated at day 7.ConclusionsWe describe, for the first time, the gene expression profile of mouse blood cells following exposure to neutrons. We have found that neutron radiation results in both distinct and common gene expression patterns compared with x-ray radiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3436-1) contains supplementary material, which is available to authorized users.

Metabolic Dysregulation after Neutron Exposures Expected from an Improvised Nuclear Device

“…Therefore, a change of phospholipids that can be converted to arachidonic acid through phospholipase A2 may be severely affected in the high-dose neutron group of this study, with downstream effects of oxylipin generation and immune system regulation. This was demonstrated in a blood gene expression-profiling study that identified enrichment in processes involved in lipid biosynthesis and metabolism in 1 Gy X-ray group vs. 1 Gy neutron group at day 1 but not day 7 postirradiation (25). On the other hand, increase of those markers at the later time point, whether statistically significant or suggestive of increased levels, indicate the existence of a delicate balance between a pro- and anti-inflammatory state implicating the immune system, as has been previously discussed (13, 47, 48).…”

“…(22). The doses were chosen based on the limited data on IND-spectrum neutrons (25, 26). A calculated RBE of 4, based on micronuclei formation for this particular mixed field (22), was used for the comparative doses in our current studies; namely the neutron doses used were 0.25 and 1 Gy, whereas the X-ray doses used were 1 and 4 Gy.…”

New High Throughput Approaches to Detect Partial-body and Neutron Exposures on an Individual Basis

“…Due to the high relative biological effectiveness of neutrons for causing cytogenetic damage [9][10][11] , the neutron dose contributes roughly 4 times the damage of an equivalent photon dose. Consequently, these neutron components are likely to have a profound impact on disease type and progression [12][13][14][15] . It is also likely that different countermeasures will be required for neutroninduced disease and photon-induced exposure 16 Significance of partial body exposures A significant proportion of individuals exposed indoors to the initial blast from an IND will be exposed non-homogeneously, to a partial body exposure, due to shielding by objects and building materials 7 .…”

New Approaches for Quantitative Reconstruction of Radiation Dose in Human Blood Cells

“…Once this basic reconstructor signature is established to estimate dose in a quantitative manner, increasingly complex scenarios can also be considered. Gene expression holds promise for distinguishing other relevant characteristics of exposure; including dose rate 9,10 such as from exposure to fallout 11 ; and partial shielding and the presence of neutrons 12,13 , which would be relevant to the blast from an improvised nuclear device 14 . Genes for discrimination of such dose modifying factors could be tested in future biodosimetric signatures.…”