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

Broustas, Constantinos G.; Harken, Andrew; Garty, Guy; Amundson, Sally A.

doi:10.1186/s12864-018-4884-6

Cited by 33 publications

(26 citation statements)

References 55 publications

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“…Taking a more granular look at the biological processes enriched among the significantly differentially expressed genes at each time and dose point revealed a diversity of responses dependent on dose and time since exposure. Among up-regulated genes, processes related to metabolism and catabolism were over-represented after doses of 3 Gy and above, consistent with results of earlier x-ray studies in C57BL/6 mice 1 day after a 4-Gy dose or 7 days after a 3-Gy dose 37,38 . Additional processes related to mitochondrial function and protein metabolism became significantly enriched among up-regulated genes following exposure to doses of 6 and 10 Gy, with even more metabolic processes emerging as significantly enriched among genes responding to 10 Gy on day 3 and later.…”

Section: Discussionsupporting

confidence: 89%

“…Visualizing the genes in Cluster 2 as a heatmap (Supplementary File 3) reveals a similar pattern across the cluster. From the heatmap it appears that in general these genes show the clearest switch between under and over expression following the 3-Gy dose, and suggest that directional switching or overshooting of expression levels may be more widespread in the response to radiation than suggested by the small number of genes previous reported to show this pattern of expression 38 , with a strong dependence on both dose and time since exposure.…”

Section: Discussionmentioning

confidence: 85%

“…Among down-regulated genes, processes related to immune functions, proliferation and differentiation, and signalling were enriched after doses of ≥3 Gy, with additional developmental, signalling, cell death, immune and metabolic processes becoming significantly over-represented after higher doses. Immunity related functions are also prominent among down-regulated genes in a number of previously published radiation studies, including 24 h after the start of total body irradiation in cancer patients 13 and 1 and 7 days after a 3- or 4-Gy x-ray dose in mice 37,38 . The effect on the immune system and reduced expression of immune-related genes appears to be relatively long lived, as significant enrichment of these processes was reported to last at least from day 2 through day 30 after whole-thorax lung irradiation of non-human primates 40 , and through the same time period after gamma-ray exposure from internally deposited 137 Cs in C57BL/6 mice 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Reversal of the direction of expression relative to controls has also been reported for individual genes following irradiation. For instance, in a study comparing gene expression responses of mice to x-ray and neutron exposure 38 , 14 genes ( Mta3, Eif5, Mtmr3, Wdr26, Anp32e, Ubac1, Bsdc1, E2f2, Slc25a51, Ube2c, Fzr1, Ccna2, Cdc25b , and Nusap1 ) were reported to be down regulated at one day after exposure and up regulated at 7 days after exposure. Of those genes, all but one ( Slc25a51 ) were identified by our maSigPro analysis as differentially expressed over time, and were members of Cluster 2, which showed initial suppression followed by recovery of transcript levels by 7 days after irradiation in mice exposed to doses less than 10 Gy (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptomic responses in mouse blood during the first week after in vivo gamma irradiation

Paul¹,

Kleiman²,

Amundson³

2019

Sci Rep

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Due to limitations of available human models for development of gene expression based radiation biodosimetry, many such studies have made use of mouse models. To provide a broad view of the gene expression response to irradiation in the mouse, we have exposed male C57BL/6 mice to 0, 1.5, 3, 6 or 10 Gy of gamma rays, sacrificing groups of the mice at 1, 2, 3, 5, or 7 days after exposure. We then profiled global gene expression in blood from individual mice using Agilent microarrays. In general, we found increasing numbers of genes differentially expressed with increasing dose, with more prolonged responses after the higher doses. Gene ontology analysis showed a similar pattern, with more biological processes enriched among the genes responding to higher doses, and at later times after exposure. Clustering the timecourse expression data using maSigPro identified four broad patterns of response, representing different gene ontology functions. The largest of these clusters included genes with initially decreased expression followed by increased expression at later times, a pattern of expression previously reported for several genes following neutron exposure. Another gene cluster showing consistent down regulation suggests genes useful for biodosimetry throughout the first week after exposure can be identified.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Transcriptomic responses in mouse blood during the first week after in vivo gamma irradiation

Paul¹,

Kleiman²,

Amundson³

2019

Sci Rep

Self Cite

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“…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 .…”

Section: Significance Of Neutronsmentioning

confidence: 99%

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

Shuryak

Turner

Perrier

et al. 2019

Preprint

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Biodosimetry-based discrimination between homogeneous total-body photon exposure and complex irradiation scenarios (partial-body shielding and/or neutron + photon mixtures) can improve treatment decisions after mass-casualty radiation-related incidents. Our study objective was to use high-throughput biomarkers to: a) detect partial-body and/or neutron exposure on an individual basis, and b) estimate separately the photon and neutron doses in a mixed exposure.We developed a novel approach, where metrics related to the shapes of micronuclei distributions per binucleated cell in ex-vivo irradiated human lymphocytes (variance/mean, kurtosis, skewness, etc.) served as predictors in machine learning or parametric analyses of the following scenarios: (A) Homogeneous gamma-irradiation, mimicking total-body exposures, vs. mixtures of irradiated blood with unirradiated blood, mimicking partial-body exposures. (B) X rays vs. various neutron + photon mixtures. Classification of samples as homogeneously vs. heterogeneously irradiated (scenario A) achieved a receiver operating characteristic curve area (AUROC) of 0.931 (uncertainty range of 0.903-0.951), and R 2 for actual vs. reconstructed mean dose was 0.87. Detection of samples with ≥ 10% neutron contribution (scenario B) achieved AUROC of 0.916 (0.893-0.943), and R 2 for reconstructing photon-equivalent dose was 0.77. These encouraging findings demonstrate a proof-of-principle for the proposed approach of analyzing micronuclei/cell distributions to detect clinically-relevant complex radiation exposure scenarios.biodosimetry approach in this scenario was to distinguish neutron + photon mixtures from pure photon exposures, and to quantify the neutron contribution.

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Analysis of deficiency of adenosine deaminase 2 pathogenesis based on single-cell RNA sequencing of monocytes

Watanabe

Gao

et al. 2021

Journal of Leukocyte Biology

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Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disease caused by loss‐of‐function variants in the ADA2 gene. DADA2 typically presents in childhood and is characterized by vasculopathy, stroke, inflammation, immunodeficiency, as well as hematologic manifestations. ADA2 protein is predominantly present in stimulated monocytes, dendritic cells, and macrophages. To elucidate molecular mechanisms in DADA2, CD14+ monocytes from 14 patients and 6 healthy donors were analyzed using single‐cell RNA sequencing (scRNA‐seq). Monocytes were purified by positive selection based on CD14 expression. Subpopulations were imputed from their transcriptomes. Based on scRNA‐seq, monocytes could be classified as classical, intermediate, and nonclassical. Further, we used gene pathway analytics to interpret patterns of up‐ and down‐regulated gene transcription. In DADA2, the frequency of nonclassical monocytes was higher compared with that of healthy donors, and M1 macrophage markers were up‐regulated in patients. By comparing gene expression of each monocyte subtype between patients and healthy donors, we identified upregulated immune response pathways, including IFNα/β and IFNγ signaling, in all monocyte subtypes. Distinctively, the TNFR2 noncanonical NF‐κB pathway was up‐regulated only in nonclassical monocytes. Patients’ plasma showed increased IFNγ and TNFα levels. Our results suggest that elevated IFNγ activates cell signaling, leading to differentiation into M1 macrophages from monocytes and release of TNFα. Immune responses and more general response to stimuli pathways were up‐regulated in DADA2 monocytes, and protein synthesis pathways were down‐regulated, perhaps as stress responses. Our identification of novel aberrant immune pathways has implications for therapeutic approaches in DADA2 (registered at clinicaltrials.gov NCT00071045).

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

Cited by 33 publications

References 55 publications

Transcriptomic responses in mouse blood during the first week after in vivo gamma irradiation

Transcriptomic responses in mouse blood during the first week after in vivo gamma irradiation

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

Analysis of deficiency of adenosine deaminase 2 pathogenesis based on single-cell RNA sequencing of monocytes

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