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Global gene expression in response to X rays in mouse models of DNA repair deficiency

ABSTRACT: There is a perceived need to develop tools for high-throughput radiation biodosimetry. In the case of an improvised nuclear device or a dirty bomb in a major city, potentially hundreds of thousands of people would have to be screened to assign exposed individuals to appropriate treatment. Gene expression represents an emerging approach to biodosimetry and could potentially provide an estimate of both absorbed dose and individual radiation-induced injury. Mice have been used as an in vivo model to elucidate the radiation response and to construct biodosimetric gene expression profiles. However, while most studies have used mouse strains with “average” radiation sensitivity, 2-4% of humans are thought to be radiosensitive. Such individuals would suffer greater radiological injury at a given dose than members of the general population, so it is of interest to determine how such sensitivity may impact the biodosimetric gene expression signatures being developed. Here, we use wild-type mice and genetically engineered mouse models deficient in two DNA repair pathways that can contribute to radiation sensitivity. Humans with ataxia telangiectasia or Atm-/- mice are deficient in double-strand break repair and show increased radiosensitivity. Atm-/- mice have a LD50/30 of 4 Gy compared with 8 Gy in the parental wild-type (WT) C57BL/6 mice. Humans with SCID, or Prkdcscid mice are deficient in non-homologous end joining, and are also radiosensitive. SCID mice have a LD50/30 of 3 Gy. These animal models represent a “worse-case” scenario, and should be viewed as an extreme of radiation sensitivity. Most radiosensitive members of the population will not have full-blown DNA repair deficiency syndromes, but these extreme models should help to define the maximum impact of DNA repair deficiency on gene expression following radiation exposure.

ORGANISM(S): Mus musculus

PROVIDER: GSE99176 | GEO | 2018/01/17

SECONDARY ACCESSION(S): PRJNA387466

REPOSITORIES: GEO

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Project description:Background: Ionizing Radiation (IR) is a known pro-inflammatory agent and in the process of development of biomarkers for radiation biodosimetry a chronic inflammatory disease condition could act as a confounding factor. Hence, it is important to develop radiation biodosimetry that can distinguish between IR-induced inflammatory responses and pre-existing disease. In this study, we compared the gene expression response of a genetically modified mouse model of inflammatory bowel disease (Il10-/-) with that of a normal wild-type mouse to potentially develop transcriptomic based biodosimetry markers for individual susceptibility to radiation. Results: Wild-type (WT) and Il10-/- mice were exposed to whole body irradiation of 7Gy (LD50/30 for IL10-/-) X-rays. Gene expression responses were studied using high throughput whole genome microarrays in peripheral blood after 24h post-irradiation. Analysis resulted in identification of 1962 and 1844 genes differentially expressed (p < 0.001, FDR < 10%) after radiation exposure in Il10-/- and WT mice respectively. A set of 155 genes were also identified as differentially expressing between WT and Il10-/- mice at the baseline pre-irradiation level. Gene ontology analysis revealed that the baseline differentially expressing genes (155) were mainly involved in Inflammatory response, Glutathione metabolism and fibrosis. Analysis of radiation responsive genes revealed commonality of immune function genes between WT and Il10-/- mice. Gene ontology analysis revealed that innate immune response and p53 signaling processes were strongly associated with up-regulated genes whereas, B-cell development process was found to be significant amongst downregulated genes in response to radiation in the two genotypes. However, specific immune response pathways like MHC class I antigen presentation and response to viral/bacterial infection were particularly associated with radiation responsive genes of Il10-/- mice but not with WT mice. Further analysis of activation status of specific canonical pathways and upstream regulators using IPA-prediction tool revealed significant difference in the activation status of T-cell and hormone mediated signaling as well as regulators of inflammation between WT and Il10-/- after irradiation.

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Global gene expression in response to X rays in mouse models of DNA repair deficiency

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