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Radiation-induced molecular alterations after whole body irradiation in a mouse model

ABSTRACT: Long non-coding RNAs (lncRNAs) are emerging as key molecules in regulating many biological processes and have been implicated in development and disease pathogenesis. Biomarkers of cancer and normal tissue response to treatment are of great interest in precision medicine and for public health and medical management of disasters such as assessing radiation injury following accidental or intentional exposure. Circulating and functional RNAs, including microRNAs (miRNAs) and lncRNAs, in whole blood and other body fluids represent potential valuable candidates as biomarkers. Early prediction of possible acute, intermediate, and delayed effects of radiation exposure will enable timely therapeutic interventions. To address whether lncRNAs could serve as biomarkers for radiation bio-dosimetry, we performed whole genome transcriptome analysis in a mouse model after whole body irradiation. Differential lncRNA expression patterns were evaluated at 16-, 24-, and 48-hour time points post irradiation in total RNA isolated from whole blood of mice exposed to 1, 2, 4, 8, and 12 Gy of gamma-rays. Sham irradiated animals served as controls. Significant alterations in the expression patterns of lncRNAs were observed after different radiation doses at the various timepoints. We identified several lncRNAs known for DNA damage response as well as immune response as radiation induced biomarkers. Long non-coding RNA targets of tumor protein 53 (P53), Trp53cor1, Dino, Pvt1 and Tug1 and an upstream regulator of p53, Meg3 were altered in response to radiation. Gm14005 (Morrbid) and Tmevpg1 were regulated by radiation across all time points and doses. These two lncRNAs have important potential as blood based radiation biomarkers; Gm14005 (Morrbid) has recently been shown to play a key role in inflammatory response while Tmevpg1 has been implicated in the regulation of interferon-gamma. Precise molecular biomarkers will not only enable the development and effective use of medical countermeasures but also may be used to detect and circumvent or mitigate normal tissue injury in cancer radiotherapy treatments.

ORGANISM(S): Mus musculus

PROVIDER: GSE104121 | GEO | 2018/05/31

REPOSITORIES: GEO

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Project description:Rapid and reliable methods for conducting biological dosimetry are a necessity in the event of a large-scale nuclear event. Timely and accurate methods are thus critical in order to correctly evaluate and identify radiation dose exposure and triage appropriately. Alterations in microRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have been reported in cells/tumors subjected to radiation exposure, implying that miRNAs play an important role in cellular stress response to radiation. To examine the possibility of using microRNA as stable blood based biomarkers for radiation response, we have used microRNA microarray analysis. Differential microRNA expression pattern was evaluated (>1.5 fold and p value <0.05) at 6, 24, 48 h and 7day time points in whole blood from mice exposed to 2, 4, 8, 12 and 15Gy irradiation. More differentially expressed microRNAs (up and down) were seen after higher dose of radiation and later time points. Among the significantly upregulated microRNAs, miR-193b-3p and mir-92a-3p were consistently upregulated for all doses at earlier time points. We observed significant downregulation of several members of the miR-17 family (miR-17-5p, miR-20a-5p, miR-93-5p and miR-106b-5p) in response to radiation from 2 Gy onwards at 24 h, 48 h and at higher doses for the 7 d time-point. Whereas miR-34a, which regulates G1/S cell cycle checkpoint activation in response to radiation induced DNA damage, showed consistent upregulation for both low and high doses at later time points up to one week after exposure. Significant down regulation of miR-150-5p, miR-101, miR-140, miR-29b, miR-193b and miR-30 family of microRNAs were seen for low and high doses of radiation for all time points up to 7day. Low dose radiation (2Gy) exposure also resulted in down regulation of a group of microRNAs after one week; whereas these microRNAs showed upregulation after high dose exposure (8, 12 and 15Gy) up to one week. This dose and time dependent differential microRNA expression pattern might be useful in evaluating radiation response during and after therapeutic radiation treatment in patients. Ultimately, a combined approach of identifying biomarkers by assessing functional miRNA, target mRNAs and the resulting proteins to assess radiation exposure after mass-casualty incidents could provide a valuable tool in developing and implementing effective and timely medical countermeasures.

Project description:Background: The effects of dose-rate and its implications on radiation biodosimetry methods are not well studied in the context of large-scale radiological scenarios. There are significant health risks to individuals exposed to an acute dose in such an event, but the most realistic scenario would be a combination of exposure to both high and low dose-rates, from both external and internal radioactivity. It is important therefore, to understand the biological response to prolonged exposure; and further, discover biomarkers that can be used to estimate the extent of damage from low-dose rate exposure and propose appropriate clinical treatment. Methods: We irradiated human whole blood ex vivo to three doses, 0.56 Gy, 2.25 Gy and 4.45 Gy, using two dose rates: 1.1Gy/min and 3.1mGy/min. After 24 hours, we isolated RNA from blood cells and hybridized these to Agilent Whole Human genome microarrays. We validated the microarray results using qRT-PCR. Results: Microarray results showed that there were 454 significantly differentially expressed genes after prolonged exposure to all doses. After acute exposure, 598 genes were differentially expressed to all doses combined. Gene ontology terms enriched in both sets of genes were related to immune processes and B cell mediated immunity. Genes responding to acute exposure was also enriched in functions related to natural killer cell activation and cell-to-cell signaling. As expected, p53 pathway was found to be significantly enriched at all doses and by both dose-rates of radiation. Prediction algorithms were able to distinguish between low dose-rate and acute exposures, on the basis of a group of genes. These maybe candidates for preliminary testing as markers for differences in gene expression based on dose-rate. Radiation induced gene expression was measured in ex vivo irradiated human blood, at the 24hr time point after irradiation. Doses (0.56 Gy, 2.2 Gy and 4.45 Gy) were delivered by two dose rates, acute dose rate of 1Gy/min and low dose rate of 3.1 mGy/min.

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Radiation-induced molecular alterations after whole body irradiation in a mouse model

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