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Effect of external high-dose rate radiation on mouse biofluid metabolomic signatures

ABSTRACT: In the event of an improvised nuclear device (IND), a complex IR exposure will occur consisting of both low (LDR) and high-dose rates (HDR). We have previously addressed LDR exposures from internal emitters or externally deposited radionuclides on biofluid small molecule signatures, but further research on the HDR component is required. Here, we exposed 8 − 10 week old male C57BL/6 mice to a cumulative dose of 3 Gy using a reference dose rate of 0.7 Gy/min or a HDR of 7 Gy/sec, collected urine and serum at 1 and 7 d, then compared the metabolite signatures using either untargeted (urine) or targeted (serum) approaches with liquid chromatography mass spectrometry platforms.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Urine

SUBMITTER: Evan Pannkuk

PROVIDER: ST002175 | MetabolomicsWorkbench | Thu Apr 14 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

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Project description:Purpose: The International Commission on Radiological Protection (ICRP) recently recommended reducing the occupational equivalent dose limit for the lens of the eye. Based primarily on a review of epidemiological data, the absorbed dose threshold is now considered to be 0.5 Gy for induction of acute opacities, reduced from the previous threshold of 2 Gy. However, direct mechanistic evidence to support an understanding of the underlying molecular mechanisms of damage is still lacking. To this end, we explored the effects of a broad dose-range of ionizing radiation exposure on gene expression changes in a human lens epithelial (HLE) cell-line in order to better understand the shape of the dose-response relationship and identify transcriptional thresholds of effects. Methods: HLE cells were exposed to doses of 0, 0.01, 0.05, 0.25, 0.5, 2, and 5 Gy of X-ray radiation at two dose rates (1.62 cGy/min and 38.2 cGy/min). Cell culture lysates were collected 20 h post-exposure and analysed using whole-genome RNA-sequencing. Pathways and dose-thresholds of biological effects were identified using benchmark dose (BMD) modeling. Results: Transcriptional responses were minimal at doses less than 2 Gy. At higher doses there were a significant number of differentially expressed genes (DEGs) (p < 0.05, fold change > |1.5|) at both dose rates, with 1308 DEGs for the low dose rate (LDR) and 840 DEGs for the high dose rate (HDR) exposure. Dose-response modeling showed that a number of genes exhibited non-linear bi-phasic responses, which was verified by digital droplet PCR. BMD analysis showed the majority of the pathways responded at BMD median values in the dose range of 1.5-2.5 Gy, with the lowest BMD median value being 0.6 Gy for the HDR exposure. The minimum pathway BMD median value for LDR exposure, however, was 2.5 Gy. Although the LDR and HDR exposures shared pathways involved in extracellular matrix reorganization and collagen production with BMD median value of 2.9 Gy, HDR exposures were more effective in activating pathways associated with DNA damage response, apoptosis, and cell cycling relative to LDR exposure. Conclusion: Overall, the results suggest that radiation induces complex non-linear transcriptional dose-response relationships that are dose-rate dependent. Pathways shared between the two dose rates may be important contributors to radiation-induced cataractogenesis. BMD analysis suggests that the majority of pathways are activated above 0.6 Gy, which supports current ICRP identified dose thresholds for deterministic effects to the lens of the eye of 0.5 Gy.

Project description:Although radiation effects have been extensively studied, the biological effects of low-dose radiation (LDR) are controversial. This study investigates LDR-induced alterations in locomotive behavior and gene expression profiles of Drosophila melanogaster. We measured locomotive behavior using larval pupation height and rapid iterative negative geotaxis (RING) assay after exposure to 0.1 Gy gamma-radiation (dose rate of 16.7 mGy/h). We also observed chronic LDR effects on development (pupation and eclosion rates) and longevity (life span). To identify chronic LDR effects on gene expression, we performed whole-genome expression analysis using gene-expression microarrays, and confirmed the results using quantitative real-time PCR. Pupation height was significantly higher after LDR treatment at the first larval instar. Locomotive behavior of male flies was significantly greater approximately 3M-BM--5 weeks after LDR, but pupation and eclosion rates and life spans were not significantly different. Genome-wide expression analysis identified 344 genes that were differentially expressed in irradiated larvae compared with those of controls. We identified several genes belonging to larval behavior functional groups such as locomotive behavior and oxidation reduction, and genes involved in conventional functional groups modulated by irradiation such as defense response, sensory and perception. Four candidate genes were confirmed as differentially expressed genes in irradiated larvae using qRT-PCR. These data suggest that LDR stimulates locomotion-related genes, and these genes can be used as potential markers for LDR. Eggs were collected from 5-day-old female flies and cultivated for 24 h on standard medium. Then, twenty larvae were manually selected and seeded on fresh standard medium in a new vial. After transfer, the experimental group of first-instar larvae was immediately irradiated with chronic gamma-radiation at a dose rate of 16.7 mGy/h. After treatment, gamma-irradiated flies and non-irradiated control flies were maintained in the same incubator at 25degC.

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Effect of external high-dose rate radiation on mouse biofluid metabolomic signatures

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