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Murine hippocampus after radiation LC-MSMS

ABSTRACT: The impact of low-dose ionizing radiation (IR) on human brain has recently attracted attention due to increased use of IR for diagnostic purposes. The aim of this study was to investigate low-dose radiation response in hippocampus. Female C57Bl/6 mice were irradiated with 0 (control), 0.063, 0.125 or 0.5 Gy and quantitative label-free proteomic analysis of hippocampus was performed after 24 months. Key pathways were validated by immunoblotting. CREB signaling and CREB-associated pathways were the most affected ones at all doses. The two lower doses seemed to induce CREB pathway, whereas the exposure to 0.5 Gy deactivated CREB. Similarly, the lowest dose (0.063 Gy) was anti-inflammatory reducing the number of activated microglia (IBA1), whilst induction of activated microglia and reactive astroglia (GFAP) was found at 0.5 Gy suggesting increased inflammation and astrogliosis, respectively. Apoptotic markers BAX and cleaved CASP-3 and oxidative stress markers (carbonylation, NRF-2) were increased only at the highest dose. Since activated CREB pathway plays a central role in learning and memory, these data suggest neuroprotection at the lowest dose (0.063 Gy) but neurodegeneration at 0.5 Gy. These effects become significant only in old animals (24 m) and support the hypothesis of radiation-induced accelerated aging in the brain.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Layer Of Hippocampus, Brain

DISEASE(S): Wounds And Injuries

SUBMITTER: Christine von Toerne

LAB HEAD: Soile Tapio

PROVIDER: PXD015729 | Pride | 2019-11-06

REPOSITORIES: Pride

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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.

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Murine hippocampus after radiation LC-MSMS

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