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Embryonic ionizing radiation exposure results in expression alterations of genes associated with cardiovascular and neurological development, function, and disease and modified cardiovascular function in zebrafish

ABSTRACT: The relationship between ionizing radiation (IR) and carcinogenesis is long established, but recently the association between IR and other diseases is starting to be recognized. Currently, there is limited information on the genetic mechanisms governing the role of IR in non-cancer related adverse health effects and in regards to an early developmental exposure. In this study, zebrafish embryos were exposed to a range of IR doses (0, 1, 2, 5, 10 Gy) at 26 hours post fertilization (hpf). No significant increase in mortality or hatching rate was observed, but a significant decrease in total larval length, head length, and eye diameter was observed in the 10 Gy dose. Transcriptomic analysis was conducted at 120 hpf to compare gene expression profiles between the control and highest IR dose at which no significant differences were observed in morphological measurements (5 Gy). 253 genes with well-established function or orthology to human genes were significantly altered. Gene ontology and molecular network analysis revealed enrichment of genes associated with cardiovascular and neurological development, function, and disease. Expression of a subset of genetic targets with an emphasis on those associated with the cardiovascular system was assessed using qPCR to confirm altered expression at 5 Gy and then to investigate alterations at lower doses (1 and 2 Gy). Strong correlation between microarray and qPCR expression values was observed, but zebrafish exposed to 1 or 2 Gy resulted in a significant expression alteration in only one of these genes (LIN7B). Moreover, heart rate was analyzed through 120 hpf following IR dosing at 26 hpf. A significant decrease in heart rate was observed at 10 Gy, while a significant increase in heart rate was observed at 1, 2, and 5 Gy. Overall these findings indicate IR exposure at doses below those that induce gross morphological changes alters heart rate and expression of genes associated with cardiovascular and neurological functions.

ORGANISM(S): Danio rerio

PROVIDER: GSE117400 | GEO | 2018/07/20

REPOSITORIES: GEO

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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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Embryonic ionizing radiation exposure results in expression alterations of genes associated with cardiovascular and neurological development, function, and disease and modified cardiovascular function in zebrafish

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