Back to search


Low dOse IR induced Gene expression and Epigenetic Responses(LOGER)

Awarded: NOK 0.59 mill.

Radiation protection requires a thorough understanding of the effects of radiation in living matter. As a quantitative basis for risk analysis, radiation effects should be investigated using realistic exposure regimens where exposure to other environmental and dietary factors affecting radiation effects are controlled. There is good knowledge of effects after high acute radiation doses, while there is still little knowledge about effects after exposure to low radiation doses / dosages over longer periods of time. There is also a need for biomarkers that can be used to identify individuals who have been exposed to radiation, also after low dosage rates. These were the goals of the project. Exposure facilities where model organisms can be exposed for a long time (chronic) for low-dose ionizing radiation are rare, especially at exposure levels similar to those that may occur after nuclear accidents such as Chernobyl and Fukushima. In a previous project (Figaro), we upgraded an already existing exposure unit to be used for rodents, (also genetically modified), and materials from a number of experiments with mice have been used in the project. The shape of the dose response curve for (very) low doses of ionizing radiation is still a highly debated research question requiring adequate information in the low dose range and it is also likely that the shape of the dose response curve varies between tissues. Several biological response pathways have been shown to be altered by medium or high doses of ionizing radiation, while far less are known after low dose exposure. Especially little is known about chronic low dose rate IR exposure and its potential to alter the regulation of gene expression via epigenetic regulator mechanisms such as DNA methylation and expression of microRNA. In this project, we found that low dose rate gamma radiation does not lead to significant changes in DNA methylation in sperm, as opposed to others findings of hypomethylation in somatic tissues after high dose rates/doses of ionizing radiation. Furthermore, we have performed gene expression studies in male gametes from testis using next generation sequencing technology and found that exposure to low dose rate gamma irradiation leads to altered gene expression. We conclude that low dose rates of ionizing radiation also lead to changes in the transcriptome with potential to affect health outcomes. Furthermore, we have identified a miRNA signature as a biomarker for exposure to low dose rates of ionizing radiation that can be useful to identify individuals exposed to low dose rates.

Vi konkludere med at lave doserater ioniserende stråling fører til endringer i transkriptomet som kan ha betydning for helseutfall. Vi har identifisert en miRNA signatur som kan fungere som biomarkør for eksponering for stråling etter lave doserater ioniserende stråling som kan benytte stil å identifisere individer som har vært utsatt for også lave doserater. Prosjektet har bidratt til ny kunnskap om effekter av lave stråledoser/doserater, som kan redusere usikkerhetene i dagens risikovurdering og valg av tiltak etter eksponering for stråling

Disease from ionizing radiation (IR) may be induced by very low doses and dose rates, but the associated risk is difficult to study both experimentally and epidemiologically. Molecular changes (including epigenetic changes) may be used as biomarkers of ex posure and early indicators of disease. Responses induced by low IR doses may be different from those of high doses and is in various aspects not linear with dose. This property will influence the shape of the dose response curve. However, very little is known about which processes are induced by which type of damage. Furthermore, the possible thresholds or hyperactivation at (very) low doses are very important parameters for prediction of the dose response curve, but their properties are unknown. Therefo re, we propose to study the gene activation and inactivation responses at low dose ionizing radiation in more detail. We will use materials from low dose rate IR exposed mice in the FIGARO project (normal and oxidative damage repair mutant mice) to invest igate in detail their methylome and transcriptional responses (mRNA and miRNA transcriptomics), as well as the corresponding protein expression levels (proteomics). This will be a first investigation into the genetic pathways and mechanisms involved in th e response to low dose rate IR. The data obtained in this study will be correlated with earlier studies done at Erasmus MC, using mice with deficiencies in DNA double strand break (DSB) repair pathways. Together, this will define a set of responses that a re correlated with DSB repair status, oxidative base damage or damage to other structures than DNA. This pilot study which exploits material from the FIGARO mouse pilot experiment - will provide novel mechanistic insight into the effects of low dose rate IR and identification of potential candidate biomarkers, and set the stage for studies that correlate "omics" data with induction of cancer or other diseases.

Funding scheme: