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Effects of chronic low dose of ionizing radiation on epigenetics and central nervous system development

Sophia Murat El Houdigui has defended his thesis on 4th May 2020, at Aix En Provence

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Authors > MURAT EL HOUDIGUI Sophia

Publication Date > 04/05/2020


After the nuclear accidents at Chernobyl and Fukushima and due to a growing use of radionuclides, radiation protection of the environment is a major concern. Studies show an increased sensitivity to ionizing radiation (IR) during development. However, there are few data on the molecular mechanisms leading to the effects of IR on embryogenesis and moreover for chronic exposures. In this context, the objective of this thesis is to better understand the effects of exposure to IR on the development of zebrafish (Danio rerio), a model organism in ecotoxicology and in biomedicine. Fertilized eggs were exposed to gamma rays emitted by a 137Cs source at low to moderate dose rates (from 0.005 mGy/h to 50 mGy/h), then analysed from the gastrula stage (6 hours) to the larval stage (5 days) by an integrative approach from molecular effects to behavioural effects.

Part of this work has focused on studying the effects of IR at an early stage of zebrafish development after exposure to IR. For this, a multi-omics approach with the study of the transcriptome and the methylome has been implemented. A transcriptomic study at the shield stage with dose rates ranging from 0.005 mGy/h to 50 mGy/h was carried out and demonstrated a moderate but significant effect on the regulation of oxidative stress and mitochondrial activity. At 5 and 50 mGy/h, the genes involved in the development of the central nervous system (CNS) and muscles are affected. The methylome study has revealed hypomethylation of the promoter sequences of genes involved in the development of the CNS and muscles, associated with a modification of gene expression. These results on early embryonic stages, highlight potential effects on the development of the CNS and muscles. The other part of this work focused on assessing the effects of IR exposure at later developmental stages using a system biology approach. For this, analyses were carried out from the molecular scale to the phenotypic scale. At the molecular level, a multi-omics analysis of the transcriptome and the proteome has highlighted the modulation of genes involved in the retinoic acid pathway, the development of the CNS and muscles in embryos and larvae exposed to 0.5; 5 and 50 mGy/h. Labelling by in-situ hybridization confirmed the misregulation of the transcription factors her4.4 in the CNS and myog in the muscles of embryos exposed to IR. At the tissue level, disruption of muscle myofibrils and alteration of neuromuscular junctions are detected in embryos exposed to 5 and 50 mGy/h.  In order to assess an individual effect at phenotypic scale, the locomotor behaviour of the larvae was assessed under stress conditions. A significant decrease in larval motility was detected between 0.5 mGy/h and 50 mGy/h.

This work has shown effects of IR on the development of the CNS and muscles from early development at the molecular level. These effects are confirmed at later stages of development. This study suggests that the molecular disturbances observed during early development are predictive of the effects observed at later developmental stages. In addition, this thesis work allows us to propose a model of "Adverse Outcome Pathway" where the deregulation of the retinoic acid pathway by exposure to IR will lead to effects on the development of the CNS and muscles.

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