Abstract

BackgroundIn humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive.MethodsMice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry.ResultsIrradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age.ConclusionsOur findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field.Electronic supplementary materialThe online version of this article (doi:10.1186/1866-1955-7-3) contains supplementary material, which is available to authorized users.

Highlights

  • In humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels

  • Knowledge about the long-term impact of prenatal irradiation has been largely based on epidemiological studies of atomic bomb survivors, in which children in utero exposed to radiation had a higher incidence of severe mental retardation and growth impairment [5]

  • Exposure to X-rays at the onset of neurogenesis elicits a behavioural response in young adult mice dependent on the timing of irradiation Male animals irradiated with different doses of X-rays (0.0, 0.2, 0.5 or 1.0 Gy) at selected time points of embryonic development (E10, E11 or E12) were subjected to a series of behavioural tests at the young adult age of 12 weeks

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Summary

Introduction

In utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Amongst other stressors like ethanol, drugs and infectious agents [3], known to cause such a perturbation of brain development, effects are strongly dependent on the timing and dosage of exposure [4]. Knowledge about the long-term impact of prenatal irradiation has been largely based on epidemiological studies of atomic bomb survivors, in which children in utero exposed to radiation had a higher incidence of severe mental retardation and growth impairment [5]. Since pregnant women can be exposed to radiation during medical examination [7] and/or treatment, during radiotherapy [8], a high concern and the clear need for increased knowledge exists concerning the long-term outcome of the exposed embryo. The possibility of late side effects, such as subclinical cognitive problems, cannot be excluded

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