A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis

Research

Tine Verreet, Roel Quintens, Debby Van Dam, Mieke Verslegers, Mirella Tanori, Arianna Casciati, Mieke Neefs, Liselotte Leysen, Arlette Michaux, Ann Janssen, Emiliano D¿Agostino, Greetje Vande Velde, Sarah Baatout, Lieve Moons, Simonetta Pazzaglia, Anna Saran, Uwe Himmelreich, Peter Paul De Deyn and Mohammed Abderrafi Benotmane

Journal of Neurodevelopmental Disorders 2015, 7:3 
doi:10.1186/1866-1955-7-3

Published: 9 January 2015

Abstract (provisional)

Background

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. Yet, the association between early damaging events and long-term neuronal
anomalies remains largely elusive.

Methods

Mice 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.

Results

Irradiation 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.

Conclusions

Our 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.