title: A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis.
abstract: 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.
authors.affiliation: Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium ; Laboratory of Neural Circuit Development and Regeneration, Department of Biology, Faculty of Science, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Tine
authors.initials: T
authors.lastname: Verreet
authors.affiliation: Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.
authors.forename: Roel
authors.initials: R
authors.lastname: Quintens
authors.affiliation: Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
authors.forename: Debby
authors.initials: D
authors.lastname: Van Dam
authors.affiliation: Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Verslegers
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, Casaccia Research Centre, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Tanori
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, Casaccia Research Centre, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Casciati
authors.affiliation: Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Neefs
authors.affiliation: Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Leysen
authors.affiliation: Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.
authors.forename: Arlette
authors.initials: A
authors.lastname: Michaux
authors.affiliation: Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Janssen
authors.affiliation: SB Dosimetry and Calibration, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.
authors.forename: Emiliano
authors.initials: E
authors.lastname: D'Agostino
authors.affiliation: Biomedical NMR Unit, Department of Imaging and Pathology, Faculty of Medicine, University of Leuven, 3000 Leuven, Belgium ; Molecular Small Animal Imaging Center (MoSAIC), Faculty of Medicine, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Greetje
authors.initials: G
authors.lastname: Vande Velde
authors.affiliation: Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Baatout
authors.affiliation: Laboratory of Neural Circuit Development and Regeneration, Department of Biology, Faculty of Science, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, Casaccia Research Centre, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Pazzaglia
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, Casaccia Research Centre, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Saran
authors.affiliation: Biomedical NMR Unit, Department of Imaging and Pathology, Faculty of Medicine, University of Leuven, 3000 Leuven, Belgium ; Molecular Small Animal Imaging Center (MoSAIC), Faculty of Medicine, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.affiliation: Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium ; Department of Neurology and Alzheimer Research Center, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
authors.forename: Peter Paul
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.
authors.forename: Mohammed Abderrafi
authors.initials: MA
authors.lastname: Benotmane
keywords: Apoptosis; Brain development; Cognitive dysfunction; MRI; Radiation