A Elizabeth de Guzman1, Mashal Ahmed2, Yu-Qing Li3, C Shun Wong4, Brian J Nieman5. 1. Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 2. Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada. 3. Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario, Canada. 4. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada. 5. Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Electronic address: brian.nieman@sickkids.ca.
Abstract
PURPOSE: Pediatric cranial radiation therapy results in lasting changes in brain structure. Though different facets of radiation response have been characterized, the relative contributions of each to altered development is unclear. We sought to determine the role of radiation-induced programmed cell death, as mediated by the Trp53 (p53) gene, on neuroanatomic development. METHODS AND MATERIALS: Mice having a conditional knockout of p53 (p53KO) or wildtype p53 (WT) were irradiated with a whole-brain dose of 7 Gy (IR; n = 30) or 0 Gy (sham; n = 28) at 16 days of age. In vivo magnetic resonance imaging was performed before irradiation and at 4 time points after irradiation, until 3 months posttreatment, followed by ex vivo magnetic resonance imaging and immunohistochemistry. The role of p53 in development was assessed at 6 weeks of age in another group of untreated mice (n = 37). RESULTS: Neuroanatomic development in p53KO mice was normal. After cranial irradiation, alterations in neuroanatomy were detectable in WT mice and emerged through 2 stages: an early volume loss within 1 week and decreased growth through development. In many structures, the early volume loss was partially mitigated by p53KO. However, p53KO had a neutral or negative impact on growth; thus, p53KO did not widely improve volume at endpoint. Partial volume recovery was observed in the dentate gyrus and olfactory bulbs of p53KO-IR mice, with corresponding increases in neurogenesis compared with WT-IR mice. CONCLUSIONS: Although p53 is known to play an important role in mediating radiation-induced apoptosis, this is the first study to look at the cumulative effect of p53KO through development after cranial irradiation across the entire brain. It is clear that apoptosis plays an important role in volume loss early after radiation therapy. This early preservation alone was insufficient to normalize brain development on the whole, but regions reliant on neurogenesis exhibited a significant benefit.
PURPOSE: Pediatric cranial radiation therapy results in lasting changes in brain structure. Though different facets of radiation response have been characterized, the relative contributions of each to altered development is unclear. We sought to determine the role of radiation-induced programmed cell death, as mediated by the Trp53 (p53) gene, on neuroanatomic development. METHODS AND MATERIALS: Mice having a conditional knockout of p53 (p53KO) or wildtype p53 (WT) were irradiated with a whole-brain dose of 7 Gy (IR; n = 30) or 0 Gy (sham; n = 28) at 16 days of age. In vivo magnetic resonance imaging was performed before irradiation and at 4 time points after irradiation, until 3 months posttreatment, followed by ex vivo magnetic resonance imaging and immunohistochemistry. The role of p53 in development was assessed at 6 weeks of age in another group of untreated mice (n = 37). RESULTS: Neuroanatomic development in p53KO mice was normal. After cranial irradiation, alterations in neuroanatomy were detectable in WT mice and emerged through 2 stages: an early volume loss within 1 week and decreased growth through development. In many structures, the early volume loss was partially mitigated by p53KO. However, p53KO had a neutral or negative impact on growth; thus, p53KO did not widely improve volume at endpoint. Partial volume recovery was observed in the dentate gyrus and olfactory bulbs of p53KO-IR mice, with corresponding increases in neurogenesis compared with WT-IR mice. CONCLUSIONS: Although p53 is known to play an important role in mediating radiation-induced apoptosis, this is the first study to look at the cumulative effect of p53KO through development after cranial irradiation across the entire brain. It is clear that apoptosis plays an important role in volume loss early after radiation therapy. This early preservation alone was insufficient to normalize brain development on the whole, but regions reliant on neurogenesis exhibited a significant benefit.
Authors: Shelli R Kesler; Charlotte Sleurs; Brenna C McDonald; Sabine Deprez; Ellen van der Plas; Brian J Nieman Journal: J Clin Oncol Date: 2021-04-22 Impact factor: 50.717
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Authors: Boris Sabirzhanov; Oleg Makarevich; James P Barrett; Isabel L Jackson; Ethan P Glaser; Alan I Faden; Bogdan A Stoica Journal: Int J Mol Sci Date: 2020-07-23 Impact factor: 6.208
Authors: Ellen van der Plas; T Leigh Spencer Noakes; Darci T Butcher; Rosanna Weksberg; Laura Galin-Corini; Elizabeth A Wanstall; Patrick Te; Laura Hopf; Sharon Guger; Brenda J Spiegler; Johann Hitzler; Russell J Schachar; Shinya Ito; Brian J Nieman Journal: Neuroimage Clin Date: 2020-09-15 Impact factor: 4.881