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.
Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
Int J Radiat Oncol Biol Phys. 2019 Feb 1;103(2):511-520. doi: 10.1016/j.ijrobp.2018.09.014. Epub 2018 Sep 20.
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.
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).
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.
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.
儿科颅部放射治疗会导致大脑结构的持久变化。虽然已经描述了放射反应的不同方面，但每种变化对发育的相对贡献尚不清楚。我们试图确定辐射诱导的程序性细胞死亡（由 Trp53（p53）基因介导）在神经解剖发育中的作用。
在 16 天大时，将具有 p53 条件性敲除（p53KO）或野生型 p53（WT）的小鼠用 7Gy（IR；n=30）或 0Gy（假照射；n=28）进行全脑照射。在照射前和照射后 4 个时间点（直到治疗后 3 个月）进行体内磁共振成像，然后进行离体磁共振成像和免疫组织化学检查。在另一组未经处理的小鼠（n=37）中，在 6 周龄时评估 p53 在发育中的作用。
p53KO 小鼠的神经解剖发育正常。在颅部照射后，WT 小鼠的神经解剖结构发生改变，并且通过 2 个阶段出现：1 周内的早期体积损失和发育过程中的生长减少。在许多结构中，p53KO 部分减轻了早期体积损失。然而，p53KO 对生长的影响为中性或负面；因此，p53KO 并未广泛改善终点的体积。在 p53KO-IR 小鼠的齿状回和嗅球中观察到部分体积恢复，与 WT-IR 小鼠相比，神经发生增加。
尽管 p53 已知在介导辐射诱导的细胞凋亡中发挥重要作用，但这是第一项研究，观察了整个大脑颅部照射后通过发育的 p53KO 的累积效应。很明显，凋亡在放射治疗后早期的体积损失中起重要作用。这种早期的保护本身不足以使整个大脑发育正常化，但依赖于神经发生的区域表现出明显的益处。
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