Irradiation to the young mouse brain impaired white matter growth more in females than in males

K Roughton,M Kalm,K Blomgren,M Boström

doi:10.1038/cddis.2013.423

Abstract

Modern therapy cures 80% of all children with brains tumors, but may also cause long-lasting side effects, so called late effects. Radiotherapy is particularly prone to cause severe late effects, such as intellectual impairment. The extent and nature of the resulting cognitive deficits may be influenced by age, treatment and gender, where girls suffer more severe late effects than boys. The reason for this difference between boys and girls is unknown, but very few experimental studies have addressed this issue. Our aim was to investigate the effects of ionizing radiation on the corpus callosum (CC) in both male and female mice. We found that a single dose of 8 Gray (Gy) to the brains of postnatal day 14 mice induced apoptosis in the CC and reduced the number of proliferating cells by one third, as judged by the number of phospho-histone H3 positive cells 6 h after irradiation (IR). BrdU incorporation was reduced (62% and 42% lower in females and males, respectively) and the number of oligodendrocytes (Olig2+ cells) was lower (43% and 21% fewer in females and males, respectively) 4 months after IR, so the lack of developing and differentiated cells was more pronounced in females. The number of microglia was unchanged in females but increased in males at this late time point. The density of microvessel profiles was unchanged by IR. This single, moderate dose of 8 Gy impaired the brain growth to some extent (8.1% and 0.4% lower brain/body weight ratio in females and males, respectively) but the CC growth was even more impaired (31% and 19% smaller in females and males, respectively) 4 months after IR compared with non-irradiated mice. In conclusion, this is the first study to our knowledge demonstrating that IR to the young rodent brain affects white matter development more in females than in males.

Highlights

Has been shown to cause hypomyelination in children treated for malignant brain tumors.[12]
In a study by Wakisaki et al.,[26] microscopic necrotic lesions were found to be widely dispersed in the white matter located in the forebrain of adult monkeys exposed to 60 Gray (Gy) fractionated cranial IR
We observed a difference between sexes in the response to IR, where females showed a greater IR-induced brain growth retardation compared with males (0.4% decrease in males and 8.1% decrease in females, Figure 4b, interaction, P 1⁄4 0.016)

Summary

Introduction

Has been shown to cause hypomyelination in children treated for malignant brain tumors.[12]. It is believed that the negative cognitive effects seen after CRT are due to, at least partly, reduced hippocampal neurogenesis.[13,14,15] Neurocognitive deficits after CRT have been linked to the loss of white matter.[16] Reddick et al.[17] showed that white matter volume decreased in patients with medulloblastoma treated with craniospinal irradiation (IR) They showed that younger age at the time of treatment had a significant negative effect on the white matter volume.[17] The corpus callosum (CC), the largest white matter commissure, is affected in children subjected to CRT, with the greatest effects observed in the most posterior subregions (isthmus and splenium).[18] These regions grow from late gestational age until adulthood, with the highest growth rates during early childhood.[19,20,21] Myelination was shown to be impaired in immature and juvenile rats subjected to cranial IR, but the effect was much more pronounced in the immature rat brain.[22]. Previous studies have shown sex-dependent differences in the hippocampus in response to cranial IR.[27,28] In the current study, we characterized the effects of IR on the white matter in both male and female mice, demonstrating more pronounced negative effects of IR in females

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Conclusion