Sex-specific radiation-induced microRNAome responses in the hippocampus, cerebellum and frontal cortex in a mouse model

Abstract

Ionizing radiation is an important treatment modality, but it is also a well-known genotoxic agent capable of damaging cells and tissues. Therefore radiation treatment can cause numerous side effects in exposed tissues and organs. Radiotherapy is a part of the front-line treatment regime for brain cancer patients, but can cause severe functional and morphological changes in exposed brain tissues. However, the mechanisms of radiation-induced effects in the brain are not well understood and are under-investigated. Recent data has implicated short RNAs, especially microRNAs, as important in radiation responses, yet nothing is known about radiation-induced changes in the brain microRNAome. We analyzed the effects of X-ray irradiation on microRNA expression in the hippocampus, frontal cortex, and cerebellum of male and female mice. Here, we report tissue-, time-, and sex-specific brain radiation responses, as well as show evidence of an interplay between microRNAs and their targets. Specifically, we show that changes in the expression of the miR-29 family may be linked, at least in part, to altered expression of de novo methyltransferase DNMT3a and changed global DNA methylation levels. Further, these sex-specific epigenetic changes may be correlated to the prevalence of radiation-induced cancers in males. We identified several microRNAs that can potentially serve as biomarkers of brain radiation exposure. In summary, our study may provide an important roadmap for further analysis of microRNA expression in different brain regions of male and female mice and for detailed dissection of radiation-induced brain responses.