Abstract
Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose.
Highlights
Radioadaptive response (RAR) was first observed in cultured human lymphocytes 30 years ago [1]
RAR has been widely observed in mammalian systems [6,7,8] such as mouse embryo cells [9], Chinese hamster fibroblasts [10], rabbit lymphocytes [11], hepatoma cell lines [12], U1-Mel human malignant melanoma cells [13], mouse germ cells [14, 15] and rat bone marrow cells [16], and can reduce cytogenetic damages, enhance cell survival and reduce tumor incidence [17,18,19,20,21]
We focused on mRNA and microRNA microarray studies, and aimed to characterize the transcriptome for RAR in AG01522 human skin fibroblasts and to examine the functional regulatory networks at the genetic level
Summary
Radioadaptive response (RAR) was first observed in cultured human lymphocytes 30 years ago [1],. This protective phenomenon is initiated by a low radiation dose (called priming dose and usually less than 200 mSv), which will alter gene expression profiles in cells and tissues [2,3,4] to induce protection against a subsequent high radiation dose (called challenging dose) [1, 5]. Zebrafish embryos pre-exposed to low-dose radiation or the low-dose irradiated embryo conditioned medium showed fewer apoptotic signals when they were exposed to a subsequent high-dose radiation
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