Abstract
BackgroundRadio-Adaptive Response (RAR) is a biological defense mechanism whereby exposure to low dose ionizing radiation (IR) mitigates the detrimental effects of high dose irradiation. RAR has been widely observed in vivo using as endpoint less induction of apoptosis. However, sex differences associated with RAR and variations between males and females on global gene expression influenced by RAR have not been still investigated. In addition, the response to radiation-induced apoptosis is associated with phosphorylation of TRP53 at both the serine 15 (ser-18 in the mouse) and serine 392 (ser-389 in mice) residues, but the role of these two phosphorylated forms in male and female RAR remains to be elucidated.ResultsWe analyzed the effect of administering priming low dose radiation (0.075 Gy of X-rays) prior to high dose radiation (1.75 Gy of γ-rays) on the level of caspase-3-mediated apoptosis and on global transcriptional expression in thymocytes of male and female mice. Here, we provide the first evidence of a differential sex effect of RAR on the reduction of thymocyte apoptosis with males showing lesser levels of caspase-3-mediated apoptosis than females. Analysis of transcriptomic profiles of 1944 genes involved in apoptosis signaling in radio-adapted thymocytes identified 17 transcripts exhibiting differential expression between both sexes. Among them, Dlc1 and Fis1 are closely related to the apoptosis mediated by the TRP53 protein. Our data demonstrate that overexpression of Dlc1 and Fis1 occur concomitantly with a highest accumulation of phosphoserine-18-TRP53 and caspase-3 in radio-adapted thymocytes of female mice. In an opposite way, both down-modulation of Fis1 and phosphoserine-389-TRP53 accumulation appear to be associated with protection from thymocyte apoptosis mediated by caspase-3 in males.ConclusionsTranscriptomic analysis performed in this work reveals for the first time sex-specific differences in gene expression influenced by RAR. Our results also suggest a sex-dependent dual role for phosphoserine-18-TRP53 and phosphoserine-389-TRP53 in the regulation of the radio-adaptive response in mouse thymocytes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3036-0) contains supplementary material, which is available to authorized users.
Highlights
Radio-Adaptive Response (RAR) is a biological defense mechanism whereby exposure to low dose ionizing radiation (IR) mitigates the detrimental effects of high dose irradiation
Priming low dose radiation prior to high-dose radiation induced differential apoptotic rates in thymocytes of male and female mice We first analyzed the levels of apoptosis by measuring the amounts of caspase-3 protein in thymocytes of male and female C57BL/6 mice irradiated with an acute single dose of 0.075 Gy of X-rays or 1.75 Gy of γ-ray, and those treated with 0.075 Gy of priming X-rays followed in 6 h by 1.75 Gy of challenging γ-rays (Fig. 2)
According to the multivariate regression model described in the Material and Methods section, we found significant differences in caspase-3 protein amounts for all radiation treatments relative to non-irradiated controls (Table 1)
Summary
Radio-Adaptive Response (RAR) is a biological defense mechanism whereby exposure to low dose ionizing radiation (IR) mitigates the detrimental effects of high dose irradiation. Radio-adaptive response (RAR) is a biological defense mechanism whereby a low dose of ionizing radiation (priming dose) protects cells against the detrimental effects of a subsequent higher radiation dose (challenging dose). This protective phenomenon was first demonstrated in vitro by Wolf and colleagues in 1984, who showed that human peripheral blood lymphocytes irradiated with tritiated thymidine had fewer chromosomal aberrations when they were subsequently irradiated with a high dose of X-rays [3]. These cells need a time interval of 4–6 hours between the priming and the challenging doses to reach the full induction of radioresistance [7]
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