Radiation‐induced bystander effects in vivo are epigenetically regulated in a tissue‐specific manner

Abstract

Exposure of animal body parts to ionizing radiation (IR) can lead to molecular changes in distant shielded “bystander” tissues and organs. Nevertheless, tissue specificity of bystander responses within the same organism has not been examined in detail. Studies on in vivo bystander effect conducted so far analyzed changes induced by single‐dose exposure. The potential of fractionated irradiation to induce bystander effects in vivo has never been studied. We analyzed changes in global DNA methylation and microRNAome in skin and spleen of animals subjected to single‐dose (acute or fractionated) whole‐body or cranial exposure to 0.5 Gy of X‐rays. We found that IR‐induced DNA methylation changes in bystander spleen and skin were distinct. Acute radiation exposure resulted in a significant loss of global DNA methylation in the exposed and bystander spleen 6 hr, 96 hr, and 14 days after irradiation. Fractionated irradiation led to hypomethylation in bystander spleen 6 hr after whole‐body exposure, and 6 hr, 96 hr, and 14 days after cranial irradiation. Contrarily, changes in the skin of the same animals were seen only 6 hr after acute whole‐body and head exposure. DNA hypomethylation observed in spleen was paralleled by a reduction of methyl‐binding protein MeCP2 expression. Irradiation also induced tissue‐specific microRNAome alterations in skin and spleen. For the first time, we have shown that IR‐induced epigenetic bystander effects that occur in the same organism are triggered by both acute and fractionated exposure and are very distinct in different bystander organs. Future studies are clearly needed to address organismal and carcinogenic repercussions of those changes. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.

Intercellular Communication in Response to Radiation Induced Stress: Bystander Effects in Vitro and in Vivo and Their Possible Clinical Implications

“…Although fractionated irradiation was also applied in vivo to study the bystander effect on the level of DNA epigenetic changes in the non-exposed spleen of cranial irradiated mice (Ilnytskyy et al, 2009), the fraction doses used were far below those clinically applied. However, the authors observed that acute irradiation induced more pronounced bystander effect than fractionated irradiation.…”

“…The radiation-induced global genome DNA methylation changes were shown to be dose-dependent, sex-and tissue specific and long-persistant. Tissue specificity of bystander responses within the same organism has also been examined by Ilnytskyy et al (2009). They analyzed changes in global DNA methylation in spleen of mice whole-body or cranial exposed to single 0.5 Gy of X-rays or to the same dose given in five 0.1 Gy fractions.…”

“…These changes also include DNA binding protein methylation, expression of methylotransferases and the methyl group binding retrotransposomal element LINE-1, and overexpression of micro RNA, miR-194. Therefore, these transcriptionally regulated epigenetic changes seem undoubtedly to be related to the radiation induced bystander effect, although they may be specific to certain tissues, because similar changes were absent in the dermal tissue , Ilnytskyy et al, 2009. TP53 overexpression, change of proliferation rate measured as Ki67 antigen expression, as well as the increase in the percentage of apoptosis and DNA double strand breaks, the marker of which was the histone H2AX phosphorylation were also observed in bystander spleen of mice exposed to 1 Gy X-rays to their heads.…”

“…Bystander effect can be particularly important in the case of the use of current techniques of irradiation, such as 3D conformal radiation therapy (3D-CRT) and intensively modulated radiotherapy (IMRT), the purpose of which is to reduce the irradiation dose in healthy tissues (Followill et al, 1997). Some data indicate that bystander effect also occurs in vivo (Koturbash et al, 2006, Ilnytskyy et al 2009). The studies of bystander effect in in vivo animal models show that the post-radiation damage can appear in tissues distant from the place of irradiation, and the effect may vary depending on the type of tissue.…”

“Abscopal” Effect of Radiation Therapy Combined with Immune-Therapy Using IFN-γ Gene Transfected Syngeneic Tumor Cells, in Rats with Bilateral Implanted N29 Tumors

“…Recent findings have also shown significant loss of global DNA methylation and a reduction of methyl-binding protein MeCP2 expression in both acutely radiation exposed and unexposed bystander spleen at 6 hr, 96 hr, and 14 days after irradiation [57]. This indicates that epigenetic effects might also be involved in the mechanism of the abscopal effect.…”