Paternal cranial irradiation induces distant bystander DNA damage in the germline and leads to epigenetic alterations in the offspring

Tamminga, Jan; Koturbash, Igor; Baker, Mike; Kutanzi, Kristy; Kathiria, Palak; Pogribny, Igor P.; Sutherland, Robert J.; Kovalchuk, Olga

doi:10.4161/cc.7.9.5806

Cited by 66 publications

(50 citation statements)

References 38 publications

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“…DNA strand breaks were measured using the modification of a random oligonucleotide primed synthesis (ROPS) assay. 17 Using this assay, we found that radiation exposure induced a significant 2.2 fold increase in the level of DNA strand breaks in testes of exposed animals ( Fig. 2A).…”

Section: Methodsmentioning

confidence: 99%

“…The presence of γH2AX foci, a direct indicator of DNA damage, was assayed using immunohistochemistry. 17 Analysis revealed that radiation exposure led to a noticeable increase in γH2AX foci in exposed testes (Fig. 2B).…”

Section: Methodsmentioning

confidence: 99%

“…The assay was performed as described before. 13,17,27 The results were expressed as a percent difference in [ 3 H] dCTP incorporation relative to control values. DNA strand break measurement.…”

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confidence: 99%

“…A modification of the random oligonucleotide-primed synthesis (ROPS) assay was used to detect the presence of DNA strand breaks in high molecular weight DNA. 17,28 The assay is based on the ability of the Klenow fragment polymerase to initiate ROPS from re-annealed 3'-OH ends of singlestranded DNA. Briefly, 3'-OH DNA fragments that exist in high molecular weight DNA are separated into single-strand fragments by heat denaturation and subsequently re-associated by cooling.…”

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confidence: 99%

“…In our previous studies, this dose led to significant deleterious effects in the progeny. 17 For the irradiation procedure, animals were placed in small (10 x 5 x 6 cm) plastic vented containers. These containers limit the movement of animals and insure the dose uniformity.…”

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confidence: 99%

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DNA damage-induced upregulation of miR-709 in the germline downregulates BORIS to counteract aberrant DNA hypomethylation

Tamminga¹,

Kathiria²,

Koturbash³

et al. 2008

Cell Cycle

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MicroRNAs as potent regulators of gene expression are involved in spermatogenesis, yet their role in response of germline to genotoxic stress is obscure. We studied the microRNAome profile of X-ray irradiated mouse testes using the microarray technique. We found that radiation exposure significantly affected microRNA expression in testes. Mir-709 was the most abundant in both control and irradiated testes, and a big difference in miR-709 levels was observed between the control and exposed group. We found that miR-709 targets the Brother of the Regulator of Imprinted Sites (BORIS), an important regulator of DNA methylation and imprinting. Here, we for the first time show that the DNA damageinduced and ATR/Rfx1-mediated increase of miR-709 expression in exposed testes may be a protective mechanism that effectively decreases a cellular level of BORIS to prevent massive aberrant erasure of DNA methylation after radiation exposure.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

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DNA damage-induced upregulation of miR-709 in the germline downregulates BORIS to counteract aberrant DNA hypomethylation

Tamminga¹,

Kathiria²,

Koturbash³

et al. 2008

Cell Cycle

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The Bystander Effect in Targeted Radiotherapy

Mothersill¹,

Seymour²

2010

Monoclonal Antibody and Peptide‐Targeted Radiotherapy of Cancer

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

Ilnytskyy

Koturbash

Kovalchuk

2008

Environ and Mol Mutagen

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111

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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.

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Paternal cranial irradiation induces distant bystander DNA damage in the germline and leads to epigenetic alterations in the offspring

Cited by 66 publications

References 38 publications

DNA damage-induced upregulation of miR-709 in the germline downregulates BORIS to counteract aberrant DNA hypomethylation

DNA damage-induced upregulation of miR-709 in the germline downregulates BORIS to counteract aberrant DNA hypomethylation

The Bystander Effect in Targeted Radiotherapy

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

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