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Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo

https://doi.org/10.1016/j.ijrobp.2006.06.012Get rights and content

Purpose: Although modern cancer radiation therapy has led to increased patient survival rates, the risk of radiation treatment-related complications is becoming a growing problem. Among various complications, radiation also poses a threat to the progeny of exposed parents. It causes transgenerational genome instability that is linked to transgenerational carcinogenesis. Although the occurrence of transgenerational genome instability, which manifests as elevated delayed and nontargeted mutation, has been well documented, the mechanisms by which it arises remain obscure. We hypothesized that epigenetic alterations may play a pivotal role in the molecular etiology of transgenerational genome instability.

Methods and Materials: We studied the levels of cytosine DNA methylation in somatic tissues of unexposed offspring upon maternal, paternal, or combined parental exposure.

Results: We observed a significant loss of global cytosine DNA methylation in the thymus tissue of the offspring upon combined parental exposure. The loss of DNA methylation was paralleled by a significant decrease in the levels of maintenance (DNMT1) and de novo methyltransferases DNMT3a and 3b and methyl-CpG–binding protein MeCP2. Along with profound changes in DNA methylation, we noted a significant accumulation of DNA strand breaks in thymus, which is a radiation carcinogenesis target organ.

Conclusions: The observed changes were indicative of a profound epigenetic dysregulation in the offspring, which in turn could lead to genome destabilization and possibly could serve as precursor for transgenerational carcinogenesis. Future studies are clearly needed to address the cellular and carcinogenic repercussions of those changes.

Keywords

Radiation
Transgeneration genome instability
Epigenetics
DNA methylation
DNA damage

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This work was supported by an Alberta Cancer Board Grant to Olga Kovalchuk. Jonathan Loree was a recipient of The Natural Sciences and Engineering Research Council of Canada (NSERC) Undergraduate Student Research Award (USRA).

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Darryl Hudson is currently with the Department of Biological Sciences, University of Guelph, Guelph, ON, Canada.

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