Genomic Maintenance & Repair

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP318) Role of epigenetic mechanisms in radiation-induced transgenerational hematopoietic carcinogenesis.

Baker, Mike*,1, Koturbash, Igor1, Stevenson, Sandie 1, Loree, Jonathan1, Kovalchuk, Olga*,1, 1 Department of Biological Sciences, Lethbridge, AB, Canada

ABSTRACT- All forms of cancer are initiated by heritable changes in the genetic code. Ionizing radiation is a well-known genotoxic agent and human carcinogen. Hematopoietic tissue is the main target of radiation carcinogenesis. Radiation exposure poses threat to the progeny of irradiated parents. Radiation is well documented to cause transgenerational genome instability which is linked to carcinogenesis. Transgenerational carcinogenesis refers to transmission of cancer risk to the untreated progeny of parents exposed to carcinogens. Parental exposure increased the risk of leukemia in children about 6-8 times. The exact mechanisms of transgenerational hematopoietic carcinogenesis have yet to be discovered. Accumulated evidence though suggests that the mechanism of this process may be epigenetic. In this study we utilized an in vivo murine model to study genetic and epigenetic alterations in hematopoietic tissue (spleen and thymus) of the progeny following paternal or maternal pre-conceptional radiation exposure. The murine model is widely used, well characterized and generally accepted for studies of radiation-induced changes in hematopoietic tissue. It has also been successfully applied to study transgenerational induction of genome instability. Notably, we found that pre-conceptional parental radiation exposure led to significant global genome DNA hypomethylation in spleen and thymus of the progeny. The decrease in global DNA methylation was paralleled by a pronounced decrease in the expression of DNA methyltransferases, particularly - de novo DNA methyltransferases DNMT3a and DNMT3b. It also affected the expression of methyl-binding proteins. In parallel, we analysed the influence of parental exposure on histone methylation status. In summary, we have shown that parental radiation exposure can induce profound epigenetic alterations that in turn could lead to genome destabilization and serve as precursors for radiation hematopoietic carcinogenesis in the un-irradiated progeny. Roles of maternal versus paternal exposure will be discussed.

Key words: radiation carcinogenesis, transgenerational carcinogenesis, DNA methylation, epigenetics

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2005 RRS