GENETICS AND EPIGENETICS OF PARENTAL EXPOSURE TO ENVIRONMENTAL MUTAGENS

by Yuri E Dubrova (University of Leicester)

Friday 25 Feb 2011, 15:00 → 16:00 Europe/Stockholm

E 306, ArrheniuslaboratorieswingE (LectureroomE 306, ArrheniuslaboratorieswingE)

GENETICS AND EPIGENETICS OF PARENTAL EXPOSURE TO ENVIRONMENTALMUTAGENS Yuri E Dubrova Department of Genetics, University of Leicester, United Kingdom •Recent studies have established that epigenetic changes play an important role in many common human diseases, including cancer. Given that the epigenetic landscape of the mammalian cell is not fixed and undergoes massive reprogramming during development, it can potentially be affected by a variety of environmental factors. As the majority of the de novoepigenetic marks, including DNA methylation, are faithfully reproduced during DNA replication, they are transmissible through many cell divisions and, in some cases, can be passed from parents to their offspring. An increasing body of experimental evidence from animal and human studies suggests that environmentally-induced epigenetic changes can be inherited by subsequent generations and can result in transgenerational phenotypic alterations, including predisposition to common diseases. •Our recent data on radiation-induced transgenerational instability in the mouse germline show that the effects of exposure to mutagens may not be restricted to the directly affected parental germ cells, but can also manifest in their non-exposed offspring. These transgenerational studies, initiated following the discovery, in vitro, of persistently elevated mutation rates in the non-exposed progeny of irradiated cells, were designed to test the hypothesis that radiation-induced instability in the germline of irradiated parents could manifest in the offspring, affecting their mutation rates, cancer predisposition and other characteristics. Our results show that mutation rates at a number of loci are substantially elevated in the germline and somatic tissues of non-exposed offspring of irradiated male mice. This remarkable transgenerational destabilization can be attributed to the presence of a subset of endogenous DNA lesions. Our data imply that instability detected in the non-exposed offspring is caused by some DNA-dependent signal transmitted from the irradiated father and implicate an epigenetic mechanism for the transgenerational instability. The potential epigenetic mechanisms underlying transgenerational instability will be discussed.