title: Radiation-induced transgenerational alterations in genome stability and DNA damage.
abstract: Mutation induction in directly exposed cells is currently regarded as the main component of the genetic risk of ionizing radiation for humans. However, recent data on the transgenerational increases in mutation rates in the offspring of irradiated parents indicate that the genetic risk could be greater than predicted previously. Here, we have analysed transgenerational changes in mutation rates and DNA damage in the germline and somatic tissues of non-exposed first-generation offspring of irradiated inbred male CBA/Ca and BALB/c mice. Mutation rates at an expanded simple tandem repeat DNA locus and a protein-coding gene (hprt) were significantly elevated in both the germline (sperm) and somatic tissues of all the offspring of irradiated males. The transgenerational changes in mutation rates were attributed to the presence of a persistent subset of endogenous DNA lesions (double- and single-strand breaks), measured by the phosphorylated form of histone H2AX (gamma-H2AX) and alkaline Comet assays. Such remarkable transgenerational destabilization of the F(1) genome may have important implications for cancer aetiology and genetic risk estimates. Our data also provide important clues on the still unknown mechanisms of radiation-induced genomic instability.
authors.affiliation: Department of Genetics, University of Leicester, Leicester, Leicestershire, UK.
authors.forename: R C
authors.initials: RC
authors.lastname: Barber
authors.forename: P
authors.initials: P
authors.lastname: Hickenbotham
authors.forename: T
authors.initials: T
authors.lastname: Hatch
authors.forename: D
authors.initials: D
authors.lastname: Kelly
authors.forename: N
authors.initials: N
authors.lastname: Topchiy
authors.forename: G M
authors.initials: GM
authors.lastname: Almeida
authors.forename: G D D
authors.initials: GD
authors.lastname: Jones
authors.forename: G E
authors.initials: GE
authors.lastname: Johnson
authors.forename: J M
authors.initials: JM
authors.lastname: Parry
authors.forename: K
authors.initials: K
authors.lastname: Rothkamm
authors.forename: Y E
authors.initials: YE
authors.lastname: Dubrova
mesh_terms: D000818:Animals; D001483:Base Sequence; D020552:Comet Assay; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D017931:DNA Primers; D004260:DNA Repair; D042822:Genomic Instability; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D009154:Mutation; D020080:Tandem Repeat Sequences
chemical_list: D017931:DNA Primers; D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase