Abstract
Recent data shows that the effects of ionizing radiation are not restricted to the directly exposed parental germ cells, but can also manifest in their nonexposed offspring, resulting in elevated mutation rates and cancer predisposition. The mechanisms underlying these transgenerational changes remain poorly understood. One of the most important steps in elucidating these mechanisms is to investigate the initial cellular events that trigger genomic instability. Here we have analyzed the effects of paternal treatment by ethylnitrosourea, an alkylating agent which is known to form specific types of DNA adducts, on the transgenerational effects in the first-generation (F1) offspring of exposed CBA/Ca and BALB/c male mice. Mutation rates at two expanded simple tandem repeat loci were significantly elevated in the F1 germline of both strains. Pre and postmeiotic exposures resulted in similar increases in mutation rate in the F1 germline. Within each strain mutation rates were equally elevated in the germline of male and female F1 offspring of the directly exposed males. The results of our study suggest that transgenerational instability is not attributed to a specific sub-set of DNA lesions, such as double strand breaks, and is most probably triggered by a stress-like response to a generalized DNA damage.
Highlights
The results of a number of recent studies demonstrate that mutation rates in the nonexposed progeny of irradiated cells remain highly elevated over many cell divisions following the initial exposure [Morgan, 2003]
CBA/Ca and BALB/c inbred stains of mice were previously used in our studies on radiation-induced transgenerational instability in mice [Barber et al, 2002; 2006; Hatch et al, 2007]
The number of mutations scored in all first- and second-generation offspring of exposed males was divided by the total number of offspring in that generation to give an estimate of germline mutation rates for the germline of F0 and F1 parents
Summary
The results of a number of recent studies demonstrate that mutation rates in the nonexposed progeny of irradiated cells remain highly elevated over many cell divisions following the initial exposure [Morgan, 2003]. It was suggested that ongoing genomic instability could result in the accumulation of mutations over a certain period of time after irradiation which, together with mutations directly induced in the irradiated cells, may significantly enhance radiation carcinogenesis [Huang et al, 2003; Goldberg, 2003]. The data on elevated mutation rates detected in the offspring of irradiated parents indicate a potential contribution of genomic instability to transgenerational carcinogenesis [Dubrova et al, 2000; Barber et al, 2002; 2006]. Taken together, these results imply that the genetic risk of ionising radiation for humans could be greater than previously predicted
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