The Dose and Dose-Rate Effects of Paternal Irradiation on Transgenerational Instability in Mice

Of the non-targeted, delayed consequences of exposure to ionising radiation, genomic instability is a particular area of concern, especially with regard to its manifestation in the non-exposed offspring of irradiated parents. However, further analysis of these effects and their implications is mainly limited by our understanding of the underlying mechanisms and the lack of reliable data for humans. As of yet, transgenerational instability has only been consistently demonstrated in animal models using high, acute doses of ionising radiation (> 1 Sv). To investigate the effects of low-dose acute and low dose-rate (chronic) irradiation and whether or not they are capable of destabilizing the genomes of the unexposed offspring, we exposed male BALB/c mice to a range of γ-ray doses (10- 100 cGy) and dose-rates (chronic and acute), and mated them to unexposed BALB/c females 10 weeks post-irradiation. The mutation frequency at the Ms6-hm locus was established in DNA samples extracted from the sperm of directly exposed mice, as well as from the sperm and brains of their F1, using the single-molecule PCR technique. A linear dose-response was observed for direct exposure across the range of acute doses, with a doubling dose of 57 cGy. Furthermore, 100 cGy of acute γ-rays was shown to be more mutagenic than chronic exposure to the same accumulated dose. However, acute exposure to 10-25 cGy failed to manifest genomic instability in the derived offspring. This was also true of low dose-rate exposure to 100 cGy. Only acute paternal exposure to 50 and 100 cGy resulted in transgenerational instability, to a similar extent for both doses. Analogous results were found for both tissues. Taken together, this would imply the presence of a stress-like response where a threshold of acute dose determines the onset of transgenerational instability. Our results also suggest that children whose fathers are subject to most forms of human exposure to ionizing radiation would be safe from the effect.