Abstract
The non-targeted effects of human exposure to ionising radiation, including transgenerational instability manifesting in the children of irradiated parents, remains poorly understood. Employing a mouse model, we have analysed whether low-dose acute or low-dose-rate chronic paternal γ-irradiation can destabilise the genomes of their first-generation offspring. Using single-molecule PCR, the frequency of mutation at the mouse expanded simple tandem repeat (ESTR) locus Ms6-hm was established in DNA samples extracted from sperm of directly exposed BALB/c male mice, as well as from sperm and the brain of their first-generation offspring. For acute γ-irradiation from 10–100 cGy a linear dose-response for ESTR mutation induction was found in the germ line of directly exposed mice, with a doubling dose of 57 cGy. The mutagenicity of acute exposure to 100 cGy was more pronounced than that for chronic low-dose-rate irradiation. The analysis of transgenerational effects of paternal irradiation revealed that ESTR mutation frequencies were equally elevated in the germ line (sperm) and brain of the offspring of fathers exposed to 50 and 100 cGy of acute γ-rays. In contrast, neither paternal acute irradiation at lower doses (10–25 cGy), nor low-dose-rate exposure to 100 cGy affected stability of their offspring. Our data imply that the manifestation of transgenerational instability is triggered by a threshold dose of acute paternal irradiation. The results of our study also suggest that most doses of human exposure to ionising radiation, including radiotherapy regimens, may be unlikely to result in transgenerational instability in the offspring children of irradiated fathers.
Highlights
The results of recent studies have shown that paternal exposure to ionising radiation and some chemical mutagens results in mutation induction in the germ line of directly affected parents, but can destabilise the genomes of their offspring [1–9]
As far as the offspring of irradiated parents are concerned, the target theory predicts that they should inherit a number of extra mutations from their irradiated parents, implying that the risk of human exposure to ionising radiation is solely attributed to the induction of mutation in the parental germ line [10]
Our results offer further insights onto the yet unknown mechanism underlying the phenomenon of radiation-induced transgenerational instability in mammals and provide a plausible explanation for the existing controversy regarding the experimental evidence for these effects in humans
Summary
The results of recent studies have shown that paternal exposure to ionising radiation and some chemical mutagens results in mutation induction in the germ line of directly affected parents, but can destabilise the genomes of their offspring [1–9]. To our previous transgenerational studies [6,7], the effects of paternal irradiation on the genomes of non-exposed first generation (F1) offspring were analysed by establishing the frequency of ESTR mutation in DNA samples extracted from their germ line (sperm) and brain. Exposure to 50 and 100 cGy of acute c-rays resulted in significant increases in ESTR mutation frequency of the germ line of irradiated males. Acute exposure to smaller doses did not destabilise the F1 genomes; importantly, the same was true for the F1 offspring of male mice that received a chronic exposure 100 cGy of low dose-rate c-rays
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