The effects of in utero irradiation on mutation induction and transgenerational instability in mice

Ruth C Barber,Robert J Hardwick,Morag E Shanks,Colin D Glen,Safeer K Mughal,Mariel Voutounou,Yuri E Dubrova

doi:10.1016/j.mrfmmm.2009.01.011

Abstract

Epidemiological evidence suggests that the deleterious effects of prenatal irradiation can manifest during childhood, resulting in an increased risk of leukaemia and solid cancers after birth. However, the mechanisms underlying the long-term effects of foetal irradiation remain poorly understood. This study was designed to analyse the impact of in utero irradiation on mutation rates at expanded simple tandem repeat (ESTR) DNA loci in directly exposed mice and their first-generation (F 1) offspring. ESTR mutation frequencies in the germline and somatic tissues of male and female mice irradiated at 12 days of gestation remained highly elevated during adulthood, which was mainly attributed to a significant increase in the frequency of singleton mutations. The prevalence of singleton mutations in directly exposed mice suggests that foetal irradiation results in genomic instability manifested both in utero and during adulthood. The frequency of ESTR mutation in the F 1 offspring of prenatally irradiated male mice was equally elevated across all tissues, which suggests that foetal exposure results in transgenerational genomic instability. In contrast, maternal in utero exposure did not affect the F 1 stability. Our data imply that the passive erasure of epigenetic marks in the maternal genome can diminish the transgenerational effects of foetal irradiation and therefore provide important clues to the still unknown mechanisms of radiation-induced genomic instability. The results of this study offer a plausible explanation for the effects of in utero irradiation on the risk of leukaemia and solid cancers after birth.

Highlights

The results of our study show that expanded simple tandem repeat (ESTR) mutation rates in the germline of in utero irradiated male and female mice remain highly elevated during adulthood
Using single-molecule PCR, the frequency of ESTR mutation was established in DNA samples prepared from sperm, bone marrow and brain taken from the in utero irradiated animals
The results of our study show that the mutagenic effects of in utero irradiation in mice are well manifested during adulthood and suggest that the susceptibility of early stages of mouse development to ionising radiation may be higher than previously thought

Summary

Introduction

The effects of in utero irradiation on mutation induction and transgenerational instability in mice R. It is well known that the developing embryo is especially sensitive to ionising radiation. To date little is known about the long-term effects of in utero exposure on mutation rates during adulthood.

Results

Conclusion