the dose and dose-rate effects of paternal irradiation on transgenerational instability in mice a radiotherapy connection父亲的辐照的剂量和剂量率效应在小鼠放疗连接继代不稳定.pdfVIP

The Dose and Dose-Rate Effects of Paternal Irradiation on Transgenerational Instability in Mice: A Radiotherapy Connection 1 2 3 2 Safeer K. Mughal , Andrey E. Myazin , Leonid P. Zhavoronkov , Alexander V. Rubanovich , Yuri E. Dubrova1* 1 Department of Genetics, University of Leicester, Leicester, United Kingdom, 2 Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia, 3 Medical Radiological Research Center of the Russian Ministry of Health and Social Development, Obninsk, Russia 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 c-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 c-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 c-rays. In contrast, neither paternal acute irradiation at lower doses (10–25 cG