Haines J.W.,Public Health England |
Coster M.R.,Public Health England |
Adam J.,Radiation and Genome Stability Unit |
Cheeseman M.,Mary Lyon Center |
And 4 more authors.
Molecular Cancer Research | Year: 2010
XRCC2 has an important role in repair of DNA damage by homologous recombination. Adult Apcmin/+ (min, multiple intestinal neoplasia) mice, wild-type or heterozygous for Xrcc2 deficiency, were sham-irradiated or 2-Gy X-irradiated. Spontaneous mammary and intestinal tumor incidences are lower in Apcmin/+ Xrcc2+/- mice than in Apcmin/+ Xrcc2+/+ mice (mammary tumors: 14% and 38%, respectively, χ2 P = 0.03; intestinal adenomas in mice reaching full life span: 108.6 and 130.1, respectively, t-test P = 0.005). Following irradiation, the increase in mammary tumors was greatest in female mice heterozygous for Xrcc2 (7.25 ± 0.50-fold in Apcmin/+ Xrcc2+/- mice compared with 2.57 ± 0.35-fold in Apcmin/+ Xrcc2+/+ mice; t-test P < 0.001). The increase in intestinal tumor multiplicity following irradiation was significantly greater in Apcmin/+ Xrcc2+/- mice (Apcmin/+ Xrcc2+/-, 4.14 ± 0.05-fold, versus Apcmin/+ Xrcc2+/+, 3.30 ± 0.05-fold; t-test P < 0.001). Loss of heterozygosity of all chromosome 18 markers was greater in intestinal tumors from Apcmin/+ Xrcc2 +/- mice than in tumors from Apcmin/+ Xrcc2+/+ mice. These findings indicate that Xrcc2 haploinsufficiency reduces spontaneous tumor incidence on an Apcmin/+ background but increases the tumorigenic response to radiation. ©2010 AACR.
Kadhim M.A.,Oxford Brookes University |
Lee R.,Helmholtz Center for Heavy Ion Research |
Moore S.R.,Radiation and Genome Stability Unit |
Macdonald D.A.,Radiation and Genome Stability Unit |
And 3 more authors.
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis | Year: 2010
Environmental 222radon exposure is a human health concern, and many studies demonstrate that very low doses of high LET α-particle irradiation initiate deleterious genetic consequences in both irradiated and non-irradiated bystander cells. One consequence, radiation-induced genomic instability (RIGI), is a hallmark of tumorigenesis and is often assessed by measuring delayed chromosomal aberrations. We utilised a technique that facilitates transient immobilization of primary lymphocytes for targeted microbeam irradiation and have reported that environmentally relevant doses, e.g. a single 3He2+ particle traversal to a single cell, are sufficient to induce RIGI. Herein we sought to determine differences in radiation response in lymphocytes isolated from five healthy male donors. Primary lymphocytes were irradiated with a single particle per cell nucleus. We found evidence for inter-individual variation in radiation response (RIGI, measured as delayed chromosome aberrations). Although this was not highly significant, it was possibly masked by high levels of intra-individual variation. While there are many studies showing a link between genetic predisposition and RIGI, there are few studies linking genetic background with bystander effects in normal human lymphocytes. In an attempt to investigate inter-individual variation in the induction of bystander effects, primary lymphocytes were irradiated with a single particle under conditions where fractions of the population were traversed. We showed a marked genotype-dependent bystander response in one donor after exposure to 15% of the population. The findings may also be regarded as a radiation-induced genotype-dependent bystander effect triggering an instability phenotype. © 2010 Elsevier B.V.