Low dose X-radiation adaptive response in spleen and prostate of<i>Atm</i>knockout heterozygous mice

Day, Tanya K.; Hooker, Antony M.; Zeng, Guoxin; Sykes, Pamela J.

doi:10.1080/09553000701420582

Cited by 22 publications

(18 citation statements)

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“…The gene Atm encodes ATM, which is a member of the PI-3 kinase protein family, and it plays a crucial role in the signal transduction network that modulates cell-cycle checkpoints, DNA repair, and other cellular responses to DNA damage. This gene is also responsible for ataxia telangiectasia (AT) [35]. The Atm KO mice present an osteopenic phenotype as early as 10 weeks old, apparently due to decreased bone marrow-derived mesenchymal progenitors.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Microsatellite Polymorphism in Inbred Knockout Mice

BaoFen

Zhao

et al. 2012

PLoS ONE

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Previously, we found that the genotype of 42 out of 198 mouse microsatellite loci, which are distributed among all chromosomes except the Y chromosome, changed from monomorphism to polymorphism (CMP) in a genetically modified inbred mouse strain. In this study, we further examined whether CMP also relates to the homologous recombination in gene knockout (KO) mouse strains. The same 42 microsatellite loci were analyzed by polymerase chain reaction (PCR) in 29 KO inbred mouse strains via short tandem sequence repeat (STR) scanning and direct sequence cloning to justify microsatellite polymorphisms. The C57BL/6J and 129 mouse strains, from which these 29 KO mice were derived, were chosen as the background controls. The results indicated that 10 out of 42 (23.8%) loci showed CMP in some of these mouse strains. Except for the trinucleotide repeat locus of D3Mit22, which had microsatellite CMP in strain number 9, the core sequences of the remaining 41 loci were dinucleotide repeats, and 9 out of 41 (21.95%) showed CMPs among detected mouse strains. However, 11 out of 29 (37.9%) KO mice strains were recognized as having CMPs. The popular dinucleotide motifs in CMP were (TG)n (50%, 2/4), followed by (GT)n (27.27%, 3/11) and (CA)n (23.08%, 3/13). The microsatellite CMP in (CT)n and (AG)n repeats were 20% (1/5). According to cloning sequencing results, 6 KO mouse strains showed insertions of nucleotides whereas 1 showed a deletion. Furthermore, 2 loci (D13Mit3 and D14Mit102) revealed CMP in 2 strains, and mouse strain number 9 showed CMPs in two loci (D3Mit22 and D13Mit3) simultaneously. Collectively, these results indicated that microsatellite polymorphisms were present in the examined inbred KO mice.

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Section: Discussionmentioning

confidence: 99%

Analysis of Microsatellite Polymorphism in Inbred Knockout Mice

BaoFen

Zhao

et al. 2012

PLoS ONE

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“…The role of p53 (TP53) is not clearly established and seems to depend on the cell type studied and the biological end point used to measure the radioadaptive response (7,8). Both ATM homozygous and heterozygous mutants demonstrated an adaptive response to radiation-induced chromatid breaks (9) and chromosomal inversion frequency (10). Nevertheless, the radioadaptive response, and therefore low-dose response, may involve more than DNA repair pathways.…”

Section: Introductionmentioning

confidence: 98%

Broad Modulation of Gene Expression in CD4⁺Lymphocyte Subpopulations in Response to Low Doses of Ionizing Radiation

et al. 2008

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To compare the responses of the different lymphocyte subtypes after an exposure of whole blood to low doses of ionizing radiation, we examined variations in gene expression in different lymphocyte subpopulations using microarray technology. Blood samples from five healthy donors were independently exposed to 0 (sham irradiation), 0.05 and 0.5 Gy of ionizing radiation. Three and 24 h after exposure, CD56+, CD4+ and CD8+ cells were negatively isolated. RNA from each set of experimental conditions was competitively hybridized on 25k oligonucleotide microarrays. Modifications of gene expression were measured after both intervals and in all cell types. Twenty-four hours after exposure to 0.5 Gy, we observed an induction of the expression of BAX, PCNA, GADD45, DDB2 and CDKN1A. However, the numbers of modulated genes greatly differed between cell types. In particular, 3 h after exposure to doses as low as 0.05 Gy, the number of down-modulated genes was 10 times greater for CD4+ cells than for all other cell types. Moreover, most of these repressed genes were taking part in the cell processes of protein biosynthesis and oxidative phosphorylation. The results suggest that several biological pathways in CD4+ cells could be sensitive to low doses of radiation. Therefore, specifically studying CD4+ cells could help to understand the mechanisms involved in low-dose response and allow their detection.

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“…While the 10 mGy X-radiation dose may have been too low to elicit any detectable changes to DNA methylation, we have previously demonstrated that mice irradiated with a single whole body dose of 10 mGy given at the same dose rate used here (13.9 mGy/min) induces a radioadaptive response causing significant changes in chromosomal inversion frequency in spleen and prostate [53], [54], [94]–[96]. A single dose of 10 mGy has also been shown to induce a radioadaptive response for a range of other endpoints [34], [36], [97]–[99].…”

Section: Discussionmentioning

confidence: 83%

“…This is predominantly due the widespread distribution of these elements, and the evidence that increased transposition activity of these elements due to a loss of methylation can increase the overall genomic instability associated with age [13]–[16], [50]–[52]. There is also evidence that methylation of the murine homologues, L1, B1 (Alu) and IAP (LTR), can display aberrant methylation in aging mice [10], [12], [53]. Based on both the human and mouse studies, we chose to utilise the L1, B1 (Alu homologue) and IAP (murine LTR) elements to monitor age or X-ray induced changes to methylation.…”

Section: Resultsmentioning

confidence: 99%

“…Based on both the human and mouse studies, we chose to utilise the L1, B1 (Alu homologue) and IAP (murine LTR) elements to monitor age or X-ray induced changes to methylation. Spleen and liver tissues were chosen for analysis at the end of the study as spleen is considered a radiosensitive organ and has been the subject of many radiation and radioadaptive studies [53]–[56] while liver has been investigated in a number of murine aging studies and has been shown to exhibit methylation changes with age [54], [55], [56]. Furthermore, both tissues have been shown to display reduced methylation following high dose radiation exposure [57], [58].…”

Section: Resultsmentioning

confidence: 99%

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A Single Whole-Body Low Dose X-Irradiation Does Not Affect L1, B1 and IAP Repeat Element DNA Methylation Longitudinally

et al. 2014

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The low dose radioadaptive response has been shown to be protective against high doses of radiation as well as aging-induced genomic instability. We hypothesised that a single whole-body exposure of low dose radiation would induce a radioadaptive response thereby reducing or abrogating aging-related changes in repeat element DNA methylation in mice. Following sham or 10 mGy X-irradiation, serial peripheral blood sampling was performed and differences in Long Interspersed Nucleic Element 1 (L1), B1 and Intracisternal-A-Particle (IAP) repeat element methylation between samples were assessed using high resolution melt analysis of PCR amplicons. By 420 days post-irradiation, neither radiation- or aging-related changes in the methylation of peripheral blood, spleen or liver L1, B1 and IAP elements were observed. Analysis of the spleen and liver tissues of cohorts of untreated aging mice showed that the 17–19 month age group exhibited higher repeat element methylation than younger or older mice, with no overall decline in methylation detected with age. This is the first temporal analysis of the effect of low dose radiation on repeat element methylation in mouse peripheral blood and the first to examine the long term effect of this dose on repeat element methylation in a radiosensitive tissue (spleen) and a tissue fundamental to the aging process (liver). Our data indicate that the methylation of murine DNA repeat elements can fluctuate with age, but unlike human studies, do not demonstrate an overall aging-related decline. Furthermore, our results indicate that a low dose of ionising radiation does not induce detectable changes to murine repeat element DNA methylation in the tissues and at the time-points examined in this study. This radiation dose is relevant to human diagnostic radiation exposures and suggests that a dose of 10 mGy X-rays, unlike high dose radiation, does not cause significant short or long term changes to repeat element or global DNA methylation.

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Low dose X-radiation adaptive response in spleen and prostate ofAtmknockout heterozygous mice

Abstract: Being heterozygous for a knockout mutation in the Atm gene does not affect the endogenous pKZ1 inversion frequency, the inversion response to single low radiation doses used here, or the induction of a radiation adaptive response for inversions in pKZ1 mouse spleen or prostate.

Cited by 22 publications

References 50 publications

Analysis of Microsatellite Polymorphism in Inbred Knockout Mice

Analysis of Microsatellite Polymorphism in Inbred Knockout Mice

Broad Modulation of Gene Expression in CD4⁺Lymphocyte Subpopulations in Response to Low Doses of Ionizing Radiation

A Single Whole-Body Low Dose X-Irradiation Does Not Affect L1, B1 and IAP Repeat Element DNA Methylation Longitudinally

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Low dose X-radiation adaptive response in spleen and prostate ofAtmknockout heterozygous mice

Abstract: Being heterozygous for a knockout mutation in the Atm gene does not affect the endogenous pKZ1 inversion frequency, the inversion response to single low radiation doses used here, or the induction of a radiation adaptive response for inversions in pKZ1 mouse spleen or prostate.

Cited by 22 publications

References 50 publications

Analysis of Microsatellite Polymorphism in Inbred Knockout Mice

Analysis of Microsatellite Polymorphism in Inbred Knockout Mice

Broad Modulation of Gene Expression in CD4+Lymphocyte Subpopulations in Response to Low Doses of Ionizing Radiation

A Single Whole-Body Low Dose X-Irradiation Does Not Affect L1, B1 and IAP Repeat Element DNA Methylation Longitudinally

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Broad Modulation of Gene Expression in CD4⁺Lymphocyte Subpopulations in Response to Low Doses of Ionizing Radiation