Dose and Dose-rate Dependence of the Frequency of HPRT Deficient T Lymphocytes in the Spleen of the<sup>137</sup>Cs γ-irradiated Mouse

Lorenz, R.; Deubel, Werner; Leuner, Katja; Gollner, Thomas; Hochhauser, Edith; Hempel, Klaus

doi:10.1080/09553009414551251

Cited by 23 publications

(20 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A), fractionation at daily intervals seemed to be more efficient for this mutational induction than fractionation at weekly intervals (median, 67 Â 10 À6 versus 31 Â 10 À6 ; P < 0.03). This finding is consistent with the report that, given the same dose, acute exposure was more effective in inducing Hprt mutations in mouse T cells (20) although the underlying mechanisms remain unknown. In contrast to the remarkable increase in the IR-induced mutant frequency at the Hprt locus, there was only a modest increase in the IR-induced mutant frequency as a function of dose at the Aprt locus.…”

Section: Resultssupporting

confidence: 83%

Reduced Apoptosis and Increased Deletion Mutations at Aprt Locus In vivo in Mice Exposed to Repeated Ionizing Radiation

et al. 2007

View full text Add to dashboard Cite

Exposure to ionizing radiation (IR) is a risk factor for carcinogenesis because it is a mutagen. However, a single 4-Gy whole body X-ray exposure only induced a modest increase of mutations at the Aprt reporter gene locus in mouse T cells. Intriguingly, when the same dose of IR was given in a fractionated protocol (1 Gy Â 4 at weekly intervals), there was a strong induction of Aprt mutations in T cells. Many of these were mutations that arose via interstitial deletions inclusive of Aprt or by intragenic deletions. We hypothesized that the weekly fractionated X-ray exposures select for somatic cells with reduced p53 expression and/or reduced apoptosis, which, in turn, may have facilitated the accumulation of interstitial deletions, as in p53-deficient mice. We indeed found that splenocytes of mice with three previous exposures (1 Gy Â 4 in total) were more resistant to X-ray-induced apoptosis than those of mice exposed to X-rays for the first time (1 Gy total). Thus, repeated X-ray radiation selects for reduced apoptosis in vivo. However, this reduced apoptosis is p53-independent, because p53 induction and the up-regulation of genes downstream of p53, such as Bax and p21, were similar between the 1-Gy and 1 Gy Â 4 groups. Reduced apoptosis probably allows the generation of more mutations, particularly deletion mutations. Because both reduced apoptosis and increased somatic mutation are risk factors for carcinogenesis, they may contribute to the paradigm in which different radiation exposure schemes are varied in their efficiency in inducing lymphomagenesis. [Cancer Res 2007;67(5):1910-7]

show abstract

Section: Resultssupporting

confidence: 83%

Reduced Apoptosis and Increased Deletion Mutations at Aprt Locus In vivo in Mice Exposed to Repeated Ionizing Radiation

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Comparison of these results with ours suggests that there may be a threshold dose at which sparing of mutant frequency induction occurs in a daily exposure plan (50 cGy being below, 1 Gy dose being above). Consistent with the existence of a threshold for sparing in mutation induction, 8-10 weeks after chronic exposures to g radiation (dose rates of 1 Gy/day and 1 Gy/week) Lorenz et al [1994] observed lower efficiency of induction of Hprt deficient mutants than after acute dosing (50 cGy/min). On a practical level, dose fractionation can induce sufficiently elevated mutant frequencies that molecular mutation spectra associated with small acute doses might be compared to spectra of background and high doses.…”

Section: Discussionsupporting

confidence: 56%

“…The occurrence of dosedependent radiation mutagenesis in mice has been demonstrated in a number of studies [Dempsey and Morley 1986;Lorenz et al, 1990Lorenz et al, , 1993Lorenz et al, , 1994Grdina et al, 1992;Kataoka et al, 1992Kataoka et al, , 1993Gaziev et al, 1995;Klarmann et al, 1995;Dobrovolsky et al, 2002;Liang et al, 2007]. However, the more extensive evaluation of time elapsed after acute g irradiation revealed that mutant frequency dependence on dose shifted between 3 and 5 weeks and 10-53 weeks, from being clearly quadratic at the peak of mutant recovery in weeks 3-5 to a statistically strong but less-defined dose relationship in the later time frame.…”

Section: Discussionmentioning

confidence: 93%

“…On the basis of the mutant frequency results presented, we hypothesize that the molecular nature, and perhaps the persistence, of the mutants induced would more closely reflect the characteristics of mutants induced by the individual small dose than those of the total dose. Unfortunately, interpretation of the effects of truly low dose rate exposures such as those employed by Lorenz et al [1994] are complicated by simultaneous induction of and selection against mutants during extended exposures.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Studies of thioguanine‐resistant lymphocytes induced by in vivo irradiation of mice

Jones

Burkhart-Schultz

Strout

et al. 2008

Environ and Mol Mutagen

View full text Add to dashboard Cite

The frequency of Hprt-deficient lymphocytes in mice after in vivo gamma irradiation, has been found to vary as a function of time elapsed after exposure and irradiation dose. The frequency of mutant lymphocytes in spleen was determined using an in vitro, clonogenic assay for thioguanine-resistant T-lymphocytes. Mice were exposed to single doses of 0-400 cGy from cesium-137 or to eight daily doses of 50 cGy. The time to maximum-induced mutant frequency was 3 weeks. The dose response was strikingly curvilinear at 3-5 weeks after irradiation, but less precisely defined for 10-53 weeks after exposure, being fit by either linear or quadratic dependence. Three weeks after eight daily 50 cGy exposures, mutant frequency was elevated above controls and mice exposed to 50 cGy (which were not distinct from the nonirradiated controls), but only 17% in that of mice given a single 400 cGy fraction. This fractionation effect and the curvilinearity of the early dose-response curve suggested that saturation of repair increased the yield of mutations at higher acute doses. The decline of spleen mutant frequency in mice observed between 5 and 10 weeks after irradiation may reflect selection against some mutants. The marked variation of mutant frequency, as a function of time after irradiation and of dose rate, emphasize the need to evaluate these variables carefully and consistently in future studies.

show abstract

“…There are very few studies of DREs on HPRT mutations in vivo in the very low DR range (21), so it is difficult to decide whether there is an inverse DRE. However, mutant frequencies were elevated in lymphocytes of humans exposed to low doses of ionizing radiation at low and͞or very low DRs (22)(23)(24)(25), relative to high DRs.…”

Section: Evidence For Inverse Dresmentioning

confidence: 99%

Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates

Vilenchik

Knudson

2000

Proc. Natl. Acad. Sci. U.S.A.

136

View full text Add to dashboard Cite

The mutagenic effect of low linear energy transfer ionizing radiation is reduced for a given dose as the dose rate (DR) is reduced to a low level, a phenomenon known as the direct DR effect. Our reanalysis of published data shows that for both somatic and germ-line mutations there is an opposite, inverse DR effect, with reduction from low to very low DR, the overall dependence of induced mutations being parabolically related to DR, with a minimum in the range of 0.1 to 1.0 cGy͞min (rule 1). This general pattern can be attributed to an optimal induction of error-free DNA repair in a DR region of minimal mutability (MMDR region). The diminished activation of repair at very low DRs may reflect a low ratio of induced (''signal'') to spontaneous background DNA damage (''noise''). Because two common DNA lesions, 8-oxoguanine and thymine glycol, were already known to activate repair in irradiated mammalian cells, we estimated how their rates of production are altered upon radiation exposure in the MMDR region. For these and other abundant lesions (abasic sites and single-strand breaks), the DNA damage rate increment in the MMDR region is in the range of 10% to 100% (rule 2). These estimates suggest a genetically programmed optimatization of response to radiation in the MMDR region.T he dose-rate effect (DRE) on mutation has important implications for genetics and radioprotection. The risk of genetic effects of ionizing radiation for both somatic and germ cells decreases with reduction of dose rate (DR). This phenomenon is called the direct DRE (reviewed in refs. 1 and 2). But some somatic cell lines show inverse DREs, with higher sensitivity to mutation induced by low linear energy transfer (LET) radiation (3-12) or to oncogenic transformation induced by fission neutrons (2) at very low DRs than at low DRs. However, some investigators have reported a direct DRE (1, 12) or no DRE (13,14), at very low DRs of continuous (13) or fractionated (14) low LET radiation. With respect to mutational DREs in germ cells, Lyon and coworkers (15) have suggested a similar inverse effect at very low DRs, whereas Russell and coworkers (16) concluded that their data did not confirm such an effect. The general view is that germ-line mutations do not show an inverse DRE (reviewed in ref. 1). Here we reanalyze these data, together with recent low LET data on DREs, and conclude that there is indeed a general pattern of inverse effects at very low DRs for both somatic and germ cells. Evidence for Inverse DREsSomatic HPRT Mutation in Mammalian Cells in Vitro. Although there are data on other genetic DREs than HPRT mutation in somatic mammalian cells (for review see refs. 1, 5, and 17), we limited our analysis to HPRT mutations because they have been the most studied. For the most part, the data were obtained by using low LET radiation, i.e., x-rays and ␥-rays. The low DR somatic mutation data that we plot in Fig. 1 all were evaluated and reviewed in at least four reviews published in the 1990s (1, 4-6) with one exception for a radiosensitive mu...

show abstract

Dose and Dose-rate Dependence of the Frequency of HPRT Deficient T Lymphocytes in the Spleen of the¹³⁷Cs γ-irradiated Mouse

Cited by 23 publications

References 22 publications

Reduced Apoptosis and Increased Deletion Mutations at Aprt Locus In vivo in Mice Exposed to Repeated Ionizing Radiation

Reduced Apoptosis and Increased Deletion Mutations at Aprt Locus In vivo in Mice Exposed to Repeated Ionizing Radiation

Studies of thioguanine‐resistant lymphocytes induced by in vivo irradiation of mice

Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates

Contact Info

Product

Resources

About

Dose and Dose-rate Dependence of the Frequency of HPRT Deficient T Lymphocytes in the Spleen of the137Cs γ-irradiated Mouse

Cited by 23 publications

References 22 publications

Reduced Apoptosis and Increased Deletion Mutations at Aprt Locus In vivo in Mice Exposed to Repeated Ionizing Radiation

Reduced Apoptosis and Increased Deletion Mutations at Aprt Locus In vivo in Mice Exposed to Repeated Ionizing Radiation

Studies of thioguanine‐resistant lymphocytes induced by in vivo irradiation of mice

Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates

Contact Info

Product

Resources

About

Dose and Dose-rate Dependence of the Frequency of HPRT Deficient T Lymphocytes in the Spleen of the¹³⁷Cs γ-irradiated Mouse