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

Abstract

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...

Radiation dose-rate effects, endogenous DNA damage, and signaling resonance

“…Data from the irradiation of spermatogonia in mice have been published by two groups led, respectively, by Lyon (3) and Russell (4,5). From their published results we have calculated the DREs and shown that their sets of data are in close agreement (1). Both show a direct DRE at DRs above 1.0 cSv͞min; i.e., the frequency of mutations increases as the rate of delivery of a given dose increases.…”

“…We previously concluded that cells are able to measure the frequency of DNA damage and to compare that frequency with a ''spontaneous,'' or background, frequency (1). The mechanism would therefore resemble that of ''stochastic resonance'' that is observed for signal-to-noise relationships in physics and physiology.…”

“…On the basis of observations on locus-specific germ-line mutations in mouse spermatogonial stem cells, Lyon concluded that there could be an increase in mutation rates below this DR, with a minimum rate of damage near 0.1 cSv͞min (reviewed in ref. 1), but this conclusion was not generally accepted. Our analysis of available data for both germ-line and somatic mutations demonstrated that this inverse DRE is characteristic and that the overall DREs are parabolic functions of the logarithms of DRs over a range of approximately six logs, with minimal mutation rates per unit of dose in the range of 0.03-1.0 cSv͞min (1).…”

“…1), but this conclusion was not generally accepted. Our analysis of available data for both germ-line and somatic mutations demonstrated that this inverse DRE is characteristic and that the overall DREs are parabolic functions of the logarithms of DRs over a range of approximately six logs, with minimal mutation rates per unit of dose in the range of 0.03-1.0 cSv͞min (1). This finding then raises the question of why the minimum occurs in this range, far above a common rate of background radiation on the order of 10 Ϫ7 cSv͞min.…”

Evasion of Early Cellular Response Mechanisms following Low Level Radiation-induced DNA Damage

“…However, in humans, the primary DSB repair pathway is somewhat errorprone, and therefore, the fidelity of the genome is not always maintained (2)(3)(4)(5). This may be particularly important following the production of low levels of DNA damage in which cellular detection mechanisms may not be fully elicited (5,6). Evidence exists (7) that increased cell death in the absence of repair following low level DNA damage may offer a way by which the cell prevents potentially promutagenic lesions from being passed on to progeny.…”