Mutation frequencies in male mice and the estimation of genetic hazards of radiation in men.

Abstract

Estimation of the genetic hazards of ionizing radiation in men is based largely on the frequency of transmitted specific-locus mutations induced in mouse spermatogonial stem cells at low radiation dose rates. The publication of new data on this subject has permitted a fresh review of all the information available. The data continue to show no discrepancy from the interpretation that, although mutation frequency decreases markedly as dose rate is decreased from 90 to 0.8 R/min (1 R = 2.6x 10' coulombs/kg) there seems to be no further change below 0.8 R/min over the range from that dose rate to 0.0007 R/min. Simple mathematical models are used to compute: (a) a maximum likelihood estimate of the induced mutation frequency at the low dose rates, and (b) a maximum likelihood estimate of the ratio of this to the mutation frequency at high dose rates in the range of 72 to 90 R/min. In the application ofthese results to the estimation of genetic hazards of radiation in man, the former value can be used to calculate a doubling dose-i.e., the dose of radiation that induces a mutation frequency equal to the spontaneous frequency. The doubling dose based on the low-dose-rate data compiled here is 110 R. The ratio of the mutation frequency at low dose rate to that at high dose rate is useful when it becomes necessary to extrapolate from experimental determinations, or from human data, at high dose rates to the expected risk at low dose rates. The ratio derived from the present analysis is 0.33. An earlier publication (1) dealt with mutation frequencies in female mice and the estimation of genetic hazards of radiation in women. The present paper provides a similar analysis for males.One of the most important pieces of experimental information for the estimation of genetic hazards of radiation in men is the mutational response of mouse spermatogonial stem cells at low radiation dose rates. The publication of new data on this subject (2), including some at the lowest dose rate so far tested, and the inclusion of additional results in this report provide an opportunity for a fresh review of all the information now available. The data are used to compute a maximum likelihood value for induced mutation frequency at low dose rates and also to compare this with the mutation frequency at high dose rates. The results are in close agreement with earlier analyses by Russell (3) and Searle (4).All of the data reported here were obtained by the mouse specific-locus method which uses seven visible markers and permits the detection of mutations involving any of the seven gene loci in the first-generation offspring of the irradiated parent (5).. Only the results from treated and control adult males are presented here, and all the offspring came from germ cells which, at the time of irradiation, were in spermatogonial stemcell, As, stage. The .radiation was y-rays (from a 13 Cs or 60Co source) or x-rays. The new data considered in this analysis consist of(a) results from exposures to 300 R of 137Cs y radiation at 0.005 R/min (1 R = ...

Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis

“…Doubling doses were higher in irradiated premeiotic and meiotic spermatogenic cell types in the present study compared to those reported from other germline mutation assays [43][44][45][46]. Notably, the Lac I mutation reporter system is effective in reporting point mutations, but is not as effective in reporting larger deletions, insertions or rearrangements.…”

Comments on the Paper by Wickliffeet al.(Radiat. Res.159, 458–464, 2003)

“…While average mutation rates increased by three-to fourfold at the highest radiation dose used, it is of some concern that the variation in mutation rate found between individual mouse families was equally large (three-to fourfold) at a given dose. Similar data were reported for more densely ionizing neutron irradiations; where sufficient data have been reported, the relative effectiveness of fission neu-256 REVIEW Generally, using conventional mutation measurements, the risk of genetic effects of sparsely ionizing radiations for both somatic and germ cells has been found to decrease with reduction of dose rate down to ϳ10 mGy/min, attributable to more effective DNA repair at lower dose rates (72). However, for the induction of ESTR mutation in spermatogonial stem cells, radiation delivered over 100 h at a dose rate of 0.166 mGy/min was found to be as effective as that given at a rate of 0.5 Gy/min (40).…”

“…Despite the very high mutation rate found for ESTR sequences, estimates of the doubling dose (the dose at which the mutation rate is increased to twice the naturally occurring rate) are little different from those found for conventional mutation analyses in mice (72). Thus Dubrova and colleagues estimated the doubling dose to be around 0.5 Gy for pre-meiotic stage irradiation and 0.33 Gy in their later studies (63,68,71).…”

Epigenetic changes and nontargeted radiation effects—Is there a link?

“…However, the data from animal models have clearly demonstrated that effects of the parental radiation exposure are transmitted through the germline to the progeny of the irradiated parent [Morgan, 2003a,b,c]. Early studies of these transgeneration effects used various tests such as the specific locus, dominant lethal, and heritable translocation assays [Generoso et al, 1980;Russell and Kelly, 1982;Green et al, 1987;Russell et al, 1998]. Other studies focused on heritable alterations in cancer incidence and teratogenesis following the parental preconception irradiation [Mohr et al, 1999;Pils et al, 1999;Nomura, 2003;Nomura et al, 2004;Dasenbrock et al, 2005].…”