title: The effect of dose rate on the frequency of specific-locus mutations induced in mouse spermatogonia is restricted to larger lesions; a retrospective analysis of historical data.
abstract: A series of 19 large-scale germ-cell mutagenesis experiments conducted several decades ago led to the conclusion that low-LET radiation delivered to mouse spermatogonia at dose rates of 0.8 R/min and below induced only about one-third as many specific-locus mutations as did single, acute exposures at 24 R/min and above. A two-hit origin of the mutations was deemed unlikely in view of the then prevailing evidence for the small size of genetic lesions in spermatogonia. Instead, the dose-rate effect was hypothesized to be the result of a repair system that exists in spermatogonia, but not in more mature male reproductive cells. More recent genetic and molecular studies on the marker genes have identified the phenotypes associated with specific states of the mutant chromosomes, and it is now possible retrospectively to classify individual past mutations as "large lesions" or "other lesions". The mutation-frequency difference between high and low dose rates is restricted to the large lesion mutations, for which the dose-curve slopes differ by a factor exceeding 3.4. For other lesion mutations, there is essentially no difference between the slopes for protracted and acute irradiations; induced other lesions frequencies per unit dose remain similar for dose rates ranging over more than 7 orders of magnitude. For large lesions, these values rise sharply at dose rates >0.8 R/min, though they remain similar within the whole range of protracted doses, failing to provide evidence for a threshold dose rate. The downward bend at high doses that had been noted for X-ray-induced specific-locus mutations as a whole and ascribed to a positive correlation between spermatogonial death and mutation load is now found to be restricted to large lesion mutations. There is a marked difference between the mutation spectra (distributions among the seven loci) for large lesions and other lesions. Within each class, however, the spectra are similar for acute and protracted irradiation.
authors.affiliation: Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, USA. lianerussell@comcast.net
authors.forename: Liane B
authors.initials: LB
authors.lastname: Russell
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Hunsicker
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004307:Dose-Response Relationship, Radiation; D004431:Ear, External; D005127:Eye Color / Q000235:genetics; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects; D056426:Genetic Loci / Q000528:radiation effects*; D006200:Hair Color / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D016296:Mutagenesis; D009152:Mutagenicity Tests / Q000379:methods*; D010641:Phenotype; D012189:Retrospective Studies; D013093:Spermatogonia / Q000528:radiation effects*; D013997:Time Factors; D014965:X-Rays / Q000009:adverse effects