A dose-response analysis of ethylnitrosourea-induced recessive specific-locus mutations in treated spermatogonia of the mouse.
A dose-response analysis was carried out with 2 independent data sets available for ethylnitrosourea-induced specific-locus mutations in spermatogonia of the mouse. It was assumed that the occurrence of mutation is binomially distributed and maximum-likelihood procedures were employed to determine the appropriateness of 4 alternative models, Linear, Linear-Quadratic, Power, and Threshold, in describing the dependence of the binomial parameter on dose. For both data sets, the Threshold model yielded a far superior fit and the threshold dose was estimated to be between 34 and 39 mg/kg. These results are supported by the relatively inefficient response of ethylnitrosourea at lower doses in inducing DNA adducts. Relevant specific-locus mutation results in the mouse for low-dose fractionated treatment as well as the recovery of mutation mosaics indicate the threshold model to be an oversimplification. Rather than a threshold dose below which 100% of the induced DNA adducts are repaired, we propose that some DNA adducts which may eventually be fixed as a mutation persist through a number of repair-competent cell divisions and do not interfere with normal cell function nor do they induce a repair response before being eventually fixed as a mutation. We interpret the thresholded response for ethylnitrosourea-induced specific-locus mutations to be due to a saturable repair process which at lower doses results in ethylnitrosourea being less efficient in inducing mutation. Once this repair process is saturated, a clear dose-related increase in the mutation rate is observed.
Favor
J
J
GSF-Institut für Säugetiergenetik, Neuherberg, F.R.G.
Sund
M
M
Neuhäuser-Klaus
A
A
Ehling
U H
UH
D000818:Animals; D003433:Crosses, Genetic; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005038:Ethylnitrosourea / Q000633:toxicity*; D005260:Female; D005808:Genes, Recessive; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008957:Models, Genetic; D015233:Models, Statistical; D009154:Mutation; D013093:Spermatogonia / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects*
D005038:Ethylnitrosourea