Chlorambucil effectively induces deletion mutations in mouse germ cells.
The chemotherapeutic agent chlorambucil was found to be more effective than x-rays or any chemical investigated to date in inducing high yields of mouse germ-line mutations that appear to be deletions or other structural changes. Induction of mutations involving seven specific loci was studied after exposures of various male germ-cell stages to chlorambucil at 10-25 mg/kg. A total of 60,750 offspring was scored. Mutation rates in spermatogonial stem cells were not significantly increased over control values; this negative result is not attributable to selective elimination of mutant cells. Mutations were, however, clearly induced in treated post-stem-cell stages, among which marked variations in mutational response were found. Maximum yield occurred after exposure of early spermatids, with approximately 1% of all offspring carrying a specific-locus mutation in the 10 mg/kg group. The stage-response pattern for chlorambucil differs from that of all other chemicals investigated to date in the specific-locus test. Thus far, all but one of the tested mutations induced by chlorambucil in post-stem-cell stages have been proved deletions or other structural changes by genetic, cytogenetic, and/or molecular criteria. Deletion mutations have recently been useful for molecular mapping and for structure-function correlations of genomic regions. For generating presumed large-lesion germ-line mutations at highest frequencies, chlorambucil may be the mutagen of choice.
Russell
L B
LB
Biology Division, Oak Ridge National Laboratory, TN 37831-8077.
Hunsicker
P R
PR
Cacheiro
N L
NL
Bangham
J W
JW
Russell
W L
WL
Shelby
M D
MD
D000818:Animals; D002699:Chlorambucil / Q000633:toxicity*; D002871:Chromosome Banding; D002872:Chromosome Deletion / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009154:Mutation / Q000187:drug effects*; D013091:Spermatogenesis / Q000187:drug effects; D013093:Spermatogonia / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects*
D002699:Chlorambucil