The response of germ cells to ethylene oxide, propylene oxide, propylene imine and methyl methanesulfonate is a matter of cell stage-related DNA repair.
We describe the consequences of a defect for nucleotide excision repair (NER) in oocytes for alkylation-induced mutagenesis in different germ-cell stages of Drosophila males. Mutant frequencies induced in NER+ condition (cross NER+female female x NER+male) were compared with those fixed in a NER- background (cross NER-female female x NER+male), using the X-linked recessive lethal assay (SLRL) for the measurement of forward mutations in 700 loci. In successive male germ-cell stages exposed to a low dose of 2.4 mM x h methyl methanesulfonate, efficient repair of premutational damage in spermatogonia and by the maternal repair system after fertilization was observed. Ethylene oxide (EO) and propylene oxide (PO) did not induce high mutant frequencies in postmeiotic germ cells when mutagenized males were mated with NER+ females: a 32-fold increase in dose from 750 ppm x h to 24,000 ppm x h EO (approximately LD50) led to no more than a 3-fold enhancement in mutant frequency. However, up to a 17-fold increase in mutant frequencies were obtained with NER- females. In matings with NER+ females, PO was about 10 times less mutagenic than EO. Suppression of the maternal NER system caused a hypermutability, which, on the average, was 2.4-fold lower than for EO. This indicates that the 2-hydroxyethyl adduct generated by EO is more efficiently repaired than the 2-hydroxypropyl adduct caused by PO. The low SLRL frequencies (0.2-0.9%) estimated for propylene imine (PI) in NER+ genotypes showed no relation to dose in the range from 1,500 to 48,000 ppm x h. In the absence of NER, mutant frequencies were increased up to 29-fold, and a dose-dependent increase in mutations was observed for PI over the entire dose range. This study shows mutation induction by EO in postmeiotic Drosophila germ cells at exposure doses that are 800-fold below those applied previously in the mouse specific-locus test on spermatogonia [with negative response; Russell et al. (1984): Mutat Res 129:381-388] and 11-fold below the EO dose for which increased dominant-lethal responses and heritable translocations were documented in mice spermatozoa and spermatids [Generoso et al. (1990): Environ Mol Mutagen 16:126-131].
Vogel
E W
EW
Department of Radiation Genetics and Chemical Mutagenesis, Leiden University, The Netherlands. vogel@rullf2.MedFac.LeidenUniv.nl
Nivard
M J
MJ
D000818:Animals; D001388:Aziridines / Q000633:toxicity*; D004260:DNA Repair; D004330:Drosophila / Q000235:genetics*; D004852:Epoxy Compounds / Q000633:toxicity*; D005027:Ethylene Oxide / Q000633:toxicity*; D005260:Female; D005854:Germ Cells / Q000187:drug effects*; D018095:Germ-Line Mutation / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008741:Methyl Methanesulfonate / Q000633:toxicity*; D051379:Mice; D009153:Mutagens / Q000633:toxicity*
D001388:Aziridines; D004852:Epoxy Compounds; D009153:Mutagens; D008741:Methyl Methanesulfonate; D005027:Ethylene Oxide; C031132:propyleneimine; C009068:propylene oxide