Vogel E W, Nivard M J
Department of Radiation Genetics and Chemical Mutagenesis, Leiden University, The Netherlands.
Environ Mol Mutagen. 1997;29(2):124-35. doi: 10.1002/(sici)1098-2280(1997)29:2<124::aid-em3>3.0.co;2-e.
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].
我们描述了果蝇雄性不同生殖细胞阶段中，卵母细胞核苷酸切除修复（NER）缺陷对烷基化诱导诱变的影响。使用X连锁隐性致死试验（SLRL）来测量700个位点的正向突变，将NER+条件下（NER+雌性×NER+雄性杂交）诱导的突变频率与NER-背景下（NER-雌性×NER+雄性杂交）固定的突变频率进行比较。在连续的雄性生殖细胞阶段，暴露于低剂量2.4 mM×h的甲磺酸甲酯中，观察到精原细胞中预突变损伤的有效修复以及受精后母本修复系统的作用。当诱变雄性与NER+雌性交配时，环氧乙烷（EO）和环氧丙烷（PO）在减数分裂后的生殖细胞中未诱导出高突变频率：EO剂量从750 ppm×h增加32倍至24,000 ppm×h（约LD50），导致突变频率仅增加不超过3倍。然而，与NER-雌性交配时，突变频率增加了高达17倍。在与NER+雌性交配时，PO的诱变能力比EO低约10倍。母本NER系统的抑制导致了超突变性，平均而言，比EO低2.4倍。这表明EO产生的2-羟乙基加合物比PO引起的2-羟丙基加合物更有效地被修复。在NER+基因型中，对丙烯亚胺（PI）估计的低SLRL频率（0.2 - 0.9%）在1500至48000 ppm×h范围内与剂量无关。在没有NER的情况下，突变频率增加了高达29倍，并且在整个剂量范围内观察到PI的突变呈剂量依赖性增加。本研究表明，在果蝇减数分裂后的生殖细胞中，EO在低于先前在小鼠精原细胞特异性位点试验中应用剂量800倍（无反应；Russell等人，1984年：《突变研究》129:381 - 388）以及低于在小鼠精子和精细胞中记录到显性致死反应和可遗传易位增加的EO剂量11倍的暴露剂量下诱导了突变。
