Vogel E W, Nivard M J
Medical Genetics Centre South-West Netherlands (MGC), Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Centre, Wassenaarseweg 72, 2300 RA, Leiden, Netherlands.
Mutat Res. 1998 Sep 20;405(2):259-71. doi: 10.1016/s0027-5107(98)00143-2.
We report here results on forward mutation induction (recessive lethal mutations, RL) in Drosophila spermatozoa and spermatids by the three 1,2-alkyl-epoxides ethylene oxide (EO), propylene oxide (PO) and butylene oxide (BO), at doses ranging from 47 to 24,000 ppm h for EO, 375 to 48,000 ppm h for PO, and 24,000 to 91,200 ppm h for BO. The results indicate for EO mutation induction at doses 500-fold below the LD50. In crosses of mutagenized NER+ males with NER+ females, the 500-fold increase in EO dose from 47 ppm h to 24,000 ppm h resulted in no more than a 17-fold enhanced mutant frequency in spermatozoa. This flat dose-response relationship is primarily the result of efficient repair of EO-induced DNA adducts in the fertilized egg, as was evident from the up to 40-fold or 240-fold increased mutant frequencies above NER- or NER+ background levels, respectively, in crosses with NER- females. With decreasing dose, MNER-/MNER+ ratios decreased from 9 to 14 at high doses down to approximately 1 at the two lowest doses, indicating that a small fraction of premutagenic lesions induced by EO cannot be repaired by the NER system of Drosophila. Linear extrapolation from high to low EO exposure led to an underestimation of the mutation frequency actually observed at low doses. The pattern of EO-induced ring chromosome loss (CL) differed in two respects from that observed for forward mutations: (a) an increase in CL frequencies was observed only at the two highest EO exposure levels, and (b) inactivation of the NER pathway by the mus201 mutant had no measurable effect on the occurrence of CL. The absence of a potentiating effect of mus201 on EO-induced clastogenicity suggests the formation of clastogenic DNA lesions not causing point mutations, and which are not repaired by NER. Consistent with an inversed correlation of reactivities towards N7-guanine and chain length of 1,2-alkyl-epoxides, the relative mutagenic efficiencies of EO:PO:BO are 100:7.2:1.8 for the NER+ groups, and 100:20:0.7 in the absence of NER. Although in Drosophila germ cells EO is also more effective as a clastogen than PO, the difference (EO:PO=100:58) is much smaller than for recessive mutations. These results provide another argument that DNA lesions generating base substitutions as opposed to those causing clastogenic damage may not be the same for these agents.
我们在此报告了环氧乙烷（EO）、环氧丙烷（PO）和环氧丁烷（BO）这三种1,2 - 烷基环氧化物在不同剂量下对果蝇精子和精细胞诱导正向突变（隐性致死突变，RL）的结果，EO的剂量范围为47至24,000 ppm·h，PO为375至48,000 ppm·h，BO为24,000至91,200 ppm·h。结果表明，EO在低于半数致死剂量500倍的剂量下即可诱导突变。在用诱变后的NER + 雄性与NER + 雌性杂交中，EO剂量从47 ppm·h增加500倍至24,000 ppm·h，精子中的突变频率增加不超过17倍。这种平坦的剂量 - 反应关系主要是由于受精卵中EO诱导的DNA加合物得到有效修复，这在与NER - 雌性杂交中分别比NER - 或NER + 背景水平高出40倍或240倍的突变频率中明显可见。随着剂量降低，MNER - /MNER + 比值从高剂量时的9至14降至两个最低剂量时的约1，表明EO诱导的一小部分前突变损伤不能被果蝇的NER系统修复。从高EO暴露水平到低暴露水平的线性外推导致对低剂量下实际观察到的突变频率估计不足。EO诱导的环状染色体丢失（CL）模式在两个方面与正向突变观察到的模式不同：（a）仅在两个最高EO暴露水平观察到CL频率增加，（b）mus201突变体使NER途径失活对CL的发生没有可测量的影响。mus201对EO诱导的致断裂性没有增强作用，这表明形成了不导致点突变且不能被NER修复的致断裂性DNA损伤。与对N7 - 鸟嘌呤的反应性和1,2 - 烷基环氧化物链长的反向相关性一致，对于NER +组，EO：PO：BO的相对诱变效率为100：7.2：1.8，在没有NER的情况下为100：20：0.7。虽然在果蝇生殖细胞中EO作为致断裂剂也比PO更有效，但差异（EO：PO = 100：58）比隐性突变小得多。这些结果提供了另一个论据，即这些试剂产生碱基取代的DNA损伤与导致致断裂性损伤的损伤可能不同。
