Adler I D, Kliesch U, Tiveron C, Pacchierotti F
GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Institut für Säugetiergenetik, Neuherberg, Oberschleissheim, Germany.
Mutagenesis. 1995 Nov;10(6):535-41. doi: 10.1093/mutage/10.6.535.
The bifunctional metabolite of 1,3-butadiene, 1,2:3,4-diepoxybutane (DEB), was tested in the mouse bone marrow micronucleus assay and in male mouse germ cell tests, namely the analysis of first cleavage divisions and the dominant lethal assay. All experiments were performed with single intraperitoneal treatment of the animals. In the micronucleus test, DEB doses of 4.5, 9.0, 18.0 and 36.0 mg/kg body weight were tested at a sampling interval of 24 h for bone marrow. The dose response for the induction of micronuclei in polychromatic erythrocytes was linear with the lowest effective dose of 9.0 mg/kg body weight. No sensitivity difference was observed between male and female mice. the cytogenetic analysis of first cleavage division chromosomes was performed after treatment of male mice with 17, 26, 34, 43 and 52 mg/kg body weight of DEB and mating the males to hormonally stimulated females on days 7, 14, 21 and 28 after treatment. The two higher doses caused general toxicity evidenced by the poor mating behavior of the males. Only 13 and 20% of the mated females were fertilized on day 7 after treatment of the males with 43 and 52 mg/kg body weight of DEB, respectively. An increased number of unfertilized oocytes was obtained from fertilized females on day 7 after treatment of the males with 34 mg/kg body weight of DEB. With a dose of 26 mg/kg body weight, it was demonstrated that chromosomal aberrations were only induced in spermatozoa (mating on day 7 after treatment) while spermatids (mating on days 14 and 21) and spermatocytes (mating on day 28) were not susceptible to the clastogenic effect of DEB. The response in spermatozoa in the dose range 17-34 mg/kg body weight was linear up to 26 mg/kg body weight and reached a plateau thereafter. The results of the dominant lethal experiments performed in the dose range 18-54 mg/kg body weight gave results similar to the cytogenetic study. With the highest dose tested, the toxicity and cytotoxicity during the first 8 mating days after treatment dramatically reduced the number of pregnant females and, consequently, the total implantations, so that no significant dominant lethal effect could be assessed. During mating days 9-12 (treated late spermatids), a significant dominant lethal effect was observed. With the two lower doses (18 and 36 mg/kg body weight), the dominant lethal effect was restricted to spermatozoa. The good correlation of the chromosomal aberrations with dominant lethal mutations confirms the chromosomal origin of dominant lethal effects. The clastogenic effect of DEB in somatic cells and in germ cells of mice was of the same order of magnitude.
1,3 - 丁二烯的双功能代谢产物1,2:3,4 - 二环氧丁烷（DEB）在小鼠骨髓微核试验以及雄性小鼠生殖细胞试验中进行了测试，后者包括对第一次卵裂分裂的分析和显性致死试验。所有实验均通过对动物进行单次腹腔注射来开展。在微核试验中，以24小时为采样间隔，对体重分别为4.5、9.0、18.0和36.0毫克/千克的DEB剂量进行了骨髓测试。多染性红细胞中微核诱导的剂量反应呈线性，最低有效剂量为9.0毫克/千克体重。未观察到雄性和雌性小鼠之间的敏感性差异。在用体重为17、26、34、43和52毫克/千克的DEB处理雄性小鼠，并在处理后第7、14、21和28天将雄性小鼠与经激素刺激的雌性小鼠交配后，进行了第一次卵裂分裂染色体的细胞遗传学分析。较高的两个剂量导致了一般毒性，表现为雄性小鼠交配行为不佳。在用体重为43和52毫克/千克的DEB处理雄性小鼠后，第7天分别只有13%和20%的交配雌性受孕。在用体重为34毫克/千克的DEB处理雄性小鼠后，第7天从受孕雌性获得的未受精卵母细胞数量增加。当剂量为26毫克/千克体重时，证明仅在精子中诱导了染色体畸变（处理后第7天交配），而精细胞（处理后第14和21天交配）和精母细胞（处理后第28天交配）对DEB的致断裂效应不敏感。体重在17 - 34毫克/千克范围内精子的反应在达到26毫克/千克体重之前呈线性，此后达到平台期。在体重为18 - 54毫克/千克范围内进行的显性致死实验结果与细胞遗传学研究结果相似。在测试的最高剂量下，处理后前8个交配日的毒性和细胞毒性显著减少了怀孕雌性的数量，从而减少了总着床数，因此无法评估显著的显性致死效应。在交配第9 - 12天（处理晚期精细胞），观察到显著的显性致死效应。对于两个较低剂量（18和36毫克/千克体重），显性致死效应仅限于精子。染色体畸变与显性致死突变的良好相关性证实了显性致死效应的染色体起源。DEB对小鼠体细胞和生殖细胞的致断裂效应程度相同。
