【摘要】：目的:采用小鼠骨髓細(xì)胞染色體畸變試驗和小鼠顯性致死突變試驗評價正丁基硫代磷酰三胺(NBPT)對體細(xì)胞和生殖細(xì)胞的致突變性。方法:小鼠骨髓細(xì)胞染色體畸變試驗中雄性小鼠分別單次灌胃給予NBPT 250、500、1 000 mg/kg,1 000 mg/kg組動物于給藥后24、48及72 h取骨髓細(xì)胞制備骨髓片,其他組動物于給藥后24 h取骨髓細(xì)胞制備骨髓片。每只動物在油鏡下分析100個中期相骨髓細(xì)胞,記錄染色體結(jié)構(gòu)畸變、數(shù)目畸變和發(fā)生裂隙的細(xì)胞數(shù)。小鼠顯性致死試驗中雄鼠分別連續(xù)灌胃給予NBPT 250、500、1 000 mg/kg 5 d后,雌鼠與雄鼠同籠交配5 d,雄鼠再于2 d后與下一輪的雌鼠交配,共進(jìn)行7個輪次的交配,每輪次1周,覆蓋雄性小鼠整個生精周期。每輪次雌鼠于同籠結(jié)束后第14天處死,計數(shù)總著床數(shù)、黃體數(shù)、死胎、活胎和吸收胎數(shù)。結(jié)果:小鼠單次灌胃NBPT 24 h后,250、500、1 000 mg/kg劑量組骨髓細(xì)胞染色體結(jié)構(gòu)畸變率分別為2.4%、3.0%和2.0%,1 000 mg/kg組24、48和72 h的骨髓細(xì)胞染色體結(jié)構(gòu)畸變率均未超過4%,與溶媒對照組比較差異均無統(tǒng)計學(xué)意義(P0.05)。各NBPT處理組染色體四倍體與裂隙的發(fā)生率也未出現(xiàn)與NBPT相關(guān)性的變化。小鼠顯性致死試驗的7個交配輪次中,NBPT 3個處理組受孕率為100%,母鼠平均著床數(shù)、黃體數(shù)、活胎數(shù)與溶媒對照組比較差異均無統(tǒng)計學(xué)意義(P0.05)。僅在NBPT 250 mg/kg組發(fā)現(xiàn)第4交配輪次母鼠著床前丟失率增高,第6輪次母鼠窩均非活胎數(shù)降低,與溶媒對照組比較差異均有統(tǒng)計學(xué)意義(P0.01)。NBPT 3個處理組各交配輪次母鼠的致死突變率大多為負(fù)值,偶見較低的正值。結(jié)論:在本試驗條件下,NBPT無致小鼠骨髓細(xì)胞染色體畸變效應(yīng),對雄性ICR小鼠無顯性致死突變作用。
[Abstract]:Aim: to evaluate the mutagenicity of normal Ding Ji phosphoryltriamine (NBPT) to somatic and germ cells by chromosome aberration test of bone marrow cells and dominant lethal mutation test in mice. Methods: in the chromosome aberration test of bone marrow cells in mice, male mice were given NBPT 250 500 mg / kg 1 000 mg/kg by single gavage, and bone marrow cells were taken from the mice at 24 h and 72 h after administration to prepare bone marrow slices. Bone marrow cells were taken from other groups 24 hours after administration. One hundred metaphase bone marrow cells were analyzed under oil microscope to record chromosomal structural aberration, number aberration and the number of cells with fissures. In the dominant lethal test of mice, male mice were fed with NBPT 250,500000 mg/kg for 5 days, female mice and male mice were mated in the same cage for 5 days, and male mice were mated with the next round of female mice 2 days later. Seven rounds of mating were carried out for one week each time. Covering the whole spermatogenic cycle of male mice. The female rats were killed on the 14th day after the same cage. The total number of implantation, the number of luteal bodies, the number of stillbirths, the number of live fetuses and the number of absorbed fetuses were counted. Results: the chromosomal structural aberration rate of bone marrow cells in NBPT group was 2.4% and 2.0000 mg/kg at 2448 and 72 h after single NBPT administration for 24 h. The results showed that the chromosome structural aberration rate of bone marrow cells in the dose group of 250,500,500 mg/kg was less than that of the control group, compared with that of the control group. The difference was not statistically significant (P0.05). The incidence of tetraploid and fissures of chromosomes in each NBPT treatment group was not correlated with NBPT. The pregnancy rate of NBPT treatment group was 100 in 7 mating cycles of dominant lethal test in mice. There was no significant difference in average implantation number, luteal body number, number of live fetus between NBPT treatment group and control group (P0.05). Only in the NBPT 250 mg/kg group, the rate of loss before implantation was increased, and the number of non-live embryos in the litter of the sixth round was decreased. Compared with the control group, the difference was statistically significant (P0.01). Conclusion: NBPT has no effect on chromosome aberration in bone marrow cells, but no dominant lethal mutation in male ICR mice.
【作者單位】： 軍事醫(yī)學(xué)科學(xué)院毒物藥物研究所國家北京藥物安全評價研究中心;軍事醫(yī)學(xué)科學(xué)院抗毒藥物與毒理學(xué)國家重點實驗室;中國食品藥品檢定研究院;YMS
【基金】：重大新藥創(chuàng)制科技重大專項基金(2013ZX09302303,2014ZX095 07009-022)
【分類號】：R114

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