Mailhes J B, Carabatsos M J, Young D, London S N, Bell M, Albertini D F
Department of Obstetrics and Gynecology, Louisiana State University Medical Center, P.O. Box 33932, Shreveport LA 71130, USA.
Mutat Res. 1999 Jan 25;423(1-2):79-90. doi: 10.1016/s0027-5107(98)00228-0.
To increase our understanding about the potential risks of chemically-induced aneuploidy, more information about the various mechanisms of aneuploidy induction is needed, particularly in germ cells. Most chemicals that induce aneuploidy inhibit microtubule polymerization. However, taxol alters microtubule dynamics by enhancing polymerization and stabilizing the polymer fraction. We tested the hypothesis that taxol induces meiotic delay, spindle defects, and aneuploidy in mouse oocytes and zygotes. Super-ovulated ICR mice received 0 (control), 2.5, 5.0, and 7.5 mg/kg taxol intraperitoneally immediately after HCG. Females were paired (1:1) with males for 17 h after taxol treatment. Mated females were given colchicine 25 h after taxol and their one-cell zygotes were collected 16 h later. Ovulated oocytes from non-mated females were collected 17 h after taxol. Chromosomes were C-banded for cytogenetic analyses. Oocytes were also collected from another group of similarly treated females for in situ chromatin and microtubule analyses. Taxol significantly (p<0.01) enhanced the proportion of oocytes exhibiting parthenogenetic activation, chromosomes displaced from the meiotic spindle, and sister-chromatid separation. Moreover, 7.5 mg/kg taxol significantly (p<0.01) increased the proportions of metaphase I and diploid oocytes and polyploid zygotes. A significant (p<0.01) dose response for taxol-induced hyperploidy in oocytes and zygotes was found. These results support the hypothesis that taxol-induced meiotic delay and spindle defects contribute to aneuploid mouse oocytes and zygotes.
为了增进我们对化学诱导非整倍体潜在风险的理解，需要更多关于非整倍体诱导的各种机制的信息，尤其是在生殖细胞中。大多数诱导非整倍体的化学物质会抑制微管聚合。然而，紫杉醇通过增强聚合作用和稳定聚合物部分来改变微管动力学。我们测试了这样一个假设，即紫杉醇会在小鼠卵母细胞和受精卵中诱导减数分裂延迟、纺锤体缺陷和非整倍体。超排的ICR小鼠在注射人绒毛膜促性腺激素（HCG）后立即腹腔注射0（对照）、2.5、5.0和7.5毫克/千克的紫杉醇。紫杉醇处理后17小时，将雌性小鼠与雄性小鼠按1:1配对。在紫杉醇处理25小时后给交配的雌性小鼠注射秋水仙碱，并在16小时后收集它们的单细胞受精卵。在紫杉醇处理17小时后收集未交配雌性小鼠排出的卵母细胞。对染色体进行C带染色以进行细胞遗传学分析。还从另一组经过类似处理的雌性小鼠中收集卵母细胞用于原位染色质和微管分析。紫杉醇显著（p<0.01）提高了表现出孤雌激活、从减数分裂纺锤体移位的染色体以及姐妹染色单体分离的卵母细胞比例。此外，7.5毫克/千克的紫杉醇显著（p<0.01）增加了中期I和二倍体卵母细胞以及多倍体受精卵的比例。发现了紫杉醇诱导卵母细胞和受精卵超倍体的显著（p<0.01）剂量反应。这些结果支持了这样的假设，即紫杉醇诱导的减数分裂延迟和纺锤体缺陷导致了非整倍体小鼠卵母细胞和受精卵的产生。
