Abnormal chromosome migration and chromosome aberrations in mouse oocytes during meiosis II in the presence of topoisomerase II inhibitor ICRF-193

Abstract

Using a mouse parthenogenetic system, effects of ICRF-193, a noncleavable complex-forming topoisomerase II inhibitor, on female meiosis II chromosomes and pronuclear chromosomes were studied. Eggs were exposed to the inhibitor (10 μM) at various times after parthenogenetic stimulation, and chromosomes of them were analyzed at the first cleavage metaphase. When eggs were exposed to the inhibitor during the period from metaphase II to anaphase II, a significant increase in incidences of structural chromosome aberrations (51.1% versus 1.3% in the control) and aneuploidy (30.3% versus 0.7% in the control) was found. Structural chromosome aberrations were observed in 10–20% of eggs following treatments during telophase II, but there was no increased incidence of aneuploidy in treatments during this meiotic stage. When pronuclear eggs at S phase were targeted by the inhibitor, no significant increase in chromosome aberrations was found. Interestingly, when chromatids moved to each pole during anaphase II in the presence of ICRF-193, most of them oriented their centromeres toward the spindle equator as if moving backwards. Moreover, lagging chromatids with the centromeres present were observed in more than 50% of treated eggs. However, chromosomal bridges that resulted from chromosome stickiness did not appear in any egg. These findings indicate that ICRF-193 can induce structural chromosome aberrations and aneuploidy in mouse secondary oocytes in meiotic stage-dependent manner. The induction of aneuploidy is due to disruption of the separation of sister centromeres at anaphase II. There appears to be mechanism(s) other than cleavable complex formation or chromosome stickiness behind the induction of structural chromosome aberrations by ICRF-193.