Okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induces premature separation of sister chromatids during meiosis I and aneuploidy in mouse oocytes in vitro.

Recent advances in understanding some of the molecular aspects of chromosome segregation during mitosis and meiosis provide a background for investigating potential mechanisms of aneuploidy in mammalian germ cells. Numerous protein kinases and phosphatases have important functions during mitosis and meiosis. Alterations in these enzyme activities may upset the normal temporal sequence of biochemical reactions and cellular organelle modifications required for orderly chromosome segregation. Protein phosphatases 1 (PP1) and 2A (PP2A) play integral roles in regulating oocyte maturation (OM) and the metaphase-anaphase transitions. Mouse oocytes were transiently exposed in vitro to different dosages (0, 0.01, 0.1, or 1.0 microg/ml) of the PP1 and PP2A phosphatase inhibitor okadaic acid (OA) during meiosis I and oocytes were cytogenetically analyzed. Significant (p < 0.05) OA dose-response increases in the frequencies of metaphase I (MI) arrested oocytes, MI oocytes with 80 chromatids instead of the normal 20 tetrads, and anaphase I telophase I (AI-TI) oocytes with two groups of an unequal number of chromatids were found. Analysis of MII oocytes revealed significant (p < 0.05) increases in the frequencies of premature sister chromatid separation, single-unpaired chromatids, and hyperploidy. Besides showing that OA is aneugenic, these data suggest that OA-induced protein phosphatase inhibition upsets the normal kinase-phosphatase equilibrium during mouse OM, resulting in precocious removal of cohesion proteins from chromosomes.