Griseofulvin-induced aneuploidy and meiotic delay in female mouse germ cells. I. Cytogenetic analysis of metaphase II oocytes.

Griseofulvin (GF) was tested in female mouse germ cells for the induction of aneuploidy and meiotic arrest. Superovulated mice were orally treated with 200, 666, 1332 or 2000 mg/kg in olive oil at the time of human chorionic gonadotrophin (HCG) injection and were sacrificed 18 h later. A dose-dependent increase in the frequency of metaphase I (M I) arrested oocytes was observed (maximum of 70%). Aneuploidy was not significantly induced. Also, the kinetics of meiotic progression up to the metaphase II (M II) stage was studied in untreated mice in order to correlate the time of treatment with the time of the first meiotic division. The results demonstrate that the majority of cells was treated with GF approximately 8 h before the M I stage. A second series of experiments were performed to test GF effects at a different treatment time. Doses of 200, 666 or 2000 mg/kg were administered 2 h post HCG. As in the first series of experiments, the animals were sacrificed 18 h post HCG. The results, compared with those obtained in the first experimental series, showed an inverse trend for meiotic arrest and aneuploidy induction. The frequency of M I arrested oocytes dropped from a maximum of 70% to a maximum of 20%, while, at the latest treatment time, a dose-dependent increase in the frequency of hyperploid oocytes was observed up to 56% aberrant cells at 2000 mg/kg. Altogether the results suggest that the arrest of meiotic division and the induction of aneuploidy by GF are caused by interaction with different targets or different developmental stages of the same target. In conclusion, GF has been shown to induce aneuploidy during the first meiotic division in a dose-related manner, together with other effects such as polyploidy, developmental delay and meiotic arrest. Also, these findings demonstrate that the sensitivity of the oocyte target(s) may be restricted to a specific time period and that a correct experimental protocol is critical for assessing the aneugenic activity of a chemical.