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Chemically induced aneuploidy in female germ cells
1ICI Pharmaceuticals Div., Alderley Park, Macclesfield, Cheshire, UK.
Abstract:
Female mice were dosed with the spindle poisons colcemid (5 mg/kg) or colchicine (2 mg/kg) or with a dihydropyridazinone (ICI 109,081; 5 mg/kg; which inhibits oocyte maturation) or with saline, the vehicle control. The dosed females (whose ovulation was synchronized using exogenous gonadotrophins) were mated with undosed males, 12 or 3 h prior to ovulation, coresponding to MI or MII stages in preovulatory oocytes. First-cleavage embryos derived from these matings were then analysed for numerical chromosome aberrations. There were no numerical aberrations in the embryos derived from control matings. Polyploid embryos were isolated from females dosed with colchicine. When females were dosed 3 h prior to ovulation (PO) 26% of the first-cleavage embryos were polyploid; in those dosed 12 h PO it was 100%. Colcemid and ICI 109,081 induced both polyploid and aneuploid embryos; with colcemid these aberrations were only observed in the embryos derived from oocytes of females dosed 3 h PO. At this sample time 4% of the embryos were polyploid and 24% were aneuploid. In contrast, the majority of aberrations induced by ICI 109,081 were observed in females dosed 12 h PO where 10% of the embryos were polyploid and 3% were aneuploid.
Insights
Mice treated with spindle poisons colchicine and colcemid, or ICI 109,081, produced embryos with chromosome abnormalities. Colchicine induced polyploidy, while colcemid and ICI 109,081 caused polyploidy and aneuploidy, depending on dosing time.
Area of Science:
- Reproductive Biology
- Developmental Biology
- Toxicology
Background:
- Oocyte maturation is a critical process for successful fertilization and embryonic development.
- Spindle poisons and maturation inhibitors can disrupt chromosome segregation during meiosis.
Purpose of the Study:
- To investigate the effects of specific chemical agents on chromosome integrity in early mouse embryos.
- To determine the impact of timing of exposure to these agents on the types and frequencies of chromosomal aberrations.
Main Methods:
- Female mice were synchronized for ovulation and administered colcemid, colchicine, ICI 109,081, or saline.
- Dosed females were mated, and resulting first-cleavage embryos were analyzed for numerical chromosome aberrations.
- Exposure timing relative to ovulation (3h or 12h prior) was varied.
Main Results:
- Colchicine treatment resulted in polyploid embryos, with 100% observed when dosed 12h prior to ovulation.
- Colcemid and ICI 109,081 induced both polyploid and aneuploid embryos.
- Colcemid-induced aberrations were primarily seen at 3h prior to ovulation (4% polyploid, 24% aneuploid), while ICI 109,081 effects were more pronounced at 12h prior (10% polyploid, 3% aneuploid).
Conclusions:
- Colchicine, colcemid, and ICI 109,081 can induce numerical chromosome aberrations in mouse embryos.
- The timing of exposure to these agents significantly influences the type and incidence of observed abnormalities.
- These findings highlight the sensitivity of oocytes to spindle-disrupting agents during maturation and fertilization.