Diazepam induces meiotic delay, aneuploidy and predivision of homologues and chromatids in mammalian oocytes

Hang Yin, Esther Baart, Ilse Betzendahl, Ursula Eichenlaub-Ritter*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

62 Citations (Scopus)

Abstract

The tranquilizer and anti-convulsant diazepam (DZ) is a suspected aneugen. In order to assess its aneugenic potential in mammalian oogenesis we exposed in vitro maturing mouse oocytes to the drug. Spindle formation and cell cycle progression, the behaviour of chromosomes and the distribution of mitochondria were characterized with respect to induction of numerical chromosomal aberrations. A concentration of 25 μg/ml DZ induced a pronounced delay in maturation and blocked a high percentage of oocytes in meiosis I. This arrest was partly reversible. Hyperploidy was slightly increased in oocytes matured in the presence of 5 μg/ml DZ and became significantly elevated in oocytes matured with 25 μg/ml DZ, relative to controls. Concomitantly, DZ induced spindle aberrations and displacement of chromosomes from the equator, but unlike in mitosis and in male meiosis most oocytes still possessed bipolar spindles. A significant fraction of meiotically delayed, metaphase I-blocked oocytes exposed to 25 μg/ml DZ contained univalents. Some DZ-treated oocytes progressing to meiosis II exhibited one or multiple single chromatids. Precocious chiasma resolution and equational segregation of chromatids from functional univalents in first anaphase (predivision) may be responsible for this condition, a mechanism also discussed in the aetiology of maternal age-related aneuploidy, DZ disturbed the spatio-temporal distribution of mitochondria during oocyte maturation, possibly by binding to peripheral-type benzodiazepine receptors on mitochondria, thus affecting the availability of ATP and calcium homeostasis. Blocks in maturation may also relate to binding of DZ to calmodulin. Data suggest that DZ exposes mammalian oocytes to predivision and aneuploidy. Thresholds, long lasting effects of DZ in vivo and sex-specific sensitivities in chemically induced aneuploidy of mammalian germ cells are critically evaluated.

Original languageEnglish
Pages (from-to)567-580
Number of pages14
JournalMutagenesis
Volume13
Issue number6
DOIs
Publication statusPublished - Nov 1998
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr R.Eichenlaub for critical reading of the manuscript. Dr I -D.Adler (GSF, OberschleiBheim) for helpful discussions and Dr D.Hutzler and E Mannweiler for their expert help with the confocal laser microscopy and the computer image analysis. The work was supported by the EU (ENV4-CT97-O471).

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