Submitted June 27, 2006
Returned for revision July 23, 2006
Accepted December 29, 2006
Toxicology
2-Methoxyestradiol Induces Spindle Aberrations, Chromosome
Congression Failure, and Nondisjunction in Mouse Oocytes
Ursula Eichenlaub-Ritter *,
Ulrike Winterscheid ,
Edgar Vogt ,
Ying Shen ,
Hans-Rudolf Tinneberg ,
and
Ralph Sorensen
* To whom correspondence should be addressed. E-mail: eiri{at}uni-bielefeld.de.
Abstract
2-Methoxyestradiol is a metabolite of 17beta-estradiol and
a natural component of follicular fluid. Local
2-methoxyestradiol concentrations may be increased by
exposures to environmental pollutants that activate
expression of enzymes in the metabolic pathway from
17beta-estradiol to 2-methoxyestradiol. It has been
suspected that this may have adverse effects on spindle
formation in maturing oocytes that affect embryo quality.
To study the dose-response we exposed denuded mouse
oocytes to 2-methoxyestradiol during in vitro maturation.
Meiotic progression, spindle morphology, centrosome
integrity, and chromosome congression were examined by
immunofluorescence and non-invasive polarizing microscopy
(PolScope). Chromosomal constitution was assessed after
spreading and C-banding. 2-Methoxyestradiol sustained
MAD2L1 expression at centromeres, and increased the number
of meiosis I-blocked oocytes in a dose-dependent manner.
It also caused dramatic dose-dependent increases in
hyperploidy of metaphase II oocytes. Some of these meiosis
II oocytes contained anaphase I-like chromosomes
suggesting that high concentrations of the
catecholestradiol interfere with physical separation of
chromosomes. Non-invasive PolScope analysis and tubulin
immunofluorescence revealed perturbations in spindle
organization resulting in severe disturbances in
chromosome alignment at the spindle equator (congression
failure) by 2-methoxyestradiol at meiosis I and II.
Pericentrin-positive centrosomes failed to align at
spindle poles, and multipolar spindles and prominent
arrays of cytoplasmic microtubule asters were induced in
2-methoxyestradiol-exposed metaphase II oocytes. In
conclusion, micro molar 2-methoxyestradiol is aneugenic in
mammalian oocytes. Exposures and conditions increasing
intrinsic local concentrations of 2-methoxyestradiol in
the ovary may, therefore, affect fertility and increase
risk for chromosomal aberrations in the oocyte and embryo.
Key words:
Environment •
Toxicology •
Estradiol •
Meiosis •
Oocyte development
