Abstract
It is suspected that certain chemicals may cause alterations in female
reproduction, including ovarian failure and birth defects. Sub-fecundity,
infertility, pregnancy loss, fetal growth retardation, and birth defects
are consequences proposed to occur. It has been estimated that about 3%
of the observed birth defects could be attributed to the exposure to
chemicals and other physical agents, and that as much as 25% of the
observed birth defects may be due to a combination of genetic and
environmental factors. Aneuploidy is a major cause of birth defects and
it is mostly derived from errors in chromosome segregation during female
germ cell development (oogenesis). The mechanisms of chemically induced
aneuploidy in the oocyte are not well understood for any chemical.
The overall aim of the present study was therefore to provide new
knowledge, which could aid in the development of a mouse experimental
system for the detection and evaluation of chemicals, with aneugenic
potential. More specifically, the present study was designed to 1)
elucidate the underlying mechanism(s) involved in the reported aneugenic
potential of bisphenol A (BPA), and to 2) evaluate the potential of
different protein components, critically involved in meiotic chromosomal
segregation, as markers for chemically induced aneuploidy in the mouse
oocyte.
As opposed to previous reports, we could not confirm that BPA induces
aneuploidy at the previously reported dose-level in C57BL 6/129 mice with
mixed background. However, we were able to demonstrate that the mice
lacking inducible nitric oxide synthase (iNOS) exhibited increased
error-prone chromosome segregation in female meiosis after BPA exposure
as compared to their wild-type counterparts. Further mechanistic
characterization revealed that the protein expression of both polo-like
kinase-1 (Plk1) and Ran GTPase (Ran) was dramatically reduced in
iNOS-deficient oocytes.
Using female C57BL/6N wildtype mice we were able to demonstrate the
specific localization of Wapl (wings apart-like) on the synaptonemal
complex, a meiosis-specific structure connecting one pair of sister
chromatids to the homologous pair of oocyte chromosomes.
Taken together, results obtained in the present study suggest that mouse
oocytes have the potential to become a useful test-model for detection
and evaluation of aneugenic chemicals. Oocytes derived from
iNOS-deficient mice may aid in understanding the interactions between the
fundamental biology of chromosomal segregation and the toxicological
aspects of aneuploidy induction. Wapl, localized on the synaptonemal
complex in female meiotic chromosomes and known to be affected by for
example dioxin and 3-methylcholanthrene, has the potential to become a
marker of chemicals, which interferes with the proper function of meiotic
chromosomes, as well as an exposure marker of Ah-receptor ligands, which
targets female germ cells.
