The mouse oocyte as a model in reproductive toxicology studies

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.

List of scientific papers

I. Zhang JW, Guan JK, Halldin K, Håkansson H, Yuan L (2007). "Deficiency of inducible nitric oxide synthase results in an error-prone segregation of meiotic chromosomes in the female mice exposed to bisphenol A." (Manuscript)

II. Zhang JW, Håkansson, H, Kuroda M, Yuan L (2007). "Wapl localization on the synaptonemal complex, a meiosis-specific proteinaceous structure that binds homologous chromosomes in the female mouse." Domestic Animals 31-Aug: Published article online