Numerical chromosome changes or aneuploidy make substantial contributions to human health. The objective of the project is to provide an understanding of the mechanisms by which environmental chemicals interact with the processes of chromosome segregation at mitotic and meiotic cell division and thus produce progeny cells with abnormal chromosome numbers. An understanding of chemically induced aneuploidy will allow the development, assessment and regulation of aneugenic chemicals, the determination as to whether there is a cellular threshold for such activity and provide information on the relative activity of aneugenic chemicals in male and female germ cells.
The project activities involve research in a series of related areas :
There are theoretical reasons to assume that for at least some chemical aneugens there may be a threshold of activity. Such a threshold would allow the use of such chemicals at doses below the threshold without impairing health. Detailed dose response studies will be undertaken with selected aneugens chosen to represent different mechanisms of actions.
Cellular targets whose modification may lead to induced aneuploidy will be investigated. These include : motor proteins, protein kinases, protein phosphotases and topoisomerases.
3) Tissue specificity and metabolism
Following the identification of the metabolic requirements for aneugenic activity in vitro, comparative studies will be performed in the tissues of rodents.
4) Comparative studies in male and female germ cells
Chemically induced aneuploidy will be analysed in both male and female germ cells with particular emphasis upon those chemicals which have produced discordant results between the two sexes.
5) Environmental significance of aneugens
Chemical aneugens for which human exposure has occurred will be evaluated in laboratory test systems.
6) System development
A major emphasis will be placed upon the application of fluorescence in situ hybridisation (FISH) techniques for the detection and assessment of chemical aneugens.
Funding SchemeCSC - Cost-sharing contracts
2300 RA Leiden