Although aneuploidy is responsible for significant adverse human health conditions such as birth defects, mental retardation, spontaneous abortions, and cancer, little is known about the possible aneugenicity of the chemicals and drugs we are exposed to. In Phase I work, a novel Saccharomyces cerevisiae-based chomosome nondisjunction assay was developed for eventual use in high throughput screening. This nondisjunction assay has a simple fluorometric readout and responds to known aneugens. Here, the assay will be adapted to an economical high throughput format. In addition, methods for increasing the predictive value of yeast-based tests will be explored in two ways. First, methods for decreasing the pharmacokinetic differences between yeast and mammalian cells including 1) increasing drug uptake, 2) decreasing drug excretion, and 3) mimicking mammalian metabolism of test compounds will be explored. Second, two different types of """"""""first hit"""""""" sensitizing mutations--centromere mutations and mitotic checkpoint mutations-- will be examined. Finally, the nondisjunction assay will be combined with a DEL-like assay to allow simultaneous assessment of both aneugenicity and carcinogenicity.
