Vinyl monomers, although generally of low inherent genetic hazard when compared with compounds such as aflatoxin B1 and benzo[a] pyrene, are of concern to toxicologists because they are produced in multimillion pound quantities. Thus, they present substantial hazards to workers involved in the manufacture of the monomers and polymers and in the subsequent fabrication of products derived from the polymers. During the present project period, effort will be focused on styrene. Styrene, after oxidation to the epoxide, forms adducts on DNA which lead to point mutations. A wide variety of adducts have been identified, all of which are on guanine. The working hypothesis in this project is that the type and frequency of mutation are dependent upon the structures and conformations of these adducts. Methodology will be developed for regio- and stereospecific synthesis of styrene oxide adducted deoxyoligonucleotides. Three-dimensional solution conformations of the adducted oligomers will be established by NMR and other biophysical techniques. NOESY and other two dimensional NMR experiments will be the key tools used to achieve this goal. Initial studies will employ duplexes in which deoxycytidine is hybridized with the adducted deoxyguanosine. A second series of studies will involve mispairing at the lesion site with the other three deoxynucleotides to ascertain what changes in hybridization capability result from adduction. Finally, in a collaborative effort with Dr. R. Stephen Lloyd, Vanderbilt Department of Biochemistry, the types and frequency of point mutations brought about by the various styrene oxide adducts will be established using the synthetic adducted oligomers. This two-pronged approach to structure-activity relationships will lead to an understanding at a molecular level of the relationship between the structure/conformation of the individual styrene oxide adducts and the mutations that result from them.
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