NUCLEAR TOXICITY OF HEAVY METALS

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Long term toxicity of selected heavy metals (Cr, Ni and cis- or transplatinum diamminedichloride) will be investigated. Special attention will be given to the significance of protein-DNA versus DNA-DNA crosslinks known to be formed by these metals. Our experimental approaches will include studies on the effects of Cr, Ni, and Pt on chromatin structure in the exposed cells (determined by sensitivity of chromatin and selected genes to digestion with nucleases, binding of DNA intercalating dyes measured by flow cytofluorometry, etc.), studies on the specificity of metal-mediated DNA-protein crosslinks (using immunochemical methods for the detection of proteins crosslinked by metals to the DNA), as well as investigations of the DNA nucleotide sequences involved in metal mediated DNA-protein crosslinking. We are especially interested to determine whether the protein DNA crosslinking patterns differ when cells are exposed to Cr, Ni, or Pt and whether the growth related cellular changes alter such crosslinking. The use of immunochemical methods permits the detection of minute amounts of proteins crosslinked to the DNA and, more importantly, provides information about their qualitative composition. It is anticipated that our results will provide basis for the evaluation of environmental effects of pollution by Cr, Ni and other heavy metal products of coal combustion. Experiments involving the cis- and transplatinum diamminedichloride are expected to contribute to the understanding of the mechanism of action of this cancer chemotherapeutic agent and to assess the long term damage to normal cells in individuals exposed to this drug.