CHROMIUM(III) GENOTOXICITY--DIRECT AND INDIRECT PATHWAYS

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DESCRIPTION: This proposal is a resubmission for an R29 FIRST award the title of which has been appropriately changed from investigations of the comutagenicity of Chromium (III)@. This submission has also been sent from the College of Arts and Sciences, Northern Arizona University where the applicant has recently (August 97) been appointed Assistant Professor in the Dept. of Chemistry. The previous submission originated from Dartmouth College. The overall goal is to elucidate the mechanism of chromium carcinogenesis since chromium, a common industrially used heavy metal has been implicated in the development of human cancers. Chromium (VI) is the form of chromium which is classified as a human carcinogen, however, this proposal hypothesises that chromium (III) is involved in chromium (VI) induced cancers since it is an intracellular metabolic product of chromium (VI). Chromium (III) is not clearl an adverse agent in human health and Cr (III) based compounds are used as dietary supplements, however the principal investigator emphasizes that, The point to consider should be intracellular Cr (III) rather than Cr (III) exposure in general. There are strong indications that such a statement is highly pertinent. The specific goal of this proposal is then to elucidate direct and indirect pathways of Cr (III)-induced DNA damage and mutation. To test whether Cr (III) is responsible for the formation of Cr-DNA adducts, different adducts will be synthesized and examined by MR spectroscopy, and other techniques including X-ray crystallography. That is, a knowledge base will be constructed for synthetic Cr-DNA adducts and this information used to detect Cr-DNA adducts formed in cultured cells treated with Cr (III) and Cr (VI). In a second series of experiments designed to test the hypothesis that C (III) causes direct damage in cells through the formation of Cr-DNA adducts an produces indirect DNA damage by inhibiting repair, cell biological studies wil be undertaken. This contrasts with the bioinorganic chemistry approach in the first series of experiments. Specifically, CHO cells, normal and deficient in different steps of nucleotide excision repair will be treated with Cr (III) complexes and DNA based lesions measured (Cr-DNA adducts, strand breaks, cross-links and alkali labile sites). Comparison will be made against model genotoxins. In a third series of experiments the mutagenicity and co-mutagenicity of bioavailable Cr (III) will be assessed. Chromosomal changes and hgprt mutation will be measured to assess direct effects, while combined treatments with known genotoxins will also be undertaken to evaluate co-mutagenicity. It is hoped that knowledge gained from these explorations of the pathways of Cr (III) genotoxicity will contribute to an understanding of the carcinogenic capacity of Cr (VI), and the potential risk to humans of ingesting bioavailable Cr (III) nutritional supplements.