The hexavalent oxidation state of chromium, chromate or Cr(VI), is a known human carcinogen. Human exposure to this carcinogen occurs in chrome-utilizing occupations and from environmental sources that are primarily anthropogenic. Despite conservation and recycling efforts in the United States, over 20,000 metric tons of chromium is released to the environment every year with over 5000 metric tons as atmospheric emissions. The ubiquity of Cr(VI) emissions to the environment has led the ATSDR to list this metal as one of the top 20 high priority toxic agents for emission reduction. While Cr(VI) is well-established as a toxic DNA damaging agent, the mechanism(s) of DNA damage and the DNA lesions that are produced are still unknown. We have recently identified of several new """"""""further oxidized"""""""" guanine lesions in DNA that arise from Cr(VI) treatment from both in vitro and cellular systems. These lesions have demonstrated many of the same biological effects in cell systems that are associated with pathologies of Cr-induced lung cancers. Based on these findings, we propose to test the hypothesis that """"""""chromate exposure leads to the formation of a subset of further oxidized guanine lesions in DNA that are ultimately responsible for the cellular events that give rise to cancer"""""""". The approach that we will use to test this hypothesis will be; 1) We will test the selective toxicity of chromate towards a set of model, DNA-repair deficient, cell lines and determine the spectrum of oxidized lesions that arise, 2) we will determine how modulation of intracellular reduction potential may affect chromate sensitivity in these cell lines and determine whether this intracellular reductant modulation effects the relative lesion distribution, 3) we propose to identify the potential for oxidation of DNA by chromium to form DNA-reductant, DNA-amino acid and DNA-protein crosslinks, and 4) we propose to determine the effect that these crosslinks have on cellular function with regard to mutations, DNA repair and gene transcription. The end result of this study will be a fundamental insight into the process by which oxidative DNA damage caused by Cr(VI) forms lesions that impair critical cellular processes. This research will also serve to identify novel biomarkers of Cr(VI) exposure and suggest repair genes that can be analyzed for polymorphisms and mutations. ? ? ?
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