The primary object of the proposed research is to investigate the interaction of particulate and soluble hexavalent chromium compounds with normal human small airway epithelial cells (HSAE) and fibroblasts (HLF), which are representative target cells for chromium toxicity and carcinogenesis. Some of these compounds are human respiratory tract toxins and carcinogens which directly damage DNA and alter DNA replication and transcription, may damage subcellular organelles, such as mitochondria, and cause mutations an neoplastic transformation at doses which also induce growth arrest and apoptotic cell death. Using cultured human and rat cells the investigator will test the hypotheses that: (increasing the fraction of cells escaping chromium-induced apoptotic cell death by pharmacologically interfering with apoptotic signaling, results in increased genomic instability and propensity towards mutation and neoplastic transformation, and (ii) chromium-induced apoptosis and/or terminal growth arrest results in part from direct damage to mitochondria, loss of mitochondrial integrity and release of cytochrome c. Implicit in this approach is an examination of the mechanisms of chromium-induced apoptosis and elucidation of signaling pathways which, if altered, might give rise to cells which are predisposed to accelerated multistage carcinogenesis. This research will help to elucidate molecular mechanisms of chromium toxicity and carcinogenesis and will have practival value in contributing to the evaluation of risk to humans exposed to chromates.
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