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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009961-04
Application #
6635494
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Thompson, Claudia L
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2005-04-30
Support Year
4
Fiscal Year
2003
Total Cost
$342,000
Indirect Cost
Name
George Washington University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
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Nickens, Kristen P; Han, Ying; Shandilya, Harini et al. (2012) Acquisition of mitochondrial dysregulation and resistance to mitochondrial-mediated apoptosis after genotoxic insult in normal human fibroblasts: a possible model for early stage carcinogenesis. Biochim Biophys Acta 1823:264-72
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Beaver, Laura M; Stemmy, Erik J; Constant, Stephanie L et al. (2009) Lung injury, inflammation and Akt signaling following inhalation of particulate hexavalent chromium. Toxicol Appl Pharmacol 235:47-56
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Vilcheck, Susan K; Ceryak, Susan; O'Brien, Travis J et al. (2006) FANCD2 monoubiquitination and activation by hexavalent chromium [Cr(VI)] exposure: activation is not required for repair of Cr(VI)-induced DSBs. Mutat Res 610:21-30
O'Brien, Travis J; Jiang, Guohui; Chun, Gina et al. (2006) Incision of trivalent chromium [Cr(III)]-induced DNA damage by Bacillus caldotenax UvrABC endonuclease. Mutat Res 610:85-92

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