Hexavalent chromium (CrVI) is a toxic DNA-damaging agent with a well-documented exposure in a large number of occupations, and it is a common environmental contaminant. Cr(VI) is listed by the ATSDR and EPA as one of the top 20 high priority toxic agents. The final oxidative form of Cr in biological systems is Cr(lll) that produces several stable DNA adducts. We have recently found that Cr(III)-DNA adducts are one of the major causes of mutagenicity of Cr(VI). Our new data indicate that Cr-DNA adducts also play an important role in toxicity of Cr(VI). Toxic responses to Cr-DNA adducts were strongly dependent on the presence of a small group of proteins that bind to Cr-damaged chromatin. This proposal is designed to test our working hypothesis that cytotoxic effects of Cr-DNA adducts are caused by the formation of secondary DNA lesions generated as a result of the recognition and processing of adducts by damage sensory proteins. Biochemical approaches and cellular models with downregulated levels of damage-processing proteins will be used to gain evidence supporting the proposed hypothesis. We constructed a series of the retroviral siRNA-encoding vectors, which will allow us to examine the role of various proteins in the cytotoxic responses in the target primary human bronchial epithelial cells that have not been previously amenable to the mechanistic studies. The results of this work are expected to advance molecular understanding of Cr(VI) injury in the major target cells and to identify damage processing proteins that enhance toxicity of Cr-DNA modifications. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012915-02
Application #
6903474
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Thompson, Claudia L
Project Start
2004-07-01
Project End
2009-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$326,561
Indirect Cost
Name
Brown University
Department
Pathology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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