Cadmium is an atmospheric pollutant, a tobacco smoke contaminant, and a human lung carcinogen. The investigators have previously demonstrated that chronic cadmium exposure to both cell lines and whole animal studies leads to the emergence of an epithelial cell sub-population with increased resistance to oxidant induced cell death. This new phenotype is hypothesized to be caused by cadmium induced alterations in gene expression, linked mechanistically to cellular glutathione levels and to a common transcription factor. Some of these resistant cells may exhibit increased proliferation (when exposed to tumor promoters) and are resistant to apoptosis. This could ultimately cause clonal expansion and tumor formation. To test these hypotheses, the investigators propose (1) study Cd- induced expression of known cytoprotectins (metallothione, GSH S-transferase, heme oxygenase-1) and enzymes that increase GSH levels (gamma glutamylcysteine synthetase and gaama glutamyl transpeptidase) in rats; (2) immunolocalize these resistance factors in presumptive lung tumor target sites (alveolar type II cells); (3) establish the role of the Ap-1 transcription factor in lung epithelial cell adaptation to cadmium and cross-tolerance to oxidants; (4) determine if malondialdehyde-DNA adducts form in Cd exposed lung epithelial cells; (5) evaluate the potential link between cadmium induced type II cell proliferation and metallothione (MT) expression; and, (6) determine whether Cd-adapted lung epithelial cells are resistant to normal apoptotic processes by oxidants and cytokines and whether phorbal esters increase the proliferative capacity to grow in culture and soft agar (as a marker for tumor promotion).

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008991-04
Application #
6178414
Study Section
Special Emphasis Panel (ZRG4-ALTX-2 (01))
Program Officer
Mastin, Patrick
Project Start
1997-08-15
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
4
Fiscal Year
2000
Total Cost
$215,065
Indirect Cost
Name
University of Vermont & St Agric College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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