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).
