Lung cells frequently produce large amounts of hormone under abnormal conditions. It is also believed that normal lung cells occasionally demonstrate a low level endocrine function. The mechanism of such hormone production by human lung cells is not yet clearly understood. To investigate the molecular mechanism of basal-level hormone synthesis by human lung tumor cells in culture and to elucidate the mechanism of the stimulation of such hormone synthesis by externally-administered agents is the primary objective of this proposal. Human beings are constantly exposed to hazardous chemicals via air, water and soil. Polycyclic hydrocarbons such as benzo(a)pyrene (BaP) and dimethylbenzyanthracene (DMBA) are present in abundance in the atmosphere of industrial cities. The respiratory system, in particular the lung tissue, receives the major share of polycyclic hydro-carbons from the air. It is believed that these chemicals are metabolized in the cell to form their active derivatives which then interact with the cellular vital macromolecular components. The working model system utilized in this investigation for the fulfillment of the projected goals is the human chorionic gonadotropin (hCG)- producing human lung cells in culture, designated as """"""""ChaGo cells."""""""" The ChaGo cells are derived from a bronchogenic carcinoma identified in a heavy smoker. As normal lung cells do not produce detectable amounts of the glycoprotein hormone, the synthesis of hCG by ChaGo cells is a manifestation of cellular dedifferentiation. Our preliminary results demonstrate that BaP or DMBA treatment of ChaGo cells further stimulates the synthesis of hCG in these cells. ChaGo cells in culture thus provide us with a system in which the cells respond to the externally-administered chemical and further accentuate the cellular dedifferentiation process, such as ectopic hormone production. With the aid of modern-day molecular biological techniques and by the use of cDNAAlphahCG and cDNABetahCG clones, the mechanism of hormone synthesis and its induction by other chemical agents in human lung cells in culture will be studied. The results that will be generated from the studies proposed in this investigation will elucidate the molecular mechanism of cellular ectopic hormone production and cellular dedifferentiation and, thus, will provide a basis for the search for antidotes for the lung disorders induced by certain pollutants in the environment.
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