Occupational exposure to asbestos fibers is associated with an increased risk of developing mesotheliomas, malignant tumors arising from the pleural or peritoneal linings. Widespread use of asbestos in the past raises public concern that environmental exposure may also produce mesotheliomas. Assessment of the risk of developing malignant mesothelioma after exposure to asbestos or other fibers is difficult because the minimum dose of fibers required to produce these tumors is unknown. Current rodent models of mesothelioma are unsatisfactory because they use extremely high doses of fibers delivered directly by intraperitoneal or intrapleural injection instead of inhalation. The objective of the proposed research is to develop a new animal model to determine the biologic effective dose of crocidolite asbestos fibers required to initiate the development of mesotheliomas. Fiber dosimetry will be expressed as the total number of fibers that deposit and persist in the pleural lining using tissue digestion, transmission electron microscopy, and video-enhanced differential interference contrast light microscopy to visualize fibers in potential target cell populations (Specific Aim #1). Two responses of potential target cells will be validated as specific and sensitive biologic markers of response to asbestos fibers deposited in the pleura. First, molecular markers for chromosomal damage induced by asbestos fibers will be developed using biotinylated DNA probes and in-situ hybridization. A mouse centromeric DNA probe will be used to detect chromosomal aneuploidy and structural aberrations. Loss of heterozygosity at the p53 tumor suppressor gene locus will be visualized by indirect immunofluorescence on metaphase spreads and interphase nuclei (Specific Aim #2). Second, quantitative markers of mesothelial cell injury and proliferation will be developed using morphometry (Specific Aim #3). Fiber dosimetry and biologic markers of response will be compared following intrapleural injection and inhalation of crocidolite asbestos fibers. These experiments will assess whether there is a correlation between the number of fibers deposited in the pleura, their persistence, and the number of population doubling times before the histologic appearance of malignant mesothelioma (Specific Aims #4 and 5). Ultimately, this new model could be used to extrapolate dose-response relationships to human exposure to asbestos and man-made mineral fibers in order to assess more accurately the risk of developing malignant mesotheliomas.
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