DNA DAMAGE-INDUCIBLE GENES AS BIOMARKERS FOR EXPOSURES TO ENVIRONMENTAL AGENTS

A biodosimetric approach to determine alpha-particle dose to the respi ratory tract epithelium from known exposures to radon has been develop ed in the rat. Cytotoxicity assays have been used to obtain dose-conve rsion factors for cumulative exposures typical of those encountered by underground uranium miners. However, this approach is not sensitive e nough to derive dose-conversion factors for indoor radon exposures. Th e expression of DNA damage-inducible genes is being investigated as a biomarker of exposure to radon progeny. Exposure of cultures of A549 c ells to alpha particles resulted in an increase in the protein levels of the DNA damage-inducible genes, p53, Cip1, and Gadd45. These protei n changes were associated with a transient arrest of cells passing thr ough the cell cycle. This arrest was typified by an increase in the nu mber of cells in the G(1) and G(2) phases and a decrease in the number of cells in the S phase. The effect of inhaled alpha particles (radon progeny) in rats was examined in the epithelial cells of the lateral wail of the anterior nasal cavity. Exposures to radon progeny resulted in a significant increase in the number of cells in the G(1) phase an d a decrease in the number of cells in the S phase. These cell-cycle c hanges were concomitant with an increase in the number of cells contai ning DNA strand breaks. These results suggest a commonality between ce ll-cycle events in vitro and in vivo following exposure to ionizing ra diation. In addition to ionizing radiation, A549 cells were exposed to 4-nitroquinoline-1-oxide, methyl methanesulphonate, crocidolite asbes tos, and glass microfiber. These studies showed that physical and chem ical agents induce different expression patterns of p53, Cip1, and Gad d153 proteins and they could be used to discriminate between toxic and nontoxic materials such as asbestos and glass microfiber. The measure ment of gene expression in A549 cells may provide a means to identify a broad spectrum of physical and chemical toxicants encountered in the environment.