DNA Damage-inducible Genes as Biomarkers for Exposures to Environmental Agents
Neil F. Johnson, Thomas R. Carpenter, Richard J. Jaramillo,
and Teresa A. Liberati
Inhalation Toxicology Research Institute, Albuquerque, New Mexico
Abstract
A biodosimetric approach to determine alpha-particle dose to the respiratory tract epithelium from known exposures to radon has been developed in the rat. Cytotoxicity assays have been used to obtain dose-conversion factors for cumulative exposures typical of those encountered by underground uranium miners. However, this approach is not sensitive enough to derive dose-conversion factors for indoor radon exposures. The expression of DNA damage-inducible genes is being investigated as a biomarker of exposure to radon progeny. Exposure of cultures of A549 cells to alpha particles resulted in an increase in the protein levels of the DNA damage-inducible genes, p53, Cip1, and Gadd45. These protein changes were associated with a transient arrest of cells passing through the cell cycle. This arrest was typified by an increase in the number of cells in the G1 and G2 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 wall of the anterior nasal cavity. Exposures to radon progeny resulted in a significant increase in the number of cells in the G1 phase and a decrease in the number of cells in the S phase. These cell-cycle changes were concomitant with an increase in the number of cells containing DNA strand breaks. These results suggest a commonality between cell-cycle events in vitro and in vivo following exposure to ionizing radiation. In addition to ionizing radiation, A549 cells were exposed to 4-nitroquinoline-1-oxide, methyl methanesulphonate, crocidolite asbestos, and glass microfiber. These studies showed that physical and chemical agents induce different expression patterns of p53, Cip1, and Gadd153 proteins and they could be used to discriminate between toxic and nontoxic materials such as asbestos and glass microfiber. The measurement of gene expression in A549 cells may provide a means to identify a broad spectrum of physical and chemical toxicants encountered in the environment. -- Environ Health Perspect 105(Suppl 4):913-918 (1997)
Key words: radiation, fibers, chemicals, DNA damage-inducible genes
This paper is based on a presentation at the symposium on Mechanisms and Prevention of Environmentally Caused Cancers held 21-25 October 1995 in Santa Fe, New Mexico. Manuscript received at EHP 16 April 1996; accepted 14 August 1996.
This research sponsored by the Office of Health and Environmental Research, U.S. Department of Energy, under contract DE-AC04-76EV01013 and by National Institutes of Health grant ES 07665-01.
Address correspondence to Dr. N.F. Johnson, Inhalation Toxicology Research Institute, P.O. Box 5890, Albuquerque, NM 87185. Telephone: (505) 845-1189. Fax: (505) 845-1198. E-mail: njohnson@lucy.tli.org
Abbreviations used: BrdU, 5-bromo-2´-deoxyuridine; MMS, methyl methanesulfonate; 4-NQO, 4-nitroquinoline-1-oxide; UV, ultraviolet; WLM, working level months.
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Last Update: June 20, 1997