DNA damage-inducible genes as biomarkers for exposures to environmental agents

Our plain-English summary of DNA damage-inducible genes as biomarkers for exposures to environmental agents, by N.F. Johnson, T.R. Carpenter, R.J. Jaramillo, et al (Environmental Health Perspectives, 1997).

The study

• Authors: N.F. Johnson, T.R. Carpenter, R.J. Jaramillo, T.A. Liberati
• Journal: Environmental Health Perspectives
• Published: 1997;105 Suppl 4(Suppl 4):913-8
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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 well 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.

In plain English

This laboratory study used a human lung cancer cell line (A549) and male rats. Cells exposed to alpha particles showed higher levels of three DNA damage-related proteins (p53, Cip1 and Gadd45) and a temporary cell-cycle pause, with fewer cells in the DNA-copying (S) phase. Rats inhaled radon decay products (radon progeny) mixed with cigarette smoke. In their nasal lining, more cells were held in the G1 phase and fewer were in S phase. In rats exposed to 500 working level months, DNA strand breaks were significantly increased 24 hours after exposure but did not differ from controls at 48 hours. The cells were also exposed to X-rays, two chemicals (4-NQO and MMS), UICC crocidolite asbestos and glass microfiber. The agents produced differing patterns of the p53, Cip1 and Gadd153 proteins. Crocidolite induced marked protein expression, while in glass microfiber-treated cells expression stayed at background levels. The cell results were reported from single experiments. The authors concluded that measuring these proteins in A549 cells may help identify many kinds of toxic agents. They said the test could screen new fibers if the difference holds for other fibers, but how it told the two fibers apart was unclear.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: cell culture experiments with a human lung cell line, plus an inhalation experiment in rats; the cell-culture protein and cell-cycle data were reported from single experiments
• Who was studied: A549 cells (a human lung carcinoma cell line), and male Fischer 344/N rats aged 8 to 10 weeks (group sizes shown in figure captions, e.g. n = 3, 4 or 5), studied at the Inhalation Toxicology Research Institute, Albuquerque, New Mexico
• Exposure: Cells: alpha particles (0.6 Gy; 0.5 Gy is also printed in the methods), X-rays (4 Gy), UICC crocidolite asbestos or glass microfiber at 2.0 per square centimetre (unit printed as 'pg/cm2' in the scanned text) for 20 hours, 4-NQO (250 ng/ml) or MMS for 1 hour. Rats: radon progeny with cigarette smoke as a carrier aerosol, for 3 to 5 hours (500 and 1000 working level months reported)
• Main results:
  • In A549 cells exposed to 0.6 Gy alpha particles, peak Gadd45 protein expression was seen 2 to 4 hours after exposure
  • In alpha-irradiated A549 cells, the fraction of cells in S phase was markedly reduced at 6 hours after exposure
  • In rats exposed to radon progeny, cells of the nasal lateral wall showed a significant increase in G1-phase cells and a decrease in S-phase cells
  • In rats exposed to 500 WLM (n = 3), the number of cells with DNA strand breaks was significantly increased over controls in rats killed 24 hours after exposure; the authors reported no difference between exposed and control rats at 48 hours (the 48-hour figure is partly garbled in the scan)
  • The physical and chemical agents produced different expression patterns of p53, Cip1 and Gadd153 proteins in A549 cells
  • Crocidolite asbestos induced marked levels of protein expression in A549 cells, while expression in glass microfiber-treated cells was at background levels
• The authors' conclusion: The authors concluded that measuring gene expression in A549 cells may provide a means to identify a broad spectrum of physical and chemical toxicants in the environment
• Limitations the authors state:
  • It was unclear to the authors how the test could tell crocidolite from glass microfiber, since fiber length is a major determinant of toxicity in vitro and the two fibers had similar size distributions
  • Use as a fiber screen depends on whether the crocidolite and glass microfiber difference holds true for other toxic and nontoxic fibers
  • It was unknown whether the DNA strand breaks in rats were caused directly by radiation or by programmed cell death (apoptosis)

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Epithelium, Cumulative Exposure, Radon Progeny, A549 Cells, Crocidolite.

Related studies

• p53, Cip1, and Gadd153 expression following treatment of A549 cells with natural and man-made vitreous fibers — N.F. Johnson, R.J. Jaramillo (1997)
• Repression of GADD153/CHOP by NF-kappaB: a possible cellular defense against endoplasmic reticulum stress-induced cell death — S. Nozaki, G.W. Sledge, et al. (2001)
• 8-Hydroxy-2'-deoxyguanosine as a marker of oxidative DNA damage related to occupational and environmental exposures — A. Pilger, H.W. Rüdiger (2006)
• Expression of genes coding for proteoglycans and Wilms' tumour susceptibility gene 1 (WT1) by variously differentiated benign human mesothelial cells — M. Gulyás, K. Dobra, et al. (1999)
• Inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells — P.A. Knobel, I.N. Kotov, et al. (2011)
• Expression of p21 in SV40 large T antigen positive human pleural mesothelioma: relationship with survival — A. Baldi, A.M. Groeger, et al. (2002)

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