DNA double-strand breaks by asbestos, silica, and titanium dioxide: possible biomarker of carcinogenic potential?

Our plain-English summary of DNA double-strand breaks by asbestos, silica, and titanium dioxide: possible biomarker of carcinogenic potential?, by Z. Msiska, M. Pacurari, A. Mishra, et al (American Journal of Respiratory Cell and Molecular Biology, 2010).

The study

• Authors: Z. Msiska, M. Pacurari, A. Mishra, S.S. Leonard, V. Castranova, V. Vallyathan
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2010;43(2):210-9
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

DNA double-strand breaks (DSBs) can result in cell death or genetic alterations when cells are subjected to radiation, exposure to toxins, or other environmental stresses. A complex DNA-damage-response pathway is activated to repair the damage, and the inability to repair these breaks can lead to carcinogenesis. One of the earliest responses to DNA DSBs is the phosphorylation of a histone, H2AX, at serine 139 (gamma-H2AX), which can be detected by a fluorescent antibody. A study was undertaken to compare the induction of DNA DSBs in normal (small airway epithelial) cells and cancer cells (A549) after exposure to asbestos (crocidolite), a proven carcinogen, silica, a suspected carcinogen, and titanium dioxide (TiO(2)), an inert particle recently reported to be carcinogenic in animals. The results indicate that crocidolite induced greater DNA DSBs than silica and TiO(2), regardless of cell type. DNA DSBs caused by crocidolite were higher in normal cells than in cancer cells. Silica and TiO(2) induced higher DNA DSBs in cancer cells than in normal cells. The production of reactive oxygen species was found to be highest in cells exposed to crocidolite, followed, in potency, by silica and TiO(2). The generation of reactive oxygen species was higher in normal cells than in cancer cells. Cell viability assay indicated that crocidolite caused the greatest cytotoxicity in both cell types. Apoptosis, measured by caspase 3/7 and poly (ADP-Ribose) polymerase activation, was highest in crocidolite-exposed cells, followed by TiO(2) and silica. The results of this study indicate that crocidolite has a greater carcinogenic potential than silica and TiO(2), judged by its ability to cause sustained genomic instability in normal lung cells.

In plain English

This was a laboratory study of human cells grown in culture, not of people. The authors exposed normal human small airway epithelial cells and A549 lung cancer cells to crocidolite asbestos, crystalline silica, or fine titanium dioxide. They measured cell damage, reactive oxygen species, DNA double-strand breaks (through a marker called gamma-H2AX) and signs of cell death. Crocidolite produced the most reactive oxygen species and the most gamma-H2AX in both cell types, followed by silica and then titanium dioxide. Breaks caused by crocidolite were somewhat higher in normal than in cancer cells, but the authors said this difference was not significant. For silica and titanium dioxide in normal cells, two methods of measuring breaks disagreed. The authors attributed this to potential problems with both methods. The authors concluded that this study and the literature suggest crocidolite has a greater ability than silica or titanium dioxide to induce carcinogenesis by causing sustained genomic instability. They also concluded that detecting these breaks may provide a measure of potential cancer risk in people exposed to crocidolite.

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 (in vitro) cell culture experiment comparing particle effects in normal and cancer human lung cells
• Who was studied: Cultured cells, not people: commercially obtained normal human small airway epithelial (SAE) cells and the A549 human lung cancer cell line (described in the methods as a human bronchial epithelial cancer cell line)
• Exposure: Crocidolite asbestos (from the Kalahari Desert, South Africa, via the National Institute of Environmental Health Sciences), crystalline silica (Min-U-Sil, quartz purity 98.7%) and fine titanium dioxide, each applied at the same working concentration; untreated (sham-exposed) cells served as controls
• Main results:
  • In A549 lung cancer cells, only crocidolite caused substantial leakage of the cell-damage enzyme LDH after 24 hours, and this result was highly variable and not statistically significant
  • The authors reported that normal SAE cells were more susceptible than the cancer cells to toxicity from all three particles
  • Crocidolite and silica produced significantly more reactive oxygen species than titanium dioxide and untreated controls
  • Hydrogen peroxide production with silica was significantly higher in the A549 cancer cells than in the normal SAE cells
  • By the chemiluminescence assay, crocidolite induced the highest gamma-H2AX levels (a marker of DNA double-strand breaks) in both cell types, followed by silica and then titanium dioxide
  • Double-strand breaks from crocidolite were somewhat higher in normal cells than in cancer cells, but the difference was not significant
  • In normal cells exposed to silica, the chemiluminescence assay found no significant increase in breaks compared with unexposed normal cells. Manual counting of gamma-H2AX foci did show a significant increase.
  • Caspase 3/7 activity (a sign of programmed cell death) was significantly raised by silica or titanium dioxide compared with untreated controls in both cell types
  • In normal SAE cells, only crocidolite caused a mild activation of PARP (a DNA-repair and cell-death enzyme), seen after 18 and 24 hours
• The authors' conclusion: The authors concluded that evidence from this study and the literature suggests crocidolite has a greater ability than silica or titanium dioxide to induce carcinogenesis by causing sustained genomic instability. They added that detecting these DNA breaks may provide a measure of potential cancer risk in people exposed to crocidolite.
• Limitations the authors state:
  • The fluorescent dyes used to measure reactive oxygen species are subject to potential artifacts
  • The two methods for measuring DNA breaks gave different results. The chemiluminescence kit may be less sensitive than manual counting.
  • Manual counting of foci under the microscope is subjective and variable and may have overestimated the number of foci
  • Some of the DNA breaks seen with crocidolite may have come from DNA fragmentation during cell death rather than from direct damage

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Carcinogenic, Carcinogenesis, Crocidolite, Reactive Oxygen Species (ROS), Apoptosis.

Related studies

• A spin label study of the effects of asbestos, quartz, and titanium dioxide dusts on the bovine erythrocyte membrane — W. Leyko, E. Gendek (1985)
• Shape-Related Toxicity of Titanium Dioxide Nanofibres — M. Allegri, M.G. Bianchi, et al. (2016)
• Kinetics of the bronchoalveolar leucocyte response in rats during exposure to equal airborne mass concentrations of quartz, chrysotile asbestos, or titanium dioxide — K. Donaldson, R.E. Bolton, et al. (1988)
• Synergistic anticancer activity of arsenic trioxide with erlotinib is based on inhibition of EGFR-mediated DNA double-strand break repair — K. Kryeziu, U. Jungwirth, et al. (2013)
• Increased incidence of DNA double-strand breaks and anti-ds DNA antibodies in blood of workers occupationally exposed to asbestos — B. Marczynski, A.B. Czuppon, et al. (1994)
• Exposure to nano-size titanium dioxide causes oxidative damages in human mesothelial cells: The crystal form rather than size of particle contributes to cytotoxicity — K. Hattori, K. Nakadate, et al. (2017)

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