Mechanisms of Toxic Injury by Asbestos Fibers: Role of Oxygen-Free Radicals

Mossman, Brooke T.; Marsh, Joanne P.

doi:10.1007/978-3-642-70630-1_8

Cited by 10 publications

(5 citation statements)

References 12 publications

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“…However, in this system, asbestos also acts as a complete carcinogen. Asbestos induces changes in both target tissues and certain cells in culture similar to those observed with phorbol ester tumor promoters [Mossman and Marsh, 1985;Mossman and Craighead, 1980;Mossman et al, 1983, 19871. The mechanisms by which asbestos and other mineral fibers might act as tumor promoters are no doubt quite different from the clastogenic and carcinogenic effects described above.…”

mentioning

confidence: 75%

Possible cellular and molecular mechanisms for asbestos carcinogenicity

Walker

Everitt

Barrett

1992

American J Industrial Med

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Asbestos fibers may exert their carcinogenic effects on mesothelial cells and bronchial epithelial cells by direct and indirect mechanisms. Direct effects can occur following the physical interaction of fibers with target cells or by the generation of free radicals from the fiber surface; indirect effects, following the interaction of fibers with inflammatory cells can result in the production of cellular mediators such as cytokines and various reactive oxygen species. As a result, target cells may be induced to proliferate and/or sustain genetic alterations, which lead to tumor development.

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mentioning

confidence: 75%

Possible cellular and molecular mechanisms for asbestos carcinogenicity

Walker

Everitt

Barrett

1992

American J Industrial Med

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“…However, in this system asbestos also has a complete carcinogenic activity. Asbestos induces changes in target tissues and in some cells in culture similar to those observed with phorbol ester tumor promotors (19,20,38,39 Further elucidation of the mechanism of action of mineral fibers, therefore, requires model systems in which a specific action can be studied. Several systems exist to study the cellular effects of asbestos (40).…”

Section: Asbestos and Multistage Carcinogenesismentioning

confidence: 90%

“…Other types of fibers also exhibit activity that is fiber-size dependent but cannot be explained strictly on the basis of size. The generation of oxygen free radicals at the surface of certain fibers may offer an explanation for the importance of surface properties (19,20).…”

Section: Introductionmentioning

confidence: 99%

Multiple mechanisms for the carcinogenic effects of asbestos and other mineral fibers.

Barrett

Lamb

Wiseman

1989

Environ Health Perspect

127

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Asbestos and other mineral fibers are carcinogenic to humans and animals but differ from many carcinogens in that they do not induce gene mutations. An understanding of these interesting human carcinogens, therefore, is an important problem in cancer research. Asbestos and other fibers induce predominately two types of cancers: mesotheliomas and bronchogenic carcinomas. Fiber size is an important factor in the carcinogenic activity of these substances as has been shown for mesothelioma induction. For bronchogenic carcinomas, but not for mesotheliomas, a synergistic effect of asbestos exposure and cigarette smoke has been observed in humans. The mechanisms by which fibers alone versus fibers in concert with other carcinogens induce cancers are probably distinct. In addition to fiber dimensions, fiber durability and surface properties of fibers are important properties affecting carcinogenicity. Evidence exists that asbestos is a complete carcinogen, an initiator and a promoter. Multiple mechanisms must be operative to explain the diverse effects of mineral fibers. Although asbestos is inactive as a gene mutagen, there is now clear evidence that it induces chromosomal mutations (aneuploidy and aberrations) in a wide variety of mammalian cells including mesothelial cells. Asbestos also induces transformation of cells in culture including mesothelial cells and fibroblasts. A mechanism for cell transformation, which is dependent on fiber dimension, has been proposed. The fibers are phagocytized by the cells and accumulate in the perinuclear region of the cells. When the cell undergoes mitosis, the physical presence of the fibers interferes with chromosome segregation and results in anaphase abnormalities. The transformed cells show aneuploidy and other chromosome abnormalities. These findings provide a mechanism at the chromosomal level by which asbestos and other mineral fibers might induce cell transformation and cancer. Identification of the critical target genes in asbestos carcinogenicity is required to understand this process, and recent progress in this area has been made. Results from several lines of investigation suggest that two distinct classes of genes, protooncogenes and tumor suppressor genes, are involved in the neoplastic process. In human mesothelioma, deletion of the short arm of chromosome 3 has been observed, which may result in the loss of a tumor suppressor gene on this chromosome. Recent results from our laboratory have also shown that an activated transforming oncogene exists in human mesotheliomas. Further molecular analysis of these cancers may help in understanding these neoplasms and the mechanisms of asbestos and other carcinogenic fibers.

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“…114 The observations suggesting that asbestos and H 2 0 2 produce DNA base changes are of importance in light of recent experimental evidence 49 linking the toxic effects of asbestos to the production of reactive oxygen metabolites in mouse macrophages and the association of asbestos, inflammation, and cancer. 48 More recently, Frenkel' 15 showed that the DNA of PMA-activated phagocytes has 5-hydroxymethyl-2-deoxyuridine (HMdU), a modified base also found in 'Yirradiated cells, suggesting that the effects of phagocyte-generated oxidants on DNA mimic those of ionizing radiation. Similar effects were seen when exogenous DNA was co-incubated with various tumor promoters and phagocytes, and the amounts of modified DNA bases correlated with tumor-promoting activity and the amount of H 2 0 2 generated.…”

Section: Oxygen-derived Free Radicals Cause Nucleoside Modificationmentioning

confidence: 99%