Asbestos surface provides a niche for oxidative modification

Abstract

Asbestos is a potent carcinogen associated with increased risks of malignant mesothelioma and lung cancer in humans. Although the mechanism of carcinogenesis remains elusive, the physicochemical characteristics of asbestos play a role in the progression of asbestos-induced diseases. Among these characteristics, a high capacity to adsorb and accommodate biomolecules on its abundant surface area has been linked to cellular and genetic toxicity. Several previous studies identified asbestos-interacting proteins. Here, with the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry, we systematically identified proteins from various lysates that adsorbed to the surface of commercially used asbestos and classified them into the following groups: chromatin ⁄ nucleotide ⁄ RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. The surfaces of crocidolite and amosite, two iron-rich types of asbestos, caused more protein scissions and oxidative modifications than that of chrysotile by in situ-generated 4-hydroxy-2-nonenal. In contrast, we confirmed the intense hemolytic activity of chrysotile and found that hemoglobin attached to chrysotile, but not silica, can work as a catalyst to induce oxidative DNA damage. This process generates 8-hydroxy-2¢-deoxyguanosine and thus corroborates the involvement of iron in the carcinogenicity of chrysotile. This evidence demonstrates that all three types of asbestos adsorb DNA and specific proteins, providing a niche for oxidative modification via catalytic iron. Therefore, considering the affinity of asbestos for histones ⁄ DNA and the internalization of asbestos into mesothelial cells, our results suggest a novel hypothetical mechanism causing genetic alterations during asbestos-induced carcinogenesis. (Cancer Sci 2011; 102: 2118-2125 A sbestos is a natural fibrous mineral that was heavily used in industry during the past century because of its durability, heat resistance and low cost. However, it has become clear that respiratory exposure to asbestos fibers, especially crocidolite and amosite, which have high biopersistence and contain abundant iron, is associated with high risks of developing malignant mesothelioma and lung cancer.(1-3) Many countries anticipate increased numbers of mesothelioma patients in the coming decades because there is an extremely long incubation period (30-40 years) for this fatal disease following asbestos exposure. (4) The molecular mechanism of asbestos-induced carcinogenesis remains elusive, (5) but both mesothelial cell injury and persistent macrophage activation are thought to be essential, if not sufficient, for mesotheliomagenesis.(6) These two events interact in vivo, leading to genetic mutations, chromosomal aberrations and aneuploidy in mesothelial cells. At least four major hypotheses related to the underlying mechanisms have been proposed. (6,7) First, the free radical theory postulates that DNA is injured by reactive oxygen species generated th...

Deferasirox Induces Mesenchymal–Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

“…We hypothesized that appropriate intervention may reduce free radical generation even after exposure to asbestos fibers. This is because generation of free radicals largely depends on catalytic iron (12,13).…”

“…Crocidolite and amosite contain abundant iron in mineral contents. In contrast, chrysotile can adsorb iron (heme from hemoglobin) on its surface through hemolytic activity (13).…”

In response to Sharing different perspectives to understand asbestos‐induced carcinogenesis: A comment to Jiang et al. (2016) by Alessandro Francesco Gualtieri (2017)

“…(iii) Asbestos bodies are representatives of corpses of macrophages, indicating that numerous thin and long asbestos fibers presumably passed through the lung parenchyma. Our data demonstrated the high affinity of hemoglobin to asbestos, forming a niche for oxidative reactions 5. (iv) We believe that catalytic Fe(II) is more important than Fe(III) in carcinogenesis because it initiates a Fenton reaction, whereas Fe(III) is almost insoluble at neutral pH.…”

“…(ii) The origin of iron is an interesting issue. We suggested the importance of hemolysis and the adsorption thereafter of hemoglobin on asbestos fibers in the lung 5. Alternatively, the recent cutting‐edge mineralogical studies by Dr Gualtieri clearly showed the components/localization of iron on asbestos1 and are of much interest for further consideration.…”

Receptor role of the annexin A2 in the mesothelial endocytosis of crocidolite fibers

“…8,9 The currently proposed three major hypotheses regarding the pathogenesis of asbestos-induced MM can be summarized as follows: 10 (1) the 'oxidative stress theory' is based on epidemiological studies showing that asbestos fibers containing iron are more carcinogenic, 11 and the fibers catalyze the generation of reactive species; 12,13 (2) the 'chromosome tangling theory' postulates that asbestos fibers damage chromosomes when mesothelial cells divide; 14,15 (3) the 'theory of adsorption of specific proteins as well as carcinogenic molecules' states that proteins and chemicals, such as components of cigarette smoke, are attached to the asbestos surface in vivo. 15 Notably, these hypotheses are based on asbestos being able to enter mesothelial cells, and these complexes could be involved in the pathogenesis. 16 In addition, chronic inflammation is suggested to be the hallmark of asbestos deposition in tissue, although it may contribute to asbestos-related carcinogenesis by the mechanisms mainly related to hypothesis 1.…”