Mitochondria-Derived Reactive Intermediate Species Mediate Asbestos-Induced Genotoxicity and Oxidative Stress–Responsive Signaling Pathways

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.
Environmental Health Perspectives (Impact Factor: 7.98). 03/2012; 120(6):840-7. DOI: 10.1289/ehp.1104287
Source: PubMed


The incidence of asbestos-induced human cancers is increasing worldwide, and considerable evidence suggests that reactive oxygen species (ROS) are important mediators of these diseases. Our previous studies suggested that mitochondria might be involved in the initiation of oxidative stress in asbestos-exposed mammalian cells.
We investigated whether mitochondria are a potential cytoplasmic target of asbestos using a mitochondrial DNA-depleted (ρ(0)) human small airway epithelial (SAE) cell model: ρ(0) SAE cells lack the capacity to produce mitochondrial ROS.
We examined nuclear DNA damage, micronuclei (MN), intracellular ROS production, and the expression of inflammation-related nuclear genes in both parental and ρ(0) SAE cells in response to asbestos treatment.
Asbestos induced a dose-dependent increase in nuclear DNA oxidative damage and MN in SAE cells. Furthermore, there was a significant increase in intracellular oxidant production and activation of genes involved in nuclear factor κB and proinflammatory signaling pathways in SAE cells. In contrast, the effects of asbestos were minimal in ρ(0) SAE cells.
Mitochondria are a major cytoplasmic target of asbestos. Asbestos may initiate mitochondria-associated ROS, which mediate asbestos-induced nuclear mutagenic events and inflammatory signaling pathways in exposed cells. These data provide new insights into the molecular mechanisms of asbestos-induced genotoxicity.

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Available from: Mercy Davidson, Oct 02, 2015
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    • "As shown in Fig. 2A, the relative mtDNA copy number was increased by 0.48-, 0.74- and 0.6-fold at 24, 30 and 48 h post-irradiation compared to the sham-irradiated control, indicating mitochondrial biogenesis was stimulated by α-particles. To further verify this result, COX activity and SDH activity were measured, since the COX complex was jointly encoded by mtDNA and nDNA, while the succinate dehydrogenase complex was encoded entirely by nDNA [28]. At 24 h after irradiation, the activity of COX was increased 0.98-fold in A549 cells compared to sham-irradiated cells, whereas the activity of SDH was only slightly affected by 25 cGy α-particles (Fig. 2B). "
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    ABSTRACT: Mitochondrial transcription factor A (TFAM), the first well-characterized transcription factor from vertebrate mitochondria, is closely related to mitochondrial DNA (mtDNA) maintenance and repair. Recent evidence has shown that the ratio of mtDNA to nuclearDNA (nDNA) is increased in both human cells and murine tissues after ionizing radiation (IR). However, the underlying mechanism has not as yet been clearly identified. In the present study, we demonstrated that in human lung adenocarcinoma A549 cells, expression of TFAM was upregulated, together with the increase of the relative mtDNA copy number and cytochrome c oxidase (COX) activity after α-particle irradiation. Furthermore, short hairpin RNA (shRNA)-mediated TFAM knockdown inhibited the enhancement of the relative mtDNA copy number and COX activity caused by α-particles. Taken together, our data suggested that TFAM plays a crucial role in regulating mtDNA amplification and mitochondrial biogenesis under IR conditions.
    Journal of Radiation Research 05/2013; 54(6). DOI:10.1093/jrr/rrt046 · 1.80 Impact Factor
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    • "Several approaches have been used. One is to remove mtDNA from the picture altogether via the use of rho zero (mtDNAdepleted ) cells (Brar et al., 2012; Davermann et al., 2002; Huang et al., 2012). This approach is clean but has the disadvantage of creating cells that are highly abnormal. "
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    ABSTRACT: Enormous strides have recently been made in our understanding of the biology and pathobiology of mitochondria. Many diseases have been identified as caused by mitochondrial dysfunction, and many pharmaceuticals have been identified as previously unrecognized mitochondrial toxicants. A much smaller but growing literature indicates that mitochondria are also targeted by environmental pollutants. We briefly review the importance of mitochondrial function and maintenance for health based on the genetics of mitochondrial diseases and the toxicities resulting from pharmaceutical exposure. We then discuss how the principles of mitochondrial vulnerability illustrated by those fields might apply to environmental contaminants, with particular attention to factors that may modulate vulnerability including genetic differences, epigenetic interactions, tissue characteristics, and developmental stage. Finally, we review the literature related to environmental mitochondrial toxicants, with a particular focus on those toxicants that target mitochondrial DNA. We conclude that the fields of environmental toxicology and environmental health should focus more strongly on mitochondria.
    Toxicological Sciences 04/2013; 134(1). DOI:10.1093/toxsci/kft102 · 3.85 Impact Factor
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    • "Similar inhibitory effects were reported previously with red-ginseng and Acantopanax in oxidative DNA damage induced by herbicide (Ollikainen et al., 1999). There have been considerable evidences that asbestos may initiate ROS production by Fenton-like reaction in exposed cells, stimulating phagocytic cells to release extracellular ROS through membrane-associated-NADPH oxidase, and by mitochondrial oxidative phosphorylation (Huang et al., 2012). In this study, treatment with chrysotile caused DNA damage, indicated by increased tail lengths, however, catalase repaired the injury, evidenced by decreased tail lengths to the control level. "
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    ABSTRACT: We investigated the cytotoxicity and oxidative DNA damage by chrysotile, one of the asbestos, in this investigation. Chrysotile enhanced malondialdehyde (MDA) levels and intracellular reactive oxygen speices generation in human airway epithelial cells. Furthermore, asbestos-induced oxidative DNA damage in lymphocytes was evaluated by single cell gel electrophoresis and quantified as DNA tail moment. Notably, phytochemicals such as curcumin, berberine, and sulforaphane presented inhibitory effect on the asbestos-induced oxidative DNA damage in lymphocytes.
    Journal of Applied Biological Chemistry 09/2012; 55(3). DOI:10.3839/jabc.2012.028
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