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: 7.03). 03/2012; 120(6):840-7. DOI: 10.1289/ehp.1104287
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Mercy Davidson, Jul 06, 2015
  • Source
    [Show abstract] [Hide abstract]
    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 · 4.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Low-molecular weight saturated aliphatic aldehydes (LSAAs), which include propanal, butanal, pentanal, hexanal, octanal, nonanal and heptanal, are volatile organic compounds (VOCs). They are ubiquitous in the environment of our daily life. Although LSAAs are harmful, with mutagenic and carcinogenic effects, the mechanisms underlying the toxicity of volatile aldehydes are still unclear. Therefore, in this study, we performed genome-wide expression profile analysis of A549 human alveolar epithelial cells exposed to seven LSSAs. We selected genes whose expression was changed more than 1.5-fold in A549 cells exposed to LSAAs by analysis of gene expression profiles using human oligonucleotide chips. Through gene expression profiling, we showed that LSSAs are related to the key biological processes “defense response”, “inflammatory response” and “immune response” in gene ontology (GO) analysis. In addition, we identified two genes that were up-regulated (GREB1, BC009808) and four that were down-regulated (UCP1, TCP11, FNDC3A, LOC645206) by all the tested LSAAs. Our data suggest that LSAAs exert toxic effects on A549 cells by modulating mRNA expression. Moreover, we suggest that genes expressed in response to LSAAs represent a molecular signature that can be widely used, in combination with more traditional techniques, to assess and predict the toxicity caused by exposure to LSAAs.
    12/2013; 4(4). DOI:10.1007/s13530-012-0140-7