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

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Published 2012 in Environmental Health Perspectives

ABSTRACT

Background: 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. Objective: We investigated whether mitochondria are a potential cytoplasmic target of asbestos using a mitochondrial DNA–depleted (ρ0) human small airway epithelial (SAE) cell model: ρ0 SAE cells lack the capacity to produce mitochondrial ROS. Methods: We examined nuclear DNA damage, micronuclei (MN), intracellular ROS production, and the expression of inflammation-related nuclear genes in both parental and ρ0 SAE cells in response to asbestos treatment. Results: 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 ρ0 SAE cells. Conclusions: 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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