Mechanisms of fiber-induced genotoxicity.

Abstract

The mechanisms of particle-induced genotoxicity have been investigated mainly with asbestos fibers. The results are summarized and discussed in this paper. DNA damage can be produced by oxidoreduction processes generated by fibers. The extent of damage yield depends on experimental conditions: if iron is present, either on fibers or in the medium, damage is increased. However, iron reactivity does not explain all the results obtained in cell-free systems, as breakage of plasmid DNA was not directly associated with the amount of iron released by the fibers. The proximity of DNA to the site of generation of reactive oxygen species (ROS) is important because these species have an extremely short half-life. Damage to cellular DNA can be produced by oxidoreduction processes that originate from cells during phagocytosis. Secondary molecules that are more stable than ROS are probably involved in DNA damage. Oxidoreduction reactions originating from cells can induce mutations. Genotoxicity is also demonstrated by chromosomal damage associated with impaired mitosis, as evidenced by chromosome missegregation, spindle changes, alteration of cell cycle progression, formation of aneuploid and polyploid cells, and nuclear disruption. In some of these processes, the particle state and fiber dimensions are considered important parameters in the generation of genotoxic effects.

Pulmonary toxicity and fibrogenic response of carbon nanotubes

“…Genotoxicity may be elicited either by the direct interaction of fibrous particles with the genetic material or by secondary damage from particle-induced ROS generation. CNT-induced sustained inflammation and oxidative stress can result in DNA damage and abnormal cell growth, possibly leading to carcinogenesis and fibrogenesis (Jaurand, 1997; Jaurand et al, 2009). A number of studies have provided evidence for the genotoxic effects of CNTs (Kisin et al, 2007, 2011; Patlolla et al, 2010a, b).…”

Integrated Profiling Reveals a Global Correlation between Epigenetic and Genetic Alterations in Mesothelioma

“…Asbestos fibers have been shown to be both cytotoxic and clastogenic in vitro (2, 3), and interference with the mitotic machinery by asbestos can lead to abnormal chromosome segregation and hence deletion events (4). Although the number of phenotypically important point mutations in pleural mesotheliomas has been shown to be relatively low (5, 6), reports of extensive gene copy number (CN) alterations in this disease are numerous, and common regions of allele loss include 1p, 3p21, 6q, 9p21, 15q11–15, and 22q (7–14).…”

Epigenetic Profiles Distinguish Pleural Mesothelioma from Normal Pleura and Predict Lung Asbestos Burden and Clinical Outcome

“…The causal link between asbestos and pleural mesothelioma has been widely accepted since 1960 (13), and the carcinogenic mechanisms of asbestos have been investigated in earnest since that time; establishing that asbestos fibers are not point mutagens, but rather both clastogenic and cytotoxic in vitro (14, 15). Additionally, methylation-induced tumor suppressor gene silencing has been observed in recent studies of mesothelioma (16–20) leading to the hypothesis that asbestos fibers contribute to epigenetic silencing of tumor suppressor genes in this disease.…”