DNA double-strand breaks by asbestos, silica, and titanium dioxide: possible biomarker of carcinogenic potential?
DNA double-strand breaks (DSBs) can result in cell death or genetic alterations when cells are subjected to radiation, exposure to toxins, or other environmental stresses. A complex DNA-damage-response pathway is activated to repair the damage, and the inability to repair these breaks can lead to carcinogenesis. One of the earliest responses to DNA DSBs is the phosphorylation of a histone, H2AX, at serine 139 (gamma-H2AX), which can be detected by a fluorescent antibody. A study was undertaken to compare the induction of DNA DSBs in normal (small airway epithelial) cells and cancer cells (A549) after exposure to asbestos (crocidolite), a proven carcinogen, silica, a suspected carcinogen, and titanium dioxide (TiO(2)), an inert particle recently reported to be carcinogenic in animals. The results indicate that crocidolite induced greater DNA DSBs than silica and TiO(2), regardless of cell type. DNA DSBs caused by crocidolite were higher in normal cells than in cancer cells. Silica and TiO(2) induced higher DNA DSBs in cancer cells than in normal cells. The production of reactive oxygen species was found to be highest in cells exposed to crocidolite, followed, in potency, by silica and TiO(2). The generation of reactive oxygen species was higher in normal cells than in cancer cells. Cell viability assay indicated that crocidolite caused the greatest cytotoxicity in both cell types. Apoptosis, measured by caspase 3/7 and poly (ADP-Ribose) polymerase activation, was highest in crocidolite-exposed cells, followed by TiO(2) and silica. The results of this study indicate that crocidolite has a greater carcinogenic potential than silica and TiO(2), judged by its ability to cause sustained genomic instability in normal lung cells.
Pathology and Physiology Research Branch, Health Effects Laboratory Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA.
Zola
Z
Msiska
Maricica
M
Pacurari
Anurag
A
Mishra
Stephen S
SS
Leonard
Vince
V
Castranova
Val
V
Vallyathan
D001194:Asbestos / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004247:DNA / Q000187:drug effects*; D053903:DNA Breaks, Double-Stranded; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012822:Silicon Dioxide / Q000494:pharmacology*; D014025:Titanium / Q000494:pharmacology*
D014408:Biomarkers, Tumor; D002273:Carcinogens; D017382:Reactive Oxygen Species; D001194:Asbestos; C009495:titanium dioxide; D012822:Silicon Dioxide; D004247:DNA; D014025:Titanium; D020169:Caspases