Iron-dependent formation of 8-hydroxydeoxyguanosine in isolated DNA and mutagenicity in <i>Salmonella typhimurium</i> TA102 induced by crocidolite

117

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.

Section: Introductionmentioning

confidence: 91%

Mechanisms of fiber-induced genotoxicity.

Jaurand

1997

117

“…We measured the dust concentrations in the chamber by sampling onto glass filters 6 hr/day, as described in "Materials and Methods." The dust concentration mean was 5.75 ± 0.87 mg/m3.…”

Section: Resultsmentioning

confidence: 99%

“…An improvement of the Ames test using the TA102 strain showed a mutagenic potential of 50 pg/cm2 crocidolite because of its sensitivity to oxidative damage (6). The hypoxanthine guanine phosphoribosyl transferase locus (HPRI) has been investigated in rat liver, Chinese ovary, or human-hamster fibroblasts, but a mutagenic effect of crocidolite could not be demonstrated for any of the the cell systems used [reviewed by Jaurand (4)].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, past in vitro studies have shown no mutagenic or weak mutagenic activity of asbestos samples [reviewed by Jaurand (5)]. Using the Salmonella typhimurium TA 102 oxidative stress sensitive strain, Faux et al (6) showed mutagenicity induced by crocidolite, but not by chrysotile (chrysotile is the most-used asbestos worldwide). However, the mammalian cell paradigm found mutagenicity for both crocidolite and chrysotile at the S, locus (7) and for 50 pg/mL chrysotile at the HLA-A locus.…”

mentioning

confidence: 99%

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Inhaled crocidolite mutagenicity in lung DNA.

Rihn

Coulais

Kauffer

et al. 2000

We used transgenic mice carrying the laI reporter gene to study the mutagenesis potential of asbestos crocidolite. The animals were exposed by nose-ondy inhalation to an aerosol containg 5.75 mg/m3 crocidolite dust for 6 hr/day and 5 consecutive days. After 1, 4, and 12 weeks, we examined four end points: the cytology of bronchoalveolar lavage, the lung load of crocidolite, the hydrophobic DNA adducts, and the mutations in the lacIreporter gene. Twelve weeks after exposure, nearly 10% of the inhaled fibers remained in the lung (227 ± 103 ng/mg lung). There was evidence of a typical inflammatory response consisting of multinudeate macrophages at weeks 4 and 12, whereas immediately after the exposure, we observed numerous polymorphonudear neutrophils. The mutant frequency significatively increased during the fourth week after the exposure: 13.5 x 10-5 in the exposed group versus 6.9 x 10-5 in the control group. The induction factor, defined by the ratio of checked mutants of exposed mice to checke mutants of control mice, was 1.96. The mutation spectrum of control lung DNA and exposed lung DNA was similar, suggesting the possible involvement ofa DNA repair decrease in crocidolite-treated animals. We used the 32p-posdabeling method and did not detect any increase of either 5 mC or bulky adduct in treated mice. This is the first study that demonstrates asbestos mutagenicity in vivo after a nose-only inhalation.

“…Asbestos-related free radical production, as well as biological damage, can be suppressed or inhibited by iron chelators, such as desferrioxamine and ferrozine, both when present in the test system and when used to pretreat fibers (17,(20)(21)(22)(23)(24). On the other hand, other chelators such as ascorbate enhance free radical production (25).…”

Section: Introductionmentioning

confidence: 99%

Chemical characterization and reactivity of iron chelator-treated amphibole asbestos.

Gold

Amandusson

Krozer

et al. 1997

Iron in amphibole asbestos is implicated in the pathogenicity of inhaled fibers. Evidence includes the observation that iron chelators can suppress fiber-induced tissue damage. This is believed to occur via the diminished production of fiber-associated reactive oxygen species. The purpose of this study was to explore possible mechanisms for the reduction of fiber toxicity by iron chelator treatments. We studied changes in the amount and the oxidation states of bulk and surface iron in crocidolite and amosite asbestos that were treated with iron-chelating desferrioxamine, ferrozine, sodium ascorbate, and phosphate buffer solutions. The results have been compared with the ability of the fibers to produce free radicals and decompose hydrogen peroxide in a cellfree system in vitro. We found that chelators can affect the amount of iron at the surface of the asbestos fibers and its valence, and that they can modify the chemical reactivity of these surfaces. However, we found no obvious or direct correlations between fiber reactivity and the amount of iron removed, the amount of iron at the fiber surface, or the oxidation state of surface iron. Our results suggest that surface Fe3+ ions may play a role in fiber-related carboxylate radical formation, and that desferrioxamine and phosphate groups detected at treated fiber surfaces may play a role in diminishing and enhancing, respectively, fiber redox activity. It is proposed that iron mobility in the silicate structure may play a larger role in the chemical reactivity of asbestos than previously assumed. Environ Health Perspect 1 05(Suppl 5):1 021-1030 (1997)