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At least 19 recordsLinked to original sources
PubMed1996

Detection of 8-oxo-2'-deoxyguanosine, a marker of oxidative DNA damage, in culture medium from human mesothelial cells exposed to crocidolite asbestos.

Crocidolite asbestos is associated with the development of mesothelioma. Although chromosomal changes have been documented in mesothelial cells, the mechanisms of interaction of crocidolite with DNA remain obscure. Since human mesothelial cells are exquisitely sensitive to asbestos, oxidative DNA damage was measured in an asbestos-exposed human mesothelial cell line (MET5A) by assaying oxidized guanine bases [8-oxo-2'-deoxyguanosine (oxo8dG), 8-oxoguanine (oxo8G), and 8-oxoguanosine (oxo8Gua)] excreted into the spent culture medium after DNA repair or turnover. At growth inhibitory, but not cytolytic concentrations, asbestos caused significant elevation of all bases in the spent medium over a 48-h period. In contrast, riebeckite, a chemically similar, nonfibrous analog of crocidolite did not cause increased adduct release. Results show that oxidative RNA and DNA bases are produced in response to asbestos in target cells of asbestos-induced cancers.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Induction of ferritin synthesis in human lung epithelial cells treated with crocidolite asbestos.

Crocidolite asbestos is a known human carcinogen containing 27% iron by weight. It has previously been shown that iron was mobilized intracellularly from crocidolite after treatment of human lung epithelial cells (A549) and that the toxicity of the fibers was directly related to how much mobilized iron was in the < 10,000 MW (low-molecular-weight, LMW) fraction [C. C. Chao, L.G. Lund, K. R. Zinn, and A. E. Aust (1994) Arch. Biochem. Biophys. 314, 384-391]. The data here show that iron mobilization from crocidolite began immediately after treatment of the A549 cells and increased linearly with time. However, the synthesis of ferritin, an iron storage protein, did not begin until after 4 h of treatment, reaching a sustained maximum after 12 h. Mobilized iron was preferentially incorporated into the nonferritin-protein fraction up to 7 h after treatment, when the amount of iron mobilized was low and before significant accumulation of newly synthesized ferritin had occurred. This suggested that these cultured cells needed additional iron for synthesis of iron-requiring proteins and that iron mobilized from crocidolite could be utilized directly for this purpose. Subsequent to this, additional mobilized iron was incorporated into newly synthesized ferritin. Even though iron from crocidolite was incorporated into newly synthesized ferritin or into other proteins, the amount of iron from crocidolite in the LMW fraction remained constant during the 24 h. Thus, it appeared that synthesis of ferritin may not have fully protected the cells from the toxic effects of iron mobilized from crocidolite.

Asbestos↗
PubMed2005

Differential in vitro cellular response induced by exposure to synthetic vitreous fibers (SVFs) and asbestos crocidolite fibers.

In this study, we analyzed the effects of synthetic vitreous fibers (SVFs) on a mesothelial (MeT5A) and a fibroblast cell line (NIH3T3), compared to those exerted by crocidolite asbestos fibers. SVFs (glass wool, rock wools) do not induce significant changes in cell mortality, whereas crocidolite asbestos fibers caused a dose-dependent cytotoxicity. We investigated the correlation between the fiber-induced cytotoxicity and the extent and type of interaction of the fibers with the cell surface, and we observed that SVFs, unlike crocidolite asbestos fibers, establish few and weak interactions. Moreover, after internalization, crocidolite asbestos fibers are often found free in the cytoplasm, whereas glass wool fibers are mainly localized inside cytoplasmic vacuoles. After treatments, we also detected signs of oxidative stress, revealed by an increased reactive oxygen species (ROS) production and by an induction of superoxide dismutase (SOD) activity. The lipoperoxidative damage was characterized by a decrease in polyunsaturated fatty acids (PUFA), an increase in the content of thiobarbituric reactive species (TBARS) and a consumption of vitamin E, as a lipophilic antioxidant. Furthermore, we investigated the effect of fiber exposure on cell proliferation. and it was found that, unlike crocidolite asbestos fibers, SVFs did not induce a significant increase in DNA synthesis.

Animals↗
PubMed2002

Crocidolite asbestos inhibits pentose phosphate oxidative pathway and glucose 6-phosphate dehydrogenase activity in human lung epithelial cells.

The cytotoxicity of asbestos has been related to its ability to increase the production of reactive oxygen species (ROS), via the iron-catalyzed reduction of oxygen and/or the activation of NADPH oxidase. The pentose phosphate pathway (PPP) is generally activated by the cell exposure to oxidant molecules. Contrary to our expectations, asbestos (crocidolite) fibers caused a dose- and time-dependent inhibition of PPP and decreased its activation by an oxidative stress in human lung epithelial cells A549. In parallel, the intracellular activity of the PPP rate-limiting enzyme, glucose 6-phosphate dehydrogenase (G6PD), was significantly diminished by crocidolite exposure. This inhibition was selective, as the activity of other PPP and glycolysis enzymes was not modified, and was not attributable to a decreased expression of G6PD. On the opposite, the incubation with glass fibers MMVF10 did not modify PPP and G6PD activity. PPP and G6PD inhibition did not correlate with the increased nitric oxide (NO) production elicited by crocidolite in A549 cells. Experiments with the purified enzyme suggest that crocidolite inhibits G6PD by directly interacting with the protein. We propose here a new mechanism of asbestos-evoked oxidative stress, wherein fibers increase the intracellular ROS levels also by inhibiting the main antioxidant pathway of the cell.

Asbestos, Crocidolite↗
PubMed1987

Enhanced lipid peroxidation and lysosomal enzyme activity in the lungs of rats with prolonged pulmonary deposition of crocidolite asbestos.

The interaction of UICC crocidolite asbestos with biological membranes in vivo was studied in rats after a single intratracheal dose of a suspension of 20 mg of fibres per rat. Development of lung fibrosis (increased level of hydroxyproline, a collagen index together with corresponding pathomorphological alteration) confirmed the penetration of crocidolite fibres into the lungs in the course of seven months exposure. The pulmonary deposition of crocidolite affected the lysosomal membranes of lung cells as manifested by (1) enhanced lipid peroxidation with (2) stimulation (release) of activity of beta-glucuronidase and cathepsin D. Enhanced lipid peroxidation and activity of beta-glucuronidase may contribute to the delayed, carcinogenic effects of crocidolite asbestos.

Animals↗
PubMed1986

Role of reactive oxygen metabolites in crocidolite asbestos toxicity to mouse macrophages.

Crocidolite asbestos is toxic to macrophages in vitro. We hypothesize that this toxicity is mediated by the generation of reactive oxygen metabolites. Elicited mouse peritoneal macrophages were found to release reactive oxygen metabolites upon incubation with crocidolite asbestos in vitro. Crocidolite toxicity to both primary cultures of mouse peritoneal macrophages and P388D1 cells, a mouse macrophage-like cell line, could be prevented by a hypoxic environment or by addition of the reactive oxygen metabolite scavengers, superoxide dismutase and catalase. In addition, if crocidolite fibers were presoaked with the iron chelator deferoxamine, no macrophage death occurred. In an attempt to mimic crocidolite-induced cytotoxicity, P388D1 cells or primary elicited macrophages were exposed to the nontoxic mineral particle titanium dioxide in the presence and absence of ferric chloride. Titanium dioxide was only lethal when ferric chloride was added. This toxicity was prevented by superoxide dismutase, catalase, or deferoxamine. These results suggest that crocidolite-induced injury to macrophages depends on the formation of reactive oxygen metabolites. Iron present in crocidolite fibers may catalyze the production of hydroxyl radical from superoxide anion and hydrogen peroxide generated during phagocytosis. These highly reactive hydroxyl radicals are postulated to mediate lethal cell injury.

Animals↗
PubMed1992

Iron mobilization from crocidolite asbestos greatly enhances crocidolite-dependent formation of DNA single-strand breaks in phi X174 RFI DNA.

The ability of the iron associated with asbestos to catalyze damage to phi X174 RFI DNA was determined and compared with iron mobilized from asbestos. Asbestos (1 mg/ml) suspended for 30 min in 50 mM NaCl containing 0.5 micrograms phi X174 RFI DNA, pH 7.5, did not catalyze detectable amounts of DNA single-strand breaks (SSB). However, addition of ascorbate (1 mM) resulted in 19, 26, 7 or 8% DNA with SSB for crocidolite, amosite, chrysotile or tremolite respectively. The percentage of DNA with SSB induced by each form of asbestos was directly related to its iron content. Inclusion of desferrioxamine B, which binds Fe(III) rendering it redox inactive, completely inhibited asbestos-dependent formation of DNA SSB, suggesting that iron was responsible for catalyzing the formation of DNA SSB. Mobilization of Fe(II) from crocidolite by citrate, EDTA or nitrilotriacetate (1 mM) in the absence of ascorbate resulted in 15, 33 or 63% DNA with SSB respectively. This activity was completely inhibited by compounds considered to be .OH scavengers, i.e. mannitol, 5,5-dimethyl-1-pyrroline N-oxide or salicylate (100 mM). Preincubation of crocidolite with citrate (1 mM) for 24 h resulted in mobilization of 52 microM iron and increased ascorbate-dependent induction of DNA SSB compared with crocidolite that was preincubated without citrate. Iron mobilized by citrate was entirely responsible for crocidolite-dependent formation of DNA SSB as evidenced by complete inhibition with desferrioxamine B. Therefore, the results of the present study strongly suggest that iron was responsible for asbestos-dependent generation of oxygen radicals, which resulted in the formation of DNA SSB. Mobilization of iron by chelators, followed by redox cycling, greatly enhanced crocidolite-dependent formation of DNA SSB. Thus, mobilization of iron in vivo by low mol. wt chelators may lead to the increased production of reactive oxygen species resulting in damage to biomolecules, such as DNA.

Asbestos↗
PubMed1991

Mobilization of iron from crocidolite asbestos by certain chelators results in enhanced crocidolite-dependent oxygen consumption.

The reactivity of iron on crocidolite asbestos with dioxygen was determined and compared with iron mobilized from crocidolite. Ferrozine, a strong Fe(II) chelator, was used to demonstrate that iron on crocidolite was redox active. More Fe(II) was mobilized from crocidolite (1 mg/ml) by ferrozine anaerobically (11.2 nmol/mg crocidolite/h) than aerobically (6.6 nmol/mg/h) in 50 mM NaCl, pH 7.5, suggesting that Fe(II) on crocidolite reacts with O2 upon aqueous suspension. However, suspension of crocidolite in 50 mM NaCl, pH 7.5, did not result in a measurable amount of O2 consumption. The addition of reducing agents (1 mM) increased the amount of Fe(II) on crocidolite, and addition of ascorbate resulted in 0.4 nmol O2 consumed/mg crocidolite/min. Therefore, iron on crocidolite had limited redox activity in the presence of ascorbate. However, mobilization of iron from crocidolite increased its redox activity. Citrate, nitrilotriacetate (NTA), or EDTA (1 mM) mobilized 79, 32, or 58 microM iron, respectively, in preincubations up to 76 h, and increased O2 consumption upon addition of ascorbate to 2.8, 7.6, or 22.0 nmol O2 consumed/mg/min, respectively. This activity depended only upon the presence of a component(s) mobilized from crocidolite by the chelators. Pretreatment of crocidolite with the iron chelator desferrioxamine B (10 mM) inhibited O2 consumption. The results of the present study suggest that iron on or in crocidolite is responsible for the redox activity of crocidolite, but that mobilization of iron by chelators such as citrate, NTA, or EDTA greatly enhances its redox activity. Thus, iron mobilization from crocidolite in vivo by low-molecular-weight chelators may lead to the increased production of reactive oxygen species which may damage biomolecules, such as DNA.

Anaerobiosis↗
PubMed1990

Cytotoxicity of long and short crocidolite asbestos fibers in vitro and in vivo.

Fiber length and diameter are important factors in the pathogenicity of asbestos. We examined the relative toxicity of long and short crocidolite asbestos fibers in vitro and in vivo. Both long and short crocidolite asbestos fibers were toxic to elicited macrophages in vitro. Similar to native crocidolite asbestos, long and short fibers stimulated the release of reactive oxygen metabolites from elicited macrophages in vitro. We evaluated whether in vitro cytotoxicity was dependent on the production of reactive oxygen metabolites. In the presence of the reactive oxygen metabolite scavenging enzymes, superoxide dismutase or catalase, the toxicity of long and short crocidolite fibers to macrophages was prevented. Furthermore, macrophages were not killed when either long or short fibers were soaked in the iron chelator, deferoxamine. Native, long, and short crocidolite fibers also caused depolarization of the mitochondrial membrane potential prior to cell death. In vivo, a single i.p. injection of long crocidolite fibers stimulates an intense inflammatory reaction, release of reactive oxygen metabolites near sites of fiber deposition, and cell death. In contrast, these events were minimal after a single injection of short fibers due to the removal of fibers from the peritoneal cavity. After five daily injections of short fibers, however, fibers were present on the surface of the mesothelium and provoked an inflammatory response. Cell death was observed on the surface of the mesothelium. Reactive oxygen metabolites were also produced near accumulations of short fibers. Our results suggest that both long and short crocidolite asbestos fibers are toxic to macrophages in vitro via an oxidant and iron-dependent mechanism. In vivo, short fibers are cytotoxic when the clearance of these fibers is prevented.

Animals↗
PubMed1997

Can microwave radiation at high temperatures reduce the toxicity of fibrous crocidolite asbestos?

Exposure of animals and humans to crocidolite asbestos fibers produces fibrosis and two types of cancers: bronchogenic carcinoma and mesothelioma. It is therefore desirable to reduce toxicity of these fibers without affecting their other characteristics. In this study, commercial crocidolite asbestos fibers were radiated with microwave radiation at different temperatures. Radiated fibers and nonradiated original fibers were then studied by Mössbauer spectroscopy to quantify the amount of ferric and ferrous ions present at structurally different sites in each crocidolite sample. They were also studied for their ability to initiate the peroxidation of linoleic acid to assess the effect of radiation on this process. Results showed that microwave radiation reduced the total Fe2+/Fe3+ ratio. This reduction produced a concomitant decrease in the ability of the radiated samples to peroxidize linoleic acid.

Aldehydes↗
PubMed1993

The production of TNF-alpha and IL-1-like activity by bronchoalveolar leucocytes after intratracheal instillation of crocidolite asbestos.

We have used a rat intratracheal instillation model to study the effect of crocidolite asbestos exposure on cytokine production by bronchoalveolar lavage (BAL) leucocytes. In unexposed controls, the normal BAL leucocytes were mostly macrophages which spontaneously produced interleukin 1 (IL-1)-like activity and tumour necrosis factor (TNF-alpha) in culture; these levels were enhanced by stimulation with LPS. In animals exposed to crocidolite asbestos, two new types of cell, neutrophils and eosinophils, were recruited into the bronchoalveolar space by 1-3 days after instillation. However, the BAL profile had returned to normal by 14 days. The production of IL-1-like activity was decreased considerably compared to control from 1 to 14 days after asbestos instillation, but was increased at 30 days. However, the leucocytes produced increased TNF-alpha as early as 3 days after asbestos instillation and maintained this elevated level throughout the experimental period. Crocidolite asbestos in vitro also stimulated normal BAL leucocytes to release significantly increased amounts of IL-1-like activity and TNF-alpha. We conclude that the deposition of crocidolite asbestos fibre in the lung by instillation causes reduced production of IL-1-like activity in the acute phase, but elevated production of both IL-1-like activity and TNF in the chronic phase, suggesting that enhanced activities of these cytokines may contribute to the development of lung pathological changes in the long term.

Animals↗
PubMedDate not supplied

Biological durability and oxidative potential of man-made vitreous fibres as compared to crocidolite asbestos fibres.

In this study we investigated relationships between redox properties and biodurability of crocidolite asbestos fibres and three different man-made vitreous fibres (MMVF): traditional stone wool fibres (MMVF 21), glass fibres (MMVF 11) and refractory ceramic fibres (RCF). Each fibre type was incubated up to 22 weeks in four different incubation media: gamble solution (GS) pH 5.0 and pH 7.4, representing blood plasma without proteins, and surfactant-like solution (SLS) pH 5.0 and pH 7.4. During incubation time aliquots of incubation mixtures were removed and analysed in a biochemical model reaction, mimicking activated phagocytes. In addition, changes of fibre morphology and chemical composition were examined using SEM- and EDX-technology. In the presence of crocidolite asbestos fibres and MMVF 21 the formation of OH*-radicals according to the Haber-Weiss sequence could be demonstrated, whereas MMVF 11 and RCF showed no reactivity. Crocidolite asbestos fibres exhibited a significant higher activity compared with the stone wool fibres at the onset of incubation. The oxidative capacities of these fibre types were shown to depend on both specific surface area and iron content. The oxidative potentials of crocidolite asbestos fibres as well as MMVF 21 were not constant during incubation over several weeks in each incubation medium. The reactivities showed sinoidal curves including reactivities much higher than those at the onset of incubation time. These irregular changes of oxidative capacity may be explained by changes of the redox state of fibre surface-complexed iron. Furthermore our results showed clear differences between incubation of fibres in GS and SLS, respectively, indicating that phospholipids play an important part in fibre dissolution behaviour and oxidative reactivity. In conclusion we suggest, that biodurability testing procedures should not exclusively concentrate on dissolution rates of fibres. They should include fibre characteristics concerning known pathogenic mechanisms to evaluate the real toxic potential of the fibre type looking at. Secondly we suggest, that phospholipids should be constituents of incubation liquids used for standardised fibre biodurability test procedures thus representing more realistic incubation conditions.

Asbestos, Crocidolite↗
PubMed2005

Expression of heme oxygenase-1 in the lungs of rats exposed to crocidolite asbestos.

Oxidative stress is thought to be the pathogenesis of pulmonary fibrosis induced by asbestos, and heme oxygenase-1 (HO-1) protects lung tissue against oxidative stress. We hypothesized that HO-1 is associated with oxidative lung injury caused by exposure to asbestos. This study was conducted to investigate the time course of HO-1 expression of lungs exposed to crocidolite asbestos in vivo. Male Wistar rats were administered 1 mg or 2 mg crocidolite asbestos suspended in saline by a single intratracheal instillation and were sacrificed at 3 d, 1 wk, 1 mo, 3 mo, and 6 mo of recovery time. The expression of HO-1 was observed by Western blot analysis and immunostaining. Protein levels of HO-1 increased at from 3 d to 6 mo following intratracheal instillation of 2 mg crocidolite asbestos. The levels of HO-1 increased at 1 wk and 1 mo following intratracheal instillation of 1 mg crocidolite asbestos. Many HO-1-positive cells were found, particularly in the alveolar macrophages, during immunostaining. These findings suggest that HO-1 may be related to lung disorder induced by dust and therefore can act as a biomarker of lung injury due to dust exposure.

Animals↗
PubMed1988

NTP Toxicology and Carcinogenesis Studies of Crocidolite Asbestos (CAS No. 12001-28-4) In F344/N Rats (Feed Studies).

Carcinogenesis studies of crocidolite asbestos were conducted with male and female F344/N rats. This form of asbestos was administered at a concentration of 1% in pelleted diet for the lifetime of the rats, starting with the dams of the study animals. The studies were started in January 1978 and ended in December 1980. Group sizes were 118 for male and female controls and 250 for male and female crocidolite asbestos-exposed rats. The offspring from mothers exposed to crocidolite asbestos and the controls were similar in size at birth but were slightly smaller at weaning and remained so throughout their life. Feed consumption and survival were comparable in the exposed and control groups. No overt toxicity was observed in the crocidolite asbestos-exposed animals. There was an elevated (P<0.05) incidence of thyroid gland C-cell adenomas (control, 4/117, 3%, vs. exposed, 23/250, 9%) and of thyroid gland C-cell carcinomas (12/117, 10%, vs. 46/250, 18%) in crocidolite asbestos-exposed female rats relative to concurrent controls. Because these control incidences were low relative to control incidences observed in other contemporary studies at this laboratory (21% for thyroid gland C-cell tumors), this slight increase was not regarded as being biologically important. The data, documents, and pathology materials from the lifetime studies of crocidolite asbestos have been audited. The audit findings show that the conduct of these studies is documented adequately and support the data and results presented in this Technical Report. Conclusions: Under the conditions of these feed studies, crocidolite asbestos was not overtly toxic and did not cause a carcinogenic response when ingested at a concentration of 1% in the diet by male and female F344/N rats for their lifetime. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative

Journal Article↗
PubMed1994

Mesothelial cell injury caused by pleural leukocytes from rats treated with intratracheal instillation of crocidolite asbestos or Corynebacterium parvum.

The pleural and peritoneal mesothelium is a major target in asbestos exposure where mesothelial cell proliferation, exfoliation, and neoplasia have been reported in workers and experimental animals. The objective of this study was to determine the role of pleural leukocytes in mesothelial cell damage caused by asbestos exposure. We therefore investigated detachment and lysis injury to mesothelial cells in vitro induced by leukocytes lavaged from the pleural space of rats exposed, by intratracheal instillation, to crocidolite asbestos. Our studies revealed that normal pleural leukocytes were composed of macrophages, lymphocytes, eosinophils, and mast cells. This population showed a small but significant recruitment of mast cells and eosinophils 3 to 14 days after instillation of crocidolite asbestos; there were also modestly increased levels of macrophages present 30 days after low doses of asbestos. One day after intratracheal instillation of 5 mg crocidolite asbestos, the pleural leukocytes caused detachment injury to mesothelial cells in vitro. This injury was markedly reduced 3 days after asbestos exposure and was undetectable by Day 14. One month after instillation of asbestos, despite doses of asbestos from 0.5 to 5 mg, pleural leukocytes showed no ability to injure mesothelial cells in vitro. In a parallel study, pleural inflammation was induced by intratracheal instillation of heat-inactivated Corynebacterium parvum. Transient mesothelial cell-detaching injury was again expressed by pleural leukocytes 1 day after C. parvum instillation. This was likely related to an increase in the percentage of neutrophils present on this day. These results show that a single administration of crocidolite asbestos, intratracheally, leads to transient activation of pleural leukocytes in terms of the ability of these cells to detach mesothelial cells from matrix. This finding implies that mesothelial cell proliferation and exfoliation found in individuals exposed to asbestos may result from persistent stimulation of pleural leukocytes caused by the continuous presence of asbestos in the lung.

Animals↗
PubMed1993

Production of interleukin 1 by rat pleural leucocytes in culture after intratracheal instillation of crocidolite asbestos.

This study was undertaken to investigate the production of interleukin 1 (IL-1) by pleural leucocytes in culture and to evaluate the influence of intratracheal instillation of crocidolite asbestos on this production. Normal pleural leucocytes spontaneously released IL-1 in culture and stimulation with lipopolysaccharide (LPS) dramatically increased production. Intratracheal instillation with crocidolite asbestos induced recruitment of pleural leucocytes in the longer term and changed IL-1 production by the leucocytes. Reduced production of IL-1 was found by one day after instillation of asbestos and this was correlated with the dose of asbestos. With increasing time after instillation, however, release of IL-1 by pleural leucocytes gradually recovered to normal until, one month after asbestos injection, the leucocytes produced augmented IL-1 in culture compared with control pleural leucocytes. Our data show that pleural leucocytes possess the potential to produce IL-1 in vitro and this capability is altered by intratracheal instillation of crocidolite asbestos. This may be relevant to development of pleural diseases associated with inhalation of asbestos.

Animals↗
PubMed1980

Electron microscopy applied to studies of the biological significance of defects in crocidolite asbestos.

Transmission electron microscopy is used in an investigation of crocidolite asbestos associated with two biological systems. Control material is extremely defective and contains in particular an abundance of Wadsley defects, (100) planar faults, and pores. Fibres sectioned in lung tissue and fibres taken from in vitro exposure to blood serum show evidence of erosion by two mechanisms--preferential attack at (100) planar defects and general surface dissolution.

Animals↗