Formation and persistence of 8-oxoguanine in rat lung cells as an important determinant for tumor formation following particle exposure.

Nehls, Peter; Seiler, Frank; Rehn, B.; Greferath, Ruth; Bruch, Joachim

doi:10.1289/ehp.97105s51291

Cited by 47 publications

(20 citation statements)

References 49 publications

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“…5B). Antibody-derived TRITC signals were nearly absent in control cells but intermediate and high in the nuclei of cells exposed to 10 or 50 mM H 2 O 2 , respectively, These results confirmed earlier findings from cell culture experiments and from in vivo studies in lung tissues of rats exposed to ROS-inducing quartz particles (Nehls et al, 1997;Seiler et al, 2001). …”

Section: Resultssupporting

confidence: 90%

“…Slides with cells or tissue sections were incubated with rabbit anti-(8-oxoG) antibody (1 g of antibody/ml of PBS/1% BSA) for 16 h at 4°C. This antibody was characterized previously in various immunoassays (radioimmunoassay, enzyme-linked immunosorbent assay, ICA) for its specific binding to 8-oxoG and the sensitive detection of the DNA oxidation product in cultured cells and in lung tissue sections (Nehls et al, 1997;Seiler et al, 2001). After washing with PBS/BSA, adducts were visualized with goat anti-(rabbit Ig) F(ab) 2 fragments conjugated to tetramethylrhodamine B isothiocyanate (TRITC; 2 g/ml PBS/1% BSA; 45 min, 37°C; Dianova, Hamburg, Germany).…”

Section: Methodsmentioning

confidence: 99%

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High Accumulation of Platinum-DNA Adducts in Strial Marginal Cells of the Cochlea Is an Early Event in Cisplatin but Not Carboplatin Ototoxicity

Thomas

Lautermann²,

Liedert³

et al. 2006

Molecular Pharmacology

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Ototoxicity is a typical dose-limiting side effect of cancer chemotherapy with cisplatin but much less so with carboplatin. To elucidate the underlying molecular pathological mechanisms, we have measured the formation and persistence of druginduced DNA adducts in the nuclei of inner ear cells of guinea pigs after short-term exposure to either cisplatin or carboplatin using immunofluorescence staining and quantitative image analysis. After application of carboplatin, all cells of the cochlea exhibited a similar burden of guanine-guanine intrastrand cross-links in DNA. In contrast, we observed a pronounced 3-to 5-fold accumulation of this cytotoxic adduct exclusively in the marginal cells of the stria vascularis between 8 and 48 h after treatment with cisplatin. In the kidney, the other critical target tissue of cisplatin toxicity, a similar high preferential formation of cytotoxic DNA adducts was measured in the tubular epithelial cells but not in other renal cell types. As for the ear, this excessive formation of DNA damage in a particular cell type was seen in animals treated with cisplatin but not those treated with carboplatin. Because cisplatin ototoxicity is often attributed to oxidative stress mediated by the generation of radical oxygen species (ROS), we have measured in parallel the levels of the lead DNA oxidation product 8-oxoguanine (8-oxoG) in cochlear cryosections. Compared with basal levels in untreated control cochleas, no additional formation of 8-oxoG was detectable up to 48 h after cisplatin treatment in the DNA of either inner-ear cell type. This suggests that the generation of ROS may be a secondary event in cisplatin ototoxicity.Platinum derivatives are frequently used in cancer chemotherapy for patients with malignancies of, for example, the urogenital tract, the lung, the colon, the stomach, or the head and neck region. It is widely accepted that the antineoplastic efficiency of cisplatin [cis-diamminedichloroplatinum (II)] as well as carboplatin (diammine-cyclobutane-dicarboxylatoplatinum) results from their interaction with the nuclear DNA of tumor cells (reviewed in Siddik, 2003). The drugs harboring two reactive groups initially induce monoadducts at nucleophilic sites (e.g., of guanine or adenine) and can lead subsequently to intra-and interstrand cross-links in the DNA. Once formed, these lesions can trigger apoptotic cascades (McKeage, 1995;Boulikas and Vougiouka, 2003) predominantly via the mitochondrial pathway (McDonald and Windebank, 2002;Lee et al., 2004). The vital role of DNA adducts in this process is confirmed by observations in human cells differing in their ability to repair drug-induced damage to their genome. Cells with impaired nucleotide excision repair functions are clearly more sensitive to cisplatin than their proficient counterparts (Furuta et al., 2002;Wu et al., 2003).On the other hand, the frequently dose limiting side effects of cisplatin on normal cells and tissues (e.g., in the inner ear and the kidney) were mainly ascribed until now to pathways not ...

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Section: Resultssupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

High Accumulation of Platinum-DNA Adducts in Strial Marginal Cells of the Cochlea Is an Early Event in Cisplatin but Not Carboplatin Ototoxicity

Thomas

Lautermann²,

Liedert³

et al. 2006

Molecular Pharmacology

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“…A separate trials on rats administrated by inhaling and intratracheally instillating crystalline SiO 2 with respirable dimension, displayed premutagenic 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG) DNA lesions (Yamano et al, 1995;Nehls et al, 1997), occurrence of pulmonary tissue lesions (Johnston et al, 2000;Albrecht et al, 2005), and development of pulmonary carcinomas (Blanco et al, 2004). Phymatoid pulmonary damage has also been surveyed in rats' long-term post-exposure to crystalline SiO 2 at low dosages of 1 mg/m 3 (Muhle et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity and DNA damage in mouse macrophages exposed to silica nanoparticles

Yang¹,

Wu²,

Lao³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Silica (SiO 2 ) nanoparticles are being progressively applied in various applications, including cosmetics, food technology, and medical diagnostics. Although crystalline SiO 2 is a known carcinogen, the carcinogenicity of SiO 2 nanoparticles remains unclear. Here, we assessed the cytotoxic effects and DNA injury induced by exposure to various dosages of SiO 2 nanoparticles at 0-2400 mg/mL (0-3200 mg/mL microscale SiO 2 as positive control) for 24 h using RAW264.7 cells, followed by methyl tetrazolium (MTT) assay. Cells were also treated by 31.25, 125, and 500 mg/mL SiO 2 nanoparticles (500 mg/mL microscale SiO 2 as positive control) for 24 h and examined by single cell gel electrophoresis assay (SCEG) and flow cytometry. Outstanding dose-related decline in cell viability was observed with enhancing dosages of SiO 2 nanoparticles by MTT assay. The inhibitory concentration 50% of SiO 2 nanoparticles and microscale SiO 2 was 16690 and 5080 mg/mL, respectively. The comet rate (comet%), length of tail, the percentage in DNA tail (TDNA%) and olive tail moment (OTM) induced by SiO 2 nanoparticles were significantly increased in comparison with control and microscale SiO 2 at 500 mg/mL. 500 mg/mL SiO 2 nanoparticles and microscale SiO 2 caused a significant increase in apoptosis rate, decreased proliferation index and increased cell proportions in G 0 /G 1 phases by contrast to the negative control (P < 0.05). This indicates that SiO 2 nanoparticles are more cytotoxic than microscale SiO 2 particles; they induce DNA injury, increase apoptosis, and decrease the proliferation index in RAW264.7 cells. DNA injury and apoptosis may be involved in reducing cell proliferation.

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“…Briefly, neutrophils were freshly isolated from blood of one healthy nonsmoking male volunteer using gradient centrifugation (26). Lymphocytes were removed and the remaining erythrocytes were lysed using cold (4 C) lysis buffer (155 mM NH 4 Cl, 10 mM KHCO 3 , 10 mM EDTA, pH 7.4). Neutrophils were washed with PBS and finally resuspended in HBSS at 6.5 Â 10 5 cells/ml.…”

Section: Co-culture With Neutrophilsmentioning

confidence: 99%

“…In the lung, inhaled particles such as crystalline silica and those present in cigarette smoke and diesel exhaust are a potent source of inflammation, and it is suggested that pulmonary carcinogenicity upon chronic particle exposure involves an influx and subsequent activation of inflammatory phagocytes (2,3). For instance, we and others have demonstrated that in vivo DNA damage and mutagenicity upon particle exposure is closely related to neutrophil recruitment to the lung (4)(5)(6). One of the properties of phagocytes that provide a possible basis for the link between inflammation and carcinogenesis is their production of DNA damaging and mutagenic reactive oxygen species (7).…”

Section: Introductionmentioning

confidence: 99%

Nitrite enhances neutrophil-induced DNA strand breakage in pulmonary epithelial cells by inhibition of myeloperoxidase

Knaapen¹,

Schins²,

Borm³

et al. 2005

Carcinogenesis

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Chronic inhalation of environmental particles is associated with pulmonary carcinogenesis. Although the mechanism has not yet been fully elucidated, influx of inflammatory cells, including neutrophils, is suggested to play a major role in this process. Typically, in the particle-exposed lung, influx of neutrophils is accompanied by an accumulation of nitrite. Previous studies indicated that nitrite may affect the toxicity of neutrophils, involving an interaction with neutrophil-derived myeloperoxidase (MPO). To evaluate the possible consequences of this interaction for inflammation-mediated genotoxicity, we investigated the effect of nitrite on neutrophil-induced DNA damage in pulmonary target cells. Therefore, activated neutrophils were co-cultured with alveolar type II epithelial cells (RLE), and DNA strand breakage was evaluated using single-cell gel electrophoresis (comet assay). In this system, addition of nitrite caused an increase in neutrophil-induced DNA strand breakage in RLE cells, which was associated with an inhibition of MPO activity. Similar results were obtained by co-culturing RLE cells with neutrophils in the presence of the specific MPO inhibitor 4-aminobenzoic acid hydrazide (4-ABAH). To further investigate the mechanism underlying these observations, in vitro experiments were performed using mixtures of nitrite, MPO and its substrate H 2 O 2 . DNA strand breakage by reagent H 2 O 2 was inhibited when it was allowed to react with MPO before addition to the RLE cells. However, when MPO and H 2 O 2 were pre-mixed in the presence of nitrite or 4-ABAH, the inhibitory effect of MPO on resultant DNA damage was reversed. Further studies using catalase indicated that DNA strand breakage by the pre-mixtures of MPO, H 2 O 2 and nitrite was H 2 O 2 -specific, suggesting that nitrite prevents consumption of H 2 O 2 by MPO. Collectively, our results show that nitrite enhances neutrophilinduced DNA strand breakage in pulmonary epithelial cells. This effect is probably due to an inhibition of MPO activity, which increases the availability of its DNA strand breaking substrate H 2 O 2 .

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Formation and persistence of 8-oxoguanine in rat lung cells as an important determinant for tumor formation following particle exposure.

Cited by 47 publications

References 49 publications

High Accumulation of Platinum-DNA Adducts in Strial Marginal Cells of the Cochlea Is an Early Event in Cisplatin but Not Carboplatin Ototoxicity

High Accumulation of Platinum-DNA Adducts in Strial Marginal Cells of the Cochlea Is an Early Event in Cisplatin but Not Carboplatin Ototoxicity

Cytotoxicity and DNA damage in mouse macrophages exposed to silica nanoparticles

Nitrite enhances neutrophil-induced DNA strand breakage in pulmonary epithelial cells by inhibition of myeloperoxidase

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