Shvedova, A. A. et al. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 289, L698-L708

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.08). 12/2005; 289(5):L698-708. DOI: 10.1152/ajplung.00084.2005
Source: PubMed


Single-walled carbon nanotubes (SWCNT) are new materials of emerging technological importance. As SWCNT are introduced into the life cycle of commercial products, their effects on human health and environment should be addressed. We demonstrated that pharyngeal aspiration of SWCNT elicited unusual pulmonary effects in C57BL/6 mice that combined a robust but acute inflammation with early onset yet progressive fibrosis and granulomas. A dose-dependent increase in the protein, LDH, and gamma-glutamyl transferase activities in bronchoalveolar lavage were found along with accumulation of 4-hydroxynonenal (oxidative biomarker) and depletion of glutathione in lungs. An early neutrophils accumulation (day 1), followed by lymphocyte (day 3) and macrophage (day 7) influx, was accompanied by early elevation of proinflammatory cytokines (TNF-alpha, IL-1beta; day 1) followed by fibrogenic transforming growth factor (TGF)-beta1 (peaked on day 7). A rapid progressive fibrosis found in mice exhibited two distinct morphologies: 1) SWCNT-induced granulomas mainly associated with hypertrophied epithelial cells surrounding SWCNT aggregates and 2) diffuse interstitial fibrosis and alveolar wall thickening likely associated with dispersed SWCNT. In vitro exposure of murine RAW 264.7 macrophages to SWCNT triggered TGF-beta1 production similarly to zymosan but generated less TNF-alpha and IL-1beta. SWCNT did not cause superoxide or NO.production, active SWCNT engulfment, or apoptosis in RAW 264.7 macrophages. Functional respiratory deficiencies and decreased bacterial clearance (Listeria monocytogenes) were found in mice treated with SWCNT. Equal doses of ultrafine carbon black particles or fine crystalline silica (SiO2) did not induce granulomas or alveolar wall thickening and caused a significantly weaker pulmonary inflammation and damage.

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Available from: Vincent Castranova, Oct 05, 2015
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    • "In recent years, some types of ENMs have been shown to be hazardous to human health. It has been reported that carbon nanotubes (CNTs) are capable of inducing reactive oxygen species (ROS) (Sharma et al., 2007) and pulmonary effects (Shvedova et al., 2005). Toxicological studies have also shown that nanosized titanium dioxide (TiO 2 ) particles have the potential to induce cytotoxic (Saquib et al., 2012; Setyawati et al., 2012), genotoxic (Shukla et al., 2011; Trouiller, Reliene, Westbrook, Solaimani, & Schiestl, 2009), and inflammatory (Grassian, O'Shaughnessy, Adamcakova-Dodd, Pettibone, & Thorne, 2007; Han, Newsome, & Hennig, 2013) effects. "
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    ABSTRACT: There is increasing recognition that some nanomaterials may pose a risk to human health and the environment. Moreover, the industrial use of the novel engineered nanomaterials (ENMs) increases at a higher rate than data generation for hazard assessment; consequently, many of them remain untested. The large number of nanomaterials and their variants (e.g., different sizes and coatings) requiring testing and the ethical pressure towards nonanimal testing means that in a first instance, expensive animal bioassays are precluded, and the use of (quantitative) structure–activity relationships ((Q)SARs) models as an alternative source of (screening) hazard information should be explored. (Q)SAR modelling can be applied to contribute towards filling important knowledge gaps by making best use of existing data, prioritizing the physicochemical parameters driving toxicity, and providing practical solutions for the risk assessment problems caused by the diversity of ENMs. This paper covers the core components required for successful application of (Q)SAR methods to ENM toxicity prediction, summarizes the published nano-(Q)SAR studies, and outlines the challenges ahead for nano-(Q)SAR modelling. It provides a critical review of (1) the present availability of ENM characterization/toxicity data, (2) the characterization of nanostructures that meet the requirements for (Q)SAR analysis, (3) published nano-(Q)SAR studies and their limitations, (4) in silico tools for (Q)SAR screening of nanotoxicity, and (5) prospective directions for the development of nano-(Q)SAR models.
    Particuology 06/2015; 21:1-19. DOI:10.1016/j.partic.2014.12.001 · 2.11 Impact Factor
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    • "The quantity of HNE-His adducts in protein samples were determined by comparing its absorbance with that of a known HNE-BSA standard curve. GSH concentration in testis homogenates was determined using ThioGlo TM -1 (Covalent Associates Inc., Corvallis, OR), a maleimide reagent , which produces highly fluorescent adducts on its reaction with SHA groups [Shvedova et al., 2005]. Glutathione content was estimated by an immediate fluorescence response registered on the addition of ThioGlo TM - 1 to the testis homogenate. "
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    ABSTRACT: Altering the fuel source from petroleum-based ultralow sulfur diesel to biodiesel and its blends is considered by many to be a sustainable choice for controlling exposures to particulate material. As the exhaust of biodiesel/diesel blends is composed of a combination of combustion products of polycyclic aromatic hydrocarbons and fatty acid methyl esters, we hypothesize that 50% biodiesel/diesel blend (BD50) exposure could induce harmful outcomes because of its ability to trigger oxidative damage. Here, adverse effects were compared in murine male reproductive organs after pharyngeal aspiration with particles generated by engine fueled with BD50 or neat petroleum diesel (D100). When compared with D100, exposure to BD50 significantly altered sperm integrity, including concentration, motility, and morphological abnormalities, as well as increasing testosterone levels in testes during the time course postexposure. Serum level of luteinizing hormone was significantly depleted only after BD50 exposure. Moreover, we observed that exposure to BD50 significantly increased sperm DNA fragmentation and the upregulation of inflammatory cytokines in the serum and testes on Day 7 postexposure when compared with D100. Histological evaluation of testes sections from BD50 exposure indicated more noticeable interstitial edema, degenerating spermatocytes, and dystrophic seminiferous tubules with arrested spermatogenesis. Significant differences in the level of oxidative stress assessed by accumulation of lipid peroxidation products and depletion of glutathione were detected on exposure to respirable BD50 and D100. Taken together, these results indicate that exposure of mice to inhalable BD50 caused more pronounced adverse effects on male reproductive function than diesel. Environ. Mol. Mutagen., 2014. © 2014 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 10/2014; 56(2). DOI:10.1002/em.21915 · 2.63 Impact Factor
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    • "The first set of experiments showed that pharyngeal aspiration of SWCNTs (10 µg/mouse) with low iron content led to increased pulmonary inflammation, lipid peroxidation and depletion of GSH in BALF (most pronounced at day 1 after exposure) and progressive development of fibrosis over a 28-day post-exposure period (Shvedova et al. 2005). Inhalation of SWCNTs with 18 % iron content (5 mg/ m 3 , 5 h/day for 4 days) also decreased the GSH level and increased levels of protein thiols and malondialdehyde in lung tissue of mice (Shvedova et al. 2008a). "
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    ABSTRACT: The development of products containing carbon nanotubes (CNTs) is a major achievement of nanotechnology, although concerns regarding risk of toxic effects linger if the hazards associated with these materials are not thoroughly investigated. Exposure to CNTs has been associated with depletion of antioxidants, increased intracellular production of reactive oxygen species and pro-inflammatory signaling in cultured cells with primary function in the immune system as well as epithelial, endothelial and stromal cells. Pre-treatment with antioxidants has been shown to attenuate these effects, indicating a dependency of oxidative stress on cellular responses to CNT exposure. CNT-mediated oxidative stress in cell cultures has been associated with elevated levels of lipid peroxidation products and oxidatively damaged DNA. Investigations of oxidative stress endpoints in animal studies have utilized pulmonary, gastrointestinal, intravenous and intraperitoneal exposure routes, documenting elevated levels of lipid peroxidation products and oxidatively damaged DNA nucleobases especially in the lungs and liver, which to some extent occur concomitantly with altered levels of components in the antioxidant defense system (glutathione, superoxide dismutase or catalase). CNTs are biopersistent high aspect ratio materials, and some are rigid with lengths that lead to frustrated phagocytosis and pleural accumulation. There is accumulating evidence showing that pulmonary exposure to CNTs is associated with fibrosis and neoplastic changes in the lungs, and cardiovascular disease. As oxidative stress and inflammation responses are implicated in the development of these diseases, converging lines of evidence indicate that exposure to CNTs is associated with increased risk of cardiopulmonary diseases through generation of a pro-inflammatory and pro-oxidant milieu in the lungs.
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