Showing papers by "Andre E. Nel published in 2006"

Toxic Potential of Materials at the Nanolevel

Abstract: Nanomaterials are engineered structures with at least one dimension of 100 nanometers or less. These materials are increasingly being used for commercial purposes such as fillers, opacifiers, catalysts, semiconductors, cosmetics, microelectronics, and drug carriers. Materials in this size range may approach the length scale at which some specific physical or chemical interactions with their environment can occur. As a result, their properties differ substantially from those bulk materials of the same composition, allowing them to perform exceptional feats of conductivity, reactivity, and optical sensitivity. Possible undesirable results of these capabilities are harmful interactions with biological systems and the environment, with the potential to generate toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials in the marketplace is urgently required and achievable.

Comparison of the Abilities of Ambient and Manufactured Nanoparticles To Induce Cellular Toxicity According to an Oxidative Stress Paradigm

Abstract: Nanomaterial properties differ from those bulk materials of the same composition, allowing them to execute novel activities. A possible downside of these capabilities is harmful interactions with biological systems, with the potential to generate toxicity. An approach to assess the safety of nanomaterials is urgently required. We compared the cellular effects of ambient ultrafine particles with manufactured titanium dioxide (TiO2), carbon black, fullerol, and polystyrene (PS) nanoparticles (NPs). The study was conducted in a phagocytic cell line (RAW 264.7) that is representative of a lung target for NPs. Physicochemical characterization of the NPs showed a dramatic change in their state of aggregation, dispersibility, and charge during transfer from a buffered aqueous solution to cell culture medium. Particles differed with respect to cellular uptake, subcellular localization, and ability to catalyze the production of reactive oxygen species (ROS) under biotic and abiotic conditions. Spontaneous ROS production was compared by using an ROS quencher (furfuryl alcohol) as well as an NADPH peroxidase bioelectrode platform. Among the particles tested, ambient ultrafine particles (UFPs) and cationic PS nanospheres were capable of inducing cellular ROS production, GSH depletion, and toxic oxidative stress. This toxicity involves mitochondrial injury through increased calcium uptake and structural organellar damage. Although active under abiotic conditions, TiO2 and fullerol did not induce toxic oxidative stress. While increased TNF-alpha production could be seen to accompany UFP-induced oxidant injury, cationic PS nanospheres induced mitochondrial damage and cell death without inflammation. In summary, we demonstrate that ROS generation and oxidative stress are a valid test paradigm to compare NP toxicity. Although not all materials have electronic configurations or surface properties to allow spontaneous ROS generation, particle interactions with cellular components are capable of generating oxidative stress.

How exposure to environmental tobacco smoke, outdoor air pollutants, and increased pollen burdens influences the incidence of asthma.

Abstract: Asthma is a multifactorial airway disease that arises from a relatively common genetic background interphased with exposures to allergens and airborne irritants. The rapid rise in asthma over the past three decades in Western societies has been attributed to numerous diverse factors, including increased awareness of the disease, altered lifestyle and activity patterns, and ill-defined changes in environmental exposures. It is well accepted that persons with asthma are more sensitive than persons without asthma to air pollutants such as cigarette smoke, traffic emissions, and photochemical smog components. It has also been demonstrated that exposure to a mix of allergens and irritants can at times promote the development phase (induction) of the disease. Experimental evidence suggests that complex organic molecules from diesel exhaust may act as allergic adjuvants through the production of oxidative stress in airway cells. It also seems that climate change is increasing the abundance of aeroallergens such as pollen, which may result in greater incidence or severity of allergic diseases. In this review we illustrate how environmental tobacco smoke, outdoor air pollution, and climate change may act as environmental risk factors for the development of asthma and provide mechanistic explanations for how some of these effects can occur.

Role of the Nrf2-Mediated Signaling Pathway as a Negative Regulator of Inflammation: Implications for the Impact of Particulate Pollutants on Asthma

Abstract: Particulate matter (PM) is an environmental factor that may contribute to the exacerbation and possibly the development of asthma. PM contain redox-active chemicals and transition metals which generate reactive oxygen species (ROS). Excessive ROS can induce oxidative stress, which proceeds in hierarchical fashion to generate cellular responses. The most sensitive cellular response to mild oxidative stress is the activation of antioxidant and phase II enzymes (tier 1). If this protection fails, further increase of oxidative stress can induce inflammation (tier 2) and cell death (tier 3). Tier 1 antioxidant defenses are critical for protecting against airway inflammation and asthma. The expression of these antioxidant enzymes is regulated by the transcription factor, Nrf2. In response to oxidative stress, Nrf2 escapes from Keap1-mediated proteasomal degradation resulting in prolonged protein half-life and its nuclear accumulation. Nrf2 interacts with the antioxidant response element (ARE) in the promoters o...

Pro-oxidative diesel exhaust particle chemicals inhibit LPS-induced dendritic cell responses involved in T-helper differentiation.

Abstract: Background Epidemiologic studies show that exposure to ambient particulate matter leads to asthma exacerbation. Diesel exhaust particles (DEPs), a model pollutant, act as an adjuvant for allergic sensitization. Increasing evidence shows that this effect could be mediated by an effect on dendritic cells (DCs). Objective Our aim was to elucidate the mechanism by which pro-oxidative DEP chemicals change DC function so that these antigen-presenting cells strengthen the immune response to an experimental allergen. Methods We exposed murine bone marrow–derived DCs and a homogeneous myeloid DC line, BC1, to DEPs and organic extracts made from these particles to determine how the induction of oxidative stress affects cellular maturation, cytokine production, and activation of antigen-specific T cells. Results DEP extracts induced oxidative stress in DCs. This change in redox equilibrium interfered in the ability of Toll-like receptor agonists to induce the expression of maturation receptors (eg, CD86, CD54, and I-A d ) and IL-12 production. This perturbation of DC function was accompanied by decreased IFN-γ and increased IL-10 induction in antigen-specific T cells. The molecular basis for the perturbation of DC function is the activation of a nuclear factor-erythroid 2 (NF-E2)–related factor 2–mediated signaling pathway that suppresses IL-12 production. NF-E2–related factor 2 deficiency abrogates the perturbation of DC function by DEPs. Conclusion These data provide the first report that pro-oxidative DEP chemicals can interfere in T H 1-promoting response pathways in a homogeneous DC population and provide a novel explanation for the adjuvant effect of DEPs on allergic inflammation. Clinical implications These data clarify the adjuvant effect of particulate air pollutants in allergic inflammatory disease.

The role of reactive oxygen species and oxidative stress in mediating particulate matter injury.

Abstract: Numerous reports link oxidative stress to particulate matter (PM)-induced adverse health effects. Increasing evidence is being collected that reactive oxygen species and oxidative stress are involved in PM-mediated injury. The physical characteristics and the chemical composition of PM play a key role in reactive oxygen species generation in vitro and in vivo. According to the hierarchical oxidative stress hypothesis, antioxidant phase II enzymes protect against PM-induced inflammation and cytotoxicity. This concept is useful in understanding PM-induced disease models, susceptibility, and biomaker development to access exposures outcomes and is useful for developing therapeutic intervention in PM-induced adverse health effects.

The cellular impacts of diesel exhaust particles: beyond inflammation and death.

Abstract: Epidemiological studies have demonstrated an association between exposure to ambient particulate matter (PM) and increasing respiratory mortality and morbidity 1. In western countries, exhausts from diesel and gasoline vehicles constitute a major portion of PM and have been suspected of increasing the risk of lung cancer 2. An important component of PM is the diesel exhaust particle (DEP), which is comprised of a carbon core that adsorbs a mixture of metals and organic chemicals, including carcinogens 3. The small size and large surface area of DEP allow these particles to penetrate deep into the lung and deposit toxic chemicals throughout the respiratory tract 2. Due to their location and function, epithelial cells are one of the first and major PM targets. The impact of DEP on airway epithelial cells includes inflammation, cytotoxicity and genotoxicity. It has been established that DEP chemicals can generate reactive oxygen species (ROS) 4. The sources of ROS generation are related to the particle content of transition metals and organic chemicals 4. Excessive ROS can lead to a state of oxidative stress, which can induce a variety of cellular responses including DNA damage 4. Moreover, many polycyclic aromatic hydrocarbons (PAH) associated with DEP are genotoxic as they form a PAH-DNA adduct 5, 6. PM-induced DNA damage includes: increased frequency of mutation; single-strand breaks; and the formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine and PAH-DNA adducts 2, 4. Airway epithelial cells are at greater risk of DNA damage because of their constant exposure to PM-induced oxidative stress …

Inhibition of T3 mediated T-cell proliferation by Ca2+-channel blockers and inhibitors of Ca2+/phospholipid-dependent kinase.

Abstract: The potential roles of Ca2+ ions in the response of T lymphocytes to stimulation with monoclonal antisera to the T3 antigen were investigated by means of pharmacological agents that predominantly inhibit the flux of C a2+ ions into cells (verapamil, nifedipine) or the activity of C a2+-dependent kinases (trifluoperazine, polymyxin B). As assessed by uptake of [3H]thymidine. proliferation induced with anti T3-recombinant IL-2 at 72 h was inhibited by >80% in the presence of nifedipine at 50 μM, and almost completely arrested (>95% inhibition) with the other agents at the same concentration. Further quantitative assays of the effects of polymyxin B and trifluoperazine on C-kinase labelling of exogenous substrate showed a major reduction with both agents, but inhibition was substantially greater with polymyxin B that with trifluoperazine (IC50= 14 and 70 μM respectively). These results were confirmed by qualitative assessment of C a2+/phospholipid-dependent phosphorylation of endogenous substrates, which demonstrated major phosphoproteins of MW 56,000. 52.000, 43,000. and 20,000, and dose-dependent reduction in labelling in the presence of polymyxin B. Similar results were obtained under more physiological conditions in intact cells labelled with 32P orthophosphate. These findings indicate several possible roles for C a2+ in T cell activation, and several possible levels of activity, including modulation of calmodulin-dependent kinases and effects on C a2+/phospholipid-dependent kinases and C a2+ channels.

Accessing the Toxic Potential of Nanomaterials

Abstract: A method based is provided for determining the toxicity of engineered nanomaterials (NM). The method comprises in vitro assays for oxidative stress associated with exposure to engineered NM, which comprise assays for: reactive oxygen species production; phase Il and glutathione antioxidant molecule expression; activation of MAP and NF-kappa B kinase signaling cascades; production of cytokines, chemokines and adhesion molecules; mitochondrial perturbation and apopotosis; and cellular uptake and subcellular localization of the NM. The method further comprises in vivo assays for oxidative stress in subjects exposed to NM.

Abstract 1207: Ambient Ultrafine Particulate Matter Enhances Atherosclerosis in apoE Null Animals

Abstract: Epidemiological studies suggest that exposure to ambient particulate matter (PM) constitutes a risk factor for atherosclerosis. Exposure to fine PM (particles with aerodynamic diameter < 2.5 μm, PM...