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WIREs Nanomed Nanobiotechnol
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Carbon black and titanium dioxide nanoparticles induce distinct molecular mechanisms of toxicity

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Increasing evidence link nanomaterials with adverse biological outcomes and due to the variety of applications and potential human exposures to nanoparticles, it is thus important to evaluate their toxicity for the risk assessment of workers and consumers. It is crucial to understand the underlying mechanisms of their toxicity as observation of similar effects after different nanomaterial exposures does not reflect similar intracellular processing and organelle interactions. A thorough understanding of mechanisms is needed not only for accurate prediction of potential toxicological impacts but also for the development of safer nanoapplications by modulating the physicochemical characteristics. Furthermore biomedical applications may also take advantage of an in depth knowledge about the mode of action of nanotoxicity to design new nanoparticle‐derived drugs. In the present manuscript we discuss the similarities and differences in molecular pathways of toxicity after carbon black (CB) and titanium dioxide (TiO2) nanoparticle exposures and identify the main toxicity mechanisms induced by these two nanoparticles which may also be indicative for the mode of action of other insoluble nanomaterials. We address the translocation, cell death induction, genotoxicity, and inflammation induced by TiO2 and CB nanoparticles which depend on their internalization, reactive oxygen species (ROS) production capacities and/or protein interactions. We summarize their distinct cellular mechanisms of toxicity and the crucial steps which may be targeted to avoid adverse effects or to induce them for nanomedical purposes. Several physicochemical characteristics could influence these general toxicity pathways depicted here and the identification of common toxicity pathways could support the grouping of nanomaterials in terms of toxicity. WIREs Nanomed Nanobiotechnol 2014, 6:641–652. doi: 10.1002/wnan.1302

This article is categorized under:

  • Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Schema of the hypothetic pathways of cell death induction by carbon black (CB) and titanium dioxide nanoparticles (TiO2 NPs) in bronchial epithelial cells. CB NP induce apoptosis by a reactive oxygen species (ROS) dependent mitochondrial pathway involving loss of the mitochondrial membrane potential (MMP), activation of bax, and release of cytochrome c resulting in activation of caspases and subsequent DNA fragmentation. TiO2 NPs induce cell death through lipid peroxidation and lysosomal membrane destabilization leading to cathepsin B release and subsequent activation of caspases and final apoptotic events. Modulation of oxidative stress by PEG catalase prevents cell death by blocking downstream events only in case of CB NPs. (Image drawn in part using Servier medical art). (Reprinted with permission from Ref . Copyright 2010 BioMed Central Ltd)
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Types of cell death induced by carbon black (CB) and titanium dioxide nanoparticles (TiO2 NPs). Various modalities of cell death could be induced by CB and TiO2 NPs in human cells.
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Proposed mechanism of nano‐endothelial leakiness. (a) The anatomy of an adherens junction. Intact monolayer of connected endothelial cells is maintained by stable vascular endothelial (VE)–cadherin homophilic interactions with neighboring cells. VE–cadherin forms a trans‐homophillic interaction at the EC domains with another cis‐paired VE–cadherin complex. β‐catenin, p120 and VE–cadherin form a complex. Formation of this ternary complex stabilizes the adherens junction. Distance of adherens junction is at least 22.5 nm. (b) Titanium dioxide (TiO2)–NM are small enough to migrate into the adherens junction; they bind and disrupt VE–cadherin homophilic interaction (1). This disruption induces the phosphorylation of Y658 of VE‐cadherin via a currently unknown kinase pathway, while the Y731 residue is phosphorylated by Src kinase. The phosphorylation at the two residues induces the loss of interaction between VE–cadherin and β‐catenin and with p120 (2). The loss of interaction of the VE–cadherin–β‐catenin–p120 complex destabilizes actin and lead to actin remodeling (3). As a result the cell retracts and leakiness occurs (4). After the binding of TiO2‐NM to VE–cadherin, VE–cadherin might be internalized and further degraded by lysosomes. Fate of VE–cadherin: phosphorylation of VE–cadherin due to NanoEL may result in internalization and lysosomal degradation. This minimizes the overall amounts of VE–cadherin near the vicinity of the cell membrane. TiO2–NM might be internalized alongside VE–cadherin as it remained bound to VE–cadherin but the final fate of the TiO2–NM is uncertain. (Reprinted with permission from Ref . Copyright 2013 Nature Publishing Group)
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Main toxicity pathways induced by titanium dioxide (TiO2) and carbon black (CB) nanoparticles. Three main pathways could be identified which are induced by TiO2 and/or CB nanoparticles and which could be shared by other nanomaterials. The internalization of nanomaterial could lead to lysosomal destabilization or accumulation. Nanomaterials could produce reactive oxygen species through surface reactions. The interaction of nanomaterial with membrane proteins could lead to activation or inhibition of cell signaling pathways. These different pathways could induce autophagy, inflammasome activation, apoptosis, or gene expressions and crucial steps may be targeted to avoid these cellular effects (red bars).
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Consequences of protein–nanomaterial interactions. Nanomaterials can interact with different types of proteins which could lead to a variety of changes in normal cell function.
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