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Nanomaterials have gained a rapid increase in use in a variety of applications that pertain to many aspects of human life. The majority of these innovations are centered on medical applications and a range of industrial and environmental uses ranging from electronics to environmental remediation. Despite the advantages of NPs, the knowledge of their toxicological behavior and their interactions with the cellular machinery that determines cell fate is extremely limited. This review is an attempt to summarize and increase our understanding of the mechanistic basis of nanomaterial interactions with the cellular machinery that governs cell fate and activity. We review the mechanisms of NP-induced necrosis, apoptosis and autophagy and potential implications of these pathways in nanomaterial-induced outcomes. Abbreviations: Ag, silver; CdTe, cadmium telluride; CNTs, carbon nanotubes; EC, endothelial cell; GFP, green fluorescent protein; GO, graphene oxide; GSH, glutathione; HUVECs, human umbilical vein endothelial cells; NP, nanoparticle; PEI, polyethylenimine; PVP, polyvinylpyrrolidone; QD, quantum dot; ROS, reactive oxygen species; SiO, silicon dioxide; SPIONs, superparamagnetic iron oxide nanoparticles; SWCNT, single-walled carbon nanotubes; TiO, titanium dioxide; USPION, ultra-small super paramagnetic iron oxide; ZnO, zinc oxide.

Cerium dioxide nanoparticles (CeO2 NPs) have diversified industrial uses and novel therapeutic applications are actively being pursued. There is lack of mechanistic data concerning the effects of CeO2 NPs on primary human cells. We aimed at characterizing the cytotoxic effects of CeO2 NPs in human peripheral blood monocytes. CeO2 NPs and their suspensions were thoroughly characterized, including using transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential analysis. Blood from healthy human volunteers was drawn through phlebotomy and CD14+ cells were isolated. Cells were exposed to CeO2 NPs (0.5–10 μg/mL) for 20 or 40 hours and mechanisms of cell injury were studied. TEM revealed that CeO2 NPs are internalized by monocytes and are found either in vesicles or free in the cytoplasm. CeO2 NP exposure leads to decrease in cell viability and treated cells exhibit characteristic hallmarks of apoptosis (activation of Bax, loss of mitochondrial membrane potential, DNA fragmentation). CeO2 NP toxicity is caused by mitochondrial damage leading to apoptosis inducing factor (AIF) release, but not due to caspase activation or reactive oxygen species production. Moreover, CeO2 NP exposure leads to autophagy, which is further increased after pharmacological inhibition of tumour suppressor protein p53. Inhibition of autophagy partially reverses cell death by CeO2 NPs. It is concluded that CeO2 NPs are toxic to primary human monocytes at relatively low doses.

BackgroundIncreasing environmental and occupational exposures to nanoparticles (NPs) warrant deeper insight into the toxicological mechanisms induced by these materials. The present study was designed to characterize the cell death induced by carbon black (CB) and titanium dioxide (TiO2) NPs in bronchial epithelial cells (16HBE14o- cell line and primary cells) and to investigate the implicated molecular pathways.ResultsDetailed time course studies revealed that both CB (13 nm) and TiO2(15 nm) NP exposed cells exhibit typical morphological (decreased cell size, membrane blebbing, peripheral chromatin condensation, apoptotic body formation) and biochemical (caspase activation and DNA fragmentation) features of apoptotic cell death. A decrease in mitochondrial membrane potential, activation of Bax and release of cytochrome c from mitochondria were only observed in case of CB NPs whereas lipid peroxidation, lysosomal membrane destabilization and cathepsin B release were observed during the apoptotic process induced by TiO2 NPs. Furthermore, ROS production was observed after exposure to CB and TiO2 but hydrogen peroxide (H2O2) production was only involved in apoptosis induction by CB NPs.ConclusionsBoth CB and TiO2 NPs induce apoptotic cell death in bronchial epithelial cells. CB NPs induce apoptosis by a ROS dependent mitochondrial pathway whereas TiO2 NPs induce cell death through lysosomal membrane destabilization and lipid peroxidation. Although the final outcome is similar (apoptosis), the molecular pathways activated by NPs differ depending upon the chemical nature of the NPs.

Increasing evidence linking nanoparticles (NPs) with different cellular outcomes necessitate an urgent need for the better understanding of cellular signalling pathways triggered by NPs. Oxidative stress has largely been reported to be implicated in NP-induced toxicity. It could activate a wide variety of cellular events such as cell cycle arrest, apoptosis, inflammation and induction of antioxidant enzymes. These responses occur after the activation of different cellular pathways. In this context, three groups of MAP kinase cascades [ERK (extracellular signal-regulated kinases), p38 mitogen-activated protein kinase and JNK (c-Jun N-terminal kinases)] as well as redox-sensitive transcription factors such as NFκB and Nrf-2 were specially investigated. The ability of NPs to interact with these signalling pathways could partially explain their cytotoxicity. The induction of apoptosis is also closely related to the modulation of signalling pathways induced by NPs. Newly emerged scientific areas of research are the studies on interactions between NPs and biological molecules in body fluids, cellular microenvironment, intracellular components or secreted cellular proteins such as cytokines, growth factors and enzymes and use of engineered NPs to target various signal transduction pathways in cancer therapy. Recently published data present the ability of NPs to interact with membrane receptors leading to a possible aggregation of these receptors. These interactions could lead to a sustained modulation of specific signalling in the target cells or paracrine and even "by-stander" effects of the neighbouring cells or tissues. However, oxidative stress is not sufficient to explain specific mechanisms which could be induced by NPs, and these new findings emphasize the need to revise the paradigm of oxidative stress to explain the effects of NPs.

The aim of this study was to investigate the modulation of an asthmatic response by titanium dioxide (TiO 2 ) or gold (Au) nanoparticles (NPs) in a murine model of diisocyanateinduced asthma.On days 1 and 8, BALB/c mice received 0.3% toluene diisocyanate (TDI) or the vehicle acetoneolive oil (AOO) on the dorsum of both ears (20 mL). On day 14, the mice were oropharyngeally dosed with 40 mL of a NP suspension (0.4 mg?mL -1 (,0.8 mg?kg -1 ) TiO 2 or Au). 1 day later (day 15), the mice received an oropharyngeal challenge with 0.01% TDI (20 mL). On day 16, airway hyperreactivity (AHR), bronchoalveolar lavage (BAL) cell and cytokine analysis, lung histology, and total serum immunoglobulin E were assessed. NP exposure in sensitised mice led to a two-(TiO 2 ) or three-fold (Au) increase in AHR, and a three-(TiO 2 ) or five-fold (Au) increase in BAL total cell counts, mainly comprising neutrophils and macrophages. The NPs taken up by BAL macrophages were identified by energy dispersive X-ray spectroscopy. Histological analysis revealed increased oedema, epithelial damage and inflammation.In conclusion, these results show that a low, intrapulmonary doses of TiO 2 or Au NPs can aggravate pulmonary inflammation and AHR in a mouse model of diisocyanate-induced asthma.