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Cytotoxicological pathways induced after nanoparticle exposure: studies of oxidative stress at the 'nano-bio' interface.

ABSTRACT: Nanotechnology is advancing rapidly; many industries are utilizing nanomaterials because of their remarkable properties. As of 2017, over 1800 "nano-enabled products" (i.e. products that incorporate a nanomaterial feature and alter the product's performance) have been used to revolutionize pharmaceutical, transportation, and agriculture industries, just to name a few. As the number of nano-enabled products continues to increase, the risk of nanoparticle exposure to humans and the surrounding environment also increases. These exposures are usually classified as either intentional or unintentional. The increased rate of potential nanoparticle exposure to humans has required the field of 'nanotoxicology' to rapidly screen for key biological, biochemical, chemical, or physical signals, signatures, or markers associated with specific toxicological pathways of injury within in vivo, in vitro, and ex vivo models. One of the common goals of nanotoxicology research is to identify critical perturbed biological pathways that can lead to an adverse outcome. This review focuses on the most common toxicological pathways induced by nanoparticle exposure and provides insights into how these perturbations could aid in the development of nanomaterial specific adverse outcomes, inform nano-enabled product development, ensure safe manufacturing practices, promote intentional product use, and avoid environmental health hazards.

SUBMITTER: Lujan H

PROVIDER: S-EPMC6062389 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Project description:Introduction:Biomedical applications of nanoparticles (NPs) as enzyme inhibitors have recently come to light. Oxides of metals native to the physiological environment (eg, Fe, Zn, Mg, etc.) are of particular interest-especially the functional consequences of their enzyme interaction. Materials and methods:Here, Fe2O3, zinc oxide (ZnO), magnesium oxide (MgO) and nickel oxide (NiO) NPs are compared to copper (Cu) and boron carbide (B4C) NPs. The functional impact of NP interaction to the model enzyme luciferase is determined by 2-dimensional fluorescence difference spectroscopy (2-D FDS) and 2-dimensional photoluminescence difference spectroscopy (2-D PLDS). By 2-D FDS analysis, the change in maximal intensity and in 2-D FDS area under the curve (AUC) is in the order Cu~B4C>ZnO>NiO>>Fe2O3>MgO. The induced changes in protein conformation are confirmed by tryptic digests and gel electrophoresis. Results:Analysis of possible trypsin cleavage sites suggest that cleavage mostly occurs in the range of residues 112-155 and 372-439, giving a major 45 kDa band. By 2-D PLDS, it is found that B4C NPs completely ablate bioluminescence, while Cu and Fe2O3 NPs yield a unique bimodal negative decay rate, -7.67×103 and -3.50×101 relative light units respectively. Cu NPs, in particular, give a remarkable 271% change in enzyme activity. Molecular dynamics simulations in water predicted that the surfaces of metal oxide NPs become capped with metal hydroxide groups under physiological conditions, while the surface of B4C becomes populated with boronic acid or borinic acid groups. These predictions are supported by the experimentally determined zeta potential. Thin layer chromatography patterns further support this conception of the NP surfaces, where stabilizing interactions were in the order ionic>polar>non-polar for the series tested. Conclusion:Overall the results suggest that B4C and Cu NP functional dynamics on enzyme biochemistry are unique and should be examined further for potential ramifications on other model, physiological or disease-relevant enzymes.

Project description:Zinc oxide nanoparticles (Nano-ZnO) are widely used in sunscreens, clothes, medicine and electronic devices. However, the potential risks of human exposure and the potential for adverse health impacts are not well understood. Previous studies have demonstrated that exposure to Nano-ZnO caused liver damage and hepatocyte apoptosis through oxidative stress, but the molecular mechanisms that are involved in Nano-ZnO-induced hepatotoxicity are still unclear. Endoplasmic reticulum (ER) is sensitive to oxidative stress, and also plays a crucial role in oxidative stress-induced damage. Previous studies showed that ER stress was involved in many chemical-induced liver injuries. We hypothesized that exposure to Nano-ZnO caused oxidative stress and ER stress that were involved in Nano-ZnO-induced liver injury. To test our hypothesis, mice were gavaged with 200 mg/kg or 400 mg/kg of Nano-ZnO once a day for a period of 90 days, and blood and liver tissues were obtained for study. Our results showed that exposure to Nano-ZnO caused liver injury that was reflected by focal hepatocellular necrosis, congestive dilation of central veins, and significantly increased alanine transaminase (ALT) and aspartate transaminase (AST) levels. Exposure to Nano-ZnO also caused depletion of glutathione (GSH) in the liver tissues. In addition, our electron microscope results showed that ER swelling and ribosomal degranulation were observed in the liver tissues from mice treated with Nano-ZnO. The mRNA expression levels of ER stress-associated genes (grp78, grp94, pdi-3, xbp-1) were also up-regulated in Nano-ZnO-treated mice. Nano-ZnO caused increased phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and eukaryotic initiation factor 2? (eIF2?). Finally, we found that exposure to Nano-ZnO caused increased ER stress-associated apoptotic protein levels, such as caspase-3, caspase-9, caspase-12, phosphorylation of JNK, and CHOP/GADD153, and up-regulation of pro-apoptotic genes (chop and bax). These results suggest that oxidative stress and ER stress-induced apoptosis are involved in Nano-ZnO-induced hepatotoxicity in mice.

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Cytotoxicological pathways induced after nanoparticle exposure: studies of oxidative stress at the 'nano-bio' interface.

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