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Chushak Y.G.,Foundation Medicine | Chapleau R.R.,Foundation Medicine | Frey J.S.,Foundation Medicine | Mauzy C.A.,Molecular Bioeffects Branch | Gearhart J.M.,Foundation Medicine
Toxicology Research | Year: 2015

The toxicity of chemicals greatly depends on their interaction with macromolecular targets. The main goal of this study was to develop an approach for predicting protein targets for chemical toxins using a molecular similarity search of toxin-target information collected in the Toxin and Toxin-Target Database. The developed method was used to identify new targets for toluene which could predict potential cellular toxicity and to validate the approach with in vitro laboratory studies. We obtained 124 potential targets for toluene from a molecular similarity search. Results were further analysed using in silico molecular docking methods. The binding of toluene to two proteins, hemoglobin and serum albumin, was validated by the measurement of binding using microscale thermophoresis. The measured binding constant between toluene and hemoglobin was 1.9 μM, while albumin demonstrated toluene-induced aggregation. These results demonstrate the applicability of an exploratory in silico toxicity tool, based on a molecular similarity search and protein-ligand docking, for identification of potential targets for chemical toxins. © 2015 The Royal Society of Chemistry. Source

Fisher J.,National Center for Toxicological Research (NCTR) | Lumen A.,National Center for Toxicological Research (NCTR) | Latendresse J.,National Center for Toxicological Research (NCTR) | Mattie D.,Molecular Bioeffects Branch
Journal of Environmental Science and Health - Part C Environmental Carcinogenesis and Ecotoxicology Reviews | Year: 2012

Functional aspects of the Hypothalamic-Pituitary-Thyroid (HPT) axis in rats and humans are compared, exposing why extrapolation of toxicant-induced perturbations in the rat HPT axis to the human HPT axis cannot be accomplished using default risk assessment methodology. Computational tools, such as biologically based dose response models for the HPT axis, are recommended to perform complex animal to human extrapolations involving the HPT axis. Experimental and computational evidence are presented that suggest perchlorate acts directly on the thyroid gland in rats. The apparent escape from perchlorate-induced inhibition of thyroidal uptake of radioactive iodide in humans is discussed along with rebound or increased thyroidal uptake of radioactive iodide observed after discontinued clinical treatment with perchlorate. © 2012 Copyright Taylor and Francis Group, LLC. Source

Braun N.J.,Molecular Bioeffects Branch | Braun N.J.,Purdue University | Comfort K.K.,Molecular Bioeffects Branch | Comfort K.K.,University of Dayton | And 2 more authors.
BioNanoScience | Year: 2013

Due to their tremendous antimicrobial properties, silver nanoparticles (AgNPs) have become incorporated into a number of consumer, industrial, and medical applications. However, AgNPs have also been shown to induce a strong cytotoxic response, brought on by an excess of cellular stress, which has severely limited the inclusion of AgNPs in nano-based biological applications, including drug delivery and bioimaging techniques. Previous investigations into magnetic field (MF) exposure have determined the potential of MFs to reduce the stress response in cellular systems; however, the ability of MF to protect cells from AgNPs has never been explored. As such, this study sought to identify if concurrent exposure to AgNPs and a 30-mT static MF could produce a diminishment of the cytotoxic and stress responses in a murine neural stem cell line (NE-4C). We discovered that the presence of MF provided a layer of protection from the negative AgNP effects, with a 15 % increase in viability noted up to a threshold concentration of 10 μg/mL. This partial recovery of AgNP-dependent cytotoxicity was found to correlate with increased ki67 expression and a substantial decrease in the NE-4C stress response including reactive oxygen species generation and NFκB and c-Jun expression. As neurological models are highly susceptible to stress, this study identified MF stimulation as a potential mechanism to counteract detrimental AgNP effects in neural cells, thereby demonstrating that a joint AgNP and MF system may be advantageous to progress neurological nano-based applications. © 2013 Springer Science+Business Media New York. Source

Debrosse M.C.,Molecular Bioeffects Branch | Debrosse M.C.,Clark University | Comfort K.K.,University of Dayton | Untener E.A.,Molecular Bioeffects Branch | And 3 more authors.
Materials Science and Engineering C | Year: 2013

Due to their unique properties, gold nanorods (GNRs) have shown tremendous potential for advancing bio-imaging and sensing applications. As these nanoparticles display size-dependent optical properties, high aspect ratio GNRs are of particular interest for these applications because of their increased scattering contrast. While studies are emerging that demonstrate successful synthesis of high aspect ratio GNRs, their behavior and fate in a physiological environment has yet to be investigated. The goal of this study was to evaluate the rate of cellular internalization and cytotoxicity of long GNRs (aspect ratio 32) in a human keratinocyte cell line. Additionally, the critical role of surface chemistry in extent of cellular interactions and cytotoxicity was evaluated. Through comparison with aspect ratio 3 GNRs, it was identified that high aspect ratio GNRs displayed enhanced cellular internalization. Furthermore, surface functionalization dictated the quantity of GNRs internalized, with tannic acid having a significant increase over polyethylene glycol. However, the augmented intracellular concentration identified with long, tannic acid GNRs resulted in a considerable degree of cytotoxicity, which was not associated with other GNR conditions. Therefore, while the inclusion of high aspect ratio GNRs may increase the capabilities for nano-based applications, there exist some unintentional toxicological consequences that must also be considered. © 2013 Elsevier B.V. Source

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