Identification of Genes That Modulate Susceptibility to Formaldehyde and Imatinib by Functional Genomic Screening in Human Haploid KBM7 Cells
Though current functional genomic screening systems are useful for investigating human susceptibility to chemical toxicity, they have limitations. Well-established, high-throughput yeast mutant screens identify only evolutionarily conserved processes. RNA interference can be applied in human cells but is limited by incomplete gene knockout and off-target effects. Human haploid cell screening is advantageous as it requires knockdown of only a single copy of each gene. A human haploid cell mutant library (KBM7-Mu), derived from a chronic myeloid leukemia (CML) patient, was recently developed and has been used to identify gen...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Shen, H., McHale, C. M., Haider, S. I., Jung, C., Zhang, S., Smith, M. T., Zhang, L. Tags: Functional Genomic Screening in a Human Haploid Cell Line Source Type: research
Table of Contents
(Source: Toxicological Sciences)
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Tags: Standing Material Source Type: research
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(Source: Toxicological Sciences)
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Tags: Standing Material Source Type: research
Editorial Board
(Source: Toxicological Sciences)
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Tags: Standing Material Source Type: research
Setting Occupational Exposure Limits for Genotoxic Substances in the Pharmaceutical Industry
In the pharmaceutical industry, genotoxic drug substances are developed for life-threatening indications such as cancer. Healthy employees handle these substances during research, development, and manufacturing; therefore, safe handling of genotoxic substances is essential. When an adequate preclinical dataset is available, a risk-based decision related to exposure controls for manufacturing is made following a determination of safe health-based limits, such as an occupational exposure limit (OEL). OELs are calculated for substances based on a threshold dose-response once a threshold is identified. In this review, we prese...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Lovsin Barle, E., Winkler, G. C., Glowienke, S., Elhajouji, A., Nunic, J., Martus, H.-J. Tags: Contemporary Review: Occupational Exposure Limits for Pharmaceutical Industry Source Type: research
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(Source: Toxicological Sciences)
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Tags: Cover Source Type: research
From the Editors Desk, Editors Highlights
(Source: Toxicological Sciences)
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Tags: Look Inside Toxsci Source Type: research
Integrating Publicly Available Data to Generate Computationally Predicted Adverse Outcome Pathways for Fatty Liver
New in vitro testing strategies make it possible to design testing batteries for large numbers of environmental chemicals. Full utilization of the results requires knowledge of the underlying biological networks and the adverse outcome pathways (AOPs) that describe the route from early molecular perturbations to an adverse outcome. Curation of a formal AOP is a time-intensive process and a rate-limiting step to designing these test batteries. Here, we describe a method for integrating publicly available data in order to generate computationally predicted AOP (cpAOP) scaffolds, which can be leveraged by domain experts to sh...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Bell, S. M., Angrish, M. M., Wood, C. E., Edwards, S. W. Tags: Computational Approach to Develop Fatty Liver AOPs Source Type: research
Organophosphate Flame Retardants Act as Endocrine-Disrupting Chemicals in MA-10 Mouse Tumor Leydig Cells
In conclusion, all the OPFRs tested affected mitochondrial activity, cell survival, and superoxide production. Basal or stimulated steroid secretion was affected by all of the OPFRs except triphenyl phosphate; BDE-47 had no effect. Hence, the OPFRs currently used as alternatives affect Leydig cells to a greater extent than the brominated flame retardants that they have replaced. (Source: Toxicological Sciences)
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Schang, G., Robaire, B., Hales, B. F. Tags: OP Flame Retardants and Endocrine Disruption Source Type: research
MMP-9-Dependent Serum-Borne Bioactivity Caused by Multiwalled Carbon Nanotube Exposure Induces Vascular Dysfunction via the CD36 Scavenger Receptor
In conclusion, pulmonary exposure to MWCNT leads to elevated MMP-9 levels and MMP-9-dependent generation of circulating bioactive factors that promote endothelial dysfunction and decreased NO bioavailability via interaction with vascular CD36. (Source: Toxicological Sciences)
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Aragon, M., Erdely, A., Bishop, L., Salmen, R., Weaver, J., Liu, J., Hall, P., Eye, T., Kodali, V., Zeidler-Erdely, P., Stafflinger, J. E., Ottens, A. K., Campen, M. J. Tags: Carbon Nanotube and Vascular Function Source Type: research
Silver Nanoparticle-Induced Autophagic-Lysosomal Disruption and NLRP3-Inflammasome Activation in HepG2 Cells Is Size-Dependent
The objective of this study was to determine the mechanism of size- and concentration-dependent cytotoxicity of AgNPs in human liver-derived hepatoma (HepG2) cells. Mechanisms of toxicity were explored at subcytotoxic concentrations (≤10 µg/ml AgNPs) and autophagy induction, lysosomal activity, inflammasome-dependent caspase-1 activation, and apoptosis were examined. Using enhanced dark-field light microscopy, hyperspectral imaging, electron microscopy, and energy dispersive X-ray spectroscopy, AgNPs were shown to rapidly accumulate in cytoplasmic vesicles for up to 24 h and 10-nm AgNPs exhibited the highest uptak...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Mishra, A. R., Zheng, J., Tang, X., Goering, P. L. Tags: Silver Nanoparticles, Autophagy, and Inflammation Source Type: research
Zinc-Oxide Nanoparticles Exhibit Genotoxic, Clastogenic, Cytotoxic and Actin Depolymerization Effects by Inducing Oxidative Stress Responses in Macrophages and Adult Mice
Zinc oxide nanoparticles (ZnO-NPs) have wide biological applications, which have raised serious concerns about their impact on the health and environment. Although, various studies have shown ZnO-NP toxicity on different cells under in vitro conditions, sufficient information is lacking regarding toxicity and underlying mechanisms under in vivo conditions. In this work, we investigated genotoxic, clastogenic, and cytotoxic effects of ZnO-NPs on macrophages and in adult mice. ZnO-NP-treated mice showed signs of toxicity such as loss in body weight, passive behavior and reduced survival. Further mechanistic studies revealed ...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Pati, R., Das, I., Mehta, R. K., Sahu, R., Sonawane, A. Tags: Zinc Oxide Nanoparticle and Integrity of DNA and Cytoskeleton Source Type: research
PBPK Model for Atrazine and Its Chlorotriazine Metabolites in Rat and Human
The previously-published physiologically based pharmacokinetic model for atrazine (ATZ), deisopropylatrazine (DIA), deethylatrazine (DEA), and diaminochlorotriazine (DACT), which collectively comprise the total chlorotriazines (TCT) as represented in this study, was modified to allow for scaling to humans. Changes included replacing the fixed dose-dependent oral uptake rates with a method that represented delayed absorption observed in rats administered ATZ as a bolus dose suspended in a methylcellulose vehicle. Rate constants for metabolism of ATZ to DIA and DEA, followed by metabolism of DIA and DEA to DACT were predicte...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Campbell, J. L., Andersen, M. E., Hinderliter, P. M., Yi, K. D., Pastoor, T. P., Breckenridge, C. B., Clewell, H. J. Tags: Pharmacokinetic Modeling of Atrazine and Metabolites Source Type: research
In Utero and Lactational TCDD Exposure Increases Susceptibility to Lower Urinary Tract Dysfunction in Adulthood
Benign prostatic hyperplasia, prostate cancer, and changes in the ratio of circulating testosterone and estradiol often occur concurrently in aging men and can lead to lower urinary tract (LUT) dysfunction. To explore the possibility of a fetal basis for the development of LUT dysfunction in adulthood, Tg(CMV-cre);Nkx3-1+/–;Ptenfl/+ mice, which are genetically predisposed to prostate neoplasia, were exposed in utero and during lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1 μg/kg po) or corn oil vehicle (5 ml/kg) after a single maternal dose on 13 days post coitus, and subsequently were aged without furt...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Ricke, W. A., Lee, C. W., Clapper, T. R., Schneider, A. J., Moore, R. W., Keil, K. P., Abler, L. L., Wynder, J. L., Lopez Alvarado, A., Beaubrun, I., Vo, J., Bauman, T. M., Ricke, E. A., Peterson, R. E., Vezina, C. M. Tags: Developmental TCDD Exposure and Urinary Tract Function Source Type: research
Toxicological Assessment of CoO and La2O3 Metal Oxide Nanoparticles in Human Small Airway Epithelial Cells
Cobalt monoxide (CoO) and lanthanum oxide (La2O3) nanoparticles are 2 metal oxide nanoparticles with different redox potentials according to their semiconductor properties. By utilizing these two nanoparticles, this study sought to determine how metal oxide nanoparticle’s mode of toxicological action is related to their physio-chemical properties in human small airway epithelial cells (SAEC). We investigated cellular toxicity, production of superoxide radicals and alterations in gene expression related to oxidative stress, and cellular death at 6 and 24 h following exposure to CoO and La2O3 (administered doses: 0, 5,...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Sisler, J. D., Pirela, S. V., Shaffer, J., Mihalchik, A. L., Chisholm, W. P., Andrew, M. E., Schwegler-Berry, D., Castranova, V., Demokritou, P., Qian, Y. Tags: Effects of Metal Oxide Nanoparticles of Airway Epithelium Source Type: research
