From the Editors Desk, Editors Highlights, Letters to the Editor
(Source: Toxicological Sciences)
Source: Toxicological Sciences - October 27, 2016 Category: Toxicology Tags: Look Inside ToxSci Source Type: research
Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress
(Source: Toxicological Sciences)
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Sun, W., Quan, N., Wang, L., Yang, H., Chu, D., Liu, Q., Zhao, X., Leng, J., Li, J. Tags: Corrigenda Source Type: research
Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons
(Source: Toxicological Sciences)
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Jeitner, T. M., Kalogiannis, M., Krasnikov, B. F., Gomolin, I., Peltier, M. R., Moran, G. R. Tags: Corrigenda Source Type: research
Analysis of the Effects of Cell Stress and Cytotoxicity on In Vitro Assay Activity Across a Diverse Chemical and Assay Space
(Source: Toxicological Sciences)
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Judson, R., Houck, K., Martin, M., Richard, A. M., Knudsen, T. B., Shah, I., Little, S., Wambaugh, J., Setzer, R. W., Kothiya, P., Phuong, J., Filer, D., Smith, D., Reif, D., Rotroff, D., Kleinstreuer, N., Sipes, N., Xia, M., Huang, R., Crofton, K., Thoma Tags: Corrigenda Source Type: research
Effects of BMS-986094, a Guanosine Nucleotide Analogue, on Mitochondrial DNA Synthesis and Function
BMS-986094, the prodrug of a guanosine nucleotide analogue (2'-C-methylguanosine), was withdrawn from clinical trials due to serious safety issues. Nonclinical investigative studies were conducted as a follow up to evaluate the potential for BMS-986094-related mitochondrial-toxicity. In vitro, BMS-986094 was applied to human hepatoma cells (HepG2 and Huh-7) or cardiomyocytes (hiPSCM) up to 19 days to assess mitochondrial DNA content and specific gene expression. There were no mitochondrial DNA changes at concentrations ≤10 µM. Transcriptional effects, such as reductions in Huh-7 MT-ND1 and MT-ND5 mRNA content and ...
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Baumgart, B. R., Wang, F., Kwagh, J., Storck, C., Euler, C., Fuller, M., Simic, D., Sharma, S., Arnold, J. J., Cameron, C. E., Van Vleet, T. R., Flint, O., Bunch, R. T., Davies, M. H., Graziano, M. J., Sanderson, T. P. Tags: Effects of a Guanosine Nucleotide Analogue on Mitochondria Source Type: research
A Demonstration of the Uncertainty in Predicting the Estrogenic Activity of Individual Chemicals and Mixtures From an In Vitro Estrogen Receptor Transcriptional Activation Assay (T47D-KBluc) to the In Vivo Uterotrophic Assay Using Oral Exposure
In vitro estrogen receptor assays are valuable tools for identifying environmental samples and chemicals that display estrogenic activity. However, in vitro potency cannot necessarily be extrapolated to estimates of in vivo potency because in vitro assays are currently unable to fully account for absorption, distribution, metabolism, and excretion. To explore this issue, we calculated relative potency factors (RPF), using 17α-ethinyl estradiol (EE2) as the reference compound, for several chemicals and mixtures in the T47D-KBluc estrogen receptor transactivation assay. In vitro RPFs were used to predict rat oral utero...
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Conley, J. M., Hannas, B. R., Furr, J. R., Wilson, V. S., Gray, L. E. Tags: Uncertainties in Estrogen Activity Predictions in Individual Chemicals and Mixtures Source Type: research
From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinsons Disease Models
Parkinson’s disease (PD) is a progressive neurodegenerative disease that affects ~5 million people around the world. PD etiopathogenesis is poorly understood and curative or disease modifying treatments are not available. Mechanistic studies have identified numerous pathogenic pathways that overlap with many other neurodegenerative diseases. Mutations in the protein optineurin (OPTN) have recently been identified as causative factors for glaucoma and amyotrophic lateral sclerosis. OPTN has multiple recognized roles in neurons, notably in mediating autophagic flux, which has been found to be disrupted in most neurodeg...
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Wise, J. P., Cannon, J. Tags: Optineurin Expression in Rodent Model of Parkinson ' s Disease Source Type: research
Can the Direct Peptide Reactivity Assay Be Used for the Identification of Respiratory Sensitization Potential of Chemicals?
This article further evaluates the ability of the DPRA to predict the respiratory sensitization potential of chemicals. In addition, the added value of applying High Performance Liquid Chromatography (HPLC)-MS and measurements after 20 minutes and 24 hours of incubation was evaluated. Eighteen respiratory sensitizers (10 haptens, 3 prehaptens, and 5 prohaptens) and 14 nonsensitizers were tested with 2-model peptides. Based on peptide depletion, a prediction model was proposed for the identification of (respiratory) sensitizers. Application of mass spectrometry and measurements at 2 time-points increased prediction accuracy...
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Dik, S., Rorije, E., Schwillens, P., van Loveren, H., Ezendam, J. Tags: Direct Peptide Reactivity Assay and Respiratory Sensitization Source Type: research
The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells
The influence of interindividual variability is not typically assessed in traditional toxicological studies. Given that chemical exposures occur in heterogeneous populations, this knowledge gap has the potential to cause undue harm within the realms of public health and industrial and municipal finances. A recent report from the National Research Council (NRC) suggests that when accounting for interindividual variation in responses, traditionally assumed nonlinear dose-response relationships (DRRs) for noncancer-causing endpoints would better be explained with a linear relationship within the low-dose region. To address th...
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Dornbos, P., Crawford, R. B., Kaminski, N. E., Hession, S. L., LaPres, J. J. Tags: Human Variability and Low-Dose Responses of TCDD Source Type: research
Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells
This study has identified for the first time, the additional mitochondrial liabilities of the major metabolite, 2-hydroxyflutamide compared with its parent drug, flutamide. Given the rapid production of this metabolite upon administration of flutamide, but not bicalutamide, we propose that the additional mitochondrial toxicity of 2-hydroxyflutamide may fundamentally contribute to the idiosyncratic DILI seen in flutamide-treated, but not bicalutamide-treated patients. (Source: Toxicological Sciences)
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Ball, A. L., Kamalian, L., Alfirevic, A., Lyon, J. J., Chadwick, A. E. Tags: Metabolite of Flutamide Causes Mitochondrial Dysfunction Source Type: research
From the Cover: Sperm Molecular Biomarkers Are Sensitive Indicators of Testicular Injury following Subchronic Model Toxicant Exposure
Traditional testis histopathology endpoints remain the gold standard for evaluating testicular insult and injury in a non-clinical setting, but are invasive and unfeasible for monitoring these effects clinically in humans. Assessing testicular injury in humans relies on semen and serum hormone analyses, both of which are insensitive and poor indicators of effect. Therefore, we hypothesized that sperm messenger RNA (mRNA) transcripts and DNA methylation marks can be used as translatable and sensitive indicators or testicular injury. Dose–response studies using adult male Fischer 344 rats subchronically exposed to mode...
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Dere, E., Wilson, S. K., Anderson, L. M., Boekelheide, K. Tags: Biomarkers of Testicular Injury in Sperm Source Type: research
New Quantitative Structure-Activity Relationship Models Improve Predictability of Ames Mutagenicity for Aromatic Azo Compounds
In this study, 2 new models were built to predict Ames mutagenicity of this class of compounds. The first one made use of descriptors based on simplified molecular input-line entry system (SMILES), calculated with the CORAL software. The second model was based on the k-nearest neighbors algorithm. The statistical quality of the predictions from single models was satisfactory. The performance further improved when the predictions from these models were combined. The prediction results from other QSAR models for mutagenicity were also evaluated. Most of the existing models were found to be good at finding toxic compounds but...
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Manganelli, S., Benfenati, E., Manganaro, A., Kulkarni, S., Barton-Maclaren, T. S., Honma, M. Tags: Improved QSAR Prediction for Azo Compounds Source Type: research
From the Cover: Tetrachlorobenzoquinone Exerts Neurological Proinflammatory Activity by Promoting HMGB1 Release, Which Induces TLR4 Clustering within the Lipid Raft
Tetrachlorobenzoquinone (TCBQ) is a confirmed active metabolite of a well-known environmental pollutant pentachlorophenol (PCP). Unfortunately, there is insufficient knowledge present available on TCBQ’s toxicity. Our previous studies indicated that TCBQ induces inflammatory response in vivo and in vitro; however, its exact mechanism needs further investigation. Toll-like receptors (TLRs) play a crucial role in conveying of inflammatory signaling, whilst high-mobility group box 1 (HMGB1) functions as a transcription-enhancing nuclear protein that regulates inflammation. Indeed, this study demonstrated that TCBQ induc...
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Fu, J., Shi, Q., Song, X., Liu, Z., Wang, Y., Wang, Y., Song, E., Song, Y. Tags: TCBQ Induces Inflammatory Processes in Neruonal Cells Source Type: research
Editors Highlight: Neonatal Activation of the Xenobiotic-Sensors PXR and CAR Results in Acute and Persistent Down-regulation of PPAR{alpha}-Signaling in Mouse Liver
In conclusion, neonatal exposure to PXR- and CAR-activators both acutely and persistently regulates critical genes involved in xenobiotic and lipid metabolism in liver. (Source: Toxicological Sciences)
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Li, C. Y., Cheng, S. L., Bammler, T. K., Cui, J. Y. Tags: PXR, CAR, and Downregulation of PPARa Signaling Source Type: research
From the Cover: Arsenic Induces Accumulation of {alpha}-Synuclein: Implications for Synucleinopathies and Neurodegeneration
Synucleinopathies, including Parkinson’s disease (PD), are neurodegenerative diseases characterized by accumulation of α-synuclein (SYN), a small neuronal protein with prion like properties that plays a central role in PD pathogenesis. SYN can misfold and generate toxic oligomers/aggregates, which can be cytotoxic. Environmental arsenic (As)-containing pesticide use correlates with increased incidence of PD. Moreover, because As exposure can lead to inhibition of autophagic flux we hypothesize that As can facilitate the accumulation of toxic SYN oligomers/aggregates and subsequent increases in markers of autoph...
Source: Toxicological Sciences - September 25, 2016 Category: Toxicology Authors: Cholanians, A. B., Phan, A. V., Ditzel, E. J., Camenisch, T. D., Lau, S. S., Monks, T. J. Tags: Arsenic, [alpha ]-Synuclein, and Neurodegeneration Source Type: research
