The Lack of Mutagenic Potential of a Guanine-Rich Triplex Forming Oligonucleotide in Physiological Conditions
Triplex forming oligonucleotides (TFOs) bind in the major groove of DNA duplex in a sequence-specific manner imparted by Hoogsteen hydrogen bonds. There have been several reports demonstrating the ability of guanine-rich TFOs to induce targeted mutagenesis on an exogenous plasmid or an endogenous chromosomal locus. In particular, a 30mer guanine-rich triplex forming oligonucleotide, AG30, optimally designed to target the supFG1 reporter gene was reported to be mutagenic in the absence of DNA reactive agents in cultured cells and in vivo. Here, we investigated the mutagenic potential of AG30 using the supFG1 shuttle vector ...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Saleh, A. F., Fellows, M. D., Ying, L., Gooderham, N. J., Priestley, C. C. Tags: Guanine-Rich Triplix Forming Oligonucleotide is not Mutagenic Source Type: research
Editors Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis
The developmental origins of obesity hypothesis posits a multifaceted contribution of factors to the fetal origins of obesity and metabolic disease. Adipocyte hyperplasia in gestation and early childhood may result in predisposition for obesity later in life. Rodent in vitro and in vivo studies indicate that some chemicals may directly affect adipose progenitor cell differentiation, but the human relevance of these findings is unclear. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARG) is the master regulator of adipogenesis. Human adipose-derived stem cells (hASC) isolated from adipose tissue ex...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Foley, B., Doheny, D. L., Black, M. B., Pendse, S. N., Wetmore, B. A., Clewell, R. A., Andersen, M. E., Deisenroth, C. Tags: PPAR-Gamma in ToxCast Chemicals Source Type: research
Is There a Critical Period for the Developmental Neurotoxicity of Low-Level Tobacco Smoke Exposure?
Secondhand tobacco smoke exposure in pregnancy increases the risk of neurodevelopmental disorders. We evaluated in rats whether there is a critical period during which tobacco smoke extract (TSE) affects the development of acetylcholine and serotonin systems, prominent targets for adverse effects of nicotine and tobacco smoke. We simulated secondhand smoke exposure by administering TSE so as to produce nicotine concentrations one-tenth those in active smoking, with 3 distinct, 10-day windows: premating, early gestation or late gestation. We conducted longitudinal evaluations in multiple brain regions, starting in early ado...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Slotkin, T. A., Stadler, A., Skavicus, S., Card, J., Ruff, J., Levin, E. D., Seidler, F. J. Tags: Critical Periods of Developmental Neurotoxicity for Tobacco Smoke Source Type: research
Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors
This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Woodhead, J. L., Brock, W. J., Roth, S. E., Shoaf, S. E., Brouwer, K. L. R., Church, R., Grammatopoulos, T. N., Stiles, L., Siler, S. Q., Howell, B. A., Mosedale, M., Watkins, P. B., Shoda, L. K. M. Tags: Mechanisms of Tolvaptan-Induced Liver Injury Source Type: research
High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells
This study developed and validated an automated multi-parametric high-content analysis (HCA) using the C18-4 spermatogonial cell line as a model. We applied these validated HCA, including nuclear morphology, DNA content, cell cycle progression, DNA synthesis, cytoskeleton integrity, and DNA damage responses, to characterize and compare the testicular toxicities of BPA and 3 selected commercial available BPA analogues, BPS, BPAF, and TBBPA. HCA revealed BPAF and TBBPA exhibited higher spermatogonial toxicities as compared with BPA and BPS, including dose- and time-dependent alterations in nuclear morphology, cell cycle, DNA...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Liang, S., Yin, L., Shengyang Yu, K., Hofmann, M.-C., Yu, X. Tags: High-Content Analysis of BPA-Induced Testicular Toxicity Source Type: research
Calcium-Sensing Receptor and Transient Receptor Ankyrin-1 Mediate Emesis Induction by Deoxynivalenol (Vomitoxin)
The common foodborne mycotoxin deoxynivalenol (DON, vomitoxin) can negatively impact animal and human health by causing food refusal and vomiting. Gut enteroendocrine cells (EECs) secrete hormones that mediate DON’s anorectic and emetic effects. In prior work utilizing a cloned EEC model, our laboratory discovered that DON-induced activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor (GPCR), and transient receptor ankyrin-1 (TRPA1), a transient receptor potential (TRP) channel, drives Ca2+-mediated hormone secretion. Consistent with these in vitro findings, CaSR and TRPA1 mediate DON-induced sat...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Wu, W., Zhou, H.-R., Bursian, S. J., Link, J. E., Pestka, J. J. Tags: Mechanisms of Denoxynivalenol (Vomitoxin) Emesis Source Type: research
Table of Contents
(Source: Toxicological Sciences)
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Tags: Standing Material Source Type: research
Subscriptions
(Source: Toxicological Sciences)
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Tags: Standing Material Source Type: research
Long Non-Coding RNAs: A Novel Paradigm for Toxicology
Long non-coding RNAs (lncRNAs) are over 200 nucleotides in length and are transcribed from the mammalian genome in a tissue-specific and developmentally regulated pattern. There is growing recognition that lncRNAs are novel biomarkers and/or key regulators of toxicological responses in humans and animal models. Lacking protein-coding capacity, the numerous types of lncRNAs possess a myriad of transcriptional regulatory functions that include cis and trans gene expression, transcription factor activity, chromatin remodeling, imprinting, and enhancer up-regulation. LncRNAs also influence mRNA processing, post-transcriptional...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Dempsey, J. L., Cui, J. Y. Tags: Contemporary Review: Long Noncoding RNAs in Toxicology Source Type: research
Editorial Board
(Source: Toxicological Sciences)
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Tags: Standing Material Source Type: research
Role of Mitochondrial Toxicity in BMS-986094-Induced Toxicity
(Source: Toxicological Sciences)
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Feng, J. Y., Tay, C. H., Ray, A. S. Tags: LETTERS TO THE EDITOR Source Type: research
Cover
(Source: Toxicological Sciences)
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Tags: Cover Source Type: research
From the Editors Desk, Editors Highlights
(Source: Toxicological Sciences)
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Tags: Look Inside ToxSci Source Type: research
Detection of Primary T Cell Responses to Drugs and Chemicals in HLA-Typed Volunteers: Implications for the Prediction of Drug Immunogenicity
A number of serious adverse drug reactions are caused by T cells. An association with HLA alleles has been identified with certain reactions, which makes it difficult to develop standardized preclinical tests to predict chemical liability. We have recently developed a T cell priming assay using the drug metabolite nitroso sulfamethoxazole (SMX-NO). We now report on reproducibility of the assay, establishment of a biobank of PBMC from 1000 HLA-typed volunteers, and generation of antigen-specific responses to a panel of compounds. Forty T cell priming assays were performed with SMX-NO; 5 gave weak responses (1.5–1.9) a...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Faulkner, L., Gibson, A., Sullivan, A., Tailor, A., Usui, T., Alfirevic, A., Pirmohamed, M., Naisbitt, D. J., Kevin Park, B. Tags: HLA-Typing in Humans and Prediction of Drug Immunogenicity Source Type: research
Transient Proteotoxicity of Bacterial Virulence Factor Pyocyanin in Renal Tubular Epithelial Cells Induces ER-Related Vacuolation and Can Be Efficiently Modulated by Iron Chelators
We report here that renal tubular epithelial cell (RTEC) line NRK-52E responds to PCN treatments with paraptosis-like activity features. Specifically, PCN-treated cells experienced dilation of endoplasmic reticulum (ER) and an extensive development of ER-derived vacuoles after about 8 h. This process was accompanied with hyper-activation of proteotoxic stress-inducible transcription factors Nrf2, ATF6, and HSF-1. The cells could be rescued by withdrawal of PCN from the culture media before the vacuoles burst and cells die of non-programmed necrosis after about 24–30 h. The paraptosis-like activity was abrogated by co...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Mossine, V. V., Waters, J. K., Chance, D. L., Mawhinney, T. P. Tags: Bacterial Virulence Factor Pyocyanin Effects on Renal Epithelial Cells Source Type: research
