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Toxicological Sciences: An Official Journal of the Society of Toxicology

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https://www.readbyqxmd.com/read/28525648/the-role-of-omics-in-the-application-of-adverse-outcome-pathways-for-chemical-risk-assessment
#1
Erica K Brockmeier, Geoff Hodges, Thomas H Hutchinson, Emma Butler, Markus Hecker, Knut Erik Tollefsen, Natalia Garcia-Reyero, Peter Kille, Dörthe Becker, Kevin Chipman, John Colbourne, Timothy W Collette, Andrew Cossins, Mark Cronin, Peter Graystock, Steve Gutsell, Dries Knapen, Ioanna Katsiadaki, Anke Lange, Stuart Marshall, Stewart F Owen, Edward J Perkins, Stewart Plaistow, Anthony Schroeder, Daisy Taylor, Mark Viant, Gerald Ankley, Francesco Falciani
In conjunction with the second International Environmental Omics Symposium (iEOS) conference, held at the University of Liverpool (UK) in September 2014, a workshop was held to bring together experts in toxicology and regulatory science from academia, government and industry. The purpose of the workshop was to review the specific roles that high-content omics datasets (e.g., transcriptomics, metabolomics, lipidomics, and proteomics) can hold within the adverse outcome pathway (AOP) framework for supporting ecological and human health risk assessments...
May 19, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28525647/evaluation-of-the-effects-of-tanezumab-a-monoclonal-antibody-against-nerve-growth-factor-on-the-sympathetic-nervous-system-in-adult-cynomolgus-monkeys-macaca-fascicularis-a-stereologic-histomorphologic-and-cardiofunctional-assessment
#2
Patrice Belanger, Paul Butler, Mark Butt, Siddhartha Bhatt, Stephen Foote, David Shelton, Mark Evans, Rosalinda Arends, Susan Hurst, Carlin Okerberg, Thomas Cummings, David Potter, Jill Steidl-Nichols, Mark Zorbas
Tanezumab, a humanized monoclonal antibody against nerve growth factor is in development for treatment of chronic pain. Three nonclinical studies assessed effects of clinically relevant and supratherapeutic doses of tanezumab on the sympathetic nervous system (SNS) of adult nonhuman primates. Study 1 evaluated potential effects of subcutaneous (SC) tanezumab (1.2 mg/kg every 8 weeks [Q8W]) on SNS in cynomolgus monkeys for 3 or 6 months and reversibility or persistence of any effects through a non-dosing/recovery period...
May 19, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28525621/ros-induced-store-operated-ca2-entry-coupled-to-parp-1-hyperactivation-is-independent-of-parg-activity-in-necrotic-cell-death
#3
Frances M Munoz, Fengjiao Zhang, Argel Islas-Robles, Serrine S Lau, Terrence J Monks
2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ), a potent nephrotoxic and nephrocarcinogenic metabolite of benzene and hydroquinone, generates reactive oxygen species (ROS) causing DNA strand breaks and the subsequent activation of DNA repair enzymes, including poly(ADP-ribose) polymerase (PARP)-1. Under robust oxidative DNA damage, PARP-1 is hyperactivated, resulting in the depletion of NAD+ and ATP with accompanying elevations in intracellular calcium concentrations (iCa2+), and ultimately necrotic cell death...
May 19, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28525602/aloin-a-component-of-the-aloe-vera-plant-leaf-induces-pathological-changes-and-modulates-the-composition-of-microbiota-in-the-large-intestine-of-f344-n-male-rats
#4
Mary D Boudreau, Greg R Olson, Volodymyr P Tryndyak, Matthew S Bryant, Robert P Felton, Frederick A Beland
In a previous study, the oral administration of an Aloe vera whole leaf extract induced dose-related mucosal and goblet cell hyperplasia in the rat colon after 13-weeks and colon cancer after two years. The primary goal of this study was to determine whether or not the administration of aloin, a component of the Aloe vera plant leaf, would replicate the pathophysiological effects that were observed in rats in the previous study with an Aloe vera whole leaf extract. Groups of 10 male F344/N rats were administered aloin at 0, 6...
May 19, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28521054/in-silico-prediction-of-drug-induced-liver-injury-based-on-adverse-drug-reaction-reports
#5
Xiang-Wei Zhu, Shao-Jing Li
Drug-induced liver injury (DILI) is a major cause of drug attrition. Currently existing Quantitative Structure-Activity Relationship (QSAR) models have limited predictive capabilities for DILI. Furthermore, their practical applications were limited by lack of new hepatotoxicity data. In this study, we first collected and curated a novel set of 122 DILI-positive and 932 DILI-negative drugs from online adverse drug reports using proportional reporting ratios as the signal detection method. Second, three strategies (under-sampling the majority class, synthetic minority over-sampling technique, and adjusting decision threshold approach) were employed to develop predictive classification models to cope with the unbalanced dataset...
May 17, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28521025/mechanism-of-as2o3-induced-action-potential-prolongation-and-using-hips-cms-to-evaluate-the-rescue-efficacy-of-drugs-with-different-rescue-mechanism
#6
Meng Yan, Lifang Feng, Yanhui Shi, Junnan Wang, Yan Liu, Fengmei Li, Baoxin Li
Arsenic trioxide (As2O3) has been verified as a breakthrough in the management of acute promyelocytic leukemia in recent decades. However, cardiotoxicity, especially long QT syndrome (LQTS) has become the most important issue during As2O3 treatment. The characterized mechanisms behind this adverse effect are inhibition of cardiac hERG channel trafficking and increase of cardiac calcium currents. In our study, we found a new pathway underlying As2O3-induced cardiotoxicity that As2O3 accelerates lysosomal degradation of hERG on plasma membrane after using brefeldin A (BFA) to block protein trafficking...
May 17, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28520973/mode-of-action-analysis-for-rat-hepatocellular-tumors-produced-by-the-synthetic-pyrethroid-momfluorothrin-evidence-for-activation-of-the-constitutive-androstane-receptor-car-and-mitogenicity-in-rat-hepatocytes
#7
Yu Okuda, Masahiko Kushida, Kayo Sumida, Hirohisa Nagahori, Yoshimasa Nakamura, Hashihiro Higuchi, Satoshi Kawamura, Brian G Lake, Samuel M Cohen, Tomoya Yamada
High dietary levels of momfluorothrin, a non-genotoxic synthetic pyrethroid, induced hepatocellular tumors in male and female Wistar rats in a 2-year bioassay. The mode of action (MOA) for rat hepatocellular tumors was postulated to occur via activation of the constitutive androstane receptor (CAR), as momfluorothrin is a close structural analogue of the pyrethroid metofluthrin, which is known to produce rat liver tumors through a CAR-mediated MOA. To elucidate the MOA for rat hepatocellular tumor formation by momfluorothrin, this study was conducted to examine effects on key and associative events of the CAR-mediated MOA for phenobarbital based on the International Programme on Chemical Safety (IPCS) framework...
May 17, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28510766/detection-of-3-3-dichlorobiphenyl-in-human-maternal-plasma-and-its-effects-on-axonal-and-dendritic-growth-in-primary-rat-neurons
#8
Sunjay Sethi, Kimberly P Keil, Hao Chen, Keri Hayakawa, Xueshu Li, Yanping Lin, Hans-Joachim Lehmler, Birgit Puschner, Pamela J Lein
3,3'-Dichlorobiphenyl (PCB 11), a byproduct of pigment production, is increasingly detected in environmental samples. While more highly chlorinated PCB congeners are known developmental neurotoxicants, nothing is known about the potential developmental neurotoxicity of PCB 11. To address this critical data gap, we measured PCB 11 levels in human maternal plasma and quantified the effects of PCB 11 and its major metabolites on morphometric parameters of neuronal connectivity in cultured primary neurons. Mass spectrometry analyses of plasma from 241 pregnant women enrolled in the MARBLES study (University of California, Davis) detected PCB 11 in all samples at concentrations ranging from 0...
May 16, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28505381/insulin-resistance-disrupts-the-interaction-between-akt-and-the-nmda-receptor-and-the-inactivation-of-the-camkiv-creb-pathway-in-minimal-hepatic-encephalopathy
#9
Saidan Ding, Weishan Zhuge, Jianjing Yang, Fangfang Wen, Zhu Xu, Xuebao Wang, Qichuan Zhuge
Hepatic cirrhosis-induced Minimal hepatic encephalopathy (MHE) has been characterized for cognitive dysfunction and central nervous system (CNS) insulin resistance (IR) has been acknowledged to be closely correlated with cognitive impairment while hepatic cirrhosis has been recognized to induce IR . Thus, this study aimed to investigate whether CNS IR occurred in MHE and induced MHE, as well as the underlying mechanism. We found IR in the MHE rats, an especially decreased level of the insulin receptor (InsR), and an increased serine phosphorylation of IRS1 in CNS...
May 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28505368/farnesoid-x-receptor-protects-against-low-dose-carbon-tetrachloride-induced-liver-injury-through-the-taurocholate-jnk-pathway
#10
Shogo Takahashi, Naoki Tanaka, Srujana Golla, Tatsuki Fukami, Kristopher W Krausz, Marianne A Polunas, Blair C Weig, Yusuke Masuo, Cen Xie, Changtao Jiang, Frank J Gonzalez
Hepatotoxicity is of major concern for humans exposed to industrial chemicals and drugs. Disruption of farnesoid X receptor (FXR), a master regulator of bile acid (BA) metabolism, enhanced the sensitivity to liver injury in mice after toxicant exposure, but the precise mechanism remains unclear. In this study, the interconnection between BA metabolism, FXR, and chemically-induced hepatotoxicity was investigated using metabolomics, Fxr-null mice and hepatocytes, and adenovirus. A single low-dose intraperitoneal injection of carbon tetrachloride (CCl4), an inducer of acute hepatitis in mice, resulted in more severe hepatocyte damage and higher induction of pro-inflammatory mediators, such as chemokine (C-C motif) ligand 2 (Ccl2), in Fxr-null mice...
May 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28505332/a-comparative-benchmark-dose-study-for-n-n-dimethylformamide-induced-liver-injury-in-a-chinese-occupational-cohort
#11
Zhijun Wu, Qiang Liu, Chunmin Wang, Bo Xu, Mingyue Guan, Meng Ye, Hai Jiang, Min Zheng, Man Zhang, Wenjin Zhao, Xiao Jiang, Shuguang Leng, Juan Cheng
Widespread contamination of N,N-dimethylformamide (DMF) has been identified in the environment of leather industries and their surrounding residential areas. Few studies have assessed the dose-response relationships between internal exposure biomarkers and liver injury in DMF exposed populations. We assessed urinary N-methylformamide (NMF) and N-acetyl-S-(N-methylcarbamoyl) cysteine (AMCC) and blood N-methylcarbmoylated hemoglobin (NMHb) levels in 698 Chinese DMF-exposed workers and 188 Non-DMF- exposed workers using ultra-performance liquid-chromatography tandem mass-spectrometry...
May 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28505322/exosomes-in-toxicology-relevance-to-chemical-exposure-and-pathogenesis-of-environmentally-linked-diseases
#12
Dilshan S Harischandra, Shivani Ghaisas, Dharmin Rokad, Anumantha G Kanthasamy
Chronic exposure to environmental toxins has been known to initiate or aggravate various neurological disorders, carcinomas and other adverse health effects. Uptake by naïve cells of pathogenic factors such as danger-associated molecules, mRNAs, miRNAs or aggregated proteins leads to disruption in cellular homeostasis further resulting in inflammation and disease propagation. While early research tended to focus solely on exosomal removal of unwanted cellular contents, more recent reports indicate that these nano-vesicles play an active role in intercellular signaling...
May 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28498972/development-of-a-combined-in-vitro-physiologically-based-kinetic-pbk-and-monte-carlo-modelling-approach-to-predict-interindividual-human-variation-in-phenol-induced-developmental-toxicity
#13
Marije Strikwold, Bert Spenkelink, Ruud A Woutersen, Ivonne M C M Rietjens, Ans Punt
With our recently developed in vitro physiologically based kinetic (PBK) modelling approach we could extrapolate in vitro toxicity data to human toxicity values applying PBK-based reverse dosimetry. Ideally information on kinetic differences among human individuals within a population should be considered. In the present study we demonstrated a modelling approach that integrated in vitro toxicity data, PBK modelling and Monte Carlo simulations to obtain insight in interindividual human kinetic variation and derive chemical specific adjustment factors (CSAFs) for phenol induced developmental toxicity...
May 11, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28486674/modifying-role-of-endothelial-function-gene-variants-on-the-association-of-long-term-pm2-5-exposure-with-blood-dna-methylation-age-the-va-normative-aging-study
#14
Jamaji C Nwanaji-Enwerem, Marie-Abele Bind, Lingzhen Dai, Youssef Oulhote, Elena Colicino, Qian Di, Allan C Just, Lifang Hou, Pantel Vokonas, Brent A Coull, Marc G Weisskopf, Andrea A Baccarelli, Joel D Schwartz
Recent studies have reported robust associations of long-term PM2.5 exposure with DNA methylation-based measures of aging; yet, the molecular implications of these relationships remain poorly understood. We evaluated if genetic variation in three biological pathways implicated in PM2.5-related disease - oxidative stress, endothelial function, and metal processing - could modify the effect of PM2.5 on DNAm-age, one prominent DNA methylation-based measure of biological age. This analysis was based on 552 individuals from the Normative Aging Study with at least one visit between 2000 and 2011 (n = 940 visits)...
May 9, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28486596/troglitazone-inhibits-bile-acid-amidation-a-possible-risk-factor-for-liver-injury
#15
Eiichiro Ogimura, Tetsuya Nakagawa, Jiro Deguchi, Shuichi Sekine, Kousei Ito, Kiyoko Bando
Troglitazone and pioglitazone were developed as thiazolidinedione-type anti-diabetes drugs, but only troglitazone was withdrawn from the markets due to severe liver injury. As both troglitazone and its sulfate metabolite are strong inhibitors of the bile salt export pump (BSEP), troglitazone-induced bile acid (BA) retention is thought to be one of the underlying mechanisms of liver injury. However, pioglitazone is also a strong BSEP inhibitor, indicating other mechanisms may also be involved in troglitazone-induced BA retention...
May 9, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28482088/therapeutic-concentrations-of-antidepressants-inhibit-pancreatic-beta-cell-function-via-mitochondrial-complex-inhibition
#16
Ekramy Elmorsy, Ayat Al-Ghafari, Ahmed N M Helaly, Ahmed S Hisab, Bettina Oehrle, Paul A Smith
Diabetes mellitus risk is increased by prolonged usage of antidepressants (ADs). Although various mechanisms are suggested for their diabetogenic potential, whether a direct effect of ADs on pancreatic β-cells is involved is unclear. We examined this idea for three ADs: paroxetine, clomipramine and, with particular emphasis, fluoxetine, on insulin secretion, mitochondrial function, cellular bioenergetics, KATP channel activity and caspase activity in murine and human cell-line models of pancreatic β-cells...
May 8, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28482072/endoplasmic-reticulum-stress-induced-chop-inhibits-pgc-1%C3%AE-and-causes-mitochondrial-dysfunction-in-diabetic-embryopathy
#17
Xi Chen, Jianxiang Zhong, Daoyin Dong, Gentao Liu, Peixin Yang
Endoplasmic reticulum (ER) stress has been implicated in the development of maternal diabetes-induced neural tube defects (NTDs). ER stress-induced C/EBP homologous protein (CHOP) plays an important role in the pro-apoptotic execution pathways. However, the molecular mechanism underlying ER stress- and CHOP-induced neuroepithelium cell apoptosis in diabetic embryopathy are still unclear. Deletion of the Chop gene significantly reduced maternal diabetes-induced NTDs. CHOP deficiency abrogated maternal diabetes-induced mitochondrial dysfunction and neuroepithelium cell apoptosis...
May 8, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28482051/biomarkers-of-chronic-acrolein-inhalation-exposure-in-mice-implications-for-tobacco-product-induced-toxicity
#18
Daniel J Conklin, Marina V Malovichko, Iris Zeller, Trinath P Das, Tatiana V Krivokhizhina, Blake H Lynch, Pawel Lorkiewicz, Abhinav Agarwal, Nalinie Wickramasinghe, Petra Haberzettl, Srinivas D Sithu, Jasmit Shah, Timothy E O'Toole, Shesh N Rai, Aruni Bhatnagar, Sanjay Srivastava
Exposure to tobacco smoke, which contains several harmful and potentially harmful constituents such as acrolein increases cardiovascular disease (CVD) risk. Although high acrolein levels induce pervasive cardiovascular injury, the effects of low-level exposure remain unknown and sensitive biomarkers of acrolein toxicity have not been identified. Identification of such biomarkers is essential to assess the toxicity of acrolein present at low levels in the ambient air or in new tobacco products such as e-cigarettes...
May 8, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28472426/chemical-or-drug-hypersensitivity-is-the-immune-system-clearing-the-danger
#19
Marc Pallardy, Rami Bechara
Hypersensitivity reaction or allergy, initially perceived as a secondary disorder, is now believed to be a major public health. For instance, contact dermatitis is a type IV delayed-type hypersensitivity reaction to skin allergens. An estimated 15-20% of the general population has acquired contact allergy. To maintain immune tolerance our immune system need to differentiate between harmful non-self and innocuous non-self. Living organisms have developed during their evolution a set of biological mechanisms to protect them from the "outside": physical barrier, inflammation, cell-based mechanisms, metabolism and elimination and biochemical pathways such as glutathione...
May 4, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28472532/high-throughput-screening-data-interpretation-in-the-context-of-in-vivo-transcriptomic-responses-to-oral-cr-vi-exposure
#20
Julia E Rager, Caroline L Ring, Rebecca C Fry, Mina Suh, Deborah M Proctor, Laurie C Haws, Mark A Harris, Chad M Thompson
The toxicity of hexavalent chromium [Cr(VI)] in drinking water has been studied extensively, and available in vivo and in vitro studies provide a robust dataset for application of advanced toxicological tools to inform the mode of action (MOA). This study aimed to contribute to the understanding of Cr(VI) MOA by evaluating high-throughput screening (HTS) data and other in vitro data relevant to Cr(VI), and comparing these findings to robust in vivo data, including transcriptomic profiles in target tissues. Evaluation of Tox21 HTS data for Cr(VI) identified 11 active assay endpoints relevant to the Ten Key Characteristics of Carcinogens (TKCCs) that have been proposed by other investigators...
May 2, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
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