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https://www.readbyqxmd.com/read/29216352/identification-of-estrogen-related-receptor-alpha-agonists-in-the-tox21-compound-library
#1
Caitlin Lynch, Jinghua Zhao, Ruili Huang, Noriko Kanaya, Lauren Bernal, Jui-Hua Hsieh, Scott S Auerbach, Kristine L Witt, B Alex Merrick, Shiuan Chen, Christina T Teng, Menghang Xia
The estrogen-related receptor alpha (ERRα) is an orphan nuclear receptor (NR) that plays a role in energy homeostasis and controls mitochondrial oxidative respiration. Increased expression of ERRα in certain ovarian, breast, and colon cancers has a negative prognosis, indicating an important role for ERRα in cancer progression. An interaction between ERRα and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has also recently been shown to regulate an enzyme in the β-oxidation of free fatty acids, thereby suggesting that ERRα plays an important role in obesity and type 2 diabetes...
December 4, 2017: Endocrinology
https://www.readbyqxmd.com/read/29182974/suspect-screening-and-non-targeted-analysis-of-drinking-water-using-point-of-use-filters
#2
Seth R Newton, Rebecca L McMahen, Jon R Sobus, Kamel Mansouri, Antony J Williams, Andrew D McEachran, Mark J Strynar
Monitored contaminants in drinking water represent a small portion of the total compounds present, many of which may be relevant to human health. To understand the totality of human exposure to compounds in drinking water, broader monitoring methods are imperative. In an effort to more fully characterize the drinking water exposome, point-of-use water filtration devices (Brita® filters) were employed to collect time-integrated drinking water samples in a pilot study of nine North Carolina homes. A suspect screening analysis was performed by matching high resolution mass spectra of unknown features to molecular formulas from EPA's DSSTox database...
November 25, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/29146384/identification-of-candidate-reference-chemicals-for-in-vitro-steroidogenesis-assays
#3
Caroline Lucia Pinto, Kristan Markey, David Dix, Patience Browne
The Endocrine Disruptor Screening Program (EDSP) is transitioning from traditional testing methods to integrating ToxCast/Tox21 in vitro high-throughput screening assays for identifying chemicals with endocrine bioactivity. The ToxCast high-throughput H295R steroidogenesis assay may potentially replace the low-throughput assays currently used in the EDSP Tier 1 battery to detect chemicals that alter the synthesis of androgens and estrogens. Herein, we describe an approach for identifying in vitro candidate reference chemicals that affect the production of androgens and estrogens in models of steroidogenesis...
November 13, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/29112451/2016-lush-science-prize
#4
Jenny McCann, Terry McCann
The Lush Prize supports animal-free testing by awarding monetary prizes totalling £250,000 to the most effective projects and individuals who have been working toward the goal of replacing animals in product or ingredient safety testing. Prizes are awarded for developments in five strategic areas: Science; Lobbying; Training; Public Awareness; and Young Researchers. In the event of a major breakthrough leading to the replacement of animal tests in the area of 21st Century Toxicology, a Black Box Prize (equivalent to the entire annual fund of £250,000) is awarded...
November 2017: Alternatives to Laboratory Animals: ATLA
https://www.readbyqxmd.com/read/29106658/investigating-the-generalizability-of-the-multiflow%C3%A2-dna-damage-assay-and-several-companion-machine-learning-models-with-a-set-of-103-diverse-test-chemicals
#5
Steven M Bryce, Derek T Bernacki, Stephanie L Smith-Roe, Kristine L Witt, Jeffrey C Bemis, Stephen D Dertinger
The in vitro MultiFlow® DNA Damage assay multiplexes p53, γH2AX, phospho-histone H3, and polyploidization biomarkers into one flow cytometric analysis (Bryce et al., 2016). The work reported herein evaluated the generalizability of the method, as well as several data analytics strategies, to a range of chemical classes not studied previously. TK6 cells were exposed to each of 103 diverse chemicals, 86 of which were supplied by the National Toxicology Program (NTP) and selected based upon responses in genetic damage assays conducted under the Tox21 program...
November 2, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29037750/environmental-toxicology-and-omics-a-question-of-sex
#6
Xuefang Liang, April Feswick, Denina Simmons, Christopher J Martyniuk
Molecular initiating events and downstream transcriptional/proteomic responses provide valuable information for adverse outcome pathways, which can be used predict the effects of chemicals on physiological systems. There has been a paucity of research that addresses sex-specific expression profiling in toxicology and due to cost, time, and logistical considerations, sex as a variable has not been widely considered. In response to this deficiency, federal agencies in the United States, Canada, and Europe have highlighted the importance of including sex as a variable in scientific investigations...
October 13, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28973688/from-classical-toxicology-to-tox21-some-critical-conceptual-and-technological-advances-in-the-molecular-understanding-of-the-toxic-response-beginning-from-the-last-quarter-of-the-20th-century
#7
Supratim Choudhuri, Geoffrey W Patton, Ronald F Chanderbhan, Antonia Mattia, Curtis D Klaassen
Toxicology has made steady advances over the last 60+ years in understanding the mechanisms of toxicity at an increasingly finer level of cellular organization. Traditionally, toxicological studies have used animal models. However, the general adoption of the principles of 3R (Replace, Reduce, Refine) provided the impetus for the development of in vitro models in toxicity testing. The present commentary is an attempt to briefly discuss the transformation in toxicology that began around 1980. Many genes important in cellular protection and metabolism of toxicants were cloned and characterized in the 80s, and gene expression studies became feasible, too...
September 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28964990/high-throughput-in-silico-prediction-of-ionization-equilibria-for-pharmacokinetic-modeling
#8
Cory L Strope, Kamel Mansouri, Harvey J Clewell, James R Rabinowitz, Caroline Stevens, John F Wambaugh
Chemical ionization plays an important role in many aspects of pharmacokinetic (PK) processes such as protein binding, tissue partitioning, and apparent volume of distribution at steady state (Vdss). Here, estimates of ionization equilibrium constants (i.e., pKa) were analyzed for 8132 pharmaceuticals and 24,281 other compounds to which humans might be exposed in the environment. Results revealed broad differences in the ionization of pharmaceutical chemicals and chemicals with either near-field (in the home) or far-field sources...
February 15, 2018: Science of the Total Environment
https://www.readbyqxmd.com/read/28866267/how-well-can-carcinogenicity-be-predicted-by-high-throughput-characteristics-of-carcinogens-mechanistic-data
#9
Richard A Becker, David A Dreier, Mary K Manibusan, Louis A Tony Cox, Ted W Simon, James S Bus
IARC has begun using ToxCast/Tox21 data in efforts to represent key characteristics of carcinogens to organize and weigh mechanistic evidence in cancer hazard determinations and this implicit inference approach also is being considered by USEPA. To determine how well ToxCast/Tox21 data can explicitly predict cancer hazard, this approach was evaluated with statistical analyses and machine learning prediction algorithms. Substances USEPA previously classified as having cancer hazard potential were designated as positives and substances not posing a carcinogenic hazard were designated as negatives...
November 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28809115/an-intuitive-approach-for-predicting-potential-human-health-risk-with-the-tox21-10k-library
#10
Nisha S Sipes, John F Wambaugh, Robert Pearce, Scott S Auerbach, Barbara A Wetmore, Jui-Hua Hsieh, Andrew J Shapiro, Daniel Svoboda, Michael J DeVito, Stephen S Ferguson
In vitro-in vivo extrapolation (IVIVE) analyses translating high-throughput screening (HTS) data to human relevance have been limited. This study represents the first report applying IVIVE approaches and exposure comparisons using the entirety of the Tox21 federal collaboration chemical screening data, incorporating assay response efficacy and quality of concentration-response fits, and providing quantitative anchoring to first address the likelihood of human in vivo interactions with Tox21 compounds. This likelihood was assessed using a maximum blood concentration to in vitro response ratio approach (Cmax/AC50), analogous to decision-making methods for clinical drug-drug interactions...
September 19, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28714573/assessment-of-the-dna-damaging-potential-of-environmental-chemicals-using-a-quantitative-high-throughput-screening-approach-to-measure-p53-activation
#11
Kristine L Witt, Jui-Hua Hsieh, Stephanie L Smith-Roe, Menghang Xia, Ruili Huang, Jinghua Zhao, Scott S Auerbach, Junguk Hur, Raymond R Tice
Genotoxicity potential is a critical component of any comprehensive toxicological profile. Compounds that induce DNA or chromosomal damage often activate p53, a transcription factor essential to cell cycle regulation. Thus, within the US Tox21 Program, we screened a library of ∼10,000 (∼8,300 unique) environmental compounds and drugs for activation of the p53-signaling pathway using a quantitative high-throughput screening assay employing HCT-116 cells (p53(+/+) ) containing a stably integrated β-lactamase reporter gene under control of the p53 response element (p53RE)...
August 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28686730/correction-real-time-cell-toxicity-profiling-of-tox21-10k-compounds-reveals-cytotoxicity-dependent-toxicity-pathway-linkage
#12
Jui-Hua Hsieh, Ruili Huang, Ja-An Lin, Alexander Sedykh, Jinghua Zhao, Raymond R Tice, Richard S Paules, Menghang Xia, Scott S Auerbach
[This corrects the article DOI: 10.1371/journal.pone.0177902.].
2017: PloS One
https://www.readbyqxmd.com/read/28628784/identifying-populations-sensitive-to-environmental-chemicals-by-simulating-toxicokinetic-variability
#13
Caroline L Ring, Robert G Pearce, R Woodrow Setzer, Barbara A Wetmore, John F Wambaugh
The thousands of chemicals present in the environment (USGAO, 2013) must be triaged to identify priority chemicals for human health risk research. Most chemicals have little of the toxicokinetic (TK) data that are necessary for relating exposures to tissue concentrations that are believed to be toxic. Ongoing efforts have collected limited, in vitro TK data for a few hundred chemicals. These data have been combined with biomonitoring data to estimate an approximate margin between potential hazard and exposure...
June 16, 2017: Environment International
https://www.readbyqxmd.com/read/28587163/a-tox21-approach-to-altered-epigenetic-landscapes-assessing-epigenetic-toxicity-pathways-leading-to-altered-gene-expression-and-oncogenic-transformation-in-vitro
#14
REVIEW
Craig L Parfett, Daniel Desaulniers
An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs...
June 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28557712/an-integrated-chemical-environment-to-support-21st-century-toxicology
#15
Shannon M Bell, Jason Phillips, Alexander Sedykh, Arpit Tandon, Catherine Sprankle, Stephen Q Morefield, Andy Shapiro, David Allen, Ruchir Shah, Elizabeth A Maull, Warren M Casey, Nicole C Kleinstreuer
SUMMARY: Access to high-quality reference data is essential for the development, validation, and implementation of in vitro and in silico approaches that reduce and replace the use of animals in toxicity testing. Currently, these data must often be pooled from a variety of disparate sources to efficiently link a set of assay responses and model predictions to an outcome or hazard classification. To provide a central access point for these purposes, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods developed the Integrated Chemical Environment (ICE) web resource...
May 25, 2017: Environmental Health Perspectives
https://www.readbyqxmd.com/read/28531190/real-time-cell-toxicity-profiling-of-tox21-10k-compounds-reveals-cytotoxicity-dependent-toxicity-pathway-linkage
#16
Jui-Hua Hsieh, Ruili Huang, Ja-An Lin, Alexander Sedykh, Jinghua Zhao, Raymond R Tice, Richard S Paules, Menghang Xia, Scott S Auerbach
Cytotoxicity is a commonly used in vitro endpoint for evaluating chemical toxicity. In support of the U.S. Tox21 screening program, the cytotoxicity of ~10K chemicals was interrogated at 0, 8, 16, 24, 32, & 40 hours of exposure in a concentration dependent fashion in two cell lines (HEK293, HepG2) using two multiplexed, real-time assay technologies. One technology measures the metabolic activity of cells (i.e., cell viability, glo) while the other evaluates cell membrane integrity (i.e., cell death, flor). Using glo technology, more actives and greater temporal variations were seen in HEK293 cells, while results for the flor technology were more similar across the two cell types...
2017: PloS One
https://www.readbyqxmd.com/read/28472532/high-throughput-screening-data-interpretation-in-the-context-of-in-vivo-transcriptomic-responses-to-oral-cr-vi-exposure
#17
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...
July 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28441746/high-performance-prediction-of-human-estrogen-receptor-agonists-based-on-chemical-structures
#18
Yuki Asako, Yoshihiro Uesawa
Many agonists for the estrogen receptor are known to disrupt endocrine functioning. We have developed a computational model that predicts agonists for the estrogen receptor ligand-binding domain in an assay system. Our model was entered into the Tox21 Data Challenge 2014, a computational toxicology competition organized by the National Center for Advancing Translational Sciences. This competition aims to find high-performance predictive models for various adverse-outcome pathways, including the estrogen receptor...
April 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28440957/the-role-of-high-throughput-screening-in-ecotoxicology-and-engineered-nanomaterials
#19
REVIEW
Andrew Barrick, Amélie Châtel, Mélanie Bruneau, Catherine Mouneyrac
The field of environmental toxicology developed as a result of growing concerns about anthropogenic influences on the environment and how to ameliorate ecological impact. Many governmental bodies are beginning to emphasize prevention rather than mitigation when addressing novel products, leading to more of a focus on identifying potential toxicity prior to release. With the exponential advances in their development and sale, novel metamaterials and biotechnology are set to dramatically outpace the capabilities of current testing strategies...
July 2017: Environmental Toxicology and Chemistry
https://www.readbyqxmd.com/read/28436609/a-semi-automated-approach-to-create-purposeful-mechanistic-datasets-from-heterogeneous-data-data-mining-towards-the-in-silico-predictions-for-oestrogen-receptor-modulation-and-teratogenicity
#20
M Bashir Surfraz, Adrian Fowkes, Jeffrey P Plante
The need to find an alternative to costly animal studies for developmental and reproductive toxicity testing has shifted the focus considerably to the assessment of in vitro developmental toxicology models and the exploitation of pharmacological data for relevant molecular initiating events. We hereby demonstrate how automation can be applied successfully to handle heterogeneous oestrogen receptor data from ChEMBL. Applying expert-derived thresholds to specific bioactivities allowed an activity call to be attributed to each data entry...
April 24, 2017: Molecular Informatics
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