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https://www.readbyqxmd.com/read/29037750/environmental-toxicology-and-omics-a-question-of-sex
#1
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
#2
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
#3
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...
September 28, 2017: 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
#4
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...
September 1, 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
#5
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 6, 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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/28414904/in-silico-prediction-of-chemicals-binding-to-aromatase-with-machine-learning-methods
#16
Hanwen Du, Yingchun Cai, Hongbin Yang, Hongxiao Zhang, Yuhan Xue, Guixia Liu, Yun Tang, Weihua Li
Environmental chemicals may affect endocrine systems through multiple mechanisms, one of which is via effects on aromatase (also known as CYP19A1), an enzyme critical for maintaining the normal balance of estrogens and androgens in the body. Therefore, rapid and efficient identification of aromatase-related endocrine disrupting chemicals (EDCs) is important for toxicology and environment risk assessment. In this study, on the basis of the Tox21 10K compound library, in silico classification models for predicting aromatase binders/nonbinders were constructed by machine learning methods...
May 15, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28350954/integrating-drug-s-mode-of-action-into-quantitative-structure-activity-relationships-for-improved-prediction-of-drug-induced-liver-injury
#17
Leihong Wu, Zhichao Liu, Scott Auerbach, Ruili Huang, Minjun Chen, Kristin McEuen, Joshua Xu, Hong Fang, Weida Tong
Drug-induced liver injury (DILI) is complex in mechanism. Different drugs could undergo different mechanisms but result in the same DILI type, while the same drug could lead to different DILI types via different mechanisms. Therefore, predicting a drug's potential for DILI should take its underlying mechanisms into consideration. To achieve that, we constructed a novel approach by incorporating the drug's Mode of Action (MOA) into Quantitative Structure-Activity Relationship (QSAR) modeling. This MOA-DILI approach was examined using a data set of 333 drugs...
April 24, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28316234/modeling-exposure-in-the-tox21-in-vitro-bioassays
#18
Fabian C Fischer, Luise Henneberger, Maria König, Kai Bittermann, Lukas Linden, Kai-Uwe Goss, Beate I Escher
High-throughput in vitro bioassays are becoming increasingly important in the risk characterization of anthropogenic chemicals. Large databases gather nominal effect concentrations (Cnom) for diverse modes of action. However, the biologically effective concentration can substantially deviate due to differences in chemical partitioning. In this study, we modeled freely dissolved (Cfree), cellular (Ccell), and membrane concentrations (Cmem) in the Tox21 GeneBLAzer bioassays for a set of neutral and ionogenic organic chemicals covering a large physicochemical space...
May 15, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28294544/identification-of-acetylcholinesterase-inhibitors-using-homogenous-cell-based-assays-in-quantitative-high-throughput-screening-platforms
#19
Shuaizhang Li, Ruili Huang, Samuel Solomon, Yitong Liu, Bin Zhao, Michael F Santillo, Menghang Xia
Acetylcholinesterase (AChE) is an enzyme responsible for metabolism of acetylcholine, a neurotransmitter associated with muscle movement, cognition, and other neurobiological processes. Inhibition of AChE activity can serve as a therapeutic mechanism, but also cause adverse health effects and neurotoxicity. In order to efficiently identify AChE inhibitors from large compound libraries, homogenous cell-based assays in high-throughput screening platforms are needed. In this study, a fluorescent method using Amplex Red (10-acetyl-3,7-dihydroxyphenoxazine) and the Ellman absorbance method were both developed in a homogenous format using a human neuroblastoma cell line (SH-SY5Y)...
March 14, 2017: Biotechnology Journal
https://www.readbyqxmd.com/read/28153528/incorporating-toxcast-and-tox21-datasets-to-rank-biological-activity-of-chemicals-at-superfund-sites-in-north-carolina
#20
Sloane K Tilley, David M Reif, Rebecca C Fry
BACKGROUND: The Superfund program of the Environmental Protection Agency (EPA) was established in 1980 to address public health concerns posed by toxic substances released into the environment in the United States. Forty-two of the 1328 hazardous waste sites that remain on the Superfund National Priority List are located in the state of North Carolina. METHODS: We set out to develop a database that contained information on both the prevalence and biological activity of chemicals present at Superfund sites in North Carolina...
April 2017: Environment International
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