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Tox21

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https://www.readbyqxmd.com/read/29650353/reprint-of-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 logistic 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...
April 10, 2018: Journal of Proteomics
https://www.readbyqxmd.com/read/29529324/the-us-federal-tox21-program-a-strategic-and-operational-plan-for-continued-leadership
#2
Russell S Thomas, Richard S Paules, Anton Simeonov, Suzanne C Fitzpatrick, Kevin M Crofton, Warren M Casey, Donna L Mendrick
The traditional approaches to toxicity testing have posed multiple challenges for evaluating the safety of commercial chemicals, pesticides, food additives/contaminants, and medical products.The challenges include number of chemicals that need to be tested, time and resource intensive nature of traditional toxicity tests, and unexpected adverse effects that occur in pharmaceutical clinical trials despite the extensive toxicological testing.Over a decade ago, the U.S. Environmental Protection Agency (EPA), National Toxicology Program (NTP), National Center for Advancing Translational Sciences (NCATS), and the Food and Drug Administration (FDA) formed a federal consortium for "Toxicology in the 21st Century" (Tox21) with a focus on developing and evaluating in vitro high-throughput screening (HTS) methods for hazard identification and providing mechanistic insights...
March 8, 2018: ALTEX
https://www.readbyqxmd.com/read/29462216/a-hybrid-gene-selection-approach-to-create-the-s1500-targeted-gene-sets-for-use-in-high-throughput-transcriptomics
#3
Deepak Mav, Ruchir R Shah, Brian E Howard, Scott S Auerbach, Pierre R Bushel, Jennifer B Collins, David L Gerhold, Richard S Judson, Agnes L Karmaus, Elizabeth A Maull, Donna L Mendrick, B Alex Merrick, Nisha S Sipes, Daniel Svoboda, Richard S Paules
Changes in gene expression can help reveal the mechanisms of disease processes and the mode of action for toxicities and adverse effects on cellular responses induced by exposures to chemicals, drugs and environment agents. The U.S. Tox21 Federal collaboration, which currently quantifies the biological effects of nearly 10,000 chemicals via quantitative high-throughput screening(qHTS) in in vitro model systems, is now making an effort to incorporate gene expression profiling into the existing battery of assays...
2018: PloS One
https://www.readbyqxmd.com/read/29377626/tox21-enricher-web-based-chemical-biological-functional-annotation-analysis-tool-based-on-tox21-toxicity-screening-platform
#4
Junguk Hur, Larson Danes, Jui-Hua Hsieh, Brett McGregor, Dakota Krout, Scott Auerbach
The US Toxicology Testing in the 21st Century (Tox21) program was established to develop more efficient and human-relevant toxicity assessment methods. The Tox21 program screens >10,000 chemicals using quantitative high-throughput screening (qHTS) of assays that measure effects on toxicity pathways. To date, more than 70 assays have yielded >12 million concentration-response curves. The patterns of activity across assays can be used to define similarity between chemicals. Assuming chemicals with similar activity profiles have similar toxicological properties, we may infer toxicological properties based on its neighbourhood...
January 29, 2018: Molecular Informatics
https://www.readbyqxmd.com/read/29277902/divergent-responsiveness-of-two-isoforms-of-the-estrogen-receptor-to-mixtures-of-contaminants-of-emerging-concern-in-four-vertebrates
#5
Satomi Kohno, Yoshinao Katsu, Nicholas Cipoletti, Lina C Wang, Zachary G Jorgenson, Shinichi Miyagawa, Heiko L Schoenfuss
Contaminants of emerging concern (CECs) are ubiquitous in aquatic environments with well-established endocrine-disrupting effects. A data matrix of 559 water samples was queried to identify two commonly occurring CECs mixtures in Great Lakes tributaries. One mixture consisted of eight agricultural CECs (AG), while another contained 11 urban CECs (UB). The known estrogenic compounds bisphenol A, estrone and nonylphenol were present in both mixtures. According to the EPA Tox21 in ToxCast database, AG and UB mixture at an environmentally relevant concentration were estimated to account for 6...
May 2018: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/29244179/sedaxane-use-of-nuclear-receptor-transactivation-assays-toxicogenomics-and-toxicokinetics-as-part-of-a-mode-of-action-framework-for-rodent-liver-tumors
#6
Richard C Peffer, David E Cowie, Richard A Currie, Daniel J Minnema
Experimental data demonstrate a mode of action (MOA) for liver tumors in male rats and mice treated with sedaxane that starts with activation of CAR, followed by altered expression of CAR-responsive genes, increased cell proliferation, and eventually clonal expansion of preneoplastic cells, leading to the development of altered foci and tumors. This MOA is non-relevant to human risk assessments. Methods and results in the MOA work for sedaxane illustrate promising directions that future MOA studies may be able to employ, in the spirit of "Tox21" and reduction of in vivo animal use: 1) currently available in vitro CAR and PXR reporter assays demonstrated that sedaxane is a direct CAR activator in mice and rats, and a weak PXR activator in rats; 2) mouse liver microarray results compared to a published CAR biomarker signature (based on 83 genes) showed a clear, statistical match, and a lack of correlation to similar biomarker signatures for AhR, PPARα, and STAT5B; 3) Ki67 immunohistochemistry and zonal image analysis showed significant increases in this marker of cell proliferation in mouse liver, without the need to dose a DNA labelling agent; and 4) toxicokinetic analysis of Cmax levels of sedaxane in blood showed a marked species difference between mice and rats that helps to explain differences in sensitivity to sedaxane...
December 13, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29216352/identification-of-estrogen-related-receptor-%C3%AE-agonists-in-the-tox21-compound-library
#7
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 α (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...
February 1, 2018: Endocrinology
https://www.readbyqxmd.com/read/29182974/suspect-screening-and-non-targeted-analysis-of-drinking-water-using-point-of-use-filters
#8
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...
March 2018: Environmental Pollution
https://www.readbyqxmd.com/read/29146384/identification-of-candidate-reference-chemicals-for-in-vitro-steroidogenesis-assays
#9
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...
March 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/29112451/2016-lush-science-prize
#10
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
#11
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
#12
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...
February 10, 2018: 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
#13
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...
January 1, 2018: 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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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