Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays

[Image: see text] Understanding potential health risks is a significant challenge due to the large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food...

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Autores principales: Sipes, Nisha S., Martin, Matthew T., Kothiya, Parth, Reif, David M., Judson, Richard S., Richard, Ann M., Houck, Keith A., Dix, David J., Kavlock, Robert J., Knudsen, Thomas B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2013
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685188/
https://www.ncbi.nlm.nih.gov/pubmed/23611293
http://dx.doi.org/10.1021/tx400021f
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author Sipes, Nisha S.
Martin, Matthew T.
Kothiya, Parth
Reif, David M.
Judson, Richard S.
Richard, Ann M.
Houck, Keith A.
Dix, David J.
Kavlock, Robert J.
Knudsen, Thomas B.
author_facet Sipes, Nisha S.
Martin, Matthew T.
Kothiya, Parth
Reif, David M.
Judson, Richard S.
Richard, Ann M.
Houck, Keith A.
Dix, David J.
Kavlock, Robert J.
Knudsen, Thomas B.
author_sort Sipes, Nisha S.
collection PubMed
description [Image: see text] Understanding potential health risks is a significant challenge due to the large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phases I and II of the U.S. EPA’s ToxCast project across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays. Half-maximal activity concentrations (AC50) were identified for 729 chemicals in 256 assays (7,135 chemical–assay pairs). Some of the most commonly affected assays were CYPs (CYP2C9 and CYP2C19), transporters (mitochondrial TSPO, norepinephrine, and dopaminergic), and GPCRs (aminergic). Heavy metals, surfactants, and dithiocarbamate fungicides showed promiscuous but distinctly different patterns of activity, whereas many of the pharmaceutical compounds showed promiscuous activity across GPCRs. Literature analysis confirmed >50% of the activities for the most potent chemical–assay pairs (54) but also revealed 10 missed interactions. Twenty-two chemicals with known estrogenic activity were correctly identified for the majority (77%), missing only the weaker interactions. In many cases, novel findings for previously unreported chemical–target combinations clustered with known chemical–target interactions. Results from this large inventory of chemical–biological interactions can inform read-across methods as well as link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities.
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spelling pubmed-36851882013-06-18 Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays Sipes, Nisha S. Martin, Matthew T. Kothiya, Parth Reif, David M. Judson, Richard S. Richard, Ann M. Houck, Keith A. Dix, David J. Kavlock, Robert J. Knudsen, Thomas B. Chem Res Toxicol [Image: see text] Understanding potential health risks is a significant challenge due to the large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phases I and II of the U.S. EPA’s ToxCast project across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays. Half-maximal activity concentrations (AC50) were identified for 729 chemicals in 256 assays (7,135 chemical–assay pairs). Some of the most commonly affected assays were CYPs (CYP2C9 and CYP2C19), transporters (mitochondrial TSPO, norepinephrine, and dopaminergic), and GPCRs (aminergic). Heavy metals, surfactants, and dithiocarbamate fungicides showed promiscuous but distinctly different patterns of activity, whereas many of the pharmaceutical compounds showed promiscuous activity across GPCRs. Literature analysis confirmed >50% of the activities for the most potent chemical–assay pairs (54) but also revealed 10 missed interactions. Twenty-two chemicals with known estrogenic activity were correctly identified for the majority (77%), missing only the weaker interactions. In many cases, novel findings for previously unreported chemical–target combinations clustered with known chemical–target interactions. Results from this large inventory of chemical–biological interactions can inform read-across methods as well as link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities. American Chemical Society 2013-04-23 2013-06-17 /pmc/articles/PMC3685188/ /pubmed/23611293 http://dx.doi.org/10.1021/tx400021f Text en Copyright © 2013 U.S. Government Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Sipes, Nisha S.
Martin, Matthew T.
Kothiya, Parth
Reif, David M.
Judson, Richard S.
Richard, Ann M.
Houck, Keith A.
Dix, David J.
Kavlock, Robert J.
Knudsen, Thomas B.
Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays
title Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays
title_full Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays
title_fullStr Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays
title_full_unstemmed Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays
title_short Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays
title_sort profiling 976 toxcast chemicals across 331 enzymatic and receptor signaling assays
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685188/
https://www.ncbi.nlm.nih.gov/pubmed/23611293
http://dx.doi.org/10.1021/tx400021f
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