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Editor’s Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis

The developmental origins of obesity hypothesis posits a multifaceted contribution of factors to the fetal origins of obesity and metabolic disease. Adipocyte hyperplasia in gestation and early childhood may result in predisposition for obesity later in life. Rodent in vitro and in vivo studies indi...

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Autores principales: Foley, Briana, Doheny, Daniel L., Black, Michael B., Pendse, Salil N., Wetmore, Barbara A., Clewell, Rebecca A., Andersen, Melvin E., Deisenroth, Chad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216650/
https://www.ncbi.nlm.nih.gov/pubmed/27664422
http://dx.doi.org/10.1093/toxsci/kfw186
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author Foley, Briana
Doheny, Daniel L.
Black, Michael B.
Pendse, Salil N.
Wetmore, Barbara A.
Clewell, Rebecca A.
Andersen, Melvin E.
Deisenroth, Chad
author_facet Foley, Briana
Doheny, Daniel L.
Black, Michael B.
Pendse, Salil N.
Wetmore, Barbara A.
Clewell, Rebecca A.
Andersen, Melvin E.
Deisenroth, Chad
author_sort Foley, Briana
collection PubMed
description The developmental origins of obesity hypothesis posits a multifaceted contribution of factors to the fetal origins of obesity and metabolic disease. Adipocyte hyperplasia in gestation and early childhood may result in predisposition for obesity later in life. Rodent in vitro and in vivo studies indicate that some chemicals may directly affect adipose progenitor cell differentiation, but the human relevance of these findings is unclear. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARG) is the master regulator of adipogenesis. Human adipose-derived stem cells (hASC) isolated from adipose tissue express endogenous isoforms of PPARG and represent a biologically relevant cell-type for evaluating activity of PPARG ligands. Here, a multi-endpoint approach based on a phenotypic adipogenesis assay was applied to screen a set of 60 chemical compounds identified in ToxCast Phase I as PPARG active (49) or inactive (11). Chemicals showing activity in the adipogenesis screen were further evaluated in a series of 4 orthogonal assays representing 7 different key events in PPARG-dependent adipogenesis, including gene transcription, protein expression, and adipokine secretion. An siRNA screen was also used to evaluate PPARG-dependence of the adipogenesis phenotype. A universal concentration-response design enabled inter-assay comparability and implementation of a weight-of-evidence approach for bioactivity classification. Collectively, a total of 14/49 (29%) prioritized chemicals were identified with moderate-to-strong activity for human adipogenesis. These results provide the first integrated screening approach of prioritized ToxCast chemicals in a human stem cell model of adipogenesis and provide insight into the capacity of PPARG-activating chemicals to modulate early life programming of adipose tissue.
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spelling pubmed-52166502017-01-11 Editor’s Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis Foley, Briana Doheny, Daniel L. Black, Michael B. Pendse, Salil N. Wetmore, Barbara A. Clewell, Rebecca A. Andersen, Melvin E. Deisenroth, Chad Toxicol Sci PPAR-Gamma in ToxCast Chemicals The developmental origins of obesity hypothesis posits a multifaceted contribution of factors to the fetal origins of obesity and metabolic disease. Adipocyte hyperplasia in gestation and early childhood may result in predisposition for obesity later in life. Rodent in vitro and in vivo studies indicate that some chemicals may directly affect adipose progenitor cell differentiation, but the human relevance of these findings is unclear. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARG) is the master regulator of adipogenesis. Human adipose-derived stem cells (hASC) isolated from adipose tissue express endogenous isoforms of PPARG and represent a biologically relevant cell-type for evaluating activity of PPARG ligands. Here, a multi-endpoint approach based on a phenotypic adipogenesis assay was applied to screen a set of 60 chemical compounds identified in ToxCast Phase I as PPARG active (49) or inactive (11). Chemicals showing activity in the adipogenesis screen were further evaluated in a series of 4 orthogonal assays representing 7 different key events in PPARG-dependent adipogenesis, including gene transcription, protein expression, and adipokine secretion. An siRNA screen was also used to evaluate PPARG-dependence of the adipogenesis phenotype. A universal concentration-response design enabled inter-assay comparability and implementation of a weight-of-evidence approach for bioactivity classification. Collectively, a total of 14/49 (29%) prioritized chemicals were identified with moderate-to-strong activity for human adipogenesis. These results provide the first integrated screening approach of prioritized ToxCast chemicals in a human stem cell model of adipogenesis and provide insight into the capacity of PPARG-activating chemicals to modulate early life programming of adipose tissue. Oxford University Press 2017-01 2016-09-23 /pmc/articles/PMC5216650/ /pubmed/27664422 http://dx.doi.org/10.1093/toxsci/kfw186 Text en © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle PPAR-Gamma in ToxCast Chemicals
Foley, Briana
Doheny, Daniel L.
Black, Michael B.
Pendse, Salil N.
Wetmore, Barbara A.
Clewell, Rebecca A.
Andersen, Melvin E.
Deisenroth, Chad
Editor’s Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis
title Editor’s Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis
title_full Editor’s Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis
title_fullStr Editor’s Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis
title_full_unstemmed Editor’s Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis
title_short Editor’s Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis
title_sort editor’s highlight: screening toxcast prioritized chemicals for pparg function in a human adipose-derived stem cell model of adipogenesis
topic PPAR-Gamma in ToxCast Chemicals
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216650/
https://www.ncbi.nlm.nih.gov/pubmed/27664422
http://dx.doi.org/10.1093/toxsci/kfw186
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