Research Article Advance Publication
Environ Health Perspect; DOI:10.1289/ehp.1510352
On the Utility of ToxCastTM and ToxPi as Methods for Identifying New Obesogens
*These authors contributed equally to this work
PDF Version (6.8 MB)
Background: In ToxCast Phase I, EPA commissioned screening of 320 pesticides, herbicides, fungicides and other chemicals in a series of high throughput assays. EPA also developed a toxicological prioritization tool, ToxPi to facilitate using ToxCast assays to predict biological function.
Objectives: We asked whether top-scoring PPARγ activators identified in ToxCast Phase I were genuine PPARγ activators and inducers of adipogenesis. Next, we identified ToxCast assays that should predict adipogenesis, developed an adipogenesis ToxPi and asked how well the ToxPi predicted adipogenic activity.
Methods: We used transient transfection to test the ability of ToxCast chemicals to modulate PPARγ and RXRα, and differentiation assays employing 3T3-L1 preadipocytes and mouse bone marrow derived mesenchymal stem cells (mBMSCs) to evaluate the adipogenic capacity of ToxCast chemicals.
Results: Only 5/21 of the top scoring ToxCast PPARγ activators were activators in our assays, 3 were PPARγ antagonists, the remainder were inactive. The bona fide PPARγ activators we identified induced adipogenesis in 3T3-L1 cells and mBMSCs. Only 7/17 chemicals predicted to be active by the ToxPi promoted adipogenesis, 1 inhibited adipogenesis, and 2/7 predicted negatives were also adipogenic. Of these 9 adipogenic chemicals, 3 activated PPARγ and 1 activated RXRα.
Conclusions: ToxCast PPARγ and RXRα assays do not correlate well with laboratory measurements of PPARγ and RXRα activity. The adipogenesis ToxPi performed poorly, perhaps due to the performance of ToxCast assays. We observed a modest predictive value of ToxCast for PPARγ and RXRα activation and adipogenesis and it is likely that many obesogenic chemicals remain to be identified.
This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.
Citation: Janesick AS, Dimastrogiovanni G, Vanek L, Boulos C, Chamorro-García R, Tang W, Blumberg B. On the Utility of ToxCastTM and ToxPi as Methods for Identifying New Obesogens. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1510352
Received: 18 June 2015
Accepted: 7 December 2015
Advance Publication: 13 January 2016
Note to readers with disabilities: EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact email@example.com. Our staff will work with you to assess and meet your accessibility needs within 3 working days.
Supplemental Material PDF (3.7 MB)
Note to readers with disabilities: EHP has provided a 508-conformant table of contents summarizing the Supplemental Material for this article (see below) so readers with disabilities may determine whether they wish to access the full, nonconformant Supplemental Material. If you need assistance accessing this or any other content on this site, please contact firstname.lastname@example.org. Our staff will work with you to assess and meet your accessibility needs within 3 working days.
Supplemental Table of Contents PDF (141 KB)
2015 Impact Factor
EHP is pleased to announce its new impact factor of 8.44, up from 7.98 last year. We thank our authors, associate editors, reviewers, and readers for their contributions and support.
CEHN July 2016 Article of the Month
“Childhood Blood Lead Levels and Symptoms of Attention Deficit Hyperactivity Disorder (ADHD): A Cross-Sectional Study of Mexican Children” (doi:10.1289/ehp.1510067) has been selected by the Children’s Environmental Health Network (CEHN) as its July 2016 Article of the Month. These CEHN summaries discuss the potential policy implications of current children’s environmental health research.
Sign Up to Receive E-mail Alerts
Recent Advance Publications
Mortality due to Vegetation-Fire Originated PM2.5 Exposure in Europe – Assessment for the Years 2005 and 2008
Long-Term Exposure to Traffic-Related Air Pollution and Risk of Incident Atrial Fibrillation: A Cohort Study
IL-33 Drives Augmented Responses to Ozone in Obese Mice
Ambient Air Pollutant Exposures and Hospitalization for Kawasaki Disease in Taiwan: A Case-Crossover Study (2000-2010)
Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data