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Environ Health Perspect; DOI:10.1289/ehp.1510352

On the Utility of ToxCastTM and ToxPi as Methods for Identifying New Obesogens

Amanda Shaine Janesick1,*, Giorgio Dimastrogiovanni2,*, Lenka Vanek1, Christy Boulos1, Raquel Chamorro-García1, Weiyi Tang1, and Bruce Blumberg1,3
Author Affiliations open
1Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, USA; 2Department of Environmental Chemistry, IIQAB-CSIC (Superior Council of Scientific Investigations), Barcelona, Spain; 3Department of Pharmaceutical Sciences, University of California, Irvine, California, USA.

*These authors contributed equally to this work

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  • 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

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