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.
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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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