Dataset Information

On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens.

ABSTRACT:

Background

In ToxCast™ Phase I, the U.S. EPA commissioned screening of 320 pesticides, herbicides, fungicides, and other chemicals in a series of high-throughput assays. The agency also developed a toxicological prioritization tool, ToxPi, to facilitate using ToxCast™ assays to predict biological function.

Objectives

We asked whether top-scoring PPAR? activators identified in ToxCast™ Phase I were genuine PPAR? 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 PPAR? and RXR?, 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™ PPAR? activators were activators in our assays, 3 were PPAR? antagonists, the remainder were inactive. The bona fide PPAR? activators we identified induced adipogenesis in 3T3-L1 cells and mBMSCs. Only 7 of the 17 chemicals predicted to be active by the ToxPi promoted adipogenesis, 1 inhibited adipogenesis, and 2 of the 7 predicted negatives were also adipogenic. Of these 9 adipogenic chemicals, 3 activated PPAR?, and 1 activated RXR?.

Conclusions

ToxCast™ PPAR? and RXR? assays do not correlate well with laboratory measurements of PPAR? and RXR? activity. The adipogenesis ToxPi performed poorly, perhaps due to the performance of ToxCast™ assays. We observed a modest predictive value of ToxCast™ for PPAR? and RXR? activation and adipogenesis and it is likely that many obesogenic chemicals remain to be identified.

Citation

Janesick AS, Dimastrogiovanni G, Vanek L, Boulos C, Chamorro-García R, Tang W, Blumberg B. 2016. On the utility of ToxCast™ and ToxPi as methods for identifying new obesogens. Environ Health Perspect 124:1214-1226;?http://dx.doi.org/10.1289/ehp.1510352.

SUBMITTER: Janesick AS

PROVIDER: S-EPMC4977052 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens.

Janesick Amanda Shaine AS Dimastrogiovanni Giorgio G Vanek Lenka L Boulos Christy C Chamorro-García Raquel R Tang Weiyi W Blumberg Bruce B

Environmental health perspectives 20160113 8

<h4>Background</h4>In ToxCast™ Phase I, the U.S. EPA commissioned screening of 320 pesticides, herbicides, fungicides, and other chemicals in a series of high-throughput assays. The agency also developed a toxicological prioritization tool, ToxPi, to facilitate using ToxCast™ assays to predict biological function.<h4>Objectives</h4>We asked whether top-scoring PPARγ activators identified in ToxCast™ Phase I were genuine PPARγ activators and inducers of adipogenesis. Next, we identified ToxCast™ ...[more]

PMID: 26757984

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Dataset Information

On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens.

Background

Objectives

Methods

Results

Conclusions

Citation

Publications

On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens.

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