title: On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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 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 PPARγ, and 1 activated RXRα.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, USA.
authors.forename: Amanda Shaine
authors.initials: AS
authors.lastname: Janesick
authors.forename: Giorgio
authors.initials: G
authors.lastname: Dimastrogiovanni
authors.forename: Lenka
authors.initials: L
authors.lastname: Vanek
authors.forename: Christy
authors.initials: C
authors.lastname: Boulos
authors.forename: Raquel
authors.initials: R
authors.lastname: Chamorro-García
authors.forename: Weiyi
authors.initials: W
authors.lastname: Tang
authors.forename: Bruce
authors.initials: B
authors.lastname: Blumberg
mesh_terms: D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D051379:Mice; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D004785:Environmental Pollutants