Academic journal article Environmental Health Perspectives

Comment on "On the Utility of ToxCast[TM] and ToxPi as Methods for Identifying New Obesogens"

Academic journal article Environmental Health Perspectives

Comment on "On the Utility of ToxCast[TM] and ToxPi as Methods for Identifying New Obesogens"

Article excerpt

Janesick and colleagues recently published an evaluation of the utility of ToxCast[TM] and Tox21 bioactivity data for predicting PPAR[gamma] activation and induction of adipogenesis. As providers of the ToxCast[TM] and Tox21 data as well as some of the chemicals employed in their follow-up study, we would like to comment on the methods Janesick and colleagues used in their application and interpretation of the data with respect to: 1) incorrect ToxCast[TM]/Tox21 citations in the main text of the article; 2) lack of consideration of methodological, platform, and reagent differences when comparing the performance of individual ToxCast[TM] and Tox21 assays with their targeted studies; 3) inconsistencies in some of the results reported by Janesick and colleagues on an individual assay basis; 4) conclusions on the relative selectivity of the RXR-active chemicals; 5) lack of consideration of technical and statistical factors; and 6) incorrect integration of corollary data.

Through the ToxCast[TM] and Tox21 programs, the U.S. Environmental Protection Agency (EPA), National Toxicology Program (NTP), and National Center for Advancing Translational Sciences (NCATS) are committed to providing free and public data to support predictive toxicology efforts aimed at evaluating the potential hazard of environmental chemicals and facilitating scientific dialogue around the approach. We note that many of the data from ToxCast[TM] and Tox21 have been published in peer-reviewed journals, including the assay systems used in the study by Janesick et al. This includes, with correct citations, the NovaScreen cell-free biochemical assay platform (Knudsen et al. 2011; Sipes et al. 2013), the Attagene multiplex reporter gene assay platform (Martin et al. 2010), and the Tox21 reporter gene assays (Huang et al. 2011). The raw and processed ToxCast[TM] and Tox21 data and the computer code used to analyze the data can be downloaded from our website (https://www.epa.gov/chemicalresearch/toxicity-forecaster-toxcasttm-data). The processed data can also be accessed using the iCSS ToxCast[TM] Dashboard (https://actor. epa.gov/dashboard/). In addition, lessons learned from ToxCast[TM] Phase I have been thoroughly reviewed (Kavlock et al. 2012) in setting the path for ToxCast[TM] Phase II.

The analysis performed by Janesick and colleagues focused heavily on comparing the results from several ToxCast[TM] and Tox21 assays with different assays employed in their study (GAL4-mPPAR[gamma] transient transactivation assay in COS7 cells, and adipogenesis assays in 3T3-L1 cells and mBMSC cells). However, the authors failed to note a broad range of methodological and reagent differences that potentially confound a direct comparison of the results. One difference is that the ToxCast[TM] and Tox21 assays were human based, while those used by Janesick and colleagues were based on mouse or simian cells and the mouse PPAR[gamma] receptor. In addition, the ToxCast[TM] Attagene reporter gene assays use a human liver HepG2 cell line, variant HG19, with enhanced cytochrome P450 activity that can provide substantially different biotransformation capability than the cells used in their study. Enhanced CYP-mediated metabolism could also indirectly activate PPAR[gamma] through generation of reactive oxygen species and electrophilic metabolites (Bondy and Naderi 1994), leading to membrane oxidation and generation of bioactive lipids (Traber and Atkinson 2007) or induction of PPAR[gamma] coactivator PGC-1[alpha] expression (Wenz 2013). Supporting this possibility, many of the chemicals labeled as "active" in the ToxCast[TM] Attagene PPAR[gamma] assays also showed concordant NRF2 activity.

Another difference between Janesick et al. and the ToxCast[TM] and Tox21 results is the source of the test chemicals. The authors stated that the chemicals were "supplied by the National Toxicology Program (NTP) from the same stocks that were utilized in ToxCast[TM] Phase I. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.