Orthogonal assay and QSAR modelling of Tox21 PPAR antagonist in vitro high-throughput screening assay

Disruption of signalling mediated by the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is associated with risk of cancer, metabolic diseases, and endocrine disruption. The purpose of this study was to identify environmental chemicals acting as PPAR gamma antagonists. Data from the Tox21 PPAR gamma antagonism assay were replicated using a reporter system in HEK293 cells. Two quantitative structure-activity relationship (QSAR) models were developed, and five REACH-registered substances predicted positive were tested in vitro. Reporter assay results were consistent with Tox21 data since all conflicting results could be explained by assay interference. QSAR models showed good predictive performance, and follow-up experiments revealed two PPAR gamma antagonists out of three non-interfering chemicals. In conclusion, the developed QSAR models and followup experiments are important steps in the discovery of potential endocrine- and metabolism-disrupting chemicals.