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Updated: Jul 7, 2025
A High-throughput Assay for the Prediction of Chemical Toxicity by Automated Phenotypic Profiling of Caenorhabditis elegans
Published on: March 14, 2019
Orthogonal assay and QSAR modelling of Tox21 PPARγ antagonist in vitro high-throughput screening assay
Jacob Ardenkjær-Skinnerup1, Ana Caroline Vasconcelos Engedal Nissen2, Nikolai Georgiev Nikolov2
1The National Food Institute, Technical University of Denmark, Kemitorvet 202, 2800 Kongens Lyngby, Denmark; The National Research Centre for the Working Environment, Lersø Parkallé 105, 2100 Copenhagen Ø, Denmark.
Abstract:
Disruption of signalling mediated by the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is associated with risk of cancer, metabolic diseases, and endocrine disruption. The purpose of this study was to identify environmental chemicals acting as PPARγ antagonists. Data from the Tox21 PPARγ 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 PPARγ antagonists out of three non-interfering chemicals. In conclusion, the developed QSAR models and follow-up experiments are important steps in the discovery of potential endocrine- and metabolism-disrupting chemicals.
Insights
Researchers identified environmental chemicals that disrupt nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) signaling. Developed quantitative structure-activity relationship (QSAR) models successfully predicted PPARγ antagonists, aiding in the discovery of potential endocrine-disrupting chemicals.
Area of Science:
- Environmental chemistry
- Toxicology
- Molecular endocrinology
Background:
- Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) signaling disruption is linked to cancer, metabolic diseases, and endocrine disruption.
- Identifying environmental chemicals that antagonize PPARγ is crucial for understanding and mitigating these health risks.
Purpose of the Study:
- To identify environmental chemicals acting as PPARγ antagonists.
- To develop and validate quantitative structure-activity relationship (QSAR) models for predicting PPARγ antagonism.
- To confirm predicted antagonists through in vitro testing.
Main Methods:
- Replication of Tox21 PPARγ antagonism assay data using a HEK293 cell reporter system.
- Development of two quantitative structure-activity relationship (QSAR) models.
- In vitro testing of five REACH-registered substances predicted by QSAR models.
Main Results:
- Reporter assay results were consistent with Tox21 data, with assay interference explaining discrepancies.
- QSAR models demonstrated good predictive performance for PPARγ antagonism.
- Follow-up experiments identified two novel PPARγ antagonists among the tested chemicals.
Conclusions:
- Developed QSAR models are effective tools for predicting PPARγ antagonists.
- In vitro validation confirmed the predictive power of the QSAR models.
- These findings represent significant progress in discovering potential endocrine- and metabolism-disrupting chemicals.
