TY - JOUR
T1 - Orthogonal assay and QSAR modelling of Tox21 PPARγ antagonist in vitro high-throughput screening assay
AU - Ardenkjær-Skinnerup, Jacob
AU - Nissen, Ana Caroline Vasconcelos Engedal
AU - Nikolov, Nikolai Georgiev
AU - Hadrup, Niels
AU - Ravn-Haren, Gitte
AU - Wedebye, Eva Bay
AU - Vogel, Ulla
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - PPARγ
KW - Tox21
KW - Endocrine disruption
KW - Metabolic disruption
KW - QSAR
KW - Breast cancer
U2 - 10.1016/j.etap.2023.104347
DO - 10.1016/j.etap.2023.104347
M3 - Journal article
C2 - 38143042
SN - 1382-6689
VL - 105
JO - Environmental Toxicology and Pharmacology
JF - Environmental Toxicology and Pharmacology
M1 - 104347
ER -
