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

Jacob Ardenkjær-Skinnerup; Ana Caroline Vasconcelos Engedal Nissen; Nikolai Georgiev Nikolov; Niels Hadrup; Gitte Ravn-Haren; Eva Bay Wedebye; Ulla Vogel

doi:10.1016/j.etap.2023.104347

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

Jacob Ardenkjær-Skinnerup, Ana Caroline Vasconcelos Engedal Nissen, Nikolai Georgiev Nikolov, Niels Hadrup, Gitte Ravn-Haren, Eva Bay Wedebye, Ulla Vogel

National Food Institute, Technical University of Denmark, Lyngby, Denmark.

Research output: Contribution to journal › Journal article › Research › peer-review

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.

Original language	English
Journal	Environmental Toxicology and Pharmacology
Volume	105
Pages (from-to)	104347
ISSN	1382-6689
DOIs	https://doi.org/10.1016/j.etap.2023.104347
Publication status	Published - Jan 2024

Keywords

HEK293 Cells
High-Throughput Screening Assays/methods
Humans
PPAR gamma/genetics
Quantitative Structure-Activity Relationship

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10.1016/j.etap.2023.104347

1 Active

FFIKA: Fornyet fokus på forskning i kemisk arbejdsmiljø
Vogel, U. B., Jensen, K. A., Jensen, A. C. Ø., Berthing, T., Andersen, M. H. G., Hougaard, K. S., Clausen, P. A., Frederiksen, M., Mortensen, A., Saber, A. T., Jacobsen, N. R., Akhtar, Y., Asp, A., Abildtrup, A., Tegner, U., Terrida, E. B., Guldbrandsen, M., Kembouche, Y., Kofoed-Sørensen, V., Nielsen, S. H., Sahlgren, N. M., Fonseca, A. S., Danielsen, P. H., Sørli, J. B., Hadrup, N., Ardenkjær-Skinnerup, J., Nøjgaard, J. N. K., Jørgensen, A. K. & Gutierrez, C. A. T.
01/01/2020 → 31/12/2026
Project: Research

1 Journal article

PPARγ antagonists induce aromatase transcription in adipose tissue cultures
Ardenkjær-Skinnerup, J., Saar, D., Petersen, P. S. S., Pedersen, M., Svingen, T., Kragelund, B. B., Hadrup, N., Ravn-Haren, G., Emanuelli, B., Brown, K. A. & Vogel, U., Apr 2024, In: Biochemical Pharmacology. 222, p. 116095
Research output: Contribution to journal › Journal article › Research › peer-review

Open Access

Cite this

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title = "Orthogonal assay and QSAR modelling of Tox21 PPARγ antagonist in vitro high-throughput screening assay",

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.",

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author = "Jacob Ardenkj{\ae}r-Skinnerup and Nissen, {Ana Caroline Vasconcelos Engedal} and Nikolov, {Nikolai Georgiev} and Niels Hadrup and Gitte Ravn-Haren and Wedebye, {Eva Bay} and Ulla Vogel",

year = "2024",

month = jan,

doi = "10.1016/j.etap.2023.104347",

language = "English",

volume = "105",

pages = "104347",

journal = "Environmental Toxicology and Pharmacology",

issn = "1382-6689",

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Orthogonal assay and QSAR modelling of Tox21 PPARγ antagonist in vitro high-throughput screening assay. / Ardenkjær-Skinnerup, Jacob; Nissen, Ana Caroline Vasconcelos Engedal; Nikolov, Nikolai Georgiev et al.
In: Environmental Toxicology and Pharmacology, Vol. 105, 01.2024, p. 104347.

Research output: Contribution to journal › Journal article › Research › peer-review

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 - 2024/1

Y1 - 2024/1

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 - kræft

KW - toksikologi

KW - HEK293 Cells

KW - High-Throughput Screening Assays/methods

KW - Humans

KW - PPAR gamma/genetics

KW - Quantitative Structure-Activity Relationship

U2 - 10.1016/j.etap.2023.104347

DO - 10.1016/j.etap.2023.104347

M3 - Journal article

C2 - 38143042

SN - 1382-6689

VL - 105

SP - 104347

JO - Environmental Toxicology and Pharmacology

JF - Environmental Toxicology and Pharmacology

ER -

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

Abstract

Keywords

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Projects

FFIKA: Fornyet fokus på forskning i kemisk arbejdsmiljø

Research output

PPARγ antagonists induce aromatase transcription in adipose tissue cultures

Cite this