Journal article
Identification of nonmonotonic concentration-responses in Tox21 high-throughput screening estrogen receptor assays
Toxicology and applied pharmacology, Vol.452, pp.116206-116206
10/01/2022
DOI: 10.1016/j.taap.2022.116206
PMCID: PMC9452481
PMID: 35988584
Abstract
Environmental endocrine-disrupting chemicals (EDCs) interfere with the metabolism and actions of endogenous hormones. It has been well documented in numerous in vivo and in vitro studies that EDCs can exhibit nonmonotonic dose response (NMDR) behaviors. Not conforming to the conventional linear or linear-no-threshold response paradigm, these NMDR relationships pose practical challenges to the risk assessment of EDCs. In the meantime, the endocrine signaling pathways and biological mechanisms underpinning NMDR remain incompletely understood. The US Tox21 program has conducted in vitro cell-based high-throughput screening assays for estrogen receptors (ER), androgen receptors, and other nuclear receptors, and screened the 10 K-compound library for potential endocrine activities. Using 15 concentrations across several orders of magnitude of concentration range and run in both agonist and antagonist modes, these Tox21 assay datasets contain valuable quantitative information that can be explored to evaluate the nonlinear effects of EDCs and may infer potential mechanisms. In this study we analyzed the concentration-response curves (CRCs) in all 8 Tox21 ERα and ERβ assays by developing clustering and classification algorithms customized to the datasets to identify various shapes of CRCs. After excluding NMDR curves likely caused by cytotoxicity, luciferase inhibition, or autofluorescence, hundreds of compounds were identified to exhibit Bell or U-shaped CRCs. Bell-shaped CRCs are about 7 times more frequent than U-shaped ones in the Tox21 ER assays. Many compounds exhibit NMDR in at least one assay, and some EDCs well-known for their NMDRs in the literature were also identified, suggesting their nonmonotonic effects may originate at cellular levels involving transcriptional ER signaling. The developed computational methods for NMDR identification in ER assays can be adapted and applied to other high-throughput bioassays.
•A method was developed to identify concentration-response shapes in Tox21 ER assays.•Hundreds of compounds exhibit nonmonotonic concentration-response curves (CRCs).•Bell-shaped CRCs are about 7 times more frequent than U-shaped CRCs.•Many compounds exhibit nonmonotonic CRCs in more than one ER assays.•The algorithm can be adapted and applied to other high-throughput bioassays.
Details
- Title: Subtitle
- Identification of nonmonotonic concentration-responses in Tox21 high-throughput screening estrogen receptor assays
- Creators
- Zhenzhen Shi - Emory UniversityMenghang Xia - National Center for Advancing Translational Sciences, NIH, Bethesda, MD, USAShuo Xiao - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ, USAQiang Zhang - Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
- Resource Type
- Journal article
- Publication Details
- Toxicology and applied pharmacology, Vol.452, pp.116206-116206
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.taap.2022.116206
- PMID
- 35988584
- PMCID
- PMC9452481
- ISSN
- 0041-008X
- eISSN
- 1096-0333
- Language
- English
- Date published
- 10/01/2022
- Academic Unit
- Neurology
- Record Identifier
- 9984302201602771
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