Citation:

Paul-Friedman, K., M. Martin, K. Crofton, C. Hsu, S. Sakamuru, J. Zhao, M. Xia, R. Huang, D. Stevreva, V. Soni, L. Varticovski, R. Raziuddin, G. Hager, AND K. Houck. Limited chemical structural diversity found to modulate thyroid hormone receptor in the Tox21 chemical library. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 127(9):1-16, (2019). https://doi.org/10.1289/EHP5314

Impact/Purpose:

Interference with receptors of the endocrine system by xenobiotic chemicals is of great importance for protecting the health of humans and wildlife. Thyroid hormone receptors (TR) are critical endocrine receptors which regulate a multitude of processes in adult and developing organisms and thyroid disruption is of high concern for neurodevelopmental and reproductive toxicity in particular. To date, only a small number of chemical classes have been identified as possible TR modulators and the receptors appear highly selective with respect to the ligand structural diversity. To evaluate the hypothesis of limited structural diversity among environmental chemicals for the thyroid hormone receptor as part of the collaborative, interagency Tox21 project. The Tox21 chemical library (8,305 unique structures) was screened in a quantitative high-throughput assay for TR agonist or antagonist activity using a cell-based reporter gene assay. Active compounds were further characterized using additional orthogonal assasy including mammalian one-hybrid assays, coactivator recruitment assays and a high-throughput fluorescent imaging, nuclear receptor translocation assay. Known agonist reference chemicals were readily identified in the TR receptor transactivation assay and a small number of novel ligands were found, mostly pharmaceutical compounds. Activation of TR through its heterodimer partner, the retinoid-x-receptor (RXR), was also readily detected by confirmation in an RXR agonist assay. Identifying antagonists with high confidence was a challenge with the presence of significant cytotoxicity and other, non-TR-specific mechanisms common to the transactivation assays. Using the follow-up assays, only three novel compounds, Mefenamic acid, Diclazuril and Risarestat, were confirmed as antagonists, all from the pharmaceutical class. The results support that the TR is a very restrictive receptor with limited structural diversity for direct ligand effects and implies that other target potential target sites in the thyroid hormone axis should be a greater priority for screening for thyroid endocrine disruptors. This work is particularly relevant to the EDSP.

Description:

Interference with receptors of the endocrine system by xenobiotic chemicals is of great importance for protecting the health of humans and wildlife. Thyroid hormone receptors (TR) are critical endocrine receptors which regulate a multitude of processes in adult and developing organisms and thyroid disruption is of high concern for neurodevelopmental and reproductive toxicity in particular. To date, only a small number of chemical classes have been identified as possible TR modulators and the receptors appear highly selective with respect to the ligand structural diversity. To evaluate the hypothesis of limited structural diversity among environmental chemicals for the thyroid hormone receptor as part of the collaborative, interagency Tox21 project. The Tox21 chemical library (8,305 unique structures) was screened in a quantitative high-throughput assay for TR agonist or antagonist activity using a cell-based reporter gene assay. Active compounds were further characterized using additional orthogonal assasy including mammalian one-hybrid assays, coactivator recruitment assays and a high-throughput fluorescent imaging, nuclear receptor translocation assay. Known agonist reference chemicals were readily identified in the TR receptor transactivation assay and a small number of novel ligands were found, mostly pharmaceutical compounds. Activation of TR through its heterodimer partner, the retinoid-x-receptor (RXR), was also readily detected by confirmation in an RXR agonist assay. Identifying antagonists with high confidence was a challenge with the presence of significant cytotoxicity and other, non-TR-specific mechanisms common to the transactivation assays. Using the follow-up assays, only three novel compounds, Mefenamic acid, Diclazuril and Risarestat, were confirmed as antagonists, all from the pharmaceutical class. The results support that the TR is a very restrictive receptor with limited structural diversity for direct ligand effects and implies that other target potential target sites in the thyroid hormone axis should be a greater priority for screening for thyroid endocrine disruptors.

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