Limited Chemical Structural Diversity Found to Modulate Thyroid Hormone Receptor in the Tox21 Chemical Library

Area of Science:

• Endocrinology
• Toxicology
• Molecular Biology

Background:

• Thyroid hormone receptors (TRs) are crucial for development and adult functions.
• Disruption of thyroid hormone signaling poses risks for neurodevelopment and reproduction.
• Identifying TR modulators is vital for human and wildlife health protection.

Purpose of the Study:

• To investigate the structural diversity of environmentally relevant chemicals that modulate TR activity.
• To test the hypothesis of limited structural diversity among TR-active compounds.

Main Methods:

• Screened 8,305 chemicals from the Tox21 library using cell-based reporter gene assays for TR agonist/antagonist activity.
• Validated hits with orthogonal assays: mammalian one-hybrid, coactivator recruitment, and nuclear receptor translocation.
• Utilized high-throughput screening and quantitative assays for comprehensive analysis.

Main Results:

• Identified known TR agonists but only one novel direct agonist (betamipron).
• Detected indirect TR activation via retinoid-X-receptor (RXR) agonism.
• Confirmed three TR antagonists (mefenamic acid, diclazuril, risarestat) despite challenges with cytotoxicity and non-specific effects.

Conclusions:

• Findings support limited structural diversity for direct TR ligand interactions.
• Suggests prioritizing other target sites in the thyroid hormone axis for future screening efforts.
• Highlights the complexity of identifying TR antagonists due to assay interferences.