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Surveying type I nuclear receptor activation by environmental toxins

Award Number: R21ES038311
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/07/2026
PERIOD OF PERFORMANCE END DATE: 08/06/2028

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Surveying type I nuclear receptor activation by environmental toxins - PROJECT SUMMARY Endocrine-disrupting chemicals (EDCs) and nanoplastics (NPs) are environmental toxins that interfere with the normal function of the endocrine system by binding to type I nuclear receptors (NR), a family of ligand-mediated transcription factors that act as key regulators of metabolism, development, reproduction, and cell proliferation. Members of the type I NR family, including estrogen receptors (ER), androgen receptors (AR), and progesterone receptors (PR), are activated through the binding of endogenous steroid hormones and exert their biological effects by controlling the expression of steroid-responsive genes in the nucleus. Unfortunately, many EDCs and NPs compete for ligand-binding domains (LBDs) of type I NRs by mimicking the size and structure of natural steroid hormones. If left untreated, such aberrant interactions often lead to debilitating physiological disorders, including neurodegeneration, inflammation, autoimmunity and cancer. Broadly speaking, the LBDs of type I NRs undergo moderate structural changes upon ligand binding that involves transition of a dynamic C-terminal helix (H12) from an extended (inactive) state to a well-folded (active) state. Our laboratory has developed a novel, in vitro assay that uses a convenient fluorescence-based readout to survey ligand-mediated H12 transitions within the ER-LBD. The assay, termed ‘FlAsH-ER’, employs bipartite tetracysteine display coupled with the biarsenical profluorophore FlAsH-EDT2 to monitor H12 transitions as a function of fluorescence intensity. Using FlAsH-ER, we have successfully monitored ligand-dependent structural changes of H12 in ER-LBDs bound to various estrogenic ligands and selective estrogen receptor modulators, and tracked ligand-independent H12 transitions in constitutively active ER mutants expressed in endocrine-resistant breast cancers. We now seek to utilize the FlAsH-ER assay to directly study how EDCs and NPs affect ligand-mediated H12 transitions within type I NRs. In Specific Aim 1 of this proposal, our work will focus on applying the FlAsH-ER assay to monitor H12 transitions within ERs that have been exposed to EDCs or NPs. This will be accomplished by treating wild-type or mutant ERs with discrete EDCs or NPs at concentrations that reflect real-world exposure levels and monitoring H12 transitions as they relate to ligand binding. Notably, such studies will allow us to directly determine how EDCs and NPs affect active-state (or inactive-state) H12 transitions within the ER. In Specific Aim 2, we expand the utility of the FlAsH-ER assay by commuting the technique to other type I NR LBDs. Here, we will use site-directed mutagenesis to generate tetracysteine-tagged AR-LBDs and PR-LBDs that will recapitulate an optimized FlAsH- binding motif upon interaction with ligand. Correlative ‘FlAsH-AR’ and ‘FlAsH-PR’ assays will then be used to determine how endogenous steroids and environmental toxins, including EPCs and NPs, affect active-state H12 transitions within each receptor subtype. Collectively, results obtained from the work outlined in this proposal will determine the molecular mechanisms that drive ligand-mediated activation of type I NRs and will facilitate the development of lead compounds to treat endocrine disorders that arise from exposure to environmental toxins.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $404,163 )
2026	2026	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Environmental Health	000	1	8/6/2026	NEW	$404,163
														Subtotal = $404,163

Grand Total All Awards = $404,163

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Surveying type I nuclear receptor activation by environmental toxins

Award Number: R21ES038311

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/07/2026

PERIOD OF PERFORMANCE END DATE: 08/06/2028

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