Evidence map›Paper›PMID 40681575›Full record

ArticleScientific reports2025

An in silico to in vivo approach identifies retinoid-X receptor activating tert-butylphenols used in food contact materials.

Brenda J Mengeling, Azhagiya Singam Ettayapuram Ramaprasad, Martyn T Smith, Dania Turkieh, Nicole C Kleinstreuer, Kamel Mansouri, Kathleen A Durkin, Michele A La Merrill, J David Furlow

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PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Brenda J MengelingDepartment of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, CA, 95616, USA.
Azhagiya Singam Ettayapuram RamaprasadMolecular Graphics and Computation Facility, College of Chemistry, University of California, Berkeley, CA, 94720, USA.
Martyn T SmithDivision of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, 94720, USA.
Dania TurkiehDepartment of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, CA, 95616, USA.
Nicole C KleinstreuerNational Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27711, USA.
Kamel MansouriNational Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27711, USA.
Kathleen A DurkinMolecular Graphics and Computation Facility, College of Chemistry, University of California, Berkeley, CA, 94720, USA.
Michele A La MerrillDepartment of Environmental Toxicology, College of Agricultural and Environmental Studies, University of California, Davis, CA, 95616, USA. mlamerrill@ucdavis.edu.
J David FurlowDepartment of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, CA, 95616, USA. jdfurlow@ucdavis.edu.

Funding

California Environmental Protection Agency Office of Environmental Health Hazard Assessment 22-E0010California Environmental Protection Agency Office of Environmental Health Hazard Assessment 22-E0016Division of Agriculture and Natural Resources, University of California CA-D-NPB-2531-HNational Institutes of Environmental Health Sciences 5P42ES004699-33
6 · The paper itself

Abstract

The potential for food contact chemicals to disrupt genetic programs in development and metabolism raises concerns. Nuclear receptors (NRs) control many of these programs, and the retinoid-X receptor (RXR) is a DNA-binding partner for one-third of the NRs. RXR disruption could generate adverse outcomes in several NR pathways. We used machine learning and other in silico methods to identify RXR-interacting candidates from a list of over 57,000 chemicals. Butylphenols comprised the largest, high-probability, structural group (58 compounds); several are food contact chemicals with widespread commercial use. In vitro ToxCast data suggested that bulky, aliphatic substitution at C4 of 2,6-di-tert-butylphenol facilitated RXR activation. We tested six butylphenols with increasing bulk at C4 in vivo for their ability to disrupt thyroid hormone receptor (TR) signaling, using an integrated luciferase reporter driven by TR-RXR binding and quantifiable morphological changes in a Xenopus laevis precocious metamorphosis assay. Three tert-butylphenols potentiated TH action at nanomolar concentrations. Molecular modeling showed the three positives formed more frequent, stable interactions with RXRα, and bulkiness at C4 increased steric complementarity with the RXR ligand-binding pocket. Our findings establish a paradigm for machine learning coupled with a convenient, in vivo validation approach to identify chemicals interacting with RXR-NR-controlled genetic pathways.

Indexed as

PhenolsRetinoid X ReceptorsAnimalsComputer SimulationHumansMachine LearningModels, MolecularProtein BindingReceptors, Thyroid HormoneSignal TransductionXenopus laevisPhenolsReceptors, Thyroid HormoneRetinoid X ReceptorsArtificial intelligenceEnvironmental exposureFood contact chemicalsMachine learningMolecular dockingNew approach methods (NAMs)Retinoid-X receptor

Identifiers

PMID40681575
PMCPMC12274580

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.