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

Journal: Scientific reports
Published Date: Jul 18, 2025

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.

Authors

  • Brenda J Mengeling
    Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, CA, 95616, USA.
  • Azhagiya Singam Ettayapuram Ramaprasad
    Molecular Graphics and Computation Facility, College of Chemistry, University of California, Berkeley, CA, 94720, USA.
  • Martyn T Smith
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, 94720, USA.
  • Dania Turkieh
    Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, CA, 95616, USA.
  • Nicole C Kleinstreuer
    National Toxicology Program, National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina 27709, United States.
  • Kamel Mansouri
    National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency , Research Triangle Park, North Carolina 27711, United States.
  • Kathleen A Durkin
    Molecular Graphics and Computation Facility, College of Chemistry, University of California, Berkeley, CA, 94720, USA.
  • Michele A La Merrill
    Department of Environmental Toxicology, College of Agricultural and Environmental Studies, University of California, Davis, CA, 95616, USA. mlamerrill@ucdavis.edu.
  • J David Furlow
    Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, CA, 95616, USA. jdfurlow@ucdavis.edu.

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