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A High-throughput Assay for the Prediction of Chemical Toxicity by Automated Phenotypic Profiling of Caenorhabditis elegans
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Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor

Chia-Wen Hsu1, Jinghua Zhao1, Ruili Huang1

  • 1National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD.

Scientific Reports
|September 27, 2014
PubMed

Insights

Environmental chemicals and drugs were screened for their effects on the farnesoid X receptor (FXR), a key regulator of metabolic homeostasis. Several compound classes, including pyrethroids and microtubule inhibitors, were found to disrupt FXR activity, offering insights into potential toxicological mechanisms.

Area of Science:

  • Endocrinology and Toxicology
  • Molecular Biology
  • Pharmacology

Background:

  • The farnesoid X receptor (FXR) is a crucial nuclear receptor regulating bile acid, lipid, and glucose metabolism.
  • Understanding how xenobiotics interact with FXR is vital for assessing potential disruptions to metabolic homeostasis.

Purpose of the Study:

  • To screen a large collection of environmental chemicals and drugs for activity against the human FXR.
  • To identify structural classes of compounds that modulate FXR function and compare their activity profiles with other nuclear receptors.

Main Methods:

  • A cell-based human FXR β-lactamase (Bla) reporter gene assay was employed to screen the Tox21 10K compound library.
  • Structure-activity relationships were analyzed, and FXR-active compounds were compared against assays for androgen receptor, estrogen receptor α, PPARs, and VDR.

Main Results:

  • Several FXR-active structural classes were identified, including anthracyclines, benzimidazoles, dihydropyridines, pyrethroids, retinoic acids, and vinca alkaloids.
  • Microtubule inhibitors significantly reduced FXR reporter gene activity, while pyrethroids acted as specific FXR antagonists.
  • Anthracyclines exhibited non-specific activity across multiple tested assays.

Conclusions:

  • This screening provides a prioritized list of chemicals for further toxicological investigation.
  • The identified compounds and their structure-activity relationships offer insights into potential mechanisms of FXR signaling disruption by xenobiotics.

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