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Related Concept Videos

Teratogenicity01:07

Teratogenicity

The ability of a drug to produce structural deformations and functional abnormalities in the developing embryo or the fetus is called teratogenicity, and the drug producing this effect is known as a teratogen. Teratogenic effects include stillbirth, miscarriage, intrauterine growth restriction, and neurocognitive delay. A teratogen may affect the embryo at different stages of development, which is important in determining the type and extent of the damage. During blastocyst formation, the early...

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Development of automated imaging and analysis for zebrafish chemical screens.
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Profiling assay performance in the DevTox germ layer reporter platform.

John T Gamble1,2, Chad Deisenroth1

  • 1Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 United States.

Current Research in Toxicology
|February 28, 2025
PubMed
Summary
This summary is machine-generated.

The DevTox Germ Layer Reporter (GLR) model platform effectively screens chemical developmental hazards. The DevTox GLR-Endo assay demonstrated the highest predictive accuracy for identifying toxicant effects on embryonic development.

Keywords:
Developmental toxicityEctodermEndodermGastrulationHigh-throughput screeningMesoderm

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Area of Science:

  • Toxicology
  • Developmental Biology
  • Stem Cell Biology

Background:

  • The U.S. Environmental Protection Agency (U.S. EPA) requires new approach methodologies (NAMs) to assess chemical risks to vulnerable populations, such as pregnant women and their offspring.
  • Traditional animal testing models have limitations in relevance, mechanistic insight, and testing capacity compared to NAMs.
  • The DevTox Germ Layer Reporter (GLR) model platform was developed for high-throughput screening of potential developmental hazards.

Purpose of the Study:

  • To evaluate the predictive accuracy of the DevTox GLR model platform for identifying developmental toxicants.
  • To assess the performance of assays targeting different embryonic lineages: endoderm, pluripotency, ectoderm, and mesoderm.
  • To determine which DevTox GLR assay provides the highest efficacy and predictive accuracy for chemical developmental hazard assessment.

Main Methods:

  • Utilized the RUES2-GLR pluripotent stem cell reporter line expressing fluorescent biomarkers for endoderm (SOX17), mesoderm (Brachyury), and ectoderm/pluripotency (SOX2).
  • Developed and validated four assays: DevTox GLR-Endo, DevTox GLR-Pluri, DevTox GLR-Ecto, and DevTox GLR-Meso.
  • Assessed chemical activity using reference sets and expanded compound sets, calculating balanced accuracy (BA) against known developmental toxicants and non-toxicants.

Main Results:

  • The DevTox GLR-Endo assay achieved a balanced accuracy (BA) of 72% against an initial training set.
  • For a chemical reference set, BAs were 92% for DevTox GLR-Endo and DevTox GLR-Pluri, 71% for DevTox GLR-Ecto, and 58% for DevTox GLR-Meso.
  • Expanded testing with 63 toxicants yielded BAs of 75% for DevTox GLR-Endo and 68% for DevTox GLR-Pluri.
  • The DevTox GLR-Endo assay consistently demonstrated the highest efficacy and predictive accuracy across evaluated compound sets.

Conclusions:

  • The DevTox GLR platform, particularly the DevTox GLR-Endo assay, shows significant promise as a NAM for prioritizing chemicals with developmental toxicity potential.
  • This stem cell-based reporter assay provides valuable mechanistic insights into chemical effects on early embryonic development.
  • The DevTox GLR-Endo assay offers a high-throughput, accurate method for assessing developmental hazards, aiding regulatory decision-making.