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Integrating Data From In Vitro New Approach Methodologies for Developmental Neurotoxicity.

Kelly E Carstens1,2, Amy F Carpenter1,2, Melissa M Martin1

  • 1Center for Computational Toxicology and Exposure, ORD, U.S. EPA, Research Triangle Park, North Carolina 27711, USA.

Toxicological Sciences : an Official Journal of the Society of Toxicology
|February 16, 2022
PubMed
Summary

New methods for developmental neurotoxicity (DNT) testing are sensitive biomarkers for chemical bioactivity. A broad screening battery effectively identifies DNT, with selective activity offering insights into disrupted cellular processes.

Keywords:
computational toxicologydevelopmental neurotoxicityhigh throughput

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Area of Science:

  • Toxicology
  • Neuroscience
  • Computational Biology

Background:

  • In vivo developmental neurotoxicity (DNT) testing is resource-intensive and lacks mechanistic insights.
  • New Approach Methodologies (NAMs) are being developed to improve DNT assessment.
  • Existing NAMs require validation for sensitivity and specificity in identifying DNT bioactivity.

Purpose of the Study:

  • To evaluate a broad screening battery of DNT NAMs for sensitive detection of chemical bioactivity.
  • To determine if selective bioactivity at non-cytotoxic concentrations indicates specific disrupted functional processes.
  • To identify optimal endpoints for classifying chemicals with in vivo DNT evidence.

Main Methods:

  • Screened 92 chemicals across 57 assay endpoints from publicly available data.
  • Utilized microelectrode array neuronal network formation assay and high-content imaging.
  • Applied hierarchical clustering to analyze cytotoxicity, network connectivity, and selective activity data.

Main Results:

  • The DNT NAM battery demonstrated high sensitivity (93%) for detecting DNT bioactivity, particularly via cytotoxicity and network connectivity.
  • Clustering of selective activity revealed informative patterns of differential biological effects but with lower sensitivity (74%).
  • False negatives were linked to limitations in tested concentrations and biological coverage.

Conclusions:

  • The multi-dimensional assay suite serves as a sensitive biomarker for DNT bioactivity.
  • Selective activity analysis provides potential insights into specific functional processes affected by chemical exposure.
  • Further research is warranted to refine NAMs and address identified limitations for improved DNT assessment.