Integrating Data From In Vitro New Approach Methodologies for Developmental Neurotoxicity

Carstens, Kelly E.; Carpenter, Amy F.; Martin, Melissa M.; Harrill, Joshua A.; Shafer, Timothy J.; Paul Friedman, Katie

doi:10.1093/toxsci/kfac018

Integrating Data From In Vitro New Approach Methodologies for Developmental Neurotoxicity

Journal Article · Wed Feb 16 00:00:00 EST 2022 · Toxicological Sciences

DOI:https://doi.org/10.1093/toxsci/kfac018· OSTI ID:1864896

Carstens, Kelly E.; Carpenter, Amy F.; Martin, Melissa M.; ; ;

Abstract

In vivo developmental neurotoxicity (DNT) testing is resource intensive and lacks information on cellular processes affected by chemicals. To address this, DNT new approach methodologies (NAMs) are being evaluated, including: the microelectrode array neuronal network formation assay; and high-content imaging to evaluate proliferation, apoptosis, neurite outgrowth, and synaptogenesis. This work addresses 3 hypotheses: (1) a broad screening battery provides a sensitive marker of DNT bioactivity; (2) selective bioactivity (occurring at noncytotoxic concentrations) may indicate functional processes disrupted; and, (3) a subset of endpoints may optimally classify chemicals with in vivo evidence for DNT. The dataset was comprised of 92 chemicals screened in all 57 assay endpoints sourced from publicly available data, including a set of DNT NAM evaluation chemicals with putative positives (53) and negatives (13). The DNT NAM battery provides a sensitive marker of DNT bioactivity, particularly in cytotoxicity and network connectivity parameters. Hierarchical clustering suggested potency (including cytotoxicity) was important for classifying positive chemicals with high sensitivity (93%) but failed to distinguish patterns of disrupted functional processes. In contrast, clustering of selective values revealed informative patterns of differential activity but demonstrated lower sensitivity (74%). The false negatives were associated with several limitations, such as the maximal concentration tested or gaps in the biology captured by the current battery. This work demonstrates that this multi-dimensional assay suite provides a sensitive biomarker for DNT bioactivity, with selective activity providing possible insight into specific functional processes affected by chemical exposure and a basis for further research.

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Sponsoring Organization:: USDOE

OSTI ID:: 1864896

Journal Information:: Toxicological Sciences, Journal Name: Toxicological Sciences Journal Issue: 1 Vol. 187; ISSN 1096-6080

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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