ArticleArchives of toxicology2020
Concentration-response evaluation of ToxCast compounds for multivariate activity patterns of neural network function.
Article in Archives of toxicology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Identifying environmental chemicals impacting neurodevelopment using a random mixture-based screening approach.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Application of a high-density microelectrode array assay using a 3D human iPSC-derived brain microphysiological system model for in vitro neurotoxicity screening of environmental compounds.Archives of toxicology · 2025Article
- Bioactivity of the ubiquitous tire preservative 6PPD and degradant, 6PPD-quinone in fish- and mammalian-based assays.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- The environmental neuroactive chemicals list of prioritized substances for human biomonitoring and neurotoxicity testing: A database and high-throughput toxicokinetics approach.Environmental research · 2025Article
- Recent advances in AI-based toxicity prediction for drug discovery.Frontiers in chemistry · 2025Review
- Effects of chronic insecticide exposure on neuronal network development in vitro in rat cortical cultures.Archives of toxicology · 2024Article
- Identification of neural-relevant toxcast high-throughput assay intended gene targets: Applicability to neurotoxicity and neurotoxicant putative molecular initiating events.Neurotoxicology · 2024Review
- How neurobehavior and brain development in alternative whole-organism models can contribute to prediction of developmental neurotoxicity.Neurotoxicology · 2024Review
- Development of a new hazard scoring system in primary neuronal cell cultures for drug-induced acute neuronal toxicity identification in early drug discovery.Frontiers in pharmacology · 2024Article
- Identification of neurotoxicology (NT)/developmental neurotoxicology (DNT) adverse outcome pathways and key event linkages with in vitro DNT screening assays.Neurotoxicology · 2023Review
- Article
- Complementary biological and computational approaches identify distinct mechanisms of chlorpyrifos versus chlorpyrifos-oxon-induced dopaminergic neurotoxicity.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Navigating the bridge between wet and dry lab toxicology research to address current challenges with high-dimensional data.Frontiers in toxicology · 2023Article
- Assaying Spontaneous Network Activity and Cellular Viability Using Multi-Well Microelectrode Arrays.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Current status and future directions for a neurotoxicity hazard assessment framework that integratesComputational toxicology (Amsterdam, Netherlands) · 2022Article
- Integrating Data From In Vitro New Approach Methodologies for Developmental Neurotoxicity.Toxicological sciences : an official journal of the Society of Toxicology · 2022Article
- Prediction of the Neurotoxic Potential of Chemicals Based on Modelling of Molecular Initiating Events Upstream of the Adverse Outcome Pathways of (Developmental) Neurotoxicity.International journal of molecular sciences · 2022Article
- Predictive modeling of biological responses in the rat liver usingComputational toxicology (Amsterdam, Netherlands) · 2021Article
- A human stem cell-derived test system for agents modifying neuronal N-methyl-D-aspartate-type glutamate receptor CaArchives of toxicology · 2021Article
- Comparison of Acute Effects of Neurotoxic Compounds on Network Activity in Human and Rodent Neural Cultures.Toxicological sciences : an official journal of the Society of Toxicology · 2021Article
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Authors and funding
8 authors.
Funding
Abstract
The US Environmental Protection Agency's ToxCast program has generated toxicity data for thousands of chemicals but does not adequately assess potential neurotoxicity. Networks of neurons grown on microelectrode arrays (MEAs) offer an efficient approach to screen compounds for neuroactivity and distinguish between compound effects on firing, bursting, and connectivity patterns. Previously, single concentrations of the ToxCast Phase II library were screened for effects on mean firing rate (MFR) in rat primary cortical networks. Here, we expand this approach by retesting 384 of those compounds (including 222 active in the previous screen) in concentration-response across 43 network activity parameters to evaluate neural network function. Using hierarchical clustering and machine learning methods on the full suite of chemical-parameter response data, we identified 15 network activity parameters crucial in characterizing activity of 237 compounds that were response actives ("hits"). Recognized neurotoxic compounds in this network function assay were often more potent compared to other ToxCast assays. Of these chemical-parameter responses, we identified three k-means clusters of chemical-parameter activity (i.e., multivariate MEA response patterns). Next, we evaluated the MEA clusters for enrichment of chemical features using a subset of ToxPrint chemotypes, revealing chemical structural features that distinguished the MEA clusters. Finally, we assessed distribution of neurotoxicants with known pharmacology within the clusters and found that compounds segregated differentially. Collectively, these results demonstrate that multivariate MEA activity patterns can efficiently screen for diverse chemical activities relevant to neurotoxicity, and that response patterns may have predictive value related to chemical structural features.
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