Citation:

Mack, C., A. Tsui-Bowen, A. Smith, K. Jensen, P. Kodavanti, V. Moser, W. Mundy, T. Shafer, AND D. Herr. Identification of neural-relevant toxcast high-throughput assay intended gene targets: Applicability to neurotoxicity and neurotoxicant putative molecular initiating events. NEUROTOXICOLOGY. Elsevier B.V., Amsterdam, Netherlands, 103:256-265, (2024). https://doi.org/10.1016/j.neuro.2024.07.001

Impact/Purpose:

This manuscript reviews the intended gene targets in Invitrodb version 3.5. Each intended gene target was categorized for its relationship to neurotoxicity/developmental neurotoxicity (NT/DNT). Subsequently, over 500 reported neurotoxic substances were investigated to examine reported molecular initiating events/key events in producing toxicity. A comparison was then made between these reported neurotoxic mechanisms and the intended gene targets. Areas for future development of high throughput assays were proposed. This work will aid both EPA scientists and the general scientific community when interpreting “hits” from high throughput assays with respect to potential NT/DNT.

Description:

The US EPA’s Toxicity Forecaster (ToxCast) is a suite of high-throughput in vitro assays to screen environmental toxicants and predict potential toxicity of uncharacterized chemicals. This work examines the relevance of ToxCast assay intended gene targets to putative molecular initiating events (MIEs) of neurotoxicants. This effort is needed as there is growing interest in the regulatory and scientific communities about developing new approach methodologies (NAMs) to screen large numbers of chemicals for neurotoxicity and developmental neurotoxicity. Assay gene function (GeneCards, NCBI-PUBMED) was used to categorize gene target neural relevance (1 = neural, 2 = neural development, 3 = general cellular process, 3¿A = cellular process critical during neural development, 4 = unlikely significance). Of 481 unique gene targets, 80 = category 1 (16.6¿%); 16 = category 2 (3.3¿%); 303 = category 3 (63.0¿%); 97 = category 3¿A (20.2¿%); 82 = category 4 (17.0¿%). A representative list of neurotoxicants (548) was researched (ex. PUBMED, PubChem) for neurotoxicity associated MIEs/Key Events (KEs). MIEs were identified for 375 compounds, whereas only KEs for 173. ToxCast gene targets associated with MIEs were primarily neurotransmitter (ex. dopaminergic, GABA)receptors and ion channels (calcium, sodium, potassium). Conversely, numerous MIEs associated with neurotoxicity were absent. Oxidative stress (OS) mechanisms were 79.1¿% of KEs. In summary, 40¿% of ToxCast assay gene targets are relevant to neurotoxicity mechanisms. Additional receptor and ion channel subtypes and increased OS pathway coverage are identified for potential future assay inclusion to provide more complete coverage of neural and developmental neural targets in assessing neurotoxicity.

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