Identifying candidate reference chemicals for in vitro testing of the retinoid pathway for predictive developmental toxicity

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Nancy C. Baker
Jocylin D. Pierro
Laura W. Taylor
Thomas B. Knudsen


Evaluating chemicals for potential in vivo toxicity based on their in vitro bioactivity profile is an important step toward animal- free testing. A compendium of reference chemicals and data describing their bioactivity on specific molecular targets, cellular pathways, and biological processes is needed to bolster confidence in the predictive value of in vitro hazard detection. Endogenous signaling by all-trans retinoic acid (ATRA) is an important pathway in developmental processes and toxicities. Employing data extraction methods and advanced literature extraction tools, we assembled a set of candidate reference chemicals with demonstrated activity on ten protein family targets in the retinoid system. The compendium was culled from Protein Data Bank, ChEMBL, ToxCast/Tox21, and the biomedical literature in PubMed. Finally, we performed a case study on one chemical in our collection, citral, an inhibitor of endogenous ATRA production, to determine whether the literature supports an adverse outcome pathway explaining the compound’s developmental toxicity initiated by disruption of the retinoid pathway. We also deliver an updated Abstract Sifter tool populated with these reference compounds and complex search terms designed to query the literature for the downstream consequences to support concordance with targeted retinoid pathway disruption.

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Baker, N., Pierro, J., Taylor, L. and Knudsen, T. (2023) “Identifying candidate reference chemicals for in vitro testing of the retinoid pathway for predictive developmental toxicity”, ALTEX - Alternatives to animal experimentation, 40(2), pp. 217–236. doi: 10.14573/altex.2202231.

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