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Quantifying the DARTable Genome for Prediction of Teratogenic Doses - a case study using retinoic acid pathway-induced developmental toxicity
Citation:
Currie, R., N. Principato, T. Knudsen, A. Kaczor, L. Yu, A. Letamendia, A. Piersma, AND S. Mitchell-Ryan. Quantifying the DARTable Genome for Prediction of Teratogenic Doses - a case study using retinoic acid pathway-induced developmental toxicity. Society of Toxicology 2021 Virtual Annual meeting, NA, Virtual, March 12 - 26, 2021. https://doi.org/10.23645/epacomptox.14489163
Impact/Purpose:
Poster presented at the Society of Toxicology Virtual Annual Meeting March 2021. The goal of the HESI DARTable Genome Working Group is to build a comprehensive framework of molecular initiating events (MIEs) and key event biomarkers that result in teratogenicity, which would enable toxicologists to profile potential teratogenicity and assess risk without relying heavily upon animal testing.
Description:
The conservation of developmental processes permits the application of a quantitative adverse outcome pathway (AOP) model to predict threshold doses that result in teratogenic effects. The goal of the HESI DARTable Genome Working Group is to build a comprehensive framework of molecular initiating events (MIEs) and key event biomarkers that result in teratogenicity, which would enable toxicologists to profile potential teratogenicity and assess risk without relying heavily upon animal testing. Here, we used the retinoic acid (RA) pathway as a case study and explored the application of a AOP model that investigates the relationship between putative molecular initiating event (MIE), retinoic acid receptor (RAR) potency, and the quantitative threshold of maternal systemic exposure necessary to produce a teratogenic effect. Utilizing publicly assessible data, we curated MIE potency, pharmacokinetic, and toxicology information for 20 chemicals known to act on the RA pathway. Potency data for all RAR isoforms was available for 12 compounds, pharmacokinetic data for 5 compounds and toxicology information for 9. Using only those compounds with all three data types, we identified a pattern between maternal exposure, RAR potency, and teratogenicity for 3 compounds in the rat and 2 in the rabbit. A maternal blood exposure (AUC24) to RAR-potency ratio of > 2 for either RARα or RARγ was associated with a lowest observed effect level (LOEL) in the rat, while a ratio < 1.3 was associated with a no observed effect level (NOEL). The LOEL and NOEL ratios in the rabbit were 0.4 and 0.13, respectively. Ratios calculated relative to RARβ did not correlate with LOELs, potentially due to the known ability of RARβ to be complemented by the other RAR subtypes. Extending this analysis to test the predictivity of these ratios for other retinoids requires data that may currently be unpublished. Further, the discordant results between species suggests that further work is necessary to understand quantitative species differences in the RAR/RA pathways and transplacental transfer. This abstract does not reflect EPA or FDA policy.
URLs/Downloads:
DOI: Quantifying the DARTable Genome for Prediction of Teratogenic Doses - a case study using retinoic acid pathway-induced developmental toxicity
QUANTIFYING THE DARTABLE GENOME FOR PREDICTION OF TERATOGENIC DOSES.PDF (PDF, NA pp, 297.459 KB, about PDF)