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AOP-based ontologies for developmental toxicity
Knudsen, T. AOP-based ontologies for developmental toxicity. Presented at European Societies of Toxicology (Eurotox) 2018, Brussels, N/A, BELGIUM, September 02 - 05, 2018. https://doi.org/10.23645/epacomptox.7078409
Here, we present case studies for AOP-based prediction of embryonic vascular disruption the ToxCast/Tox21 dataset. AOP-based ontologies support mechanistic interpretation of HTS data that potentially link molecular targets with quantitative cellular, tissue and phenotypic responses in developmental toxicity.
New approach methodologies (NAMs) based on high-throughput screening (HTS) assays can test large numbers of chemicals for bioactivity but interpretation of the data remains a challenge, especially for complex processes such as developmental toxicity. A pragmatic solution is to map HTS assay endpoints to Adverse Outcome Pathways (AOP) that contextualize cell and tissue biology with weight of evidence for critical determinants of phenotype. Here, we present case studies for AOP-based prediction of embryonic vascular disruption the ToxCast/Tox21 dataset. Vascular development is tightly regulated by genetic signals and environmental factors linked to morphogenesis and microphysiology. The AOP-based model [https://aopwiki.org/wiki/index.php/Aop:43] resolved >1000 ToxCast compounds by several dozen molecular functions for developmental angiogenesis. Putative vascular disrupting chemical (pVDC) bioactivity was evaluated for 38 chemicals utilizing 9 diverse assays covering the angiogenic cycle, including: transgenic zebrafish, complex human cell co-cultures, engineered microscale systems, and human-synthetic models. The predicted response was concordant with the observed response summated across the 9 angiogenesis assays. Preliminary analysis of RNAseq profiles for two diverse pVDCs (TNP-470, 5HPP-33) revealed a common effect on FXR and LXR pathways consistent with HTS profiles in ToxCast/Tox21, suggesting a possible link to RXR heterodimerization. AOP-based ontologies support mechanistic interpretation of HTS data that potentially link molecular targets with quantitative cellular, tissue and phenotypic responses in developmental toxicity. This abstract does not reflect US EPA policy.
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