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Adverse Outcome Pathways and Computational Toxicology Applications of a Multi-database Review of Retinoid Signaling in Skeletal Development
Citation:
Pierro, J., Nancy C. Baker, AND T. Knudsen. Adverse Outcome Pathways and Computational Toxicology Applications of a Multi-database Review of Retinoid Signaling in Skeletal Development. Society of Toxicology 2021 Virtual Annual Meeting, Virtual, NC, March 12 - 26, 2021. https://doi.org/10.23645/epacomptox.14466411
Impact/Purpose:
Poster presented to the Society of Toxicology annual meeting in March 2021.
Description:
Locally-regulated all-trans retinoic acid (ATRA) gradients are important determinants of skeletal morphogenesis and can be disrupted by diverse genetic or environmental factors, leading to homeotic transformations and malformations of skeletal structures. Adverse Outcome Pathway (AOP) frameworks for ATRA metabolism, signaling, and homeostasis allow for the development of scalable computational models to support new approach methodologies (NAMs) for chemical hazard identification that aims to improve predictive toxicology with less reliance on animal testing. Here a model was developed to deduce which chemicals were connected to both ATRA pathway bioactivity and prenatal skeletal defects. 375 chemicals from ToxRefDB and/or ToxCast possessed altered skeletal phenotypes in prenatal DevTox studies. The skeletal defects were organized into 10 skeletal phenotype regions of interest cranial (neurocranial, orofacial, viscerocranial); axial (thoracic cage, vertebral, cauda); appendicular (stylopod, zeugopod, autopod); and other non-specific skeletal structures. For each chemical, distribution of phenotype(s) was scored as a fraction of 1 for inclusion in ToxPi k-means clustering; the clustering resulted in the identification of trends in skeletal defects due to shared characteristics among chemicals. To complete the key model, we evaluated results from >8,070 chemicals in ToxCast/Tox21 across 13 in vitro HTS assays for components in the retinoid system. Over 40 chemicals were identified for constructing data-driven models to link this HTS data with skeletal Adverse Outcomes (AOs) in ToxRefDB and ToxCast. This abstract does not represent the views of the Agency.
URLs/Downloads:
DOI: Adverse Outcome Pathways and Computational Toxicology Applications of a Multi-database Review of Retinoid Signaling in Skeletal Development
PIERRO_SOT_RETINOIDSKELETAL_2.25.21_V3.PDF (PDF, NA pp, 2047.953 KB, about PDF)