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New Approach Methods’ Model Analysis and Adverse Outcome Pathway Development Validating Retinoid Signaling Associated with Skeletal Dysmorphogenesis
Citation:
Pierro, J., N. Baker, B. Ahir, AND T. Knudsen. New Approach Methods’ Model Analysis and Adverse Outcome Pathway Development Validating Retinoid Signaling Associated with Skeletal Dysmorphogenesis. 10th Annual Meeting of the American Society for Cellular and Computational Toxicology (ASCCT), Research Triangle Park, NC, October 12 - 14, 2021. https://doi.org/10.23645/epacomptox.16811035
Impact/Purpose:
Presentation for the 10th Annual Meeting of the American Society for Cellular and Computational Toxicology (ASCCT) between Tuesday, October 12, 2021 – Thursday, October 14, 2021. Here a data-driven model was constructed to identify chemicals associated with both ATRA pathway bioactivity and prenatal skeletal defects. These findings shed light on potential avenues for new mechanistic discoveries related to retinoic acid pathway disruption and associated skeletal dysmorphogenesis.
Description:
All-trans retinoic acid (ATRA) gradients determine skeletal patterning morphogenesis and can be disrupted by diverse genetic or environmental factors, leading to fetal skeleton malformations. Adverse Outcome Pathway (AOP) frameworks for ATRA metabolism, signaling, and homeostasis allow for the development of new approach methodologies (NAMs) to improve predictive toxicology without animal experimentation. Here, a data-driven model was constructed to identify chemicals associated with both ATRA pathway bioactivity and prenatal skeletal defects. We identified altered skeletal phenotypes in prenatal developmental toxicity studies in ToxRefDB and/or ToxCast high-throughput screening (HTS) and identified 375 chemicals associated with the alterations. Defects were organized into four skeletal phenotype groupings: cranial, post-cranial axial, appendicular, and other non-specified skeletal defects. To build a multivariate statistical model, HTS results from >8,070 chemicals in ToxCast/Tox21 across 13 in vitro assays, representing key nodes in the retinoid signaling system were evaluated and compared to candidate reference chemicals for in vitro testing. There were 52 chemicals were identified for constructing data-driven models to link this in vitro data with adverse skeletal outcomes for computational modeling. These preliminary findings will guide the development of dynamic modeling and AOPs for mechanistic validation to strengthen evidence for causality. Furthermore, NAMs identified 27 without previous evidence of retinoic acid pathway disturbance and skeletal defects. These findings shed light on potential avenues for new mechanistic discoveries related to retinoic acid pathway disruption and associated skeletal dysmorphogenesis. This abstract does not represent the official views of EPA or any government agency.
URLs/Downloads:
DOI: New Approach Methods’ Model Analysis and Adverse Outcome Pathway Development Validating Retinoid Signaling Associated with Skeletal Dysmorphogenesis
PIERRO ASCCT2021_RETINOIDSKELETAL_V.PDF (PDF, NA pp, 2313.503 KB, about PDF)