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Identification of Chemicals Associated with Retinoid Signaling Pathway Disturbance and Skeletal Dysmorphogenesis via New Approach Methods’ Model and Adverse Outcome Pathway Development
Citation:
Pierro, J., B. Ahir, N. Baker, AND T. Knudsen. Identification of Chemicals Associated with Retinoid Signaling Pathway Disturbance and Skeletal Dysmorphogenesis via New Approach Methods’ Model and Adverse Outcome Pathway Development. Society of Toxicology 61st Annual Meeting and ToxExpo 2022, San Diego, California, March 27 - 31, 2022. https://doi.org/10.23645/epacomptox.19630437
Impact/Purpose:
Presentation to the Society of Toxicology 61st Annual Meeting and ToxExpo March . Purpose is to present on retinoic acid pathway disruption's association with fetal skeletal defects.
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 370 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 48 chemicals that 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 20 chemicals without previous evidence of retinoic acid pathway disturbance and nor skeletal defects association. 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: Identification of Chemicals Associated with Retinoid Signaling Pathway Disturbance and Skeletal Dysmorphogenesis via New Approach Methods’ Model and Adverse Outcome Pathway Development
PIERRO_SOT2022_RETINOIDSKELETAL_FINAL.PDF (PDF, NA pp, 1097.374 KB, about PDF)