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Identification of Chemicals Associated with Retinoid Signaling Pathway Disturbance and Skeletal Dysmorphogenesis for the Development of Computational Toxicology Models for New Approach Methods’ (NAMs) Hazard Predictions
Citation:
Pierro, J., B. Ahir, N. Baker, AND T. Knudsen. Identification of Chemicals Associated with Retinoid Signaling Pathway Disturbance and Skeletal Dysmorphogenesis for the Development of Computational Toxicology Models for New Approach Methods’ (NAMs) Hazard Predictions. Society of Birth Defects Research and Prevention 62nd Annual Conference (2022), Vancouver, British Columbia, CANADA, June 25 - 29, 2022. https://doi.org/10.23645/epacomptox.19692319
Impact/Purpose:
Presentation to the Society of Birth Defects Research and Prevention 62nd Annual Conference June 2022. Our findings guided the development of potential AOPs (pAOPs) and will further advance our dynamic mechanistic modeling to strengthens evidence for causality. Furthermore, NAMs identified 20 chemicals without previous evidence of retinoic acid pathway disturbance and skeletal defects association. 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. Here, a data-driven model was constructed to identify chemicals associated with both ATRA pathway bioactivity and prenatal skeletal defects. We classified 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 10 in vitro assays, representing key nodes in the retinoid signaling system were evaluated and compared to candidate reference chemicals for in vitro testing. A set of 48 chemicals were identified for constructing data-driven models to link this in vitro data with adverse skeletal outcomes for computational modeling. 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. Our findings guided the development of potential AOPs (pAOPs) and will further advance our dynamic mechanistic modeling to strengthen evidence for causality. Furthermore, NAMs identified 20 chemicals without previous evidence of retinoic acid pathway disturbance and 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 for the Development of Computational Toxicology Models for New Approach Methods’ (NAMs) Hazard Predictions
JDP_PLATFORM_2022_V6.PDF (PDF, NA pp, 1928.985 KB, about PDF)