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Adverse Outcome Pathway (AOP) framework for embryonic vascular disruption and developmental defects (SOT)
Citation:
Knudsen, T. Adverse Outcome Pathway (AOP) framework for embryonic vascular disruption and developmental defects (SOT). Presented at SOT, Baltimore, MD, March 12 - 16, 2017. https://doi.org/10.23645/epacomptox.5084296
Impact/Purpose:
presentation at SOT_2017 symposium Cardiopulmonary consequences of gestational toxicant exposure: Getting to the Heart of the Matter
Description:
Vascular development commences with de novo assembly of a primary capillary plexus (vasculogenesis) followed by its expansion (angiogenesis) and maturation (angio-adaptation) into a hierarchical system of arteries and veins. These processes are tightly regulated by genetic signals and environmental factors linked to morphogenesis and microphysiology. Gestational exposure to some chemicals disrupts vascular development leading to adverse outcomes. To broadly assess consequences of gestational toxicant exposure on vascular development, an Adverse Outcome Pathway (AOP) framework was constructed that integrates data from ToxCast high-throughput screening (HTS) assays with pathway-level information from the literature and public databases. The AOP-based model resolved the ToxCast library (1065 compounds) into a matrix based on several dozen molecular functions critical for developmental angiogenesis. A sample of 38 ToxCast chemicals selected across the matrix tested model performance. Putative vascular disrupting chemical (pVDC) bioactivity was assessed by multiple laboratories utilizing diverse angiogenesis assays, including: transgenic zebrafish, complex human cell co-cultures, engineered microscale systems, and human-synthetic models. The ToxCast pVDC signature predicted vascular disruption in a manner that was chemical-specific and assay-dependent. An AOP for developmental vascular toxicity was constructed that focuses on inhibition of VEGF receptor (VEGFR2). This receptor tyrosine kinase is a master switch for angiogenic sprouting and expansion when activated by VEGFA during early development and flow-sensing angio-adaptation during later development; as such, the molecular initiating event (MIE) may be invoked by pre-receptor (VEGFA production) or post-receptor (kinase activity) mechanisms. Key downstream events include: altered endothelial function (exploratory behavior, migration, proliferation, apoptosis) leading to vascular insufficiency. This AOP is currently under internal review by OECD-EAGMST for inclusion in the AOP-Wiki [https://aopwiki.org/wiki/index.php/Aop:43]. In a regulatory context, this AOP brings new concepts for assessing adverse outcomes relevant to risk assessment and efficient use of resources for validation through predictive models linking developmental toxicity to vascular disruption. (This work does not reflect EPA policy)
URLs/Downloads:
DOI: Adverse Outcome Pathway (AOP) framework for embryonic vascular disruption and developmental defects (SOT)
SOT_AOP43_TUES_FINAL_M.PDF (PDF, NA pp, 3698.244 KB, about PDF)