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Systems toxicology model of neurovascular development (Teratology Society Annual Meeting)
Citation:
Saili, K., T. Zurlinden, N. Baker, AND T. Knudsen. Systems toxicology model of neurovascular development (Teratology Society Annual Meeting). Presented at Teratology Society Annual Meeting, Denver, Colorado, June 24 - 28, 2017.
Impact/Purpose:
Abstract for presentation at the Teratology Society meeting on the pathways underlying neurovascular interactions that dictate blood-brain barrier (BBB) development are understudied as a mechanism of developmental toxicity. These findings can be applied to a nascent systems model for BBB development that incorporates new genes into a biological wiring model for endothelial-neuronal-microglial interactions.
Description:
Angiogenesis is required for normal central nervous system development. The embryonic neuroepithelium does not generate vascular progenitors but is instead vascularized by angiogenic sprouts from the perineural vascular plexus. The pathways underlying neurovascular interactions that dictate blood-brain barrier (BBB) development are understudied as a mechanism of developmental toxicity. A systems toxicology model of the neurovascular unit would be useful to predict how chemical exposures disrupt angiogenesis and neurogenesis. The ToxCast high-throughput chemical screening program has compiled data from 1192 molecular endpoint assays on 9076 chemicals. A subset of 46 ToxCast chemicals were evaluated for effects on angiogenesis (human umbilical vein endothelial cells, HUVECs) and neurogenesis (human neuroprogenitor cells, NPCs). Four classes of compounds were identified based on activity in angiogenesis (A) and/or neurogenesis (N) assays (A+/N+, A-/N-, A-/N+, and A+/N-). Chemical groupings were composed of 23, 4, 13, and 6 chemicals, respectively. The union of positive ToxCast assays for any chemical was compared to identify assays uniquely associated with each classification group and yielded 150, 1, 45, and 47 unique assays, respectively. Gene set enrichment analysis using the gene targets associated with the 150 A+/N+ assays returned three highly enriched KEGG pathways, neuroactive ligand-receptor interaction, calcium signaling pathway, and AGE-RAGE signaling pathway in diabetic complications, including 10 genes that were conserved in two of these pathways. These findings can be applied to a nascent systems model for BBB development that incorporates the identified 10 genes into a biological wiring model for endothelial-neuronal-microglial interactions. This abstract does not reflect US EPA policy.