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Computational model of the neurovascular unit (cNVU) for predictive toxicology of blood-brain-barrier development
Zurlinden, T., K. Saili, R. Spencer, N. Baker, AND T. Knudsen. Computational model of the neurovascular unit (cNVU) for predictive toxicology of blood-brain-barrier development. Presented at SOT Annual Meeting, San Antonio, Texas, March 11 - 15, 2018. https://doi.org/10.23645/epacomptox.6813050
Development of a functional blood-brain barrier (BBB) is a complex process regulated by multiple cell types across gestation. To address the complexities of chemical exposure on the developing BBB, a cell agent-based model was built to recapitulate key events during development of the neurovascular unit.
Development of a functional blood-brain barrier (BBB) is a complex process regulated by multiple cell types. BBB development consists of several key events during heterotypic cellularization of the embryonic neuroepithelium: vascular invasion and patterning from the perineural vascular plexus; neuroprogenitor proliferation, migration and differentiation in the subventricular zone; and cytokine/growth factor signaling co-opted from microglia, resident macrophages originating in the yolk sac. Disruption of these key events could lead to BBB developmental toxicity. For example, microglia disruption during development is hypothesized to disrupt BBB formation via decreased vessel branching and compromised vessel stabilization. To examine the effects of chemical exposure on the developing BBB, a cell agent-based model was built to recapitulate key events during development of the neurovascular unit. This computer model enables stochastic interactions between microglia and endothelial cells via a complex signaling network (Notch/dll4, CSF1, VEGFA, VEGFC, sFlt1). Molecular elements in these pathways were linked to available receptor targets through EPA’s ToxCast high throughput screening (HTS) dataset in order to translate bioactivity results from the HTS dataset into quantitative predictions of BBB dysmorphogenesis. A simulated dose-escalation study was conducted with Mancozeb, which had an incremental concentration response on ToxCast assays for three critical signals mediating microglial-endothelial interplay: CSF1 at low concentrations, VEGFC at an intermediate concentration range, and VEGFA at the upper bound. The predicted no-effect-level (pNEL) on the system transitioned into a predicted lowest effect level (pLEL) at 30% inhibition of CSF1R. The model outcome was decreased microglia abundance and reduced branching of the invading vascular network. The pLEL (0.3 μm) from this computational NVU (cNVU) model agreed with the Mancozeb-specific tubulogenesis point-of-departure (0.6 μm) reported from in vitro cell culture system investigating tubulogenesis in human umbilical vein endothelial cells (HUVEC) from the VALA sciences platform. Taken together, development and validation the cNVU model could help predict chemical perturbations to the complex biology of the developing BBB. This abstract may not reflect US EPA policy.
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