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Formation of the Blood-Brain Barrier and Susceptibilities to Toxicants
Citation:
Saili, K., T. Zurlinden, N. Baker, AND T. Knudsen. Formation of the Blood-Brain Barrier and Susceptibilities to Toxicants. Presented at Teratology Society, Clearwater, FL, June 23 - 27, 2018. https://doi.org/10.23645/epacomptox.6828743
Impact/Purpose:
Recent evidence suggests that gene expression within the blood-brain barrier (BBB) may be involved in the etiology of some neurodevelopmental disorders. Proteins important for brain angiogenesis were identified from a comprehensive literature review and used to model a multicellular control system for BBB formation. Initial predictions were qualified against a test set of in vitro angiogenesis and neurogenesis inhibition assays for neurovascular developmental toxicity, suggesting an effective means to identify potential BBB disrupters using in vitro data and in silico models.
Description:
Recent evidence suggests that gene expression within the blood-brain barrier (BBB) may be involved in the etiology of some neurodevelopmental disorders. For example, autism spectrum disorder (ASD) has been linked to SLC7A5, an amino acid transporter localized at the BBB that plays an essential role in maintaining normal levels of large, nonpolar amino acids. The BBB arises from the interactions of cells in the neurovascular unit (NVU), which comprises endothelial cells (ECs), pericytes, microglia, and neuroprogenitor cells (i.e., radial glia that give rise to neurons and astrocytes). Vascularization of the embryonic brain in mice commences with angiogenic sprouting of the perineural vascular plexus by GD9.5, corresponding roughly to week 8 in human gestation. Radial glia-guided invasion, pericyte-EC association, tight junction formation, and microglia-mediated anastomosis are key cellular features in the nascent BBB. These processes can be mapped to key events in an adverse outcome pathway (AOP) for developmental neurovascular toxicity. Proteins important for brain angiogenesis were identified from a comprehensive literature review and used to model a multicellular control system for BBB formation. Next, a classification model built with ToxCast data was used to predict potential BBB toxicants. Initial predictions were qualified against a test set of in vitro angiogenesis and neurogenesis inhibition assays for neurovascular developmental toxicity, suggesting an effective means to identify potential BBB disrupters using in vitro data and in silico models. This abstract does not reflect US EPA policy.
URLs/Downloads:
DOI: Formation of the Blood-Brain Barrier and Susceptibilities to Toxicants
SAILI_BBB_TS_180620_FINAL1_M.PDF (PDF, NA pp, 4748.437 KB, about PDF)