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Scaling Barriers: Cellular Dynamics and Models of Blood-Brain Barrier Developmental Toxicity
Citation:
Saili, K., W. Slikker, F. Ginhoux, A. Silvin, J. Plavicki, A. Rodd, B. Obermeier, AND T. Zurlinden. Scaling Barriers: Cellular Dynamics and Models of Blood-Brain Barrier Developmental Toxicity. Presented at Society of Toxicology, Baltimore, MD, March 10 - 14, 2019.
Impact/Purpose:
This is a symposium proposal that will address the integrative biology and systems toxicology underlying blood-brain barrier toxicodynamics and highlight the cutting edge in vivo, in vitro, and in silico models currently utilized for early life-stage considerations.
Description:
SESSION DESCRIPTION: BACKGROUND: This session will focus on a critical vascular interface, the blood-brain-barrier (BBB), with regard to embryology and toxicology. The BBB is a core of the neurovascular unit (NVU) comprising microvascular endothelial cells, pericytes, astrocytes, microglia, and neurons. These cell types function in various capacities throughout development to regulate the distribution of substances from the circulatory system to the developing brain (i.e., toxicokinetics). Although historically described as ‘leaky,’ the leading perspective in the field has recently shifted toward an understanding that the BBB is functional soon after it forms. BBB research tends to focus on toxicokinetics, but less is known about the toxicodynamic impact that drugs and chemicals may have on the developing BBB. Moreover, it is unclear whether such impacts would lead to developmental neurotoxicity (DNT). Evidence from mouse models and human genetics suggests that altered BBB development and function has a role in the etiology of neurobehavioral disorders such as autism spectrum disorder, supporting the hypothesis that chemical disruption of the developing BBB may also lead to DNT. While current models representing the state of the science in this field have not demonstrated a direct link between BBB perturbation by chemical exposures and subsequent DNT, this hypothesis remains to be adequately tested. Alternative models may provide tools toward understanding this ‘black box’ in BBB toxicology. This proposal will address the integrative biology and systems toxicology underlying BBB toxicodynamics and highlight the cutting edge in vivo, in vitro, and in silico models currently utilized for early life-stage considerations. TOPICS: The speaker lineup will begin with an overview that frames the importance, yet paucity of developmental BBB research, followed by talks progressing from in vivo to in vitro and in silico BBB models. The first co-chair will provide an introduction to the workshop theme by describing key cell types and timing of embryonic BBB development across species. This introduction will also briefly cover other areas of the brain (e.g., circumventricular organs) and their barriers; provide an overview of the state of the art in BBB models that will be described in more detail by the session speakers; and briefly survey traditional, toxicokinetic models and BBB transporters. The first platform speaker will introduce the cortical BBB and describe a mammalian in vivo model used to investigate the role of microglia in establishing BBB integrity during embryonic development. The next speaker will discuss an embryonic, transgenic zebrafish model being used to investigate the role of pericytes in mediating developmental BBB toxicity. The next speaker will introduce a 3D in vitro model designed to test BBB permeability to therapeutic antibodies. The final speaker will discuss novel multiscale in silico models for unraveling complex cellular dynamics of BBB development in a computational neurovascular unit (cNVU) system, whereby toxicity pathways interact with fundamental morphoregulatory signaling (e.g., Wnt, Shh, Delta/Notch) during windows of vulnerability to developmental neurotoxicants. To wrap up the workshop, the second co-chair will emphasize the importance of establishing alternative BBB models that reduce animal testing, in addition to providing translational context for developmental BBB research by discussing the importance of these studies in relation to children’s environmental health protection.