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Blood-Brain Barrier Development: Systems Modeling and Predictive Toxicology
Saili, K., T. Zurlinden, A. Schwab, A. Silvin, N. Baker, S. Hunter, F. Ginhoux, AND T. Knudsen. Blood-Brain Barrier Development: Systems Modeling and Predictive Toxicology. Birth Defects Research, Part C: Embryo Today: Reviews. John Wiley & Sons, Ltd., Indianapolis, IN, 109(20):1680-1710, (2017). https://doi.org/10.1002/bdr2.1180
An incomplete understanding of BBB developmental biology is a roadblock to understanding the effects of chemical exposures on aspects of brain development and function (i.e., developmental neurotoxicity; DNT) that may be associated with BBB disruption. Here, we focus on BBB development and DNT from two perspectives: (1) embryological (formation of brain microvasculature through angiogenesis) and (2) teratological (AOPs for developmental disruption).
The blood-brain barrier (BBB) serves as a gateway for passage of drugs, chemicals, nutrients, metabolites and hormones between vascular and neural compartments. Here, we review the current understanding of BBB development with regard to microphysiology of the neurovascular unit (NVU) and predicting effects of BBB disruption on brain development. Our focus is on modeling these complex systems in vitro and in silico. Extant in silico models (e.g., QSAR, PBPK) provide tools to predict the probability of drug/chemical passage across the BBB; in vitro platforms for high-throughput screening (HTS) and high-content imaging (HCI) provide novel data streams for profiling chemical-biological interactions (e.g., ToxCast/Tox21); and the design of engineered microphysiological systems (e.g., human NVU on a chip) provide an intermediate level of tissue organization for exploration. Sophisticated computer models are needed that bring together pharmacokinetic models with cellular dynamic models and can formally describe complex NVU systems across gestation under various physiological or toxicological scenarios. Integration of kinetic-dynamic information for the BBB/NVU will reduce uncertainty in translating in vitro data and in silico models for use in risk assessments that aim to protect children’s health.