Human 3D In Vitro Models for Developmental Neurotoxicity

Abstract

Developmental neurotoxicity (DNT) testing of industrial chemicals is an increasingly perceived societal need in light of strong increases in neurodevelopmental disorders including autism. The current testing approach for DNT in vivo does not satisfy these needs because despite enormous costs and animal use, there appears to be limited predictivity for its health effects in humans. The Center for Alternatives to Animal Testing (CAAT) in the United States and Europe along with its partners has steered a process of developing in vitro strategies for DNT, which is summarized here. This process has prioritized models, cellular key events, reference compounds, and others. This shaped a 3DNT approach, which aims to employ three-dimensional (3D) microphysiological models such as an induced pluripotent stem cells–derived mini-brain model from our laboratory. These complex models have to be complemented with, favorably 3D, models of homogenous cell models for pathway identification; an example of a 3D dopaminergic neurons (LUHMES) model is given. The human mini-brain model offers opportunities beyond studying developmental effects. It is also undergoing further amendments such as the addition of microglia and a blood–brain barrier. A major recent breakthrough showed that the model could be frozen for stockpiling and transport. This enables us to make the model readily available via commercial vendors. For this purpose, a Johns Hopkins spin-off biotech company, Organome LLC, was formed.