Title: Computational modeling of neural tube closure defects

Abstract: Closure of the caudal neural tube is a critical event that occurs early in development, around day 27 human gestation. Its failure underlies spina bifida and other neural tube defects (NTD), which are among the most prevalent human congenital malformations. Human and environmental safety assessment of chemicals relies primarily on legally required in vivo studies in pregnant animals. Ethical concerns, the need for greater chemical coverage whilst utilizing less resources, and growing insight in the limited predictability of animal models for human health, drive the need to find alternatives for animal experiments. However, the complexity of mammalian physiology often hampers one-on-one replacement of individual animal studies with inherently reductionistic in vitro assays. The ONTOX project proposes an approach from the perspective of human biology, physiology and toxicology, that takes an open view towards the knowledge that is needed to sufficiently cover all aspects necessary for chemical safety assessment. Within ONTOX, we focus on building and testing a computational multicellular agent-based model (ABM), based on a physiological map of human neural tube closure. By extensively mining the developmental biology and toxicology literature, a physiological map of human neural tube closure was created using the systems biology tool CellDesigner [Heusinkveld et al. (2021)]. This map revolves around all-trans-retinoic acid (ATRA)- related molecular pathways for neural tube closure and disruption. Here, the morphogenetic events are recapitulated in the Compucell3D.org modeling environment by translating the physiological map into a dynamic ABM that depicts physical aspects of neurulation (neural fold elevation, folding and fusion). Model input parameters include different perturbation scenarios (eg, dosing the model with apoptosis-inducing compounds). Output parameters include effects of simulated chemical exposure on developmental processes critical for neural tube closure, such as median and dorsolateral hinge points formation. These are modeled as a function of key morphoregulatory signals and recapitulate NTDs known from in vivo vertebrate genetic models. The predictions of our model will be validated using a set of dedicated in vitro assays in conjunction with existing knowledge on in vivo developmental neurotoxicity. By simulating a complex biological process such as the neural tube closure, we demonstrate that computational models of biological processes will provide a revolutionary approach to chemical safety assessment in the near future with less reliance on animal testing.

Host: Julio Monti Belmonte