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Title:
Mapping the Brain Physiological Maze: an innovative approach for advancing developmental neurotoxicology

Authors:
Eliska Kuchovska, Kristina Bartmann, Luiz Ladeira, Arif Dönmez, Lynn-Christin Saborowski, Nicolai Görts, Denis Polozij, Farina Bendt, Mats Schade, Georgea Raad, Alessio Gamba, Bernard Staumont, Malene Lislien, Agata Antonita Rita Impellizzeri, Tim Hofer, Oddvar Myhre, Hubert Dirven, Liesbet Geris and Ellen Fritsche

Abstract:
Our understanding of human brain development often relies on animal-derived data introducing potential inaccuracies due to species differences. Consequently, new approach methodologies (NAMs) designed to assess the hazard of chemicals on the developing brain should be firmly grounded in human physiology to ensure their reliability and efficiency as tools. Therefore, we aimed to develop a comprehensive physiological map of the developing human brain, serving as a foundational knowledge base that provides insights into the biological underpinnings and physiological mechanisms crucial for healthy brain development. To construct this map, we conducted a meticulous non-systematic literature review, deliberately excluding animal in vivo data. The used sources encompassed information derived from human fetal tissues, as well as human primary and iPSC-derived differentiating neural progenitor cells. Additionally, we enriched the literature findings with experimental data involving the inhibition and activation of specific signaling pathways using a primary human in vitro model reflecting the fetal developing brain. The resulting data were mapped using CellDesigner software and visualized on the Minerva platform while maintaining comprehensive documentation of the included data. The developed map consists of various submaps, each focusing on the development of distinct brain cells such as neural progenitor cells, neurons, oligodendrocytes, radial glia, and astrocytes covering neurodevelopmental processes of proliferation, migration, differentiation, and synaptogenesis. Particularly noteworthy is the advanced status of the oligodendrocyte development map, which not only incorporates experimental data derived from modulations in signaling pathways but also integrates markers of neurodevelopmental disorders. Furthermore, the map incorporates additional layers in the form of an interaction map highlighting cell-cell interactions during brain development and a graphical summary outlining key neurodevelopmental processes. This comprehensive map serves as the foundational element of the ontological framework in the European H2020 ONTOX project. It will be integrated with an adverse outcome pathway network and utilized in the creation of dynamic computational models. Ultimately, these tools combined with in silico and in vitro NAMs will facilitate the prediction of chemical effects on the developing human brain in line with the principles of next-generation risk assessment, enable testing of large numbers of chemicals, and eliminate the necessity for highly resource-intensive and variable animal testing.