A cross-platform approach to characterize and screen potential neurovascular unit toxicants

Development of the neurovascular unit (NVU) is a complex, multistage process that requires orchestrated cell signaling mechanisms across several cell types and ultimately results in the formation of the blood-brain barrier. Typical high-throughput screening (HTS) assays investigate single biochemical or single cell responses following chemical insult. As the NVU comprises multiple cell types interacting at various stages of development, a methodology for combining high-throughput results across pertinent cell-based assays is needed to investigate potential chemical-induced disruption to the development of this complex cell system. To this end, we developed a novel method for screening putative NVU disruptors across diverse assay platforms to predict chemical perturbation of the developing NVU. Here, HTS assay results measuring chemical-induced perturbations to cellular key events across angiogenic and neurogenic outcomes were combined to create a cell-based prioritization of NVU hazard. Using activity from each biological outcome, chemicals were grouped into similar modes of action and used to train a logistic regression literature model. This model utilizes the chemical-specific pairwise mutual information score for PubMed MeSH annotations to represent how often a chemical was shown to produce a specific outcome in the published literature space. Taken together, this study presents a methodology to investigate NVU developmental hazard using cell-based HTS assays and literature evidence to prioritize screening of putative NVU disruptors. The results from these screening efforts demonstrate how chemicals that represent a range of putative vascular disrupting compound (pVDC) scores based on angiogenic endpoints can also produce effects on neurogenic outcomes such as neurite outgrowth, neuroprogenitor/neural crest migration, representing an additional method for understanding the range of possible modes of action for disruption of the developing NVU. This dataset is associated with the following publication: Zurlinden, T., K. Saili, N. Baker, T. Toimela, T. Heinonen, and T. Knudsen. A cross-platform approach to characterize and screen potential neurovascular unit toxicants. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 96(September 2020): 300-315, (2020).

                                            [
  "020:00"
]
                                        

                                            {
  "fn": "Thomas Knudsen",
  "hasEmail": "mailto:knudsen.thomas@epa.gov"
}
                                        

                                            [
  {
    "title": "SupplWorkbook.xlsx",
    "mediaType": "application/vnd.openxmlformats-officedocument.spreadsheetml.sheet",
    "downloadURL": "https://pasteur.epa.gov/uploads/10.23719/1518764/SupplWorkbook.xlsx"
  }
]
                                        

                                            [
  "high-throughput screening",
  "neurovascular unit",
  "point-wise mutual information",
  "tipping points",
  "vEmbryo",
  "virtual embryo",
  "virtual tissues"
]
                                        

                                            [
  "020:095"
]
                                        

                                            {
  "name": "U.S. EPA Office of Research and Development (ORD)",
  "subOrganizationOf": {
    "name": "U.S. Environmental Protection Agency",
    "subOrganizationOf": {
      "name": "U.S. Government"
    }
  }
}
                                        

                                            [
  "https://doi.org/10.1016/j.reprotox.2020.06.010"
]
                                        

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