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An Integrative Systems Toxicology Model for Neurovascular Developmental Toxicity
Citation:
Saili, K., T. Zurlinden, N. Baker, AND T. Knudsen. An Integrative Systems Toxicology Model for Neurovascular Developmental Toxicity. Presented at Society of Toxicology, San Antonio, TX, March 11 - 15, 2018. https://doi.org/10.23645/epacomptox.6822884
Impact/Purpose:
The blood-brain barrier (BBB) limits passage of toxicants into brain tissue and may be an important tissue interface for developmental neurotoxicity, although the extent to which drugs and chemicals interact with BBB anatomical development is not well known. These results highlight potential molecular initiating events that may impact neurogenesis through BBB disruption, and this model integrates new in vitro cell-based tests with existing ToxCast data to translate cell-cell interactions within the neurovascular unit into a predictive toxicology framework of BBB disruption.
Description:
The blood-brain barrier (BBB) limits passage of toxicants into brain tissue and may be an important tissue interface for developmental neurotoxicity, although the extent to which drugs and chemicals interact with BBB anatomical development is not well known. We utilized a computational systems model of the neurovascular unit (cNVU) in concert with in vitro ToxCast chemical effects data on neurogenesis and angiogenesis assays to build a predictive model of BBB developmental disruption. A subset of 38 ToxCast chemicals was tested for effects on endothelial cell (HUVEC) and neuroprogenitor cell (hNPC, hNC, hNN) behaviors at a range of concentrations. ToxPi potency scores were derived for each chemical across a range of 8 neurogenesis and 9 angiogenesis cellular behaviors. We identified 3 major clusters of cellular effects (neurogenic, neuro-/endothelial, and negligible). There were 311 ToxCast assays associated with the positive effects groups, 32 of which could be mapped to one of 18 critical nodes in a nascent systems model of NVU development that was used to predict putative BBB disruptors from among the compounds tested, in addition to the complete ToxCast chemical library. PFOS for example, a perfluorinated compound of human health concern, had the highest NVU-relevant ToxPi score suggesting a potential effect on BBB development. PFOS affected network formation in the neurogenic, but not angiogenic systems. It also tested positive in several inflammatory assays in ToxCast (e.g., TGFβ1, VCAM1, MCSF, IL8, CSF1R, TIE2) suggesting an integrative model would reveal an impact on cytokine signaling. Moreover, at least one study found that PFOS exposure increased BBB permeability. Both PFOS and the synthetic thalidomide analogue, 5HPP-33, tested positive for angiogenesis disruption as predicted by ToxCast hits on VEGF signaling (e.g., VEGFR1, VEGFR2, VEGFR3). Both of these compounds also impacted neurogenic endpoints in vitro and suppressed TGFβ1, one of three ToxCast assays directly implicated in neuroprogenitor development in the cNVU model. These results highlight potential molecular initiating events that may impact neurogenesis through BBB disruption. Taken together, this model integrates new in vitro cell-based tests with existing ToxCast data to translate cell-cell interactions within the NVU into a predictive toxicology framework of BBB disruption. This abstract does not reflect US EPA policy.
URLs/Downloads:
DOI: An Integrative Systems Toxicology Model for Neurovascular Developmental Toxicity
SAILI_SOT_2018_POSTER_20180305_FINAL_M.PDF (PDF, NA pp, 1658.156 KB, about PDF)