title: From the Cover: AstrocytesAre Protective Against Chlorpyrifos Developmental Neurotoxicity in Human Pluripotent Stem Cell-Derived Astrocyte-Neuron Cocultures.
abstract: Human neural progenitor cells are capable of independent, directed differentiation into astrocytes, oligodendrocytes and neurons and thus offer a potential cell source for developmental neurotoxicity (DNT) systems. Human neural progenitor-derived astrocyte-neuron cocultured at defined ratios mimic cellular heterogeneity and interaction in the central nervous system. Cytochrome P450 enzymes are expressed at a relatively high level in astrocytes and may play a critical role in the biotransformation of endogenous or exogenous compounds, including chlorpyrifos, an organophosphate insecticide that affects the central nervous system. P450 enzymes metabolize chlorpyrifos to chlorpyrifos-oxon, which is then metabolized primarily to 3, 5, 6-trichloropyridinol in addition to diethylphosphate and diethylthiophosphate. These end metabolites are less neurotoxic than chlorpyrifos and chlorpyrifos-oxon. Our objective was to identify the interactive role of astrocytes and neurons in chlorpyrifos-induced human DNT. In neuron-only cultures, chlorpyrifos inhibited neurite length, neurite number and branch points per neuron in a dose-dependent manner during a 48 h exposure, starting at 10 μM. However, in astrocyte-neuron cocultures, astrocytes protected neurons from the effects of chlorpyrifos at higher concentrations, up to and including 30 μM chlorpyrifos and endogenous astrocyte P450 enzymes effectively metabolized chlorpyrifos. The P450 inhibitor SKF525A partly negated the protective effect of astrocytes, allowing reduction in branch points with chlorpyrifos (10 μM). Thus, the scalable and defined astrocyte-neuron cocultures model that we established here has potentially identified a role for P450 enzymes in astrocytic neuroprotection against chlorpyrifos and provides a novel model for addressing DNT in a more accurate multicellular environment.
authors.affiliation: Department of Animal and Dairy Science, Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, USA.|Department of Animal and Dairy Science, Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, USA.
authors.forename: Xiangkun
authors.initials: X
authors.lastname: Yang
authors.affiliation: ArunA Biomedical, Athens, Georgia, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Majumder
authors.affiliation: Department of Animal and Dairy Science, Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Swetenburg
authors.affiliation: Department of Animal and Dairy Science, Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, USA.|Department of Animal and Dairy Science, Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.
authors.forename: Forrest T
authors.initials: FT
authors.lastname: Goodfellow
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Bartlett
authors.affiliation: Department of Animal and Dairy Science, Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, USA.|Department of Animal and Dairy Science, Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.|ArunA Biomedical, Athens, Georgia, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Stice
mesh_terms: D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D002454:Cell Differentiation; D004390:Chlorpyrifos / Q000378:metabolism / Q000633:toxicity*; D018920:Coculture Techniques; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D058953:Neural Stem Cells / Q000187:drug effects* / Q000473:pathology; D000071446:Neuronal Outgrowth / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000473:pathology
chemical_list: D003577:Cytochrome P-450 Enzyme System; D004390:Chlorpyrifos
keywords: astrocyte-neuron cocultures; chlorpyrifos; cytochrome P450; developmental neurotoxicity; human neural progenitor