title: A human stem cell-based model for identifying adverse effects of organic and inorganic chemicals on the developing nervous system.
abstract: The aim of our study was to investigate whether a human neural stem cell line derived from umbilical cord blood (HUCB-NSC) can serve as a reliable test model for developmental neurotoxicity (DNT). We assessed the sensitivity of HUCB-NSCs at different developmental stages to a panel of neurotoxic (sodium tellurite, methylmercury chloride, cadmium chloride, chlorpyrifos, and L-glutamate) and non-neurotoxic (acetaminophen, theophylline, and D-glutamate) compounds. In addition, we investigated the effect of some compounds on key neurodevelopmental processes like cell proliferation, apoptotic cell death, and neuronal and glial differentiation. Less differentiated HUCB-NSCs were generally more sensitive to neurotoxicants, with the notable exception of L-glutamate, which showed a higher toxicity to later stages. The relative potencies of the compounds were: cadmium chloride > methylmercury chloride >> chlorpyrifos >> L-glutamate. Fifty nanomolar methylmercury chloride (MeHgCl) inhibited proliferation and induced apoptosis in early-stage cells. At the differentiated stage, 1 muM MeHgCl induced selective loss of S100 beta-expressing astrocytic cells. One millimolar L-glutamate did not influence the early stages of HUCB-NSC development, but it affected late stages of neuronal differentiation. A valuable system for in vitro DNT assessment should be able to discriminate between neurotoxic and non-neurotoxic compounds and show different susceptibilities to chemicals according to developmental stage and cell lineage. Although not exhaustive, this work shows that the HUCB-NSC model fulfils these criteria and may serve as a human in vitro model for DNT priority setting.
authors.affiliation: NeuroRepair Department, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Leonora
authors.initials: L
authors.lastname: Buzanska
authors.forename: Joanna
authors.initials: J
authors.lastname: Sypecka
authors.forename: Silvia
authors.initials: S
authors.lastname: Nerini-Molteni
authors.forename: Anna
authors.initials: A
authors.lastname: Compagnoni
authors.forename: Helena T
authors.initials: HT
authors.lastname: Hogberg
authors.forename: Riccardo
authors.initials: R
authors.lastname: del Torchio
authors.forename: Krystyna
authors.initials: K
authors.lastname: Domanska-Janik
authors.forename: Jens
authors.initials: J
authors.lastname: Zimmer
authors.forename: Sandra
authors.initials: S
authors.lastname: Coecke
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D019256:Cadmium Chloride / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004390:Chlorpyrifos / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology*; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity; D009414:Nerve Growth Factors / Q000032:analysis / Q000378:metabolism; D009420:Nervous System / Q000187:drug effects* / Q000254:growth & development; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D011237:Predictive Value of Tests; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000032:analysis / Q000378:metabolism; D012680:Sensitivity and Specificity; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D015415:Biomarkers; D008767:Methylmercury Compounds; D009414:Nerve Growth Factors; D009498:Neurotoxins; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; D018698:Glutamic Acid; D019256:Cadmium Chloride; D004390:Chlorpyrifos; C004925:methylmercuric chloride