title: A not cytotoxic nickel concentration alters the expression of neuronal differentiation markers in NT2 cells.
abstract: Nickel, a known occupational/environmental hazard, may cross the placenta and reach appreciable concentrations in various fetal organs, including the brain. The aim of this study was to investigate whether nickel interferes with the process of neuronal differentiation. Following a 4 week treatment with retinoic acid (10μM), the human teratocarcinoma-derived NTera2/D1 cell line (NT2 cells) terminally differentiate into neurons which recapitulate many features of human fetal neurons. The continuous exposure of the differentiating NT2 cells to a not cytotoxic nickel concentration (10μM) increased the expression of specific neuronal differentiation markers such as neural cell adhesion molecule (NCAM) and microtubule associated protein 2 (MAP2). Furthermore, nickel exposure increased the expression of hypoxia-inducible-factor-1α (HIF-1α) and induced the activation of the AKT/PKB kinase pathway, as shown by the increase of P(Ser-9)-GSK-3β, the inactive form of glycogen synthase kinase-3β (GSK-3β). Intriguingly, by the end of the fourth week the expression of tyrosine hydroxylase (TH) protein, a marker of dopaminergic neurons, was lower in nickel-treated than in control cultures. Thus, likely by partially mimicking hypoxic conditions, a not-cytotoxic nickel concentration appears to alter the process of neuronal differentiation and hinder the expression of the dopaminergic neuronal phenotype. Taken together, these results suggest that nickel, by altering normal brain development, may increase susceptibility to neuro-psychopathology later in life.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ceci
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Barbaccia
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address: pistritto@med.uniroma2.it.
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Pistritto
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009532:Nickel / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D019006:Neural Cell Adhesion Molecules; D009532:Nickel; D014446:Tyrosine 3-Monooxygenase; D051057:Proto-Oncogene Proteins c-akt
keywords: Glycogen synthase kinase/GSK-3β; Hypoxia-inducible-factor-1α/HIF-1α; Microtubule-associated-protein2/MAP2; Neural cell adhesion molecule/NCAM; Tyrosine hydroxylase/TH