Effect of nickel exposure on neuronal differentiation

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. For this purpose we have utilized the human teratocarcinoma-derived NTera2/D1 cell line (NT2 cells), which represent a widely recognized model system of human neural progenitors. Following a 4 week treatment with retinoic acid (10 μM), 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 (10 μM) increased the expression of specific neuronal differentiation markers such as Microtubule Associated Protein 2 (MAP2) and Neural Cell Adhesion Molecule (NCAM). Nickel exposure also 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 phosphorylated AKT/PKB kinase and P(Ser-9)-GSK-3β, the inactive form of glycogen synthase kinase-3β (GSK-3β). Stabilization of Hypoxia-Inducible-Factor 1α (HIF-1α) appears to be correlated to a reduced expression of the class III histone deacetylase SIRT1, known to be involved in neural differentiation. Intriguingly, by the end of the fourth week of differentiation, 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, the exposure to 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. Great part of this work has been recently published in Neurotoxicology (Ceci C., Barbaccia M.L., Pistritto G. A not cytotoxic nickel concentration alters the expression of neuronal differentiation markers in NT2 cells. Neurotoxicology. 2015 Jan 19;47C:47-53).