title: 3-methylcholanthrene induces neurotoxicity in developing neurons derived from human CD34+Thy1+ stem cells by activation of aryl hydrocarbon receptor.
abstract: Developing neurons, derived from the human umbilical cord blood stem cells (hUCBSCs), were investigated for their stage-specific responses against 3-methylcholanthrene (MC), a well-known polycyclic aromatic hydrocarbon. Three-dimensional (3D) molecular docking demonstrates the strong hydrogen bonding and hydrophobic interactions of MC with amino acids of aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) within 4 Å and subsequent inhibition of cAMP response element-binding protein (CREB), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Protein-protein docking also confirms that induced levels of AHR inhibit the neurogenesis-related transcription factor (CREB) with maximum docking scores. In concurrence with in silico data, MC exposure significantly up regulates the expression and activity of AHR, CYP1A1 and glutathione S-transferase P1-1 (GSTP1-1) and down regulates the expression of CREB, AMPA and NMDA receptors in hUCBSC-derived neuronal cells at various maturity (0, 2, 4, 8 days of differentiation). MC-mediated significant down regulation in the expression of stage-specific neuronal markers (Nestin, neural cell adhesion molecule-NCAM, synaptophysin-SYP, CREB, AMPA and N-methyl-D-aspartate receptor subunit 2A-NR2A) was also noticed in cells all through the differentiation. Data identify the possible interference of MC in neuronal transmission and neurogenesis.
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Post Box: 80, MG Marg, Lucknow, 226001, India.
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Singh
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Kashyap
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Tripathi
authors.forename: Dharmendra K
authors.initials: DK
authors.lastname: Yadav
authors.forename: Firoz
authors.initials: F
authors.lastname: Khan
authors.forename: Sadaf
authors.initials: S
authors.lastname: Jahan
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Khanna
authors.forename: Sanjay
authors.initials: S
authors.lastname: Yadav
authors.forename: Aditya B
authors.initials: AB
authors.lastname: Pant
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000737:chemistry / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D003198:Computer Simulation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008748:Methylcholanthrene / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D008861:Microsomes / Q000201:enzymology; D062105:Molecular Docking Simulation; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D018091:Receptors, AMPA / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D018800:Thy-1 Antigens / Q000032:analysis
chemical_list: D018952:Antigens, CD34; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D019363:Cytochrome P-450 CYP1A1; D051549:Glutathione S-Transferase pi; D008748:Methylcholanthrene; D018091:Receptors, AMPA; D018336:Receptors, Aryl Hydrocarbon; D016194:Receptors, N-Methyl-D-Aspartate; D018800:Thy-1 Antigens; C111235:AHR protein, human; C497396:ARNT protein, human; C115163:CREB1 protein, human; C569463:CYP1A1 protein, human; C496556:GSTP1 protein, human