title: Arsenic and Its Methylated Metabolites Inhibit the Differentiation of Neural Plate Border Specifier Cells.
abstract: Exposure to arsenic in food and drinking water has been correlated with adverse developmental outcomes, such as reductions in birth weight and neurological deficits. Additionally, studies have shown that arsenic suppresses sensory neuron formation and skeletal muscle myogenesis, although the reason why arsenic targets both of these cell types in unclear. Thus, P19 mouse embryonic stem cells were used to investigate the mechanisms by which arsenic could inhibit cellular differentiation. P19 cells were exposed to 0, 0.1, or 0.5 μM sodium arsenite and induced to form embryoid bodies over a period of 5 days. The expression of transcription factors necessary to form neural plate border specifier (NPBS) cells, neural crest cells and their progenitors, and myocytes and their progenitors were examined. Early during differentiation, arsenic significantly reduced the transcript and protein expression of Msx1 and Pax3, both needed for NPBS cell formation. Arsenic also significantly reduced the protein expression of Sox 10, needed for neural crest progenitor cell production, by 31-50%, and downregulated the protein and mRNA levels of NeuroD1, needed for neural crest cell differentiation, in a time- and dose-dependent manner. While the overall protein expression of transcription factors in the skeletal muscle lineage was not changed, arsenic did alter their nuclear localization. MyoD nuclear translocation was significantly reduced on days 2-5 between 15 and 70%. At a 10-fold lower concentration, monomethylarsonous acid (MMA III) appeared to be just as potent as inorganic arsenic at reducing the mRNA levels Pax3 (79% vs84%), Sox10 (49% vs 65%), and Msx1 (56% vs 56%). Dimethylarsinous acid (DMA III) also reduced protein and transcript expression, but the changes were less dramatic than those with MMA or arsenite. All three arsenic species reduced the nuclear localization of MyoD and NeuroD1 in a similar manner. The early changes in the differentiation of neural plate border specifier cells may provide a mechanism for arsenic to suppress both neurogenesis and myogenesis.
authors.affiliation: †Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, South Carolina 29634, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCoy
authors.affiliation: ‡Department of Chemistry, Clemson University, 219 Hunter Laboratories, Clemson, South Carolina 29634, United States.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Stadelman
authors.affiliation: ‡Department of Chemistry, Clemson University, 219 Hunter Laboratories, Clemson, South Carolina 29634, United States.
authors.forename: Julia L
authors.initials: JL
authors.lastname: Brumaghim
authors.affiliation: §Environmental Toxicology Graduate Program, Clemson University, 132 Long Hall, Clemson, South Carolina 29634, United States.
authors.forename: Jui-Tung
authors.initials: JT
authors.lastname: Liu
authors.affiliation: †Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, South Carolina 29634, United States.|§Environmental Toxicology Graduate Program, Clemson University, 132 Long Hall, Clemson, South Carolina 29634, United States.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Bain
mesh_terms: D000818:Animals; D018053:Arsenites / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002101:Cacodylic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D054258:Neural Plate / Q000166:cytology; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism; D017670:Sodium Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018053:Arsenites; D051792:Basic Helix-Loop-Helix Proteins; D002101:Cacodylic Acid; D051957:MSX1 Transcription Factor; D017570:MyoD Protein; D009942:Organometallic Compounds; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D055757:SOXE Transcription Factors; D017670:Sodium Compounds; D014157:Transcription Factors; C484084:Msx1 protein, mouse; C501008:Neurod1 protein, mouse; C527924:Sox10 protein, mouse; C472511:dimethylarsinous acid; C406082:monomethylarsonous acid; C068686:Pax3 protein, mouse; C017947:sodium arsenite