title: Arsenic-induced gene expression changes in the neural tube of folate transport defective mouse embryos.
abstract: Arsenic injected intraperitoneally (i.p.) during early organogenesis to small pregnant laboratory rodents (mouse, rat, and hamster) induces several congenital defects in the progeny. Among those abnormalities consistently and predominantly observed are exencephaly and encephalocele. These severe defects of the central nervous system originate from a corrupted process of neurulation and are better known as neural tube defects (NTDs). In order to understand the mechanism of arsenate-induced NTDs, we designed studies in which highly sensitive Folr2 nullizygous mice were injected intraperitoneally with sodium arsenate at the beginning of the neural tube formation process. This specific knockout mouse and the arsenic exposure conditions were chosen as they were known to provide a high incidence of exencephaly in exposed embryos. We have applied gene expression technology to the anterior neural tube. This allowed us to study arsenic-induced changes in patterns of gene expression that may contribute to the development of neural tube defects in these mice. Using extensive data analysis approaches including hierarchical clustering and gene ontology analysis, we identified several candidate genes as well as important ontology groups that may be responsible for arsenic's teratogenicity. Changes in the expression of several genes in response to arsenic treatment in our model had previously been demonstrated by other investigators to also induce NTDs in murine model systems. These include: engrailed 1 (En-1), platelet derived growth factor receptor alpha (Pdgfralpha) and ephrinA7 (EphA7). We also found several gene ontology groups that could be implicated in arsenic's underlying teratogenicity: morphogenesis, oxidative phosporylation, redox response, and regulation of I-kappaB kinase/NF-kappaB cascade. Additionally, we revealed new target genes which may be responsible for arsenic disrupted oxidative phosphorylation.
authors.affiliation: Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, 77030, USA. bwlodarczyk@ibt.tamhsc.edu
authors.forename: Bogdan J
authors.initials: BJ
authors.lastname: Wlodarczyk
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cabrera
authors.forename: Denise S
authors.initials: DS
authors.lastname: Hill
authors.forename: Daniel
authors.initials: D
authors.lastname: Bozinov
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhu
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000367:Age Factors; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins; D004622:Embryo, Mammalian; D036342:Ephrins / Q000235:genetics / Q000378:metabolism; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis / Q000379:methods; D009436:Neural Tube Defects / Q000139:chemically induced*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D002352:Carrier Proteins; C080330:En1 protein, mouse; D036342:Ephrins; D058973:Folate Receptors, GPI-Anchored; D018398:Homeodomain Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C075278:platelet-derived growth factor A; D005492:Folic Acid; D001151:Arsenic