title: Valproic acid substantially downregulated genes folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3, N-acetylcysteine alleviated most of the induced gene alterations in chicken embryo model.
abstract: Valproic acid induced teratogenicity at genetic and somatic levels, the action mechanism is still unclear. We hypothesized that folate receptor gene (folr1) and others may be interacting to elicit neural tube defect (NTD), while N-acetylcysteine (NAC) may be beneficial for protection. In chicken embryo model, the experiment was conducted in two parts. The first part was carried out to test the optimum dose of VPA. The second part was conducted to test the protective effect of NAC at doses 10 and 20 mM. VPA induced dysvascularization, incomplete somite enclosure, histone deacetylase (HDAC) inhibition, folate deficiency, homocysteine accumulation, SOD inhibition, glutathione depletion, elevated MDA and hydrogen peroxide. NAC alleviated most of these adverse effects. The microarray analysis revealed 17 genes downregulated and four upregulated. The relevancy covered translation (23%), signal transduction (23%), transcription (16%), cell adhesion (16%), neural cell migration (8%), transport (7%), and organismal development (7%). The genes insulin-like growth factor 2 receptor gene (IGF2R), regulator of G-protein signaling 4 gene (RGS4), alpha 3 (VI) collagen gene (COL6A3), endothelin receptor type b gene (EDNRB), and Krüppel-like factor 6 gene (KLF6) substantially downregulated in reality were directly intermodulating and associated with NTD. VPA downregulated folr1 gene in a dose responsive manner without affecting pax-3 gene, which was ascribed to the metahypoxic state. Conclusively, VPA affects 21 genes: 17 downregulated and four upregulated. VPA dose responsively downregulates gene folr1 without affecting pax-3 gene. These adverse effects can be partially alleviated by N-acetylcysteine.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taiwan; misspeng@ms2.hinet.net.
authors.forename: Chiu-Lan
authors.initials: CL
authors.lastname: Hsieh
authors.forename: Kuan-Chou
authors.initials: KC
authors.lastname: Chen
authors.forename: Chi-Yang
authors.initials: CY
authors.lastname: Ding
authors.forename: Wan-Jane
authors.initials: WJ
authors.lastname: Tsai
authors.forename: Jia-Fong
authors.initials: JF
authors.lastname: Wu
authors.forename: Chiung-Chi
authors.initials: CC
authors.lastname: Peng
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D030161:Avian Proteins / Q000235:genetics* / Q000378:metabolism; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D058975:Folate Receptor 1 / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000097:blood; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006655:Histone Deacetylases / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000196:embryology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D030161:Avian Proteins; D024142:Collagen Type VI; D058975:Folate Receptor 1; D051741:Kruppel-Like Transcription Factors; D051761:Paired Box Transcription Factors; D020710:RGS Proteins; D017527:Receptor, IGF Type 2; D017466:Receptors, Endothelin; D014635:Valproic Acid; D005492:Folic Acid; D006655:Histone Deacetylases; D000111:Acetylcysteine