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

Chiu Lan Hsieh, Kuan Chou Chen, Chi Yang Ding, Wan Jane Tsai, Jia Fong Wu, Chiung Chi Peng

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)993-1004
Number of pages12
JournalRomanian Journal of Morphology and Embryology
Volume54
Issue number4
Publication statusPublished - 2013

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Somatomedin Receptors
Endothelin Receptors
Acetylcysteine
Valproic Acid
Chickens
Down-Regulation
Embryonic Structures
Genes
Neural Tube Defects
Folic Acid
GTP-Binding Protein Regulators
Somites
Histone Deacetylases
Homocysteine
Microarray Analysis
Cell Adhesion
Hydrogen Peroxide
Cell Movement
Glutathione

Keywords

  • Folate receptor gene folr1
  • Histone deacetylase inhibitor
  • N-acetylcysteine
  • Neural tube defect (NTD)
  • Pax-3 gene
  • Valproic acid teratogenicity

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Embryology
  • Developmental Biology
  • Cell Biology

Cite this

@article{cb8f6a7ceb664beba8e99a77d899fee5,
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 Kr{\"u}ppel-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.",
keywords = "Folate receptor gene folr1, Histone deacetylase inhibitor, N-acetylcysteine, Neural tube defect (NTD), Pax-3 gene, Valproic acid teratogenicity",
author = "Hsieh, {Chiu Lan} and Chen, {Kuan Chou} and Ding, {Chi Yang} and Tsai, {Wan Jane} and Wu, {Jia Fong} and Peng, {Chiung Chi}",
year = "2013",
language = "English",
volume = "54",
pages = "993--1004",
journal = "Romanian Journal of Morphology and Embryology",
issn = "1220-0522",
publisher = "Editura Academiei Romane",
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TY - JOUR

T1 - 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

AU - Hsieh, Chiu Lan

AU - Chen, Kuan Chou

AU - Ding, Chi Yang

AU - Tsai, Wan Jane

AU - Wu, Jia Fong

AU - Peng, Chiung Chi

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Folate receptor gene folr1

KW - Histone deacetylase inhibitor

KW - N-acetylcysteine

KW - Neural tube defect (NTD)

KW - Pax-3 gene

KW - Valproic acid teratogenicity

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SN - 1220-0522

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