title: The proteomic and genomic teratogenicity elicited by valproic acid is preventable with resveratrol and α-tocopherol.
abstract: BACKGROUND
  Previously, we reported that valproic acid (VPA), a common antiepileptic drug and a potent teratogenic, dowregulates RBP4 in chicken embryo model (CEM) when induced by VPA. Whether such teratogenicity is associated with more advanced proteomic and genomic alterations, we further performed this present study.
  
  
  RESULTS
  VPA (60 µM) was applied to 36 chicken embryos at HH stage 10 (day-1.5). Resveratrol (RV) and vitamin E (vit E) (each at 0.2 and 2.0 µM) were applied simultaneously to explore the alleviation effect. The proteins in the cervical muscles of the day-1 chicks were analyzed using 2D-electrophoresis and LC/MS/MS. While the genomics associated with each specific protein alteration was examined with RT-PCR and qPCR. At earlier embryonic stage, VPA downregulated PEBP1 and BHMT genes and at the same time upregulated MYL1, ALB and FLNC genes significantly (p<0.05) without affecting PKM2 gene. Alternatively, VPA directly inhibited the folate-independent (or the betaine-dependent) remethylation pathway. These features were effectively alleviated by RV and vit E.
  
  
  CONCLUSIONS
  VPA alters the expression of PEBP1, BHMT, MYL1, ALB and FLNC that are closely related with metabolic myopathies, myogenesis, albumin gene expression, and haemolytic anemia. On the other hand, VPA directly inhibits the betaine-dependent remethylation pathway. Taken together, VPA elicits hemorrhagic myoliposis via these action mechanisms, and RV and vit E are effective for alleviation of such adverse effects.
authors.affiliation: Research Institute of Biotechnology, Hungkuang University, 34 Chung-Chie Rd., Shalu County, Taichung Hsien, Taiwan 43302.
authors.forename: Yeh
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biotechnology, Changhua University of Education, 1 Jin-De Rd., Changhua, Taiwan 50007.
authors.forename: Ping-Xiao
authors.initials: PX
authors.lastname: Lin
authors.affiliation: Graduate Institute of Biotechnology, Changhua University of Education, 1 Jin-De Rd., Changhua, Taiwan 50007.
authors.forename: Chiu-Lan
authors.initials: CL
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Shing St., Taipei, Taiwan 11031.
authors.forename: Chiung-Chi
authors.initials: CC
authors.lastname: Peng
authors.affiliation: Research Institute of Biotechnology, Hungkuang University, 34 Chung-Chie Rd., Shalu County, Taichung Hsien, Taiwan 43302; Research Institute of Medicinal Sciences, College of Medicine, Taipei Medical University, 250 Wu-Xing St., Taipei, Taiwan 11031.
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Peng
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002642:Chick Embryo; D002853:Chromatography, Liquid; D064448:Filamins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism; D020543:Proteome; D000077185:Resveratrol; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013723:Teratogens / Q000633:toxicity*; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000633:toxicity*; D024502:alpha-Tocopherol / Q000494:pharmacology*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000927:Anticonvulsants; D050940:Betaine-Homocysteine S-Methyltransferase; D002352:Carrier Proteins; D064448:Filamins; D008565:Membrane Proteins; D018994:Myosin Light Chains; D049488:Phosphatidylethanolamine Binding Protein; D020543:Proteome; D000077185:Resveratrol; D012709:Serum Albumin; D013267:Stilbenes; D013723:Teratogens; D013963:Thyroid Hormones; D014635:Valproic Acid; D024502:alpha-Tocopherol; D000097810:Thyroid Hormone-Binding Proteins