The proteomic and genomic teratogenicity elicited by valproic acid is preventable with resveratrol and α-tocopherol

• Published in: PloS one Vol. 9; no. 12; p. e116534
• Main Authors: Chen, Yeh, Lin, Ping-Xiao, Hsieh, Chiu-Lan, Peng, Chiung-Chi, Peng, Robert Y
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.12.2014; Public Library of Science (PLoS)
• Subjects: Acids; alpha-Tocopherol - pharmacology; Anemia; Animals; Anticonvulsants - toxicity; Antiepileptic agents; Betaine; Betaine-homocysteine S-methyltransferase; Betaine-Homocysteine S-Methyltransferase - genetics; Betaine-Homocysteine S-Methyltransferase - metabolism; Biology and Life Sciences; Biotechnology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell cycle; Chick Embryo; Chicks; Chromatography, Liquid; Cytochrome; Deoxyribonucleic acid; DNA; Education; Eggs; Embryos; Filamins - genetics; Filamins - metabolism; Folic acid; Gene expression; Gene Expression Regulation - drug effects; Genes; Hemolytic anemia; Hemorrhage; Homocysteine; Insulin; Juveniles; Kinases; Laboratory animals; Membrane Proteins - genetics; Membrane Proteins - metabolism; Muscles; Musculoskeletal system; Myogenesis; Myosin Light Chains - genetics; Myosin Light Chains - metabolism; Phosphatase; Phosphatidylethanolamine Binding Protein - genetics; Phosphatidylethanolamine Binding Protein - metabolism; Polymerase chain reaction; Proteins; Proteome; Proteomics; Resveratrol; Serum Albumin - genetics; Serum Albumin - metabolism; Signal transduction; Stilbenes - pharmacology; Tandem Mass Spectrometry; Teratogenicity; Teratogens - toxicity; Thyroid Hormone-Binding Proteins; Thyroid Hormones - genetics; Thyroid Hormones - metabolism; Tocopherol; Two dimensional analysis; Valproic acid; Valproic Acid - toxicity; Vitamin B; Vitamin E
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116534

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. 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. 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.