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Abstract
BackgroundPreviously, 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.Methodology/Principal FindingsVPA (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.ConclusionsVPA 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.
Highlights
Valproic acid (VPA, 2-propylpentanoic acid)) is a short-chain fatty acid commonly used as an anticonvulsant [1] in the long-term treatment of epilepsy [2,3,4,5], which has been recently identified as a histone deacetylase (HDAC) inhibitor, leading to the acetylation of histone tails and regulation of gene expression [6, 7]
We reported that the cause eliciting malformation and mortality by valproic acid (VPA) involved multi-mechanism, such as inhibition of histone deacetylase (HDAC), suppressed superoxide dismutase (SOD) and glutathione regenerative cycle; enhanced reactive oxygen species (ROS) stress, and neural tube defect (NTD) [3;5, 6], downregulated gene folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3 [5]
Gene RKIP is expressed in prostate epithelium, brain, liver, lung, testis, muscles and stomach [32, 33]
Summary
Valproic acid (VPA, 2-propylpentanoic acid)) is a short-chain fatty acid commonly used as an anticonvulsant [1] in the long-term treatment of epilepsy [2,3,4,5], which has been recently identified as a histone deacetylase (HDAC) inhibitor, leading to the acetylation of histone tails and regulation of gene expression [6, 7]. We have reported that VPA induced a diversity of teratogenic features in chicken embryo model (CEM) [4, 8, 9]. 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 directly inhibited the folate-independent (or the betaine-dependent) remethylation pathway. These features were effectively alleviated by RV and vit E.
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