Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System

Chuang, Chao Ming; Chang, Chi Huang; Wang, Hui Er; Chen, Kuan Chou; Peng, Chiung Chi; Hsieh, Chiu Lan; Peng, Robert Y.

doi:10.1371/journal.pone.0043692

Cited by 19 publications

(25 citation statements)

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“…VPA is a notorious teratogenic antiepileptic and thymoregulator, inducing neural tube defects in mammalian embryos, probably by inhibition of histone deacetylase, interference with folate metabolism and inducing oxidative stress. However, the mechanism of action remains not well known [25][26][27]. VPA exerts its pharmacological effects mainly in the central nervous system by inhibition of the citric acid cycle and elevation of γ-aminobutyric acid (GABA) level [26].…”

Section: Introductionmentioning

confidence: 99%

Development of a generic zebrafish embryo PBPK model and application to the developmental toxicity assessment of valproic acid analogs

Siméon

Brotzmann

Fisher

et al. 2020

Reproductive Toxicology

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In order to better explain, predict, or extrapolate to humans the developmental toxicity effects of chemicals to zebrafish (Danio rerio) embryos, we developed a physiologically-based pharmacokinetic (PBPK) model designed to predict organ concentrations of neutral or ionizable chemicals, up to 120 hours post-fertilization. Chemicals' distribution is modeled in the cells, lysosomes, and mitochondria of ten organs of the embryo. The model's partition coefficients are calculated with sub-models using physicochemical properties of the chemicals of interest. The model accounts for organ growth and changes in metabolic clearance with time. We compared ab initio model predictions to data obtained on culture medium and embryo concentrations of valproic acid (VPA) and nine analogs during continuous dosing under the OECD test guideline 236. We further improved the predictions by estimating metabolic clearance and partition coefficients from the data by Bayesian calibration. We also assessed the performance of the model at reproducing data published by Brox et al. (2016) on VPA and 16 other chemicals. We finally compared dose-response relationships calculated for mortality and malformations on the basis of predicted whole embryo concentrations versus those based on nominal water concentrations. The use of target organ concentrations substantially shifted the magnitude of doseresponse parameters and the relative toxicity ranking of chemicals studied.

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Section: Introductionmentioning

confidence: 99%

Development of a generic zebrafish embryo PBPK model and application to the developmental toxicity assessment of valproic acid analogs

Siméon

Brotzmann

Fisher

et al. 2020

Reproductive Toxicology

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“…De novo carnitine biosynthesis is closely linked to two important metabolic pathways, namely the methionine and tricarboxylic acid (TCA) cycles. Carnitine accumulation may implicate an adequate source of SAM and α ‐KGA with significantly inhibited CPT1 . The question arises, could these pharmacological effects of RV and vitamin E disturb the therapeutic effects of VPA?…”

Section: Discussionmentioning

confidence: 99%

“…Carnitine accumulation may implicate an adequate source of SAM and a-KGA with significantly inhibited CPT1. 32,34 The question arises, could these pharmacological effects of RV and vitamin E disturb the therapeutic effects of VPA? It appears that the answer is 'no'.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol and vitamin E rescue valproic acid‐induced teratogenicity: The mechanism of action

Hsieh

Chen

Lin

et al. 2014

Clin Exp Pharma Physio

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1. Valproic acid (VPA) induces haemorrhagic liposis of the cervical muscles in the chicken embryo model (CEM). Vitamin E and resveratrol (RV) exhibit prominent anti-oxidative and glutathione (GSH)-protecting effects. 2. In the present study we hypothesized that vitamin E and RV would ameliorate VPA induced haemorrhagic liposis in chick embryos. To this end, 120 Day 0 fertilized eggs were divided into 10 groups (n = 12 in each). The effects of different combinations of VPA (60 mmol/L), RV (0.2 and 2.0 mmol/L) and vitamin E (0.2 and 2.0 mmol/L) applied to Hamburger and Hamilton (HH) Stage 10 (Day 1.5) embryos were tested in the CEM using established methods. 3. Both RV and vitamin E (both at 2.0 mmol/L) effectively rescued neural tube defects in the early stage CEM and inhibited the malformation rate compared with that in the control group (8.4% and 5.0% vs 36.5 ± 3.0%, respectively; P < 0.05) and suppressed serum homocysteine and S-adenosylhomocysteine concentrations, downregulated cervical muscular carnitine, triglycerides, H2 O2 , malondialdehyde, interleukin-6 and ACC expression (P < 0.05 for all) and upregulated CPT1 expression and GSH (P < 0.05 for both). 4. The haemorrhagic liposis of cervical muscles can be alleviated by RV and vitamin E. It appears that the main mechanism of action of RV and vitamin E in rescuing VPA-induced teratogenicity is through the suppression of reactive oxygen species and upregulation of GSH.

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“…VPA acts on class I and IIa HDACs, which collectively deacetylate a variety of nuclear and cytoplasmic proteins, so its effects are inevitably pleiotropic. For example, VPA induces oxidative stress, with increased levels of reactive oxygen species, and anti-oxidants can alleviate some of its teratogenic effects [18,19]. …”

Section: Introductionmentioning

confidence: 99%

The histone deacetylase inhibitor sodium valproate causes limited transcriptional change in mouse embryonic stem cells but selectively overrides Polycomb-mediated Hoxb silencing

Boudadi

Stower

Halsall

et al. 2013

Epigenetics & Chromatin

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BackgroundHistone deacetylase inhibitors (HDACi) cause histone hyperacetylation and H3K4 hypermethylation in various cell types. They find clinical application as anti-epileptics and chemotherapeutic agents, but the pathways through which they operate remain unclear. Surprisingly, changes in gene expression caused by HDACi are often limited in extent and can be positive or negative. Here we have explored the ability of the clinically important HDACi valproic acid (VPA) to alter histone modification and gene expression, both globally and at specific genes, in mouse embryonic stem (ES) cells.ResultsMicroarray expression analysis of ES cells exposed to VPA (1 mM, 8 h), showed that only 2.4% of genes showed a significant, >1.5-fold transcriptional change. Of these, 33% were down-regulated. There was no correlation between gene expression and VPA-induced changes in histone acetylation or H3K4 methylation at gene promoters, which were usually minimal. In contrast, all Hoxb genes showed increased levels of H3K9ac after exposure to VPA, but much less change in other modifications showing bulk increases. VPA-induced changes were lost within 24 h of inhibitor removal. VPA significantly increased the low transcription of Hoxb4 and Hoxb7, but not other Hoxb genes. Expression of Hoxb genes increased in ES cells lacking functional Polycomb silencing complexes PRC1 and PRC2. Surprisingly, VPA caused no further increase in Hoxb transcription in these cells, except for Hoxb1, whose expression increased several fold. Retinoic acid (RA) increased transcription of all Hoxb genes in differentiating ES cells within 24 h, but thereafter transcription remained the same, increased progressively or fell progressively in a locus-specific manner.ConclusionsHoxb genes in ES cells are unusual in being sensitive to VPA, with effects on both cluster-wide and locus-specific processes. VPA increases H3K9ac at all Hoxb loci but significantly overrides PRC-mediated silencing only at Hoxb4 and Hoxb7. Hoxb1 is the only Hoxb gene that is further up-regulated by VPA in PRC-deficient cells. Our results demonstrate that VPA can exert both cluster-wide and locus-specific effects on Hoxb regulation.

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Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System

Cited by 19 publications

References 50 publications

Development of a generic zebrafish embryo PBPK model and application to the developmental toxicity assessment of valproic acid analogs

Development of a generic zebrafish embryo PBPK model and application to the developmental toxicity assessment of valproic acid analogs

Resveratrol and vitamin E rescue valproic acid‐induced teratogenicity: The mechanism of action

The histone deacetylase inhibitor sodium valproate causes limited transcriptional change in mouse embryonic stem cells but selectively overrides Polycomb-mediated Hoxb silencing

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