PUBLICATION
The anti-epileptic drug valproic acid causes malformations in the developing craniofacial skeleton of zebrafish larvae
- Authors
- Gebuijs, I.G.E., Metz, J.R., Zethof, J., Carels, C.E.L., Wagener, F.A.D.T.G., Von den Hoff, J.W.
- ID
- ZDB-PUB-200716-8
- Date
- 2020
- Source
- Mechanisms of Development 163: 103632 (Journal)
- Registered Authors
- Metz, Juriaan R.
- Keywords
- Bone, Cartilage, Craniofacial development, Embryology, Valproic acid, Zebrafish
- MeSH Terms
-
- Animals
- Cartilage/abnormalities*
- Cartilage/drug effects
- Cartilage/growth & development
- Cartilage/pathology
- Cell Differentiation/drug effects
- Chondrogenesis/drug effects
- Chondrogenesis/genetics
- Cleft Lip/chemically induced
- Cleft Lip/genetics
- Cleft Lip/physiopathology
- Cleft Palate/chemically induced
- Cleft Palate/genetics
- Cleft Palate/physiopathology
- Embryo, Nonmammalian
- Gene Expression Regulation, Developmental/drug effects
- Head/abnormalities
- Head/physiopathology
- Humans
- Larva/drug effects
- Larva/genetics
- Larva/growth & development
- Neural Crest/drug effects
- Neural Crest/growth & development
- Neural Crest/pathology
- Skull/abnormalities*
- Skull/growth & development
- Valproic Acid/adverse effects
- Valproic Acid/pharmacology*
- Zebrafish/genetics
- Zebrafish/growth & development
- Zebrafish Proteins/genetics*
- PubMed
- 32668265 Full text @ Mech. Dev.
Citation
Gebuijs, I.G.E., Metz, J.R., Zethof, J., Carels, C.E.L., Wagener, F.A.D.T.G., Von den Hoff, J.W. (2020) The anti-epileptic drug valproic acid causes malformations in the developing craniofacial skeleton of zebrafish larvae. Mechanisms of Development. 163:103632.
Abstract
Valproic acid (VPA) is an anti-epileptic drug known to cause congenital craniofacial abnormalities, including orofacial clefts (OFC). The exact mechanisms by which VPA leads to craniofacial skeletal malformations are poorly understood. In this study, we investigated the effects of VPA on cartilage and bone formation in the zebrafish larval head during 1-13 hpf (early) and 25-37 hpf (late) development in which cranial neural crest cells (CNCCs) arise and then proliferate and differentiate, respectively. Double-staining for cartilage and bone at 5 dpf revealed that VPA reduced cartilage and bone formation in a dose-dependent manner after both early or late exposure. Several different CNCC-derived cartilage and bone elements were affected in both groups. In the early group (100 μM VPA), the posterior head length and the ethmoid plate were reduced in length (both p < 0.01), while mineralization of 4 out of 9 bone elements was often lacking (all p < 0.01). In the late group (100 μM VPA), also the posterior head length was reduced as well as the length of the ceratohyals (both p < 0.01). Similar to early exposure, mineralization of 3 out of 9 bone elements was often lacking (all p < 0.01). These results indicate that both CNCC formation (early) and differentiation (late) are hampered by VPA treatment, of which the consequences for bone and cartilage formation are persistent at 5 dpf. Indeed, we also found that the expression of several genes related to cartilage and bone was upregulated at 5 dpf. These data indicate a compensatory reaction to the lack of cartilage and bone. Altogether, VPA seems to induce craniofacial malformations via disturbed CNCC function leading to defects in cartilage and bone formation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping