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The anti-epileptic drug valproic acid causes malformations in the developing craniofacial skeleton of zebrafish larvae.
Gebuijs, I G E; Metz, J R; Zethof, J; Carels, C E L; Wagener, F A D T G; Von den Hoff, J W.
Afiliación
  • Gebuijs IGE; Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands; Department of Animal Ecology and Physiology, Radboud University, Nijmegen, the Netherlands.
  • Metz JR; Department of Animal Ecology and Physiology, Radboud University, Nijmegen, the Netherlands.
  • Zethof J; Department of Animal Ecology and Physiology, Radboud University, Nijmegen, the Netherlands.
  • Carels CEL; Department of Oral Health Sciences, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • Wagener FADTG; Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
  • Von den Hoff JW; Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. Electronic address: hans.vondenhoff@radboudumc.nl.
Mech Dev ; 163: 103632, 2020 09.
Article en En | MEDLINE | ID: mdl-32668265
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cráneo / Cartílago / Ácido Valproico / Proteínas de Pez Cebra Tipo de estudio: Etiology_studies Límite: Animals / Humans Idioma: En Revista: Mech Dev Asunto de la revista: EMBRIOLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Irlanda
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cráneo / Cartílago / Ácido Valproico / Proteínas de Pez Cebra Tipo de estudio: Etiology_studies Límite: Animals / Humans Idioma: En Revista: Mech Dev Asunto de la revista: EMBRIOLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Irlanda