Abstract
BackgroundCraniofacial anomalies are among the most frequent birth defects worldwide, and are thought to be caused by gene‐environment interactions. Genetically manipulated zebrafish simulate human diseases and provide great advantages for investigating the etiology and pathology of craniofacial anomalies. Although substantial advances have been made in understanding genetic factors causing craniofacial disorders, limited information about the etiology by which environmental factors, such as teratogens, induce craniofacial anomalies is available in zebrafish.ResultsZebrafish embryos displayed craniofacial malformations after teratogen treatments. Further observations revealed characteristic disruption of chondrocyte number, shape and stacking. These findings suggested aberrant development of cranial neural crest (CNC) cells, which was confirmed by gene expression analysis of the CNC. Notably, these observations suggested conserved etiological pathways between zebrafish and mammals including human. Furthermore, several of these chemicals caused malformations of the eyes, otic vesicle, and/or heart, representing a phenocopy of neurocristopathy, and these chemicals altered the expression levels of the responsible genes.ConclusionsOur results demonstrate that chemical‐induced craniofacial malformation is caused by aberrant development of neural crest. This study indicates that zebrafish provide a platform for investigating contributions of environmental factors as causative agents of craniofacial anomalies and neurocristopathy.
Highlights
Craniofacial anomalies represent a diverse group of deformities related to the differentiation and growth of the head and facial bones, and comprise over one-third of all congenital birth defects.[1]
The ethmoid plate, trabeculae and Meckel's cartilage consist of chondrocytes, which originate from neural crest (NC) cells,[25,71] and our findings suggest that the development of NC cells was disrupted by these teratogens
We addressed two questions as follows: (a) Do teratogens which induce craniofacial anomalies in mammals cause the same anomalies in zebrafish? (b) Do teratogens target the development of cranial neural crest (CNC) cells, leading to craniofacial anomalies in zebrafish? Our findings provided three novel messages. (a) Twelve teratogens that cause craniofacial abnormalities in mammals were found to disturb craniofacial development in zebrafish. (b) The craniofacial anomalies occurred due to a decrease in the number of chondrocytes and to disturbing the chondrocyte size and stacking, as well as affecting CNC numbers. (c) Our results showed an association between craniofacial defects induced by teratogens and neurocristopathy, and indicated that zebrafish is a suitable model animal for studying environmental risk factors for neurocristopathy
Summary
Craniofacial anomalies represent a diverse group of deformities related to the differentiation and growth of the head and facial bones, and comprise over one-third of all congenital birth defects.[1]. Craniosynostosis, hemifacial microsomia, and holoprosencephaly are other common symptoms These malformations are closely linked to neural crest (NC) cell development, with defects in the formation, migration, and differentiation of NC cells, which are a cell population formed in vertebrates during embryogenesis.[3,4]. The disruption of NC cell development leads to diverse clinical pathologies, collectively termed neurocristopathy.[8-10] These malformations are thought to be caused by genetic mutations in specific genes. Genetic modifications of the disease-related genes in zebrafish simulate the clinical phenotypes found in humans.[28-33]. This evidence supports the hypothesis that zebrafish provide a novel platform for analyzing gene-environment interactions that affect craniofacial malformations. Our findings suggest that chemicalinduced craniofacial malformation is caused by a defect
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