Abstract
ObjectivesTo evaluate the association between hypoxia during embryo development and oral clefts in an animal model, and to evaluate the association between polymorphisms in the HIF-1A gene with oral clefts in human families.Material and MethodsThe study with the animal model used zebrafish embryos at 8 hours post-fertilization submitted to 30% and 50% hypoxia for 24 hours. At 5 days post-fertilization, the larvae were fixed. The cartilage structures were stained to evaluate craniofacial phenotypes. The family-based association study included 148 Brazilian nuclear families with oral clefts. The association between the genetic polymorphisms rs2301113 and rs2057482 in HIF-1A with oral clefts was tested. We used real time PCR genotyping approach. ANOVA with Tukey's post-test was used to compare means. The transmission/disequilibrium test was used to analyze the distortion of the inheritance of alleles from parents to their affected offspring.ResultsFor the hypoxic animal model, the anterior portion of the ethmoid plate presented a gap in the anterior edge, forming a cleft. The hypoxia level was associated with the severity of the phenotype (p<0.0001). For the families, there was no under-transmitted allele among the affected progeny (p>0.05).ConclusionHypoxia is involved in the oral cleft etiology, however, polymorphisms in HIF-1A are not associated with oral clefts in humans.
Highlights
Oral clefts are a common birth defect seen worldwide[16]
We used zebrafish as a model to evaluate the association between hypoxia during embryo development and oral clefts; and we evaluated the association between genetic polymorphisms in HIF-1A with oral clefts in human families
The results showed that hypoxia resulted in obvious craniofacial malformations regardless of the hypoxia level
Summary
Oral clefts are a common birth defect seen worldwide[16]. Oral clefts can be divided into isolated (non-syndromic) and syndromic forms. Isolated oral clefts affect about 1.7 per 1,000 live births, with ethnic and geographic variation[15]. These conditions are complex alterations resulting from multiple genetic and environmental factors[16]. Hypoxia is an environmental factor involved in the etiology of different birth defects[27]. Oral clefts are a possible hypoxia-induced birth defects. Some evidence in human populations suggests an association between these two conditions, such as maternal cigarette smoking, acardiac twining, and living in very high altitudes (>6500 feet from sea level)[6,7,10,13]. Data on birth defects in the highlands of South America showed a significantly higher risk for oral clefts when compared to the population living at sea level[6]
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