Heterozygosity in Mice Enhances Susceptibility to Phenytoin-Induced Hypoxic Stress Causing Cleft Palate.

OBJECTIVE

Cleft palate is among the most frequent congenital defects in humans. While gene-environment multifactorial threshold models have been proposed to explain this cleft palate formation, only a few experimental models have verified this theory. This study aimed to clarify whether gene-environment interaction can cause cleft palate through a combination of specific genetic and environmental factors.

METHODS

heterozygosity in mice () was selected as a genetic factor since human gene mutations may cause nonsyndromic cleft palate. As an environmental factor, hypoxic stress was induced in pregnant mice by administration of the antiepileptic drug phenytoin, a known arrhythmia inducer, during palatal development from embryonic day (E) 11 to E14. Embryos were dissected at E13 for histological analysis or at E17 for recording of the palatal state.

RESULTS

Phenytoin administration downregulated cell proliferation in palatal processes in both wild-type and embryos. () expression was slightly downregulated in the anterior palatal process of embryos. Although embryos do not show cleft palate under normal conditions, phenytoin administration induced a significantly higher incidence of cleft palate in embryos compared to wild-type littermates.

CONCLUSION

Our data suggest that cleft palate may occur because of the additive effects of downregulation as a result of heterozygosity and decreased cell proliferation upon hypoxic stress. Human carriers of mutations may have to take more precautions during pregnancy to avoid exposure to environmental risks.