Environmental and epigenetic effects on phenotype exposure in heterozygous mice carrying damaging recessive mutations

The aim of the project was to help explain the reduced penetrance of human congenital heart disease. We tested whether changing environmental conditions or epigenetic balance of the developing embryo might have exposed abnormal phenotype in otherwise normal heterozygous animals carrying recessive damaging mutations in cardiac genes (using Zic2 and Pcsk5 mouse mutants). We have shown that neither administration of selected epigenetic inhibitors nor exposure to hypoxia of pregnant females, triggered significantly higher incidence nor more severe phenotype in Zic2 and Pcsk5 heterozygous embryos, suggesting that the function of those two genes in heart development might not be “sensitive” to external factors. We have, however, identified the best doses of epigenetic drugs that affect developing embryos without causing any harm to the pregnant females and we have successfully administered them by the least invasive route: in drinking water or via gavage. These will be very useful in planning further similar experiments.