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Cardiovascular defects among the progeny of mouse phenylketonuria females
J D McDonald1, C A Dyer, L Gailis
1Department of Biological Sciences, Wichita State University, Kansas 67260-0026, USA.
Insights
Hyperphenylalaninemic mothers in a mouse model exhibit offspring with cardiovascular defects, primarily vascular. This highlights the teratogenic impact of elevated maternal phenylalanine during gestation.
Area of Science:
- Developmental Biology
- Genetics
- Maternal Health
Background:
- Maternal phenylketonuria (PKU) is linked to adverse outcomes in offspring.
- Cardiovascular defects are a significant concern in human maternal PKU syndrome.
- Understanding the developmental impact of maternal metabolic conditions is crucial.
Purpose of the Study:
- To investigate cardiovascular defects in offspring of hyperphenylalaninemic mothers using a genetic mouse model.
- To correlate observed defects with maternal biochemical conditions and genotypes.
- To establish a model for studying maternal diet effects and normal cardiovascular development.
Main Methods:
- Utilized a genetic mouse model mimicking human phenylketonuria (PKU).
- Examined offspring of hyperphenylalaninemic mothers for cardiovascular anomalies starting at 14.5 days post-conception.
- Correlated defect incidence with maternal blood phenylalanine levels and genotypes.
Main Results:
- A spectrum of cardiovascular defects, predominantly vascular, was observed in progeny of hyperphenylalaninemic mothers.
- Defect severity correlated with maternal, not fetal, Pah genotype.
- Elevated maternal phenylalanine created a teratogenic intrauterine environment.
Conclusions:
- This mouse model effectively replicates congenital cardiovascular defects associated with maternal PKU.
- The findings underscore the teratogenic role of elevated maternal phenylalanine.
- The model facilitates research into maternal diet interventions and normal cardiovascular development.
Abstract:
In a genetic mouse model of human phenylketonuria we have examined the offspring of hyperphenylalaninemic mothers for the presence of cardiovascular defects, an important feature of the pathology of the human maternal phenylketonuria syndrome. Beginning at 14.5 d after conception (75% through gestation), a variety of cardiovascular defects became apparent among the progeny of the hyperphenylalaninemic females. These defects ranged from mild to serious and correlated with the maternal but not the fetal Pah genotype. Nearly all of the defects were vascular, however, whereas the most reported in humans so far have been cardiac. The predisposing biochemical condition in this mouse disease model seems to be the same as in the human disease; elevated maternal blood phenylalanine levels concentrated across the placental barrier to produce a teratogenic developmental environment. This model for congenital cardiovascular defects should enhance two related areas of research. 1) It should allow a more thorough investigation of the relationship between maternal diet and maternal phenylketonuria birth defects, and 2) it should provide an experimental tool to gain insight into the normal process of cardiovascular development.