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Characterizing the effects of in utero exposure to valproic acid on murine fetal heart development
Nicola A Philbrook, Ana Nikolovska, Rebecca D Maciver
1Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Insights
Valproic acid (VPA) exposure during pregnancy causes heart defects in mice. Increased Mef2c gene expression does not appear to cause VPA-induced cardiotoxicity.
Area of Science:
- Developmental biology
- Pharmacology
- Cardiology
Background:
- Valproic acid (VPA), an antiepileptic drug, is increasingly used for psychiatric conditions.
- In utero VPA exposure is linked to congenital heart defects, potentially via histone deacetylase inhibition.
- VPA exposure increases Myocyte Enhancing Factor 2C (Mef2c) expression, impacting cardiac development and function.
Purpose of the Study:
- To investigate the effects of VPA on murine heart development and cardiac function.
- To determine if altered Mef2c gene expression mediates VPA-induced cardiotoxicity.
Main Methods:
- Pregnant CD-1 mice received VPA (400 mg/kg) on gestational day (GD) 9.
- Cardiac function was assessed using high-resolution ultrasound (GD 14-18).
- Fetal hearts were analyzed histologically (GD 19), and Mef2c expression was quantified (GD 16).
Main Results:
- VPA exposure resulted in structural cardiac anomalies in fetal mice.
- Cardiac contractility was altered in VPA-exposed fetuses, showing variable changes.
- Mef2c gene expression on GD 16 did not correlate with VPA-induced cardiotoxicity.
Conclusions:
- VPA exposure during pregnancy induces structural and functional cardiac abnormalities in developing mouse hearts.
- Altered Mef2c gene expression is not the primary mechanism driving VPA-induced cardiotoxicity in this model.
Background:
Recently, the use of the antiepileptic drug valproic acid (VPA) for the treatment of psychiatric conditions has been on the rise. However, studies have shown that in utero VPA exposure can affect embryonic development, including being associated with congenital heart defects. One proposed mechanism of VPA-initiated teratogenicity is the inhibition of histone deacetylase, which is involved in the regulation of transcription factors that regulate cardiogenesis. Myocyte enhancing factor 2C (Mef2c), a transcription factor involved in the development of cardiac structure and cardiomyocyte differentiation, has been shown to increase in response to in utero VPA exposure, associating with contractile dysfunction and myocardial disorganization.
Methods:
To characterize the effects of VPA on murine heart development, pregnant CD-1 mice were dosed with 400 mg/kg of VPA on gestational day (GD) 9. Using high-resolution ultrasound, we examined the effects of VPA on cardiac contractile function on GD 14-18, with fetal hearts being harvested on GD 19 for histological analysis. Lastly, we conducted quantitative real-time polymerase chain reaction to measure the relative Mef2c gene expression in GD 16 murine hearts.
Results:
We observed structural anomalies at GD 19 in the hearts of VPA-treated mice. Additionally, our results showed alterations in measures of cardiac contractility, with a decrease or increase in cardiac contractile ability in VPA-treated mice depending on the GD and measurement taken.
Conclusions:
These results further characterize the effects of VPA on heart development and suggest that alterations in Mef2c gene expression, at least on GD 16, do not mediate VPA-induced cardiotoxicity in CD-1 mice.
