Characterizing the effects of in utero exposure to valproic acid on murine fetal heart development

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Nikolovska, Ana
valproic acid , congenital heart defects , cardiac contractility , high resolution ultrasound imaging
Many antiepileptic drugs on the market, including valproic acid (VPA), have a wide range of therapeutic effects in addition to treating epilepsy. In recent years, the use of VPA in the treatment of psychiatric conditions has been on the rise. However, studies have shown that in utero exposure to VPA can have detrimental effects on embryonic development. Specifically, in utero exposure to VPA has been associated with a higher risk of congenital heart defects. In spite of this, expectant mothers are advised to continue taking it throughout pregnancy to prevent seizures. One proposed mechanism of VPA-initiated teratogenicity is the inhibition of histone deacetylase (HDAC), which is involved in the regulation of transcription factors associated with cardiogenesis. Myocyte enhancing factor 2C (Mef2c), a transcription factor involved in development of cardiac structure and cardiomyocyte differentiation, has been shown to increase in response to in utero VPA exposure. Furthermore, this increase in gene expression has been associated with contractile dysfunction and myocardial disorganization. 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 and ultrasounds were performed on GD 14 to 18, prior to harvesting the fetal hearts on GD 19. Using high-resolution ultrasound (HRUS) technology, we examined the effects of VPA on cardiac contractile function, followed by histology to evaluate the effects of VPA on myocardial organization and ventricular lumen diameter. Lastly, we conducted qRT-PCR to measure the relative Mef2c gene expression in GD 16 murine hearts. Qualitative analysis of the murine hearts at GD 19 showed structural anomalies only in the hearts of VPA-treated mice. Additionally, our results showed a decrease in contractile ability of VPA-treated mice compared to the control group on GD 18 and an increase in both anterior and posterior myocardial wall contraction on GD 14 and GD 15. We did not find any effects of VPA on the gene expression of Mef2c. Together these results further characterize the effects of VPA on heart development and suggest that increased Mef2c gene expression, at least on GD 16, does not mediate VPA-induced cardiotoxicity.
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