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Heart malformation is an early response to valproic acid in developing zebrafish

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Abstract

Valproic acid (VPA) is a branched short-chain fatty acid primarily used in epilepsy, but is also used in bipolar disorder, migraine, and psychotic disorders. Despite its wide range of use, it is a teratogen resulting in various congenital abnormalities. Although a large number of scientific studies evidenced the teratogenic effects, there are limited data on embryonic exposure to VPA at specific or different stages of early embryogenesis. Based on this, the present study was planned to investigate the embryonic exposure to VPA at specific and different hours post fertilization (hpf) in zebrafish embryonic model. In first set of experiments, embryos from spawning groups of adult zebrafish were exposed to different molar concentrations of VPA at 2.5 hpf, and in the second set of experiments, embryos were exposed to VPA 100 μM at 24 hpf, 36 hpf, 48 hpf, 72 hpf, and 96 hpf. The parameters examined were hatching rate, mortality, morphology, body length, pericardial sac size, heartrate, anatomical changes in heart, skeletal and notochord till 120 hpf. It was observed that the embryos exposed to VPA at 2.5 hpf suffered from cardiac abnormalities including heart malformation, bradycardia, circulatory failure, and pericardial sac enlargement which was more apparent in embryos exposed to 100 μM VPA. In the second set of experiments, embryos exposed to VPA 100 μM at 24 hpf and 36 hpf suffered from heart malformations, but there was no incidence of cardiac malformation in embryos exposed to VPA at 48 hpf, 72 hpf, and 96 hpf. From the results, it was evident that exposure to VPA at early developmental stage of embryogenesis produced congenital cardiac abnormalities. Since VPA is a selective HDAC inhibitor, histone acetylation with aberrant gene expression during cardiogenesis might be the underlying cause of cardiac malformation.

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Acknowledgments

The authors are thankful to the management of the Erode College of Pharmacy and Research Institute, Erode, Tamil Nadu, India, for providing necessary facilities to carry out the research work.

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Authors and Affiliations

  1. Department of Pharmacology, The Erode College of Pharmacy, Veppampalayam, Vallipurathampalayam (Po), Erode, Tamil Nadu, 638112, India

    Venugopalan Rajesh, Natarajan Deepan, Vijayakumar Anitha & Duraisamy Kalaiselvan

  2. Department of Pharmaceutical Analysis, The Erode College of Pharmacy, Veppampalayam, Vallipurathampalayam (Po), Erode, Tamil Nadu, 638112, India

    Subramanian Jayaseelan

  3. Department of Pharmaceutical Chemistry, The Erode College of Pharmacy, Veppampalayam, Vallipurathampalayam (Po), Erode, Tamil Nadu, 638112, India

    Palanivel Sivakumar

  4. Department of Pharmaceutics, The Erode College of Pharmacy, Veppampalayam, Vallipurathampalayam (Po), Erode, Tamil Nadu, 638112, India

    Vellaiyachamy Ganesan

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  1. Venugopalan Rajesh
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  2. Natarajan Deepan
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  3. Vijayakumar Anitha
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Contributions

VR and ND designed the research. Experimental evaluation was performed by VR, ND, VA, and DK. VR analyzed the data and wrote the manuscript. SJ, PS, and VG revised the manuscript. All authors read and approved the final version of the manuscript. All data were generated in-house and no paper mill was used in this study.

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Correspondence to Venugopalan Rajesh.

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Early life periods of zebrafish are not protected as animals until the stage of being capable of self-feeding (5 days post fertilization). So, no specific permissions were required for the activities involved in this study.

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Rajesh, V., Deepan, N., Anitha, V. et al. Heart malformation is an early response to valproic acid in developing zebrafish. Naunyn-Schmiedeberg's Arch Pharmacol 393, 2387–2409 (2020). https://doi.org/10.1007/s00210-020-01949-4

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