Gestational valproic acid exposure induces epigenetic modifications in murine decidua.

Sidra Shafique, Louise M Winn

Placenta 2021 Apr

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Valproic acid (VPA), a widely prescribed antiepileptic drug and an effective treatment for bipolar disorder and neuropathic pain, results in multiple developmental defects following in utero exposure. Uterine decidua provides nutritional and physical support during implantation and early embryonic development. Perturbations in the molecular mechanisms within decidual tissue during early pregnancy might affect early embryonic growth, result in early pregnancy loss or cause complications in the later gestational stage. VPA is a known histone deacetylase inhibitor and epigenetic changes such as histone hyperacetylation and methylation have been proposed as a mechanism of VPA-induced teratogenesis. This study investigated the effects of in utero VPA exposure on histone modifications in murine decidual tissue. Pregnant CD-1 mice were exposed to 400 mg/kg VPA or saline on GD9 via subcutaneous injection. Decidual tissue from each gestational sac was harvested at 1, 3 and 6 h following exposure. Levels of acetylated histones H3, H4 and H3K56, as well as methylated histones H3K9 and H3K27 were acid extracted and assessed by western blotting followed by acid histone extraction. VPA exposure induced a significant increase (p < 0.05) in the levels of acetylated H3 at 1, 3 h; acetylated H4 at 1, 3 and 6 h and trimethylated H3K9 at 6 h. In contrast, no significant perturbations were noted in the levels of monomethylated H3K9, trimethylated H3K27 and acetylated H3K56. The results from this study suggest that VPA-induced decidual histone modifications might play an important role as a mechanism of VPA-induced teratogenesis during early embryonic growth. Copyright © 2021 Elsevier Ltd. All rights reserved.