Role of Cbp, p300 and Akt in valproic acid induced neural tube defects in CD-1 mouse embryos

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2020-08, Vol.95, p.86-94
• Main Authors: Shafique, Sidra, Winn, Louise M.
• Format: Article
• Language: English
• Subjects: Abnormalities, Drug-Induced - genetics; Abnormalities, Drug-Induced - metabolism; Akt; Animals; Cbp/p300; CREB-Binding Protein - genetics; CREB-Binding Protein - metabolism; Down-Regulation; E1A-Associated p300 Protein - genetics; E1A-Associated p300 Protein - metabolism; Embryo, Mammalian - drug effects; Embryo, Mammalian - metabolism; Mice; Mouse embryo; Neural tube defects; Neural Tube Defects - chemically induced; Neural Tube Defects - genetics; Neural Tube Defects - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Teratogen; Valproic Acid
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2020.05.008

•Valproic acid exposure in the pregnant CD-1 mouse model downregulates Cbp, p300 and Akt1 mRNA levels in GD9 embryos.•Akt protein levels are significantly decreased in GD9 mouse embryos following in utero valproic acid exposure.•Maternal valproic acid exposure is not associated with altered embryonic Cbp and p300 protein levels in the CD-1 mouse model. Valproic acid (VPA), an antiepileptic and mood-stabilizing drug, is prescribed to women of reproductive age. VPA is associated with a 1–2% increase in neural tube defects in offspring following gestational exposure and results in epigenetic modifications induced by perturbations in transcription cofactors. Cbp and p300, two transcription cofactors, play key roles in embryonic neural development. p300 is a downstream target of Akt, a protein kinase B associated with cell survival and anti-apoptotic mechanisms, as part of the Akt-p300 axis. We examined the effects of in utero VPA exposure on Cbp, p300, and Akt in gestational day (GD)9, GD10 and GD13 CD-1 mouse embryos following a teratogenic maternal dose of 400 mg/kg. Embryos were collected at 0, 1, 3 and 6 h post-dosing on GD9, 24 h post-dosing on GD10 and on GD13. GD10 embryos were grouped according to the status of neural tube closure in control, closed and open groups. GD13 heads were grouped as control, exposed but non-exencephalic and exencephalic. Our data indicate that Cbp, p300 and Akt mRNA levels were downregulated at 1 and 3 h post-exposure in GD9 embryos while Cbp and p300 protein levels remained stable. Akt protein levels were significantly increased 1 h post-exposure. No significant changes were observed in either mRNA or protein expression in embryos with closed or open neural tubes compared to the control group at GD10. Downregulated expression of Cbp, p300, and Akt may play a key role in VPA-induced neural tube defects considering their vitally important role in embryonic development.