PMID- 32445665 OWN - NLM STAT- MEDLINE DCOM- 20210428 LR - 20210428 IS - 1873-1708 (Electronic) IS - 0890-6238 (Linking) VI - 95 DP - 2020 Aug TI - Role of Cbp, p300 and Akt in valproic acid induced neural tube defects in CD-1 mouse embryos. PG - 86-94 LID - S0890-6238(20)30136-2 [pii] LID - 10.1016/j.reprotox.2020.05.008 [doi] AB - 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. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Shafique, Sidra AU - Shafique S AD - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada. FAU - Winn, Louise M AU - Winn LM AD - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada; School of Environmental Studies, Queen's University, Kingston, ON K7L 3N6, Canada. Electronic address: winnl@queensu.ca. LA - eng PT - Journal Article DEP - 20200520 PL - United States TA - Reprod Toxicol JT - Reproductive toxicology (Elmsford, N.Y.) JID - 8803591 RN - 614OI1Z5WI (Valproic Acid) RN - EC 2.3.1.48 (CREB-Binding Protein) RN - EC 2.3.1.48 (Crebbp protein, mouse) RN - EC 2.3.1.48 (E1A-Associated p300 Protein) RN - EC 2.3.1.48 (Ep300 protein, mouse) RN - EC 2.7.11.1 (Akt1 protein, mouse) RN - EC 2.7.11.1 (Akt2 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Abnormalities, Drug-Induced/genetics/*metabolism MH - Animals MH - *CREB-Binding Protein/genetics/metabolism MH - Down-Regulation MH - *E1A-Associated p300 Protein/genetics/metabolism MH - Embryo, Mammalian/drug effects/metabolism MH - Mice MH - Neural Tube Defects/chemically induced/genetics/*metabolism MH - *Proto-Oncogene Proteins c-akt/genetics/metabolism MH - *Valproic Acid OTO - NOTNLM OT - Akt OT - Cbp/p300 OT - Mouse embryo OT - Neural tube defects OT - Teratogen OT - Valproic acid COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/05/24 06:00 MHDA- 2021/04/29 06:00 CRDT- 2020/05/24 06:00 PHST- 2020/01/23 00:00 [received] PHST- 2020/05/12 00:00 [revised] PHST- 2020/05/15 00:00 [accepted] PHST- 2020/05/24 06:00 [pubmed] PHST- 2021/04/29 06:00 [medline] PHST- 2020/05/24 06:00 [entrez] AID - S0890-6238(20)30136-2 [pii] AID - 10.1016/j.reprotox.2020.05.008 [doi] PST - ppublish SO - Reprod Toxicol. 2020 Aug;95:86-94. doi: 10.1016/j.reprotox.2020.05.008. Epub 2020 May 20.