PMID- 38280688
OWN - NLM
STAT- MEDLINE
DCOM- 20240305
LR  - 20240305
IS  - 1873-1708 (Electronic)
IS  - 0890-6238 (Linking)
VI  - 124
DP  - 2024 Mar
TI  - Investigating the effects of valproic acid on placental epigenetic modifications 
      and development in the CD-1 mouse model.
PG  - 108551
LID - S0890-6238(24)00018-2 [pii]
LID - 10.1016/j.reprotox.2024.108551 [doi]
AB  - Gestational exposure to the anticonvulsant drug valproic acid (VPA) is associated 
      with congenital malformations and neurodevelopmental disorders through its action 
      as a histone deacetylase inhibitor. VPA can elicit placental toxicity and affect 
      placental growth and development. The objective of this study was to evaluate the 
      impact of maternal exposure to VPA on the mouse placenta following exposure on 
      gestational day (GD) 13 since previous studies have shown that mice exposed at 
      this time during gestation give birth to offspring with an autism spectrum 
      disorder-like phenotype. We exposed CD-1 dams to a teratogenic dose (600 mg/kg) 
      of VPA or saline on GD13 and assessed fetoplacental growth and development on 
      GD18. We evaluated epigenetic modifications, including acetylated histone H4 
      (H4ac), methylated H3K4 (H3K4me2) using immunohistochemistry, and global DNA 
      methylation in the placenta at 1, 3, and 24 h following maternal exposure on 
      GD13. In utero exposure to VPA on GD13 significantly decreased placental weight 
      and increased fetal resorptions. Moreover, VPA significantly increased the 
      staining intensity of histone H4 acetylation and H3K4 di-methylation across the 
      placenta at 1 and 3 h post maternal dose. Our results also demonstrate that VPA 
      significantly decreased global DNA methylation levels in placental tissue. These 
      results show that gestational exposure to VPA interferes with placental growth 
      and elicits epigenetic modifications, which may play a vital role in VPA-induced 
      developmental toxicity.
CI  - Copyright (c) 2024 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Jackson, Brianna L
AU  - Jackson BL
AD  - Queen's University, Kingston, Ontario K7L 3N6, Canada; Department of Biomedical 
      and Molecular Sciences, Kingston, Ontario K7L 3N6, Canada.
FAU - Shafique, Sidra
AU  - Shafique S
AD  - Queen's University, Kingston, Ontario K7L 3N6, Canada; Department of Biomedical 
      and Molecular Sciences, Kingston, Ontario K7L 3N6, Canada.
FAU - Natale, Bryony V
AU  - Natale BV
AD  - Queen's University, Kingston, Ontario K7L 3N6, Canada; Department of Biomedical 
      and Molecular Sciences, Kingston, Ontario K7L 3N6, Canada.
FAU - Natale, David R C
AU  - Natale DRC
AD  - Queen's University, Kingston, Ontario K7L 3N6, Canada; Department of Biomedical 
      and Molecular Sciences, Kingston, Ontario K7L 3N6, Canada.
FAU - Winn, Louise M
AU  - Winn LM
AD  - Queen's University, Kingston, Ontario K7L 3N6, Canada; Department of Biomedical 
      and Molecular Sciences, Kingston, Ontario K7L 3N6, Canada; School of 
      Environmental Studies, Queen's University, Kingston, Ontario K7L 3N6, Canada. 
      Electronic address: winnl@queensu.ca.
LA  - eng
PT  - Journal Article
DEP - 20240126
PL  - United States
TA  - Reprod Toxicol
JT  - Reproductive toxicology (Elmsford, N.Y.)
JID - 8803591
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 0 (Histones)
SB  - IM
MH  - Pregnancy
MH  - Female
MH  - Mice
MH  - Animals
MH  - *Valproic Acid/toxicity
MH  - *Autism Spectrum Disorder
MH  - Histones/metabolism
MH  - Placenta/metabolism
MH  - Epigenesis, Genetic
OTO - NOTNLM
OT  - Epigenetics
OT  - Placental toxicity
OT  - Teratogen
OT  - Valproic acid
COIS- Declaration of Competing Interest The authors declare the following financial 
      interests/personal relationships which may be considered as potential competing 
      interests: Louise Winn reports financial support was provided by Canadian 
      Institutes of Health Research. If there are other authors, they 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- 2024/01/28 07:44
MHDA- 2024/03/05 06:47
CRDT- 2024/01/27 19:19
PHST- 2023/11/02 00:00 [received]
PHST- 2024/01/20 00:00 [revised]
PHST- 2024/01/23 00:00 [accepted]
PHST- 2024/03/05 06:47 [medline]
PHST- 2024/01/28 07:44 [pubmed]
PHST- 2024/01/27 19:19 [entrez]
AID - S0890-6238(24)00018-2 [pii]
AID - 10.1016/j.reprotox.2024.108551 [doi]
PST - ppublish
SO  - Reprod Toxicol. 2024 Mar;124:108551. doi: 10.1016/j.reprotox.2024.108551. Epub 
      2024 Jan 26.