PMID- 34737154
OWN - NLM
STAT- MEDLINE
DCOM- 20220316
LR  - 20220316
IS  - 1872-9738 (Electronic)
IS  - 0892-0362 (Linking)
VI  - 89
DP  - 2022 Jan-Feb
TI  - NRF2 activation inhibits valproic acid-induced neural tube defects in mice.
PG  - 107039
LID - S0892-0362(21)00093-3 [pii]
LID - 10.1016/j.ntt.2021.107039 [doi]
AB  - Valproic acid (VPA) is a widely prescribed medication that has traditionally been 
      used to treat epilepsy, yet embryonic exposure to VPA increases the risk of the 
      fetus developing neural tube defects (NTDs). While the mechanism by which VPA 
      causes NTDs is unknown, we hypothesize that VPA causes dysmorphogenesis through 
      the disruption of redox-sensitive signaling pathways that are critical for proper 
      embryonic development, and that protection from the redox disruption may decrease 
      the prevalence of NTDs. Time-bred CD-1 mice were treated with 
      3H-1,2-dithiole-3-thione (D3T), an inducer of nuclear factor erythroid 2-related 
      factor 2 (NRF2)-a transcription factor that activates the intracellular 
      antioxidant response to prevent redox disruptions. Embryos were then collected 
      for whole embryo culture and subsequently treated with VPA in vitro. The 
      glutathione (GSH)/glutathione disulfide (GSSG) redox potential (E(h)), a measure 
      of the intracellular redox environment, was measured in the developing mouse 
      embryos. Embryos treated with VPA exhibited a transiently oxidizing GSH/GSSG 
      E(h), while those that received D3T pretreatment prior to VPA exposure showed no 
      differences compared to controls. Moving to an in utero mouse model, time-bred 
      C57BL/6 J dams were pretreated with or without D3T and then exposed to VPA, after 
      which all embryos were collected for morphological analyses. The prevalence of 
      open neural tubes in embryos treated with VPA significantly decreased with D3T 
      pretreatment, as did the severity of the observed defects evaluated by a 
      morphological assessment. These data show that NRF2 induction via D3T 
      pretreatment protects against VPA-induced redox dysregulation and decreases the 
      prevalence of NTDs in developing mouse embryos.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Piorczynski, Ted B
AU  - Piorczynski TB
AD  - Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 
      84602, USA.
FAU - Lapehn, Samantha
AU  - Lapehn S
AD  - Department of Environmental Health Sciences, University of Michigan, Ann Arbor, 
      MI 48109, USA.
FAU - Ringer, Kelsey P
AU  - Ringer KP
AD  - Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 
      84602, USA.
FAU - Allen, Spencer A
AU  - Allen SA
AD  - Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 
      84602, USA.
FAU - Johnson, Garett A
AU  - Johnson GA
AD  - Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 
      84602, USA.
FAU - Call, Krista
AU  - Call K
AD  - Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 
      84602, USA.
FAU - Lucas, S Marc
AU  - Lucas SM
AD  - Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 
      84602, USA.
FAU - Harris, Craig
AU  - Harris C
AD  - Department of Environmental Health Sciences, University of Michigan, Ann Arbor, 
      MI 48109, USA.
FAU - Hansen, Jason M
AU  - Hansen JM
AD  - Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 
      84602, USA. Electronic address: jason_hansen@byu.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211029
PL  - United States
TA  - Neurotoxicol Teratol
JT  - Neurotoxicology and teratology
JID - 8709538
RN  - 0 (NF-E2-Related Factor 2)
RN  - 614OI1Z5WI (Valproic Acid)
SB  - IM
MH  - Animals
MH  - Embryo, Mammalian
MH  - Female
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-E2-Related Factor 2/metabolism
MH  - *Neural Tube Defects/chemically induced/metabolism/prevention & control
MH  - Pregnancy
MH  - *Valproic Acid/toxicity
OTO - NOTNLM
OT  - Embryogenesis
OT  - Glutathione
OT  - NRF2
OT  - Neural tube defects
OT  - Valproic acid
EDAT- 2021/11/06 06:00
MHDA- 2022/03/17 06:00
CRDT- 2021/11/05 06:00
PHST- 2020/09/30 00:00 [received]
PHST- 2021/10/14 00:00 [revised]
PHST- 2021/10/17 00:00 [accepted]
PHST- 2021/11/06 06:00 [pubmed]
PHST- 2022/03/17 06:00 [medline]
PHST- 2021/11/05 06:00 [entrez]
AID - S0892-0362(21)00093-3 [pii]
AID - 10.1016/j.ntt.2021.107039 [doi]
PST - ppublish
SO  - Neurotoxicol Teratol. 2022 Jan-Feb;89:107039. doi: 10.1016/j.ntt.2021.107039. 
      Epub 2021 Oct 29.