PMID- 34902770
OWN - NLM
STAT- MEDLINE
DCOM- 20220505
LR  - 20220505
IS  - 1432-0436 (Electronic)
IS  - 0301-4681 (Linking)
VI  - 123
DP  - 2022 Jan-Feb
TI  - NRF2 activation protects against valproic acid-induced disruption of neurogenesis 
      in P19 cells.
PG  - 18-29
LID - S0301-4681(21)00068-2 [pii]
LID - 10.1016/j.diff.2021.12.002 [doi]
AB  - Valproic acid (VPA) is a commonly prescribed antiepileptic drug that causes fetal 
      valproate syndrome (FVS) in developing embryos exposed to it. Symptoms of FVS 
      include neural tube defects (NTDs), musculoskeletal abnormalities, and 
      neurodevelopmental difficulties. One proposed mechanism of VPA-induced 
      developmental toxicity is via oxidative stress, defined as the disruption of 
      redox-sensitive cell signaling. We propose that redox imbalances caused by VPA 
      exposure result in improper cellular differentiation that may contribute to FVS. 
      In undifferentiated P19 mouse embryonal carcinoma cells treated with VPA, 
      glutathione disulfide (GSSG) concentrations were higher and the glutathione 
      (GSH)/GSSG redox potential (E(h)) was more oxidizing compared to vehicle-treated 
      control cells, both of which are indications of potential intracellular oxidative 
      stress. Interestingly, VPA had no effect on GSH or GSSG levels in differentiated 
      P19 neurons. Undifferentiated cells pretreated with 3H-1,2-dithiole-3-thione 
      (D3T), an inducer of the nuclear factor erythroid 2-related factor 2 (NRF2) 
      antioxidant response that combats cellular redox disruption, were protected from 
      VPA-induced alterations to the GSH/GSSG system. To assess differential periods of 
      susceptibility, P19 cells were exposed to VPA at various time points during their 
      neuronal differentiation. Cells exposed to VPA early in the differentiation 
      process did not undergo normal neurogenesis as measured by POU domain, class 5, 
      transcription factor 1 (OCT4) and tubulin beta-3 chain (betaIII-tubulin), markers of 
      cell stemness and neuronal differentiation, respectively. Neurogenesis was 
      improved with D3T pretreatments prior to VPA exposure. Furthermore, 
      differentiating P19 cells treated with VPA exhibited increased protein oxidation 
      that was diminished with D3T pretreatment. These findings demonstrate that VPA 
      inhibits neurogenesis and propose NRF2-mediated redox homeostasis as a means to 
      promote normal neuronal differentiation, thereby potentially decreasing the 
      prevalence of FVS outcomes.
CI  - Copyright (c) 2021 International Society of Differentiation. Published by Elsevier 
      B.V. 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 - Larsen, Madison W
AU  - Larsen MW
AD  - Department of Cell Biology and Physiology, Brigham Young University, Provo, UT, 
      84602, USA.
FAU - Lee, Sariah J
AU  - Lee SJ
AD  - Department of Cell Biology and Physiology, Brigham Young University, Provo, UT, 
      84602, 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 - 20211207
PL  - England
TA  - Differentiation
JT  - Differentiation; research in biological diversity
JID - 0401650
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Tubulin)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - GAN16C9B8O (Glutathione)
RN  - ULW86O013H (Glutathione Disulfide)
RN  - Valproic acid antenatal infection
SB  - IM
MH  - Abnormalities, Drug-Induced
MH  - Animals
MH  - Glutathione/metabolism
MH  - Glutathione Disulfide
MH  - Mice
MH  - *NF-E2-Related Factor 2/genetics/metabolism
MH  - Neurogenesis
MH  - Tubulin
MH  - *Valproic Acid/adverse effects/toxicity
OTO - NOTNLM
OT  - Fetal valproate syndrome
OT  - Glutathione
OT  - NRF2
OT  - P19
OT  - Valproic acid
EDAT- 2021/12/14 06:00
MHDA- 2022/05/06 06:00
CRDT- 2021/12/13 20:26
PHST- 2021/08/04 00:00 [received]
PHST- 2021/11/25 00:00 [revised]
PHST- 2021/12/06 00:00 [accepted]
PHST- 2021/12/14 06:00 [pubmed]
PHST- 2022/05/06 06:00 [medline]
PHST- 2021/12/13 20:26 [entrez]
AID - S0301-4681(21)00068-2 [pii]
AID - 10.1016/j.diff.2021.12.002 [doi]
PST - ppublish
SO  - Differentiation. 2022 Jan-Feb;123:18-29. doi: 10.1016/j.diff.2021.12.002. Epub 
      2021 Dec 7.