PMID- 30194517
OWN - NLM
STAT- MEDLINE
DCOM- 20190813
LR  - 20200225
IS  - 1559-1182 (Electronic)
IS  - 0893-7648 (Linking)
VI  - 56
IP  - 5
DP  - 2019 May
TI  - Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses 
      Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid.
PG  - 3736-3750
LID - 10.1007/s12035-018-1328-x [doi]
AB  - Prenatal treatment with the antiepileptic drug valproic acid (VPA) is associated 
      with a significant risk of somatic anomalies, neurodevelopmental delays, and 
      7-10x increase in the incidence of autism spectrum disorders (ASD) in children. 
      Rodents exposed to VPA in pregnancy show birth defects, deficits in 
      neurodevelopment, and cognitive/social anomalies resembling those of ASD 
      children. Mechanisms of VPA neurobehavioral toxicity are still unclear but as VPA 
      is a non-selective inhibitor of histone deacetylases, epigenetic modifications 
      are likely involved. This study was aimed to evaluate the transgenerational 
      impact of prenatal VPA exposure on mouse early behavioral development, studying 
      F(1), F(2), and F(3) generations after VPA challenge on gestational day (GD) 
      10.5. We also analyzed in brain and in peripheral blood mononuclear cells the 
      expression levels of different endogenous retrovirus (ERV) families, potential 
      biomarkers of derailed brain development, since human ERVs have been implicated 
      in the pathogenesis of neurodevelopmental disorders (NDDs) such as ASD. Somatic 
      effects of VPA were evident only in F(1) generation and more markedly in the 
      female sex. Across F(1) and F(2) generations, VPA delayed righting reflex, 
      increased motor activity, and reduced ultrasonic vocalizations. The behavioral 
      changes in F(3) are milder though in the same direction. VPA increased expression 
      of most ERVs across the three generations in brain and blood. In utero VPA 
      induced neurodevelopmental alterations more marked in the maternal lineage that 
      persisted also in F(3), suggesting ERVs as possible downstream effectors of the 
      VPA epigenetic alterations.
FAU - Tartaglione, Anna Maria
AU  - Tartaglione AM
AD  - Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanita, 
      V.le Regina Elena 299, 00161, Rome, Italy.
FAU - Cipriani, Chiara
AU  - Cipriani C
AD  - Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 
      Rome, Italy.
FAU - Chiarotti, Flavia
AU  - Chiarotti F
AD  - Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanita, 
      V.le Regina Elena 299, 00161, Rome, Italy.
FAU - Perrone, Benedetta
AU  - Perrone B
AD  - Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanita, 
      V.le Regina Elena 299, 00161, Rome, Italy.
FAU - Balestrieri, Emanuela
AU  - Balestrieri E
AD  - Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 
      Rome, Italy.
FAU - Matteucci, Claudia
AU  - Matteucci C
AD  - Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 
      Rome, Italy.
FAU - Sinibaldi-Vallebona, Paola
AU  - Sinibaldi-Vallebona P
AD  - Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 
      Rome, Italy.
AD  - Institute of Translational Pharmacology, National Research Council, Rome, Italy.
FAU - Calamandrei, Gemma
AU  - Calamandrei G
AUID- ORCID: 0000-0003-3762-3132
AD  - Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanita, 
      V.le Regina Elena 299, 00161, Rome, Italy. gemma.calamandrei@iss.it.
FAU - Ricceri, Laura
AU  - Ricceri L
AD  - Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanita, 
      V.le Regina Elena 299, 00161, Rome, Italy.
LA  - eng
GR  - 13/cal 508/Istituto Superiore di Sanita/
PT  - Journal Article
DEP - 20180907
PL  - United States
TA  - Mol Neurobiol
JT  - Molecular neurobiology
JID - 8900963
RN  - 614OI1Z5WI (Valproic Acid)
MH  - Animals
MH  - *Behavior, Animal
MH  - Brain/pathology
MH  - Endogenous Retroviruses/*genetics
MH  - Female
MH  - Inheritance Patterns/*genetics
MH  - Male
MH  - Mice
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects/blood/*pathology/*virology
MH  - Principal Component Analysis
MH  - Transcription, Genetic
MH  - Valproic Acid/*adverse effects/blood
OTO - NOTNLM
OT  - Autism spectrum disorders
OT  - Maternal and paternal lineages
OT  - Neurodevelopment
OT  - Transgenerational effects
EDAT- 2018/09/09 06:00
MHDA- 2019/08/14 06:00
CRDT- 2018/09/09 06:00
PHST- 2018/04/24 00:00 [received]
PHST- 2018/08/22 00:00 [accepted]
PHST- 2018/09/09 06:00 [pubmed]
PHST- 2019/08/14 06:00 [medline]
PHST- 2018/09/09 06:00 [entrez]
AID - 10.1007/s12035-018-1328-x [pii]
AID - 10.1007/s12035-018-1328-x [doi]
PST - ppublish
SO  - Mol Neurobiol. 2019 May;56(5):3736-3750. doi: 10.1007/s12035-018-1328-x. Epub 
      2018 Sep 7.