Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid

Anna Maria Tartaglione, Chiara Cipriani, Flavia Chiarotti, Benedetta Perrone, Emanuela Balestrieri, Claudia Matteucci, Paola Sinibaldi-Vallebona, Gemma Calamandrei, Laura Ricceri

Research output: Contribution to journalArticlepeer-review

Abstract

Prenatal treatment with the antiepileptic drug valproic acid (VPA) is associated with a significant risk of somatic anomalies, neurodevelopmental delays, and 7-10× 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 F1, F2, and F3 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 F1 generation and more markedly in the female sex. Across F1 and F2 generations, VPA delayed righting reflex, increased motor activity, and reduced ultrasonic vocalizations. The behavioral changes in F3 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 F3, suggesting ERVs as possible downstream effectors of the VPA epigenetic alterations.

Original languageEnglish
Pages (from-to)3736-3750
Number of pages15
JournalMolecular Neurobiology
Volume56
Issue number5
DOIs
Publication statusPublished - May 2019

Keywords

  • Animals
  • Behavior, Animal
  • Brain/pathology
  • Endogenous Retroviruses/genetics
  • Female
  • Inheritance Patterns/genetics
  • Male
  • Mice
  • Pregnancy
  • Prenatal Exposure Delayed Effects/blood
  • Principal Component Analysis
  • Transcription, Genetic
  • Valproic Acid/adverse effects

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