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

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