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

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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.

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Acknowledgements

The authors thank Luigia Cancemi for expert animal care and Cosimo Curianò for his assistance in graphical editing. This work was supported by ISS 13/cal 508 “Identification of early markers in mouse models of autism spectrum disorders: role of endogenous retroviruses.”

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Authors and Affiliations

  1. Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, V.le Regina Elena 299, 00161, Rome, Italy

    Anna Maria Tartaglione, Flavia Chiarotti, Benedetta Perrone, Gemma Calamandrei & Laura Ricceri

  2. Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy

    Chiara Cipriani, Emanuela Balestrieri, Claudia Matteucci & Paola Sinibaldi-Vallebona

  3. Institute of Translational Pharmacology, National Research Council, Rome, Italy

    Paola Sinibaldi-Vallebona

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  1. Anna Maria Tartaglione
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  2. Chiara Cipriani
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  9. Laura Ricceri
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Correspondence to Gemma Calamandrei.

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All studies were carried out in accordance with the European and Italian legislation (2010/63/EU, Dl 26/2014, specific authorization 223/2011-B to GC).

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The authors declare that they have no conflict of interest.

Electronic Supplementary Material

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Supplementary Fig. 4

F1 generation: a) body weight and b) body temperature shown by VPA- and VEH pups at different postnatal days of testing; c) Mean duration of USVs: VPA females showed shorter duration of calls than VEH at pnd 10. (PDF 882 kb)

Supplementary Fig. 5

Left panel: Scatterplots of first component obtained by PCA from two behavioral variables, locomotion and USVs (1st PCA comp Behaviour, y axis) and first component obtained by PCA from four ERV families, ETnII-β, ETnII-γ, MusD and IAP (1st PCA comp ERVs, x axis) across generations when all data are included in the analysis (i.e. both ML and PL datasets for F2 and F3); Right panel: Scatterplots of the same behavioural and ERV PCA components across generations after excluding PL datasets (from both F2 and F3 generations). Note how PL values were those closer to VEH ones: excluding them it makes treatment groups more distinguishable. (PDF 55 kb)

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Tartaglione, A.M., Cipriani, C., Chiarotti, F. et al. Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid. Mol Neurobiol 56, 3736–3750 (2019). https://doi.org/10.1007/s12035-018-1328-x

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