Abstract
Autism spectrum disorder (ASD) is a heterogeneously pervasive developmental disorder in which various genetic and environmental factors are believed to underlie its development. Recently, epigenetics has been suggested as a novel concept for ASD aetiology with a proposition that epigenetic marks can be transgenerationally inherited. Based on this assumption of epigenetics, we investigated the transgenerational inheritance of ASD-like behaviours and their related synaptic changes in the VPA animal model of ASD. The first generation (F1) VPA-exposed offspring exhibited autistic-like impaired sociability and increased marble burying. They also showed increased seizure susceptibility, hyperactivity and decreased anxiety. We mated the VPA-exposed F1 male offspring with naïve females to produce the second generation (F2), and then similarly mated the F2 to deliver the third generation (F3). Remarkably, the autism-like behavioural phenotypes found in F1 persisted to the F2 and F3. Additionally, the frontal cortices of F1 and F3 showed some imbalanced expressions of excitatory/inhibitory synaptic markers, suggesting a transgenerational epigenetic inheritance. These results open the idea that E/I imbalance and ASD-like behavioural changes induced by environmental insults in mice can be epigenetically transmitted, at least, to the third generation. This study could help explain the unprecedented increase in ASD prevalence.
Highlights
In a mature cell through alterations in chromatin structure by histone modification and DNA methylation[9,10]
There was no significant difference between the control group and the valproic acid (VPA)-exposed group (Fig. 1B)
These results suggested that VPA does not affect the reproductive capacity as well as the viability of mice offspring
Summary
In a mature cell through alterations in chromatin structure by histone modification and DNA methylation[9,10]. Epigenetic inheritance can be widely influenced by the environment such as diet, as what has been elucidated in the agouti viable yellow (Avy) mice[14], and chemical exposures during pregnancy as elucidated in medaka fish[15] Other parental conditions such as lifetime stress can change the epigenetic marks in the germ cells[16]. Bertram and his colleagues reported that maternal undernutrition in guinea pigs caused dramatic changes in heart structure and hypothalamic-pituitary-adrenal (HPA) function across two generations[17] This concept can have important implications in the environmental factors affecting pregnancy outcome and causing neurodevelopmental disorders in the offspring such as ASD. The outcome of this study will provide insights into the contributing factors of increased ASD prevalence over the years
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