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Paternal valproic acid exposure in mice triggers behavioral alterations in offspring
Daisuke Ibi1, Yu Fujiki1, Nayu Koide1
1Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Insights
Paternal exposure to sodium valproate (VPA) in rodents alters offspring behavior and epigenetics. This suggests VPA may impact germline epigenomes, affecting brain development and leading to neurodevelopmental changes.
Area of Science:
- Neuroscience
- Epigenetics
- Developmental Biology
Background:
- Sodium valproate (VPA) is a widely used antiepileptic drug with non-epileptic applications.
- Maternal VPA exposure is linked to increased autism spectrum disorder (ASD) risk in children.
- The impact of paternal VPA exposure on offspring is largely unknown.
Purpose of the Study:
- To investigate the effects of paternal VPA exposure on rodent offspring's behavior.
- To examine potential epigenetic alterations in offspring following paternal VPA exposure.
- To explore the role of histone acetylation in mediating these effects.
Main Methods:
- Rodent models were utilized to assess behavioral changes in offspring after paternal VPA exposure.
- Cognitive memory, NMDA antagonist-induced hyperactivity, and sensorimotor gating were evaluated.
- Levels of acetylated histone H3 in the offspring's brain and sires' testes were measured.
Main Results:
- Paternal VPA exposure impaired object cognitive memory and suppressed hyperactivity in both male and female offspring.
- Sensorimotor gating was disturbed in female offspring only.
- Paternal VPA exposure decreased acetylated histone H3 in offspring brains, despite increasing it in sires' testes.
Conclusions:
- Paternal VPA exposure can induce behavioral and epigenetic changes in offspring.
- These alterations may be mediated by germline epigenome modifications, specifically histone acetylation.
- Findings highlight potential risks associated with paternal VPA exposure on neurodevelopment.
Abstract:
Sodium valproate (VPA) is the most widely used antiepileptic drug and is increasingly also being used for several non-epileptic indications including migraines and bipolar disorder. It is known that maternal VPA exposure during pregnancy increases the risk of autism spectrum disorder (ASD) in children. Animal model studies have shown that maternal treatment with VPA in rodents conveys an increased risk for ASD-like phenotypes at the molecular, cellular, and behavioral levels. In contrast, the effect of paternal VPA exposure on behaviors in offspring is unknown. This study seeks to investigate whether paternal VPA exposure in rodents triggers behavioral and epigenetic alterations in offspring. The results show that paternal VPA exposure impairs object cognitive memory, suppresses the hyperactivity evoked by an NMDA receptor antagonist in male and female offspring, and disturbs sensorimotor gating in only females. In addition, since VPA is well known as an inhibitor of histone deacetylases, we examined the levels of acetylated histone H3 in the frontal cortex and hippocampus in the offspring of VPA-exposed sires. Interestingly, paternal VPA exposure down-regulates the levels of acetylated histone H3 in the brain in offspring even though VPA exposure increased acetylated histone H3 levels in the testes of sires. Collectively, these findings suggest that paternal VPA exposure may disturb the histone acetylation balance in the brain of offspring through changes in the germline epigenome, leading to behavioral alterations in offspring.
