Sevoflurane Exposure Results in Sex-Specific Transgenerational Upregulation of Target IEGs in the Subiculum.

Large body of animal work and emerging clinical findings have suggested that early exposure to anesthetics may result in increased risk of learning disabilities and behavioral impairments. Recent studies have begun to investigate anesthesia-induced epigenetic modifications to elucidate their role in behavioral and neurodevelopmental abnormalities. Here we examine sevoflurane-induced transgenerational modifications of subicular neuronal DNA methylation and expression of immediate early genes (IEGs), arc and junB, crucial to synaptic plasticity and normal neuronal development. We show that 6 h sevoflurane exposure in postnatal day 7 rat pups resulted in decreased neuronal 5-methycytosine, indicating reduced DNA methylation. This effect is transgenerationally expressed in offspring born to exposed mothers which is of importance considering that decreased DNA methylation in the brain has been linked with functional decline in learning and memory. We further show that sevoflurane exposure induces upregulation of Arc and JunB mRNA expression, 42.7% and 35.2%, respectively. Transgenerational changes in Arc and JunB mRNA were sexually dimorphic only occurring in males born to exposed females, expressed as upregulation of Arc and JunB mRNA, 71.6% and 74.0%, respectively. We further investigated correlation between altered arc promoter methylation and observed upregulation of Arc mRNA and observed that sevoflurane reduced methylation in the 5-upstream promoter region of females exposed to sevoflurane. Transgenerational hypomethylation and modifications to IEGs crucial to synaptic plasticity, observed following neonatal sevoflurane exposure could contribute to morphological and cognitive deficits known to occur with neonatal sevoflurane exposure.