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

Abstract

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 [1][2][3][4]. Recent studies have begun to investigate anesthesia-induced epigenetic modifications to elucidate their role in behavioral and neurodevelopmental abnormalities. Here we examine sevofluraneinduced transgenerational modifications of subicular neuronal DNA methylation and expression of immediate early genes (lEGs), arc and junB, crucial to synaptic plasticity and normal neuronal development. We show that 6h sevoflurane exposure in postnatal day 7 rat pups resulted in a decrease in 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 [5]. 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 lEGs crucial to synaptic plasticity, observed following neonatal sevoflurane exposure could contribute to morphological and cognitive deficits known to occur with neonatal sevoflurane exposure.

DNA Methylation Manipulation of Memory Genes Is Involved in Sevoflurane Induced Cognitive Impairments in Aged Rats

“…Our studies and others revealed that exposure to inhaled anesthetics could result in synaptic and cognitive dysfunction ( Ni et al, 2015 , 2017 ). Recent work has begun to investigate anesthesia triggered epigenetic modifications within the neonatal rats ( Chastain-Potts et al, 2019 ). However, the manipulation of DNA methylation and its precise mechanism for memory genes in the aged hippocampus and their relationships with anesthesia related cognitive variation remained to be determined.…”

A Methyltransferase Inhibitor (Decitabine) Alleviates Intergenerational Effects of Paternal Neonatal Exposure to Anesthesia With Sevoflurane

“…33 While Chastain-Potts et al reported that dams neonatally exposed to sevoflurane had hypomethylated and overexpressed subiculum Arc and Junb genes, and their expression was also upregulated in the male offspring. 34 Also, a study of the germ cell effects of obesity in humans found that multiple genes were either hypo-or hypermethylated in the spermatozoa of male patients just 1 week after bariatric surgery. 35 Although this study was not specifically designed to investigate the epigenetic germ cell effects of anesthesia/surgery, the findings of epigenetic changes in the spermatozoa days after the surgery suggest that the anesthesia/surgery may contribute to such changes in humans.…”

Sex differences in neurodevelopmental abnormalities caused by early-life anaesthesia exposure: a narrative review

“…To better address neonatal anaesthesia influences on the epigenome, we challenged PND7 rat pups to 6 h of sevoflurane and assessed methylation status in the subiculum, 83 the output structure of the hippocampus. DNA methylation critically regulates neurodevelopment by suppressing the expression of genes until those genes are needed in ontogeny.…”

“…Two recent studies have linked neonatal anaesthesia exposure to long-term genetic and epigenetic dysregulation that can be passed to male, but not female, offspring. 15,83 This includes widespread hypomethylation of neuronal DNA in subiculum, with concomitant upregulation of immediate early genes JunB and Arc that regulate gene transcriptional activity. 83 It is plausible that anaesthetics perturb the expression of coregulatory proteins such as SRC-1 that work in concert with other coregulators to establish sexual dimorphism in the developing brain, raising the possibility that anaesthetics can interfere with hormonal development.…”