Role of Epigenetic Mechanisms in Transmitting the Effects of Neonatal Sevoflurane Exposure to the Next Generation of Male, but not Female, Rats

Abstract

(Br J Anaesth. 2018;121:406–416) Neonatal anesthesia-induced abnormalities and their mechanisms are poorly understood, even in exposed animals. Some studies have shown that rats, especially male rats, develop behavioral deficiencies and exacerbated hypothalamic-pituitary adrenal responses to stress when exposed as neonates to anesthetic. Furthermore, recent studies suggest that these deleterious effects could be carried into the next generation via epigenetic mechanisms (noncoding RNAs, DNA methylation). There is a pressing need for further research, in order to establish safety guidelines for anesthesia in children, The authors of the present study exposed neonatal rats to sevoflurane and evaluated their progeny for inherited behavioral and molecular alterations.

A poisoned chalice: the heritage of parental anaesthesia exposure

“…This work by Ju and colleagues 6 confirms and extends previously published reports from several investigators using rodent models of sex-specific differences in behavioural outcome after anaesthesia exposure. 8,9 In nearly all cases, outcomes after anaesthesia exposure follow a pattern seen after neonatal stroke or trauma where males perform worse than females.…”

“…The initial focus was on histone modifications, which showed that anaesthetics can modulate histone acetylation and as such may have deleterious effects on transcription of genes crucial for proper synapse formation and cognitive development. 7 The study by Ju and colleagues 6 is an interesting confirmation of early behavioural observations 5 and recently published evidence. 7 Whether the epigenetic changes involve key transcription factors [e.g.…”

“…3,4 To further substantiate possible transgenerational effects of early life anaesthesia exposure, rodent experimental data reveal altered learning capabilities after halothane and enflurane exposure in second generation offspring. 5 In this issue of the British Journal of Anaesthesia, Ju and colleagues 6 present interesting new mechanistic insights on how behavioural and cognitive deficits, associated with early life anaesthesia exposure, can be transmitted to following generations. The authors exposed 5-day-old rat pups to sevoflurane for 6 hr, and showed that this treatment paradigm induced lasting behavioural deficits not only in these animals, but also in their male progeny.…”

“…More directly coupled to anaesthesia care, a contributing factor may relate to differences in the management of acute pain in the USA and Europe, including acute postoperative pain. 5,6 An important solution to this problem is a better understanding of the natural history of pain after operative procedures, and…”

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

“…63 Xu and colleagues 12 reported that sevoflurane anaesthesia at a concentration of 2.1% for 6 h on PND4, PND5, or PND6 substantially reduced distance travelled and time spent in open arms in adult male rats but had no effect on either parameter in adult female rats. Using a similar sevoflurane regimen, Ju and colleagues 15 challenged male and female rat pups on PND5 and tested them in the elevated plus maze in early adulthood. Notably, females spent approximately equal amounts of time in the open and closed arms of the maze, but males travelled a shorter distance and spent less time in the open arms.…”