Abstract
This study aimed to investigate DNA methylation levels in patients undergoing major breast surgery under opioid-based general anesthesia. Blood samples were collected from eleven enrolled patients, before, during and after anesthesia. PBMC were isolated and global DNA methylation levels as well as DNA methyltransferase (DNMT) and cytokine gene expression were assessed. DNA methylation levels significantly declined by 26%, reversing the direction after the end of surgery. Likewise, DNMT1a mRNA expression was significantly reduced at all time points, with lowest level of −68%. DNMT3a and DNMT3b decreased by 65 and 71%, respectively. Inflammatory cytokines IL6 and TNFα mRNA levels showed a trend for increased expression at early time-points to end with a significant decrease at 48 h after surgery. This exploratory study revealed for the first time intraoperative global DNA hypomethylation in patients undergoing major breast surgery under general anesthesia with fentanyl. The alterations of global DNA methylation here observed seem to be in agreement with DNMTs gene expression changes. Furthermore, based on perioperative variations of IL6 and TNFα gene expression, we hypothesize that DNA hypomethylation may occur as a response to surgical stress rather than to opiate exposure.
Highlights
Epigenetic alterations modulate gene expression by changes in chromatin structure mainly brought about by covalent modifications of histone proteins and by DNA methylation (Bernstein et al, 2007)
The present study aimed to investigate DNA methylation variations, as well as DNA methyltransferase (DNMT), IL6 and TNFα gene expression in peripheral blood mononuclear cells (PBMC) of patients undergoing major surgery which were intraoperatively exposed to fentanyl according to current clinical practice
From October 2016 to June 2017, eleven patients undergoing major breast surgery performed under general anesthesia, referring to the Anesthesiology unit of “Policlinico di Sant’Orsola” were enrolled to the present study, after verifying the inclusion and exclusion criteria and signing the informed consent
Summary
Epigenetic alterations modulate gene expression by changes in chromatin structure mainly brought about by covalent modifications of histone proteins and by DNA methylation (Bernstein et al, 2007). Opioid-induced hyperalgesia (OIH) is a hypersensitivity to painful stimuli that can develop after exposure to opioid analgesics (Bannister and Dickenson, 2010). It occurs in opioid treatment for Intraoperative DNA Hypomethylation acute or chronic pain causing an unexplained paradoxical pain sensitivity (Roeckel et al, 2016). A possible role for epigenetic mechanisms in an OIH context has been deemed, based on epigenetic changes underpinning chronic pain conditions and on suggestive preclinical data (Doehring et al, 2011; Liang et al, 2013; Liang et al, 2015; Ligon et al, 2016)
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