Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics

Abstract

The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.

Keywords: Brain; General anesthetic; Sevoflurane; Corticosterone; Cortisol; Histone acetylation; Deoxyribonucleic acid methylation; Intergenerational effects; Gamma aminobutyric acid

Core tip: The GABAergic general anesthetics may act as stressors and endocrine disruptors in neonates and young adults. They may induce two distinct types of long-term adverse effects: Neuroendocrine effects (the somatic effects) and epigenetic reprogramming of germ cells (the germ cell effects). The latter may pass neurobehavioral abnormalities to male offspring. Compared to the somatic cells, the germ cells may be more sensitive to the deleterious effects of general anesthetics, raising the possibility that the offspring may be affected even when levels of anesthesia are not harmful to the exposed parents. Further rigorous experimental testing of all these possibilities is required.