The potential role of stress and sex steroids in heritable effects of sevoflurane†

Abstract

Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane.

Keywords: DNA methylation; GABA type A receptor; K+-2Cl- (KCC2) Cl- exporter; Na+-K+-Cl- (NKCC1) Cl- importer; corticosterone; estradiol; general anesthetic; intergenerational effects; sevoflurane; testosterone.

Figure 1

A diagram illustrating hypothetical pathways that involve the positive feedback interaction between GABA_AR signaling, stress, and sex steroids in the mediation of heritable effects of sevoflurane. (See text for details.) These hypothetical pathways are proposed based on our published experimental findings and/or data in the literature that are discussed in this minireview; nevertheless, these are hypotheses that require rigorous experimental verification. The red arrows illustrate positive, stimulatory effects and the green arrow illustrates a negative, inhibitory effect. The blue arrows illustrate effects of steroids on parental germ cells. Our experimental data indicate that sevoflurane acts via GABA_AR-independent mechanisms to increase systemic levels of testosterone (T) in males only [69]. Sevoflurane, by acting via GABA_AR-mediated mechanisms, increases systemic levels of 17-β-estradiol (E2) in males and females [68, 69]. Our findings show that sevoflurane increases expressions of aromatase and estrogen receptor α (Erα), but not estrogen receptor β (Erβ), and systemic E2 levels. E2, by acting via ERα, increases the Na⁺-K⁺-Cl⁻ cotransporter (Nkcc1)/K⁺-Cl⁻ cotransporter (Kcc2) ratio. Therefore, E2 may shift GABA_AR signaling toward excitatory and further enhances GABA_AR excitatory signaling through direct interaction with GABA_AR, as evident from increased sevoflurane-induced electroencephalography (EEG)-detectable seizure-like activities [68, 69]. The enhanced excitatory GABA_AR signaling leads to a further increase in sevoflurane-stimulated production of E2. Sevoflurane, by enhancing excitatory GABA_AR signaling in corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus, stimulates the hypothalamic–pituitary–adrenal (HPA) axis and corticosterone (CORT) production [59, 67–69]. The stress response reduces the KCC2 cell-surface expression in the hypothalamic neurons [59], leading to a shift in GABA_AR signaling toward excitatory, and, as a result, to greater upregulation of the HPA and hypothalamic-pituitary-gonadal (HPG) axes. Sevoflurane, by increasing E2 levels and expression of Erα, reduces the CORT-dependent negative feedback on the HPA axis [101, 102], leading to greater stress response, more excitatory GABA_AR signaling via reduced cell surface KCC2 expression, and greater GABA_AR signaling-mediated production of E2. Based on data in the literature on epigenetic effects of stress in germ cells [138, 140–143] and on our own findings [58, 59], we hypothesize that CORT mediates effects of sevoflurane in parental germ cells, at least in part through epigenetic modifications. The heritable effects of EDCs, as well as transcriptomic activities of ERα and androgen receptors (AR) [9, 15, 136, 137, 145–147], allow us to hypothesize that E2 and T may also mediate heritable effects of sevoflurane through their actions in parental germ cells.