Roles of Testosterone and Estradiol in Mediation of Acute Neuroendocrine and Electroencephalographic Effects of Sevoflurane During the Sensitive Period in Rats

Abstract

Testosterone (T), predominantly acting through its derivative 17b-estradiol (E2), regulates the brain's sexual differentiation in rodents during the perinatal sensitive period, which mirrors the window of vulnerability to the adverse effects of general anesthetics. The mechanisms of anesthesia's adverse effects are poorly understood. We investigated whether sevoflurane alters T and E2 levels and whether they contribute to sevoflurane's acute adverse effects in postnatal day 5 Sprague-Dawley rats. The rats underwent electroencephalography recordings for 2 h of baseline activity or for 1 h before and another hour during 2.1% sevoflurane exposure, followed by collection of trunk blood and brain tissue. Pharmacological agents, including the GABA type A receptor inhibitor bicuculline and the aromatase inhibitor formestane, were administered 30 min before sevoflurane anesthesia. Sevoflurane increased serum T levels in males only. All other effects of sevoflurane were similar in both sexes, including increases in serum levels of E2, hypothalamic mRNA levels of aromatase, estrogen receptor a (Era) [not estrogen receptor b (Erb)], Na +-K +-Cl − cotransporter (Nkcc1)/K +-Cl − cotransporter (Kcc2) mRNA ratio, electroencephalography-detectable seizures, and stresslike corticosterone secretion. Bicuculline and formestane alleviated these effects, except the T level increases. The ERa antagonist MPP, but not the ERb antagonist PHTPP, reduced electroencephalography-detectable seizures and normalized the Nkcc1/Kcc2 mRNA ratio. Collectively, sevoflurane exacerbates levels of T in males and E2 in both sexes during the period of their organizational effects in rodents. Sevoflurane acts through GABA A R-mediated, systemic T-independent elevation of E2 to cause electroencephalography-detectable seizures, stress-like corticosterone secretion, and changes in the expression of genes critical for brain development.

The effect of neuroactive steroids in sex differences in the developmental neurotoxicity of the anaesthetic

“…Estradiol usually activates the nuclear receptors estrogen receptor α and β. Our study found that it is ERα but not ERβ that increases in the hypothalamus and that it is ERα antagonists that inhibit EEG epileptic activity induced by sevoflurane exposure 22 . However, early experiments have shown that it can also affect synaptic function acutely through non‐genomic effects, which are rapid effects caused by the activity of membrane‐associated estrogen receptors activated by selective receptor agonists 58,59 .…”

“…Our team has been committed to the research of the anesthetic puberty neurotoxicity mechanism, including previous published results show that the rodents after receiving sevoflurane, males of testosterone and estradiol levels detected on the rise,and causing seizures that can be detected by electroencephalogram (EEG), concurrently, changes in stress‐like corticosterone secretion and key genes for brain development were also detected. The results suggest that sevoflurane increases estradiol (E2) levels throughout the body by increasing E2 levels in the brain 22 . Another study showed that exposure to the volatile anaesthetic sevoflurane resulted in increased estradiol levels in male mice, as well as neurodevelopmental abnormalities resulting in cognitive impairment by activating the GABAA receptor (GABAAR) signalling pathway, which were mitigated by preconditioning male mice with the estradiol synthesis inhibitor Formestane and the NKCC1 inhibitor Bumetanide 23 .…”

“…The results suggest that sevoflurane increases estradiol (E2) levels throughout the body by increasing E2 levels in the brain. 22 Another study showed that exposure to the volatile anaesthetic sevoflurane resulted in increased estradiol levels in male mice, as well as neurodevelopmental abnormalities resulting in cognitive impairment by activating the GABAA receptor (GABAAR) signalling pathway, which were mitigated by preconditioning male mice with the estradiol synthesis inhibitor Formestane and the NKCC1 inhibitor Bumetanide. 23 Using ketamine treatment on male and female mice, in order to study the influence of many factors, female mice are divided into proestrus and estrus, and behavioural tests, male and female mice estrus was observed in PPI and spatial memory tests all have obvious flaws, but proestrus female mice behaviour do not change.…”

Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism

“…Supplements of testosterone increase Ar gene expression in human studies [72, 73]. These observations are interesting in the context of published evidence showing that exposure to sevoflurane increases testosterone levels in male animals [74, 75] and that a surge of testosterone takes place during germ cell and gonadal sex differentiation [70]. It is therefore possible that Ar and related nuclear hormone receptors are responsible for bookmarking regions responsible for sevoflurane induced epimutations.…”

Sevoflurane Exposure Induces Neuronal Injury and Disturbs Myelin development During the Susceptible Phase in Neonatal Mice

“…A previous study showed that sevo in the early postnatal period can cause depolarization of the cell membrane and excitatory damage by acting on GABA A R at the postsynaptic membrane of nerve cells (Martynyuk et al 2017). A recent study showed that sevo caused a signi cant increase in NKCC1 expression in the rat hypothalamus at postnatal day 5, which was reversed by the GABA A R blocker, bicuculline (Bic) (Li et al 2020). However, GABA A R and NKCC1 have not been speci cally investigated in the mechanism of myelin development and neuronal injury.…”