Intergenerational Effects of Sevoflurane in Young Adult Rats

Abstract

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sevoflurane administered to neonatal rats induces neurobehavioral abnormalities and epigenetic reprogramming of their germ cells; the latter can pass adverse effects of sevoflurane to future offspring. As germ cells are susceptible to reprogramming by environmental factors across the lifespan, the authors hypothesized that sevoflurane administered to adult rats could induce neurobehavioral abnormalities in future offspring, but not in the exposed rats themselves. Methods Sprague-Dawley rats were anesthetized with 2.1% sevoflurane for 3 h every other day between postnatal days 56 and 60. Twenty-five days later, exposed rats and nonexposed controls were mated to produce offspring. Results Adult male but not female offspring of exposed parents of either sex exhibited deficiencies in elevated plus maze (mean ± SD, offspring of both exposed parents vs. offspring of control parents, 35 ± 12 vs. 15 ± 15 s, P < 0.001) and prepulse inhibition of acoustic startle (offspring of both exposed parents vs. offspring of control parents, 46.504 ± 13.448 vs. 25.838 ± 22.866%, P = 0.009), and increased methylation and reduced expression of the potassium ion-chloride ion cotransporter KCC2 gene (Kcc2) in the hypothalamus. Kcc2 was also hypermethylated in sperm and ovary of the exposed rats. Surprisingly, exposed male rats also exhibited long-term abnormalities in functioning of the hypothalamic-pituitary-gonadal and -adrenal axes, reduced expression of hypothalamic and hippocampal Kcc2, and deficiencies in elevated plus maze (sevoflurane vs. control, 40 ± 24 vs. 25 ± 12 s, P = 0.038) and prepulse inhibition of startle (sevoflurane vs. control, 39.905 ± 21.507 vs. 29.193 ± 24.263%, P < 0.050). Conclusions Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprogramming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.

The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats

“…Statistical details are presented in the text and figure legends. The sample sizes in this study were based on previous experience with the same experimental techniques and measured parameters (Edwards et al, 2010;Tan et al, 2014;Xu et al, 2015;Zhang et al, 2016;Ju et al, 2017Ju et al, , 2018Ju et al, , 2019. We studied the ability of sevoflurane to cause EEG-detectable seizures in the P9, P10, or P11 male rats in all four experimental groups, i.e., the control rats and rats that were exposed to sevoflurane for 6 h on P4, P5, or P6 after pretreatment with the vehicle, formestane, or bumetanide.…”

“…In an attempt to improve the safety of pediatric anesthesia, numerous studies have proposed various mediating mechanisms of the adverse effects of general anesthetics in neonatal animal models, further confirming the mechanistic complexity of this phenomenon ( Vutskits and Xie, 2016 ; Lin et al, 2017 ). Our approach in this field is based on an assumption that the developing brain is especially vulnerable to the deleterious effects of general anesthetics because, at least in part, the anesthetics exert their adverse effects by affecting mechanisms specific to this age period ( Edwards et al, 2010 ; Tan et al, 2014 ; Xu et al, 2015 ; Zhang et al, 2016 ; Ju et al, 2017 , 2018 , 2019 ).…”

General anesthesia, germ cells and the missing heritability of autism: an urgent need for research

“…As germ cells are susceptible to reprogramming by environmental factors across the lifespan, Martynyuk’s lab also tested whether sevoflurane could induce neurobehavioral abnormalities in offspring when the anesthetic is administered to young adult rats [ 94 ]. They found similar, not identical, abnormalities in parental germ cells and in male offspring of exposed sires and dams.…”

“…This phenomenon is consistent with the increased risk for male offspring pathology in intergenerational responses to GA exposure as detected in Ju et al . [ 92 , 94 ]. Additionally, other studies in chemical disruption of germ cells have found male offspring more likely suffer adverse neurobehavioral effects [ 13 ].…”

General Anesthetic-Induced Neurotoxicity in the Immature Brain: Reevaluating the Confounding Factors in the Preclinical Studies

“…Subsequent preclinical studies demonstrated that GA caused a vast amount of acute injury and long-term cognitive impairments in rodents [6][7][8][9][10][11][12][13] and nonhuman primates (NHP) [9,10,[14][15][16][17][18][19][20][21][22][23]. Even worse, exposure to GA in neonatal rodents produced adverse effects on the learning and memory of their offspring via epigenetic modulation [24][25][26][27]. Taken together, these solid preclinical findings suggest that exposure of the developing brain to GA contributes to the long-term adverse neurodevelopmental outcome.…”