Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats

Ju, Ling-Sha; Yang, Jianjun; Morey, Timothy E.; Gravenstein, Nikolaus; Seubert, Christoph N.; Resnick, James L.; Zhang, J.-Q.; Martynyuk, Anatoly E.

doi:10.1016/j.bja.2018.04.034

Cited by 55 publications

(62 citation statements)

References 28 publications

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“…Neonatal male rats born to (of sounds a bit biblical!) mothers who were exposed to sevoflurane before pregnancy have reduced expression of the KCC2 gene 28. This gene has been implicated in the development of autism spectrum disorders in humans.…”

Section: Pre-clinical Studiesmentioning

confidence: 99%

Does general anesthesia affect neurodevelopment in infants and children?

McCann

Soriano

2019

BMJ

135

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General anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates. The possibility of anesthetic induced neurotoxicity occurring in children has led to concerns about the safety of pediatric anesthesia. A spectrum of behavioral changes has been documented after general anesthetic exposure in young children, including emergence delirium, which may be evidence of toxicity. Most clinical studies are retrospective; specifics about medications or monitoring are unavailable and many of the outcomes may not be sensitive to detect small neurocognitive deficits. Some of these retrospective studies have shown an association between anesthesia exposure at a young age and neurocognitive deficits, but others have not. Practitioners and families should be reassured that although general anesthetics have the potential to induce neurotoxicity, very little clinical evidence exists to support this.

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Section: Pre-clinical Studiesmentioning

confidence: 99%

Does general anesthesia affect neurodevelopment in infants and children?

McCann

Soriano

2019

BMJ

135

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“…We analyzed levels of mRNA for aromatase, Era, Erb, Nkcc1, and Kcc2 in the hypothalamus via reverse transcription-PCR (qRT-PCR) in a StepOnePlus ™ Real-Time PCR System (Applied Biosystems, Foster City, CA, United States) as previously described by our laboratory (12). We extracted RNA from the samples using an RNeasy Plus Kit (Qiagen, Valencia, CA, United States), reverse transcribed with a high-capacity cDNA reverse transcription kit (Bio-Rad Laboratories, Hercules, CA, United States), and analyzed via qRT-PCR.…”

Section: Quantitative Mrna Measurementsmentioning

confidence: 99%

“…Experimental evidence indicates that GABAergic anesthetic agents, such as propofol, isoflurane, or sevoflurane, administered to neonatal rats, acutely induce electroencephalography (EEG)-detectable seizures and increased systemic levels of the main stress hormone corticosterone (8)(9)(10). The long-term effects of these anesthetics comprise an abnormal (increased) hypothalamic and hippocampal Na + -K + -Cl − cotransporter (Nkcc1)/K + -Cl − cotransporter (Kcc2) mRNA ratio, an exacerbated hypothalamic-pituitary-adrenal (HPA) axis responses to stress, and behavioral deficiencies (8,9,(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…Delays/ impairments in the transition to inhibitory GABA A R signaling have been linked in humans and animal models to several cognitive neuropsychiatric disorders, such as autism spectrum disorder, schizophrenia, and Rett syndrome (16)(17)(18). Inhibition of the NKCC1 activity at the time of neonatal anesthesia ameliorates anesthetic-caused EEG-detectable seizures and many of the long-term developmental effects of GABAergic anesthetics in rats, suggesting that anesthetic-exacerbated excitatory GABA A R signaling at the time of anesthesia can be an initial step in the pathways that mediate the developmental effects of GABAergic anesthetics (8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…We did so by measuring sevoflurane-caused EEGdetectable seizures, changes in systemic levels of T, E2, and corticosterone, and changes in the expression of hypothalamic aromatase, Era, Erb, Nkcc1, and Kcc2 under different treatment conditions to modulate GABA A R and T/E2 signaling pathways. T/E2 may affect sexual differentiation in the rodent brain during this age period through lasting organizational effects (25) and sevoflurane may induce long-term developmental abnormalities (8,9,11,12). For that reason, understanding the involvement of sevoflurane-altered levels of T and E2 in mediating the acute adverse effects of sevoflurane in neonatal rats at the time of anesthesia may help to explain the mechanistic basis of more complex long-term deficiencies induced by the anesthetic.…”

Section: Introductionmentioning

confidence: 99%

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

Lin

et al. 2020

Front. Endocrinol.

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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.

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Pregnancy drugs, fetal germline epigenome, and risks for next‐generation pathology: A call to action

Escher

Robotti²

2019

Environ and Mol Mutagen

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Drugs taken during pregnancy can affect three generations at once: the gestating woman (F0), her exposed fetus (F1), and the fetal germ cells that confer heritable information for the grandchildren (F2). Unfortunately, despite growing evidence for connections between F0 drug exposures and F2 pathology, current approaches to risk assessment overlook this important dimension of risk. In this commentary, we argue that the unique molecular vulnerabilities of the fetal germline, particularly with regard to global epigenomic reprogramming, combined with empirical evidence for F2 effects of F1 in utero drug and other exposures, should change the way we consider potential long‐term consequences of pregnancy drugs and alter toxicology's standard somatic paradigm. Specifically, we (1) suggest that pregnancy drugs common in the postwar decades should be investigated as potential contributors to the “missing heritability” of many pathologies now surging in prevalence; (2) call for inclusion of fetal germline risks in pregnancy drug safety assessment; and (3) highlight the need for intensified research to ascertain generational impacts of diethylstilbestrol, a vanguard question of human germline toxicity. Only by fully addressing this important dimension of transplacental exposure can we responsibly evaluate safety of drug exposures during pregnancy and convey the full scope of risks, while also retrospectively comprehending the generational legacy of recent history's unprecedented glut of evolutionarily novel intrauterine exposures. Environ. Mol. Mutagen. 60:445–454, 2019. © 2019 Wiley Periodicals, Inc.

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Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats

Abstract: Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.

Cited by 55 publications

References 28 publications

Does general anesthesia affect neurodevelopment in infants and children?

Does general anesthesia affect neurodevelopment in infants and children?

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

Pregnancy drugs, fetal germline epigenome, and risks for next‐generation pathology: A call to action

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