Sevoflurane anesthesia during pregnancy in mice induces cognitive impairment in the offspring by causing iron deficiency and inhibiting myelinogenesis

Zuo, Yong; Li, Bowen; Jinhong, Xie; Ma, Zhao; Thirupathi, Anand; Yu, Peng; Gao, Guofen; Zhou, Haiqing; Zhou, Changle; Xu, Hongmeng; Chang, Yan‐Zhong; Shi, Zhenhua

doi:10.1016/j.neuint.2020.104693

Cited by 28 publications

(47 citation statements)

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“…Initially, we hypothesized in previous reports that sevoflurane might cause cognitive impairment in the offspring of pregnant mice through iron accumulation and subsequent activation of oxidative stress mechanisms. When pregnant mice were treated with 2% Sev for 6 hr, which mimics large anesthesia operations, we found that sevoflurane reduced iron levels in the hippocampus and cerebral cortex of the offspring 28 days after birth, and reduced cognitive function in the offspring (Zuo et al, 2020). Sevoflurane‐induced iron deficiency inhibits myelin development, leading to cognitive impairment in offspring.…”

Section: Sevoflurane Brain Iron Metabolism Disorder and Cognitive Imentioning

confidence: 99%

“…The effects of maternal exposure to sevoflurane on nerve tissue damage and cognitive impairment in the fetus and offspring were related to sevoflurane concentration, duration, and frequency of use, and some results were not entirely consistent (Lee, 2017; Suehara, 2016; Wu, 2018). Some reports have shown that mothers exposed to sevoflurane concentrations above 2% for more than 3 hr have impaired cognitive function in their offspring (Hirotsu, 2019; Luo et al, 2016; Zuo et al, 2020). We do not know whether low concentrations of sevoflurane and short duration of treatment cause iron deficiency in offspring, and this requires future research.…”

Section: Sevoflurane Brain Iron Metabolism Disorder and Cognitive Imentioning

confidence: 99%

“…Disturbance of iron homeostasis can lead to some diseases, for example, iron overload can induce AD (Lane et al., 2018). Recently, sevoflurane anesthesia during pregnancy in mice has been shown to cause iron deficiency and inhibit neuromyelin formation, leading to cognitive impairment in offspring (Zuo et al, 2020). In this review, based on our previous report, we discuss the pathology associated with fetal toxicity resulting from exposure to anesthetics during pregnancy.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal sevoflurane exposure: Effects of iron metabolic dysfunction on offspring cognition and potential mechanism

Zuo

Chang

Thirupathi

et al. 2020

Intl J of Devlp Neuroscience

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For decades, the neurotoxicity caused by anesthetics in mammalian brain development has gained increasing attention. Exposure to anesthetics leads to neurotoxicity and apoptosis of nerve cells, which in turn induces cognitive dysfunction. Although most of the data came from animal studies, general anesthetics have been shown to have adverse effects on cognitive function in infants and young children in recent years. This concern has led to a number of retrospective studies that observed an association between general anesthesia in pregnant women and neurobehavioral problems in fetuses or offspring. Every year, many pregnant women undergo non‐obstetric anesthesia due to various reasons such as traffic accidents, fetal interventions, acute appendicitis, symptomatic cholelithiasis, and trauma. A matter of concern for these pregnant women is whether anesthesia has a detrimental effect on fetal brain development in the womb and whether the fetus has cognitive impairment after birth. In humans, the association of anesthetic exposure in infants with the long‐term impairment of neurologic functions has been reported in several retrospective clinical studies. Recently, we have found that sevoflurane anesthesia during pregnancy in mice‐induced cognitive impairment in the offspring by causing iron deficiency and inhibiting myelinogenesis. Sevoflurane is a commonly used general anesthetic in the hospitals, which can induce neurotoxicity and cause cognitive impairment in fetuses, infants, children, and adults. However, the exact mechanism of sevoflurane‐induced damage to the central nervous system (CNS) is not fully understood. Based on our recent results, this paper reviewed the effects of sevoflurane on cognitive impairment and pathological changes such as neurogenesis, neuronal apoptosis, and iron metabolism dysfunction in the offspring.

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Section: Sevoflurane Brain Iron Metabolism Disorder and Cognitive Imentioning

confidence: 99%

Section: Sevoflurane Brain Iron Metabolism Disorder and Cognitive Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prenatal sevoflurane exposure: Effects of iron metabolic dysfunction on offspring cognition and potential mechanism

Zuo

Chang

Thirupathi

et al. 2020

Intl J of Devlp Neuroscience

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“…repetitive behavior and hyperactivity, and memory impairment [14,[16][17][18][19][20][21][22][23]. Many of the deficiencies associated with exposure to anesthetic agents may be long-lasting, leaving irreversible adverse effects.…”

Section: Introductionmentioning

confidence: 99%

“…It is unclear whether environmental exposures result in epigenetic alterations of the germline that can be transmitted to subsequent generations resulting in ASD [1,2,26]. To address this issue, we chose to study to effect of sevoflurane, the most widely used GA agent currently, with a well-established effects on neurotoxicity as a result of direct exposure [14,16,[19][20][21][22][23]. We exposed pregnant mouse females during the time of development when the embryo is undergoing neurogenesis and the germline undergoes epigenetic reprogramming.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Forestier

Corcés

2021

Preprint

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One in 54 children in the U.S. is diagnosed with Autism Spectrum Disorder (ASD). De novo germline and somatic mutations cannot account for all cases of ASD, suggesting that epigenetic alterations triggered by environmental exposures may be responsible for a subset of ASD cases. Human and animal studies have shown that exposure of the developing brain to general anesthetic (GA) agents can trigger neurodegeneration and neurobehavioral abnormalities but the effects of general anesthetics on the germ line have not been explored in detail. We exposed pregnant mice to sevoflurane during the time of embryonic development when the germ cells undergo epigenetic reprogramming and found that more than 38% of the directly exposed F1 animals exhibit impairments in anxiety and social interactions. Strikingly, 44-47% of the F2 and F3 animals, which were not directly exposed to sevoflurane, show the same behavioral problems. We performed ATAC-seq and identified more than 1,200 differentially accessible sites in the sperm of F1 animals, 69 of which are also present in the sperm of F2 animals. These sites are located in regulatory regions of genes strongly associated with ASD, including Arid1b, Ntrk2, and Stmn2. These findings suggest that epimutations caused by exposing germ cells to sevoflurane can lead to ASD in the offspring, and this effect can be transmitted through the male germline inter and trans-generationally.

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Effects of sevoflurane exposure during different stages of pregnancy on the brain development of rat offspring

Cui

et al. 2021

J Anesth

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Objective This study explored the effects of sevoflurane exposure during different stages of pregnancy on the brain development of offspring. Methods Thirty-six pregnant SD rats were randomly divided into 4 groups: control, sevoflurane exposure in early (S1) pregnancy, sevoflurane exposure in middle (S2) pregnancy, and sevoflurane exposure in late (S3) pregnancy. After natural birth, the learning and memory capacity of offspring rats was analyzed using the Morris water maze experiment. The hippocampi of offspring rats were collected. The levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the hippocampus were measured by ELISA. Additionally, the Nissl bodies in the hippocampus were analyzed using Nissl staining. Immunohistochemistry was used to examine the expression of BDNF and CPEB2 in the hippocampus of offspring. Proteins related to the NR4A1/NF-κB pathway were analyzed using western blotting. Results The memory and learning capacity of offspring rats was significantly reduced in the S1 and S2 groups compared to the control group (p < 0.05), while there was no obvious difference between the control and S3 groups (p > 0.05). The level of IL-1β was significantly increased (p < 0.05) in the S1 group compared with the control group. Sevoflurane anesthesia received in early and middle pregnancy could significantly affect the formation of Nissl bodies in the hippocampi of offspring rats. In addition, the expression of BDNF and CPEB2 in the hippocampi of offspring rats was greatly decreased in the S1 group compared with the control group (p < 0.05). The expression of NR4A1 in the hippocampi of rat offspring was significantly decreased in the S1 and S2 groups compared with the control group (p < 0.05). The expression of proteins related to the NF-κB pathway was increased in the S1 group compared to the control group (p < 0.05). Conclusions The neurotoxic effect of maternal sevoflurane anesthesia on the brain development of offspring is higher when the exposure occurs in early pregnancy than in late pregnancy, and its mechanism might involve the NR4A1/NF-κB pathway to increase the secretion of inflammatory cytokines.

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Sevoflurane anesthesia during pregnancy in mice induces cognitive impairment in the offspring by causing iron deficiency and inhibiting myelinogenesis

Cited by 28 publications

References 28 publications

Prenatal sevoflurane exposure: Effects of iron metabolic dysfunction on offspring cognition and potential mechanism

Prenatal sevoflurane exposure: Effects of iron metabolic dysfunction on offspring cognition and potential mechanism

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

Effects of sevoflurane exposure during different stages of pregnancy on the brain development of rat offspring

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