Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats
Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats
复制标题
表观遗传机制在将新生七氟醚暴露影响传递给下一代雄性大鼠而非雌性大鼠中的作用
DOI：
10.1016/j.bja.2018.04.034
复制
发表时间：
2018-08-01
影响因子：
9.8
通讯作者：
Martynyuk, A. E.
中科院分区：
文献类型：
--
作者：
Ju, L. -S.;Yang, J. -J.;Martynyuk, A. E.
背景：临床研究报告了在生命早期接触全身麻醉的人存在学习障碍和注意缺陷/多动障碍。大鼠，主要是雄性，在新生儿时暴露于gaba能麻醉剂，表现出行为异常，对应激反应加剧，下丘脑K+- 2cl (-) Cl-输出（Kcc2）表达减少。后者与精神疾病的发展有关，包括男性主要的自闭症谱系障碍。我们测试了父母早期接触七氟醚（儿科最常用的麻醉剂）是否会影响下一代未接触七氟醚的大鼠。方法：对出生后第5天未暴露或暴露于七氟醚的Sprague-Dawley大鼠（F0）的后代（F1）进行行为和脑基因表达评估。结果：七氟醚暴露父母的后代在行为测试和Kcc2表达方面表现异常，而非雌性。暴露双亲的雄性F1大鼠空间记忆和海马及下丘脑Kcc2表达均受损。仅暴露母鼠的子代惊悸正迷宫和脉冲前抑制水平升高，但空间记忆正常，下丘脑Kcc2表达受损，但海马Kcc2表达正常。与暴露于F0相比，它们的后代对应激表现出正常的皮质酮反应。亚硫酸酯测序显示F0精子和F1雄性海马及下丘脑中Kcc2启动子CpG位点甲基化增加，这与特定F1组中Kcc2表达的变化一致。结论：新生儿暴露于七氟醚可通过表观遗传修饰Kcc2表达影响下一代雄性，而F1雌性的风险降低。
Background: Clinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K+-2Cl(-) Cl- exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. We tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats.Methods: Offspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations.Results: Male, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups.Conclusions: Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.