Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang, 050024, Hebei Province, China.
First Hospital of Hebei Medical University, Shijiazhuang, 050030, Hebei Province, China.
Neurochem Int. 2020 May;135:104693. doi: 10.1016/j.neuint.2020.104693. Epub 2020 Feb 6.
Maternal anesthetic exposure during pregnancy is associated with an increased risk of cognitive impairment in offspring. The balance of cerebral iron metabolism is essential for the development of brain tissue. Iron deficiency affects the myelinogenesis and nerve tissue development, especially in fetus or infant, which has a key role in cognitive function. We aimed to investigate whether maternal sevoflurane (Sev) exposure caused cognitive impairment in offspring through inducing iron deficiency and inhibiting myelinogenesis. Pregnant mice (gestation stage day 14) were treated with 2% Sev for 6 h. Cognitive function of offspring mice was determined by the Morris water maze and Context fear conditioning test. Iron levels were assayed by Perl's iron staining and synchrotron imaging. Hippocampus and cortex tissues or cerebral microvascular endothelial cells of offspring mice (postnatal day 35) were harvested and subjected to Western blot and/or immunhistochemistry to assess ferritin, transferrin receptor 1(TfR1), Ferroportin-1 (FpN1), myelin basic protein (MBP), tight junction protein ZO-1, occludin, and claudin-5 levels. Beginning with postnatal day 30, the offspring were treated with iron therapy for 30 days, and the indicators above were tested. Our results showed Sev dramatically decreased the iron levels of brain and impaired cognitive function in offspring mice. Sev decreased the expression of heavy chain ferritin (FtH), light chain ferritin (FtL), MBP, ZO-1, occludin, claudin-5, and FpN1, and increased TfR1 in hippocampus and cortex or cerebral microvascular endothelial cells of offspring mice, indicating that Sev caused the iron deficiency and impaired the myelinogenesis in the brain of offspring. Interestingly, iron therapy prompted the myelinogenesis and improved impaired cognitive function at postnatal day 60. Our research uncovered a new mechanism which showed that iron deficiency induced by Sev and myelin formation disorder due to decreased iron of brain may be an important risk factor for cognitive impairment in offspring. It was necessary for offspring to be supplied iron supplement whose mother suffered exposure to sevoflurane during pregnancy.
孕期母体麻醉剂暴露与后代认知障碍风险增加有关。脑铁代谢平衡对于脑组织的发育至关重要。铁缺乏会影响髓鞘形成和神经组织发育，尤其是在胎儿或婴儿期，这对认知功能起着关键作用。我们旨在研究母体七氟醚（Sev）暴露是否通过引起铁缺乏和抑制髓鞘形成而导致后代认知障碍。将怀孕的小鼠（妊娠第 14 天）用 2% Sev 处理 6 小时。通过 Morris 水迷宫和情境恐惧条件反射试验来确定后代小鼠的认知功能。通过 Perl 铁染色和同步辐射成像来测定铁含量。采集后代小鼠（出生后第 35 天）的海马体和皮质组织或大脑微血管内皮细胞，进行 Western blot 和/或免疫组织化学分析，以评估铁蛋白、转铁蛋白受体 1（TfR1）、铁蛋白受体 1（FpN1）、髓鞘碱性蛋白（MBP）、紧密连接蛋白 ZO-1、occludin 和 Claudin-5 水平。从出生后第 30 天开始，对后代进行 30 天的铁治疗，然后测试上述指标。我们的结果表明，Sev 显著降低了大脑中的铁含量，并损害了后代小鼠的认知功能。Sev 降低了海马体和皮质或大脑微血管内皮细胞中重链铁蛋白（FtH）、轻链铁蛋白（FtL）、MBP、ZO-1、occludin、Claudin-5 和 FpN1 的表达，并增加了 TfR1，表明 Sev 引起铁缺乏并损害了后代大脑的髓鞘形成。有趣的是，铁治疗在出生后 60 天促使髓鞘形成并改善了受损的认知功能。我们的研究揭示了一种新的机制，表明 Sev 引起的铁缺乏和由于脑铁减少导致的髓鞘形成障碍可能是后代认知障碍的一个重要危险因素。对于母体在怀孕期间暴露于七氟醚的后代，有必要补充铁。
