目的:已知在怀孕期间通过感染的母体免疫激活(MIA)是后代神经发育障碍和自闭症谱系障碍(ASD)发展的环境危险因素,但感染诱导的异常神经发育事件与ASD发展风险增加之间的分子相关性仍然难以捉摸。
方法:充分考虑到ASD的极高遗传异质性和风险基因的普遍性,且效应大小最小,基于基因和途径的关联分析是用人类胚胎大脑发育和ASD的转录组和DNA甲基化景观进行的,和MIA的时程转录谱。我们在E10.5通过LPS注射诱导MIA后两天对小鼠异常神经发育进行了转录分析。
结果:一个新的证据证明了改变四种免疫和代谢相关的风险途径,包括淀粉和蔗糖代谢,核糖体,内质网中的蛋白质加工,和逆行内源性大麻素信号通路,主要参与MIA调节胎儿脑发育异常以导致ASD风险增加的过程。这里,我们观察到,这些风险途径中的几乎所有关键基因在胚胎期(E)10.5-12.5天显著差异表达,这被认为是使用小鼠动物模型研究MIA和ASD之间紧密关联的小鼠胚胎脑发育的最佳巧合窗口.
结论:研究表明MIA会导致免疫和代谢途径失调,导致胚胎神经发育异常,从而促进后代ASD症状的发展。
OBJECTIVE: Maternal immune activation (MIA) via infection during pregnancy is known to be an environmental risk factor for neurodevelopmental disorders and the development of autism spectrum disorders (ASD) in the offspring, but it still remains elusive that the molecular relevance between infection-induced abnormal neurodevelopmental events and an increased risk for ASD development.
METHODS: Fully considering the extremely high genetic heterogeneity of ASD and the universality of risk-gene with minimal effect-sizes, the gene and pathway-based association analysis was performed with the transcriptomic and DNA methylation landscapes of temporal human embryonic brain development and ASD, and the time-course transcriptional profiling of MIA. We conducted the transcriptional profiling of mouse abnormal neurodevelopment two days following induced MIA via LPS injection at E10.5.
RESULTS: A novel evidence was proved that illustrated altering four immune and metabolism-related risk pathways, including starch and sucrose metabolism, ribosome, protein processing in endoplasmic reticulum, and retrograde endocannabinoid signaling pathway, which were prominent involvement in the process of MIA regulating abnormal fetal brain development to induce an increased risk of ASD. Here, we have observed that almost all key genes within these risk pathways are significantly differentially expressed at embryonic days (E) 10.5-12.5, which is considered to be the optimal coincidence window of mouse embryonic brain development to study the intimate association between MIA and ASD using mouse animal models.
CONCLUSIONS: There search establishes that MIA causes dysregulation of immune and metabolic pathways, which leads to abnormal embryonic neurodevelopment, thus promoting development of ASD symptoms in offspring.