Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, 50 College Street, South Hadley, MA 01075, USA.
Department of Medical Microbiology and Immunology, and the M.I.N.D. Institute, University of California at Davis, CA 95817, USA.
Brain Behav Immun. 2021 Mar;93:66-79. doi: 10.1016/j.bbi.2020.12.014. Epub 2020 Dec 21.
Stress during pregnancy and maternal inflammation are two common prenatal factors that impact offspring development. Asthma is the leading chronic condition complicating pregnancy and a common source of prenatal stress and inflammation.
The goal of this study was to characterize the developmental impact of repeated allergic asthma inflammation during pregnancy on offspring behavioral outcomes and brain inflammation.
Pregnant female C57BL/6 mice were sensitized with ovalbumin (OVA) or PBS vehicle control and then randomly assigned to receive daily aerosol exposures to the same OVA or PBS treatment during early, gestational days (GD) 2-GD9, or late pregnancy, GD10-GD17. Maternal sera were collected after the first and last aerosol induction regimen and measured for concentrations of corticosterone, anti-OVA IgE, and cytokine profiles. Juvenile male and female offspring were assessed for locomotor and social behaviors and later as adults assessed for anxiety-like, and marble burying behaviors using a series of behavioral tasks. Offspring brains were evaluated for region-specific differences in cytokine concentrations.
In early gestation, both PBS and OVA-exposed dams had similar serum corticosterone concentration at the start (GD2) and end (GD9) of daily aerosol inductions. Only OVA-exposed dams showed elevations in cytokines that imply a diverse and robust T helper cell-mediated immune response. Male offspring of early OVA-exposed dams showed decreases in open-arm exploration in the elevated plus maze and increased marble burying without concomitant changes in locomotor activity or social interactions. These behavioral deficits in early OVA-exposed male offspring were associated with lower concentrations of G-CSF, IL-4, IL-7, IFNγ, and TNFα in the hypothalamus. In late gestation, both PBS and OVA-exposed dams had increased corticosterone levels at the end of daily aerosol inductions (GD17) compared to at the start of inductions (GD10). Male offspring from both PBS and OVA-exposed dams in late gestation showed similar decreases in open arm exploration on the elevated plus maze compared to OVA male offspring exposed in early gestation. No behavioral differences were present in female offspring across all treatment groups. However, females of dams exposed to OVA during early gestation displayed similar reductions as males in hypothalamic G-CSF, IL-7, IL-4, and IFNγ.
The inflammatory responses from maternal allergic asthma in early gestation and resulting increases in anxiety-like behavior in males support a link between the timing of prenatal insults and sex-specific developmental outcomes. Moreover, the heightened stress responses in late gestation and concomitant dampened inflammatory response to allergic asthma suggest that interactions between the maternal immune and stress-response systems shape early life fetal programming.
孕期压力和母体炎症是影响后代发育的两个常见产前因素。哮喘是妊娠期间常见的慢性疾病,也是产前压力和炎症的常见来源。
本研究旨在描述孕期反复过敏哮喘炎症对后代行为结果和大脑炎症的发育影响。
致敏雌性 C57BL/6 小鼠用卵清蛋白(OVA)或 PBS 载体对照进行致敏,然后随机分配接受早期(妊娠天 GD2-GD9)或晚期(妊娠天 GD10-GD17)妊娠时每日气溶胶暴露于相同的 OVA 或 PBS 处理。在第一次和最后一次气溶胶诱导后收集母体血清,并测量皮质酮、抗 OVA IgE 和细胞因子谱的浓度。幼雄性和雌性后代进行运动和社交行为评估,然后作为成年动物使用一系列行为任务评估焦虑样行为和大理石掩埋行为。评估后代大脑中特定区域细胞因子浓度的差异。
在妊娠早期,接受 PBS 和 OVA 暴露的母体在每日气溶胶诱导开始(GD2)和结束(GD9)时具有相似的血清皮质酮浓度。只有 OVA 暴露的母体显示出细胞因子升高,表明存在多样化和强大的 Th 细胞介导的免疫反应。早期 OVA 暴露的母鼠雄性后代在高架十字迷宫的开放臂探索中减少,大理石掩埋增加,而运动活动或社交互动没有变化。这些早期 OVA 暴露雄性后代的行为缺陷与下丘脑 G-CSF、IL-4、IL-7、IFNγ 和 TNFα 浓度降低有关。在妊娠晚期,接受 PBS 和 OVA 暴露的母体在每日气溶胶诱导结束(GD17)时的皮质酮水平均高于诱导开始(GD10)时。来自 PBS 和 OVA 暴露的母鼠在妊娠晚期的雄性后代在高架十字迷宫的开放臂探索中均显示出与早期 OVA 暴露的雄性后代相似的减少。在所有治疗组中,雌性后代均未出现行为差异。然而,在早期妊娠时暴露于 OVA 的母体的雌性后代显示出与雄性后代相似的下丘脑 G-CSF、IL-7、IL-4 和 IFNγ 减少。
早期妊娠时母体过敏哮喘的炎症反应以及雄性后代焦虑样行为的增加支持了产前损伤时间与性别特异性发育结果之间的联系。此外,妊娠晚期应激反应增强以及对过敏哮喘的炎症反应减弱表明,母体免疫和应激反应系统之间的相互作用塑造了胎儿早期生活的编程。