PDF(Pubmed)
Abstract：
Inflammation during pregnancy is associated with an increased risk for neurodevelopmental disorders (NDD). Increased gestational inflammation can be a result of an immune condition/disease, exposure to infection, and/or environmental factors. Epidemiology studies suggest that cases of NDD are on the rise. Similarly, rates of asthma are increasing, and the presence of maternal asthma during pregnancy increases the likelihood of a child being later diagnosed with NDD such as autism spectrum disorders (ASD). Particulate matter (PM), via air pollution, is an environmental factor known to worsen the symptoms of asthma, but also, PM has been associated with increased risk of neuropsychiatric disorders. Despite the links between asthma and PM with neuropsychiatric disorders, there is a lack of laboratory models investigating combined prenatal exposure to asthma and PM on offspring neurodevelopment. Thus, we developed a novel mouse model that combines exposure to maternal allergic asthma (MAA) and ultrafine iron-soot (UIS), a common component of PM. In the current study, female BALB/c mice were sensitized for allergic asthma with ovalbumin (OVA) prior to pregnancy. Following mating and beginning on gestational day 2 (GD2), dams were exposed to either aerosolized OVA to induce allergic asthma or phosphate buffered saline (PBS) for 1 h. Following the 1-h exposure, pregnant females were then exposed to UIS with a size distribution of 55 to 169 nm at an average concentration of 176 ± 45 μg/m3) (SD), or clean air for 4 h, over 8 exposure sessions. Offspring brains were collected at postnatal days (P)15 and (P)35. Cortices and hippocampal regions were then isolated and assessed for changes in cytokines using a Luminex bead-based multiplex assay. Analyses identified changes in many cytokines across treatment groups at both timepoints in the cortex, including interleukin-1 beta (IL-1β), and IL-17, which remained elevated from P15 to P35 in all treatment conditions compared to controls. There was a suppressive effect of the combined MAA plus UIS on the anti-inflammatory cytokine IL-10. Potentially shifting the cytokine balance towards more neuroinflammation. In the hippocampus at P15, elevations in cytokines were also identified across the treatment groups, namely IL-7. The combination of MAA and UIS exposure (MAA-UIS) during pregnancy resulted in an increase in microglia density in the hippocampus of offspring, as identified by IBA-1 staining. Together, these data indicate that exposure to MAA, UIS, and MAA-UIS result in changes in the neuroimmune environment of offspring that persist into adulthood.
摘要：
怀孕期间的炎症与神经发育障碍（NDD）的风险增加有关。妊娠期炎症增加可能是免疫状况/疾病的结果，接触感染，和/或环境因素。流行病学研究表明，NDD病例正在上升。同样，哮喘的发病率正在上升，并且在怀孕期间母体哮喘的存在增加了孩子后来被诊断为NDD的可能性，例如自闭症谱系障碍（ASD）。颗粒物(PM),通过空气污染，是一种会加重哮喘症状的环境因素，而且,PM与神经精神疾病的风险增加有关。尽管哮喘和PM与神经精神疾病之间存在联系，缺乏研究产前哮喘和PM联合暴露对后代神经发育的影响的实验室模型。因此，我们开发了一种新的小鼠模型，该模型结合了暴露于母体过敏性哮喘（MAA）和超细铁烟（UIS），PM的共同组成部分。在目前的研究中,雌性BALB/c小鼠在妊娠前用卵清蛋白(OVA)致敏过敏性哮喘.在交配并在妊娠第2天（GD2）开始后，将水坝暴露于雾化OVA以诱发过敏性哮喘或磷酸盐缓冲盐水（PBS）1小时。然后将怀孕的雌性暴露于大小分布为55至169nm的UIS，平均浓度为176±45μg/m3）（SD），或清洁空气4小时，超过8次曝光会议。在出生后第(P)15天和第(P)35天收集后代大脑。然后分离皮质和海马区,并使用基于Luminex珠的多重测定评估细胞因子的变化。分析发现，在皮质的两个时间点，治疗组的许多细胞因子的变化，包括白细胞介素-1β（IL-1β），和IL-17,其在所有治疗条件下与对照相比保持从P15升高至P35。MAA加UIS的组合对抗炎细胞因子IL-10有抑制作用。潜在地将细胞因子平衡转向更多的神经炎症。在P15时的海马中，细胞因子的升高也在治疗组之间进行了鉴定，即IL-7。怀孕期间MAA和UIS暴露（MAA-UIS）的组合导致后代海马中小胶质细胞密度增加，如通过IBA-1染色鉴定的。一起,这些数据表明暴露于MAA，UIS,MAA-UIS会导致后代神经免疫环境的变化，并持续到成年。
