Prenatal Maternal Stress, Exposure to Environmental Chemicals, and Cognitive Development: Potential Roles for Inflammation and the Developing Gut Microbiome

项目总结 生活在贫困城市社区的儿童认知延迟的风险高得不成比例，原因是 生物和心理社会暴露。制定策略来支持这些弱者的认知发展- 有能力的社区是一个紧迫的卫生优先事项，但由于缺乏对机制的了解而受到阻碍 对这些流行病模式负责。我们的项目将通过关注两种类型的前任来解决这一差距 假设(心理社会压力和环境污染物)和2个潜在的机械途径(炎症- 信息和肠道微生物群)，它们可能是可修改的。我们的中心假设是这些通路 改变神经发育过程(包括神经发生、神经迁移、轴突生长、髓鞘形成、 和功能脑网络的组装)，并在心理社会应激/EN- 环境污染物暴露与认知发展。我们将通过三个具体目标来检验这一假设： (1)确定包括新冠肺炎大流行在内的心理社会压力是否影响认知发展- 通过改变炎性轮廓和肠道微生物群发育的模式而发生改变。(2)确定是否 接触环境污染物(重金属和多氯联苯)会影响认知发展。 通过改变炎性轮廓和微生物群的作用。(3)识别与这些机械有关的神经回路- 通过最先进的多模式神经成像对4岁儿童的厌食通路。拟议的研究将 充分利用现有的、基于概率的全州怀孕队列，最终将包括1100名女性 以及它们的后代。将通过父母提供产前母亲应激和化学暴露的测量方法 学习。我们也有母体的血清和尿液，胎盘，新生儿血斑，对蛾子的采访- 3个月、9个月和24个月的健康和发育情况以及3个月的粪便样本。我们将招收300名儿童 在这项辅助研究中，增加了纵向粪便采样和神经认知测试(区分能力量表- Ii)和4岁时的神经成像。招聘将集中在城市贫困地区和郊区的家庭 环境污染物暴露水平较低的地区进行比较。我们将分析炎症性 孕妇血清和新生儿血点中的标志物，进行鸟枪式元基因组测序。 共采集1000份粪便标本，对900份母体尿样进行肾上腺素和去甲肾上腺素分析。 在怀孕期间的三个时间点进行选择，作为一种客观的压力测量。成像将包括结构磁共振、弥散成像 Sion张量成像(DTI)和静息状态fMRI扫描。我们将生成皮质下结构的测量结果 体积、全球和区域皮质厚度和表面积、白质微结构和功能 大脑连接，以实现我们的目标。这项跨学科的提案将产生积极影响，因为它将 极大地提高了我们对心理社会应激源和 环境化学物质影响认知发展并为制定干预措施奠定基础 通过针对炎症途径和/或微生物群来减轻这些暴露的影响。

PROJECT SUMMARY Children in distressed urban communities have a disproportionally high risk for cognitive delays due to both biological and psychosocial exposures. Developing strategies to support cognitive development in these vulner- able communities is an urgent health priority but is hampered by a lack of knowledge regarding the mechanisms responsible for these epidemiological patterns. Our project will address this gap, by focusing on 2 types of ex- posures (psychosocial stress and environmental contaminants) and 2 potential mechanistic pathways (inflam- mation and the gut microbiome), which are potentially modifiable. Our central hypothesis is that these pathways alter neurodevelopmental processes (including neurogenesis, neural migration, neurite outgrowth, myelination, and the assembly of functional brain networks) and act as important mediators between psychosocial stress/en- vironmental contaminant exposure and cognitive development. We will test this hypothesis via 3 specific aims: (1) Determine whether psychosocial stress, including from the COVID-19 pandemic, influences cognitive devel- opment via altered inflammatory profiles and patterns of gut microbiome development. (2) Determine whether exposure to environmental contaminants (heavy metals & polychlorinated biphenyls) influences cognitive devel- opment via altered inflammatory profiles and the microbiome. (3) Identify neural circuits involved in these mech- anistic pathways via state-of-the-art multimodal neuroimaging of 4-year-old children. The proposed study will capitalize on an existing, probability-based statewide pregnancy cohort that will eventually include 1,100 women and their offspring. Measures of prenatal maternal stress and chemical exposures will be available via the parent study. We also have access to maternal serum and urine, placentas, newborn blood spots, interviews with moth- ers on health and development at 3, 9, and 24 months and a 3-month fecal sample. We will recruit 300 children into this ancillary study, adding longitudinal fecal sampling and neurocognitive testing (Differential Ability Scales- II) and neuroimaging at 4 years of age. Recruitment will focus on families in distressed urban areas and suburban areas with lower levels of environmental contaminant exposure for comparison. We will analyze inflammatory markers in maternal serum and newborn blood spots, perform shotgun metagenomics sequencing on approxi- mately 1000 fecal samples, and analyze epinephrine and norepinephrine in 900 maternal urine samples, col- lected at three points in pregnancy, as an objective measure of stress. Imaging will include structural MRI, diffu- sion tensor imaging (DTI), and resting state fMRI scans. We will generate measures of subcortical structure volumes, global and regional cortical thickness and surface area, white matter microstructure, and functional brain connectivity to address our aims. This multi-disciplinary proposal will have a positive impact because it will substantially advance our understanding of the biological mechanisms by which psychosocial stressors and environmental chemicals influence cognitive development and lay the groundwork for developing interventions to mitigate the impact of these exposures by targeting inflammatory pathways and/or the microbiome.