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

产前母亲压力、环境化学物质暴露和认知发展：炎症和肠道微生物群发育的潜在作用

• 批准号: 10536059
• 负责人: Rebecca Knickmeyer
• 金额: $ 70.69万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536059
• 关键词: 4 year old; Activities of Daily Living; Address; Age; American; Ancillary Study; Archives; Area; Biological; Blood; Brain; COVID-19 pandemic; Chemical Exposure; Child; Child Development; Child Health; Cognition; Cognitive; Communities; Conceptions; Development; Diffusion Magnetic Resonance Imaging; Distress; Emotional; Environmental Pollution; Epidemiology; Epinephrine; Exposure to; Family; First Pregnancy Trimester; Health; Health Priorities; Heavy Metals; Ice; Image; Inflammation; Inflammatory; Intervention; Interview; Knowledge; Link; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Methods; Michigan; Mothers; Natural Disasters; Natural experiment; Neurites; Newborn Infant; Norepinephrine; Nutritional; Outcome; Paper; Parents; Partner in relationship; Pathway interactions; Pattern; Phenotype; Placenta; Plasma; Polychlorinated Biphenyls; Prefrontal Cortex; Pregnancy; Probability; Process; Protocols documentation; Psychosocial Stress; Research; Rest; Risk Factors; Role; Sampling; Second Pregnancy Trimester; Shotguns; Spottings; Stress; Structure; Surface; System; Testing; Thick; Time; Toxicant exposure; United States National Institutes of Health; Urban Community; Urine; Woman; base; cognitive development; cohort; critical period; environmental chemical; fetal; functional MRI scan; gut microbiome; gut-brain axis; high risk; high risk infant; improved; improved outcome; indexing; inflammatory marker; maternal serum; maternal stress; metagenome; metagenomic sequencing; microbial; microbiome; microbiome research; migration; multidisciplinary; multimodal neuroimaging; myelination; neural circuit; neurocognitive test; neurogenesis; neuroimaging; novel strategies; novel therapeutic intervention; offspring; postnatal; prenatal; prenatal exposure; prenatal stress; psychosocial; psychosocial stressors; recruit; relating to nervous system; stressor; suburb; urban area; vulnerable community; white matter

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.

项目摘要 由于两者都 生物和社会心理暴露。制定策略以支持这些脆弱性认知发展 - 有能力的社区是紧急的健康优先事项，但由于缺乏有关机制的知识而受到阻碍 负责这些流行病学模式。我们的项目将通过重点关注两种类型的Ex- 姿势（社会心理应力和环境污染物）和2种潜在的机械途径（inseram- Mation和肠道微生物组），可能会改变。我们的中心假设是这些途径 改变神经发育过程（包括神经发生，神经迁移，神经突生长，髓鞘形成， 以及功能性脑网络的组装），并作为社会心理应力/启动之间的重要介体 环境污染物的暴露和认知发展。我们将通过3个特定目的检验这一假设： （1）确定社会心理压力（包括来自199大流行）的社会心理压力是否会影响认知能力 - 通过改变肠道微生物组发育的炎症特征和模式的选择。 （2）确定是否 暴露于环境污染物（重金属和多氯联苯）会影响认知发展 通过改变的炎症特征和微生物组进行操作。 （3）确定与这些机甲有关的神经回路 通过最新的4岁儿童的多模式神经影像学的态途径。拟议的研究将 利用现有的，基于概率的全州怀孕队列，最终将包括1,100名妇女 和他们的后代。父母将获得产前孕产妇应力和化学暴露的度量 学习。我们还可以使用孕产妇血清和尿液，胎盘，新生儿血斑，采访飞蛾 - 在3、9和24个月的健康与发展方面以及3个月的粪便样本。我们将招募300名儿童 进入这项辅助研究，添加纵向粪便采样和神经认知测试（差异能力尺度 - ii）和神经影像在4岁时。招聘将集中于苦恼的城市和郊区的家庭 与环境污染物暴露水平较低的区域进行比较。我们将分析炎症 孕产妇血清和新生儿血斑的标记，在大约 大约有1000个粪便样品，并分析900个母体尿液样品中的肾上腺素和去甲肾上腺素 在怀孕的三点中，作为应力的客观度量。成像将包括结构性MRI，分散 sion张量成像（DTI）和静止状态fMRI扫描。我们将生成皮层结构的度量 体积，全球和区域皮质厚度和表面积，白质微观结构以及功能 大脑连接以解决我们的目标。这个多学科的建议将产生积极的影响，因为它将 大大提高了我们对社会心理压力源和的生物学机制的理解 环境化学物质会影响认知发展并为制定干预措施奠定基础 通过靶向炎症途径和/或微生物组来减轻这些暴露的影响。