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: 10688283
• 负责人: Rebecca Knickmeyer
• 金额: $ 65.84万
• 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/10688283
• 关键词: 4 year old; Activities of Daily Living; Address; Age; American; Ancillary Study; Archives; Area; Biological; Biological Markers; Blood; Brain; COVID-19 pandemic; Chemical Exposure; Child; Child Development; Child Health; Cognition; Cognitive; Communities; Conceptions; Development; Diffusion Magnetic Resonance Imaging; Distress; Emotional; Environmental Pollutants; Epidemiology; Epinephrine; Exposure to; Family; First Pregnancy Trimester; Health; Health Priorities; Heavy Metals; Hurricane; Ice; Image; Inflammation; Inflammatory; Intervention; Interview; Knowledge; Link; Magnetic Resonance Imaging; Measures; Mediating; Mediator; Methods; Michigan; Mothers; Natural Disasters; Natural experiment; Neurites; Newborn Infant; Norepinephrine; Nutritional; Outcome; Paper; Parents; 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; Serum; Shotguns; Spottings; Stress; Structure; Surface; System; Testing; Thick; Toxicant exposure; United States National Institutes of Health; Urban Community; Urine; Woman; cognitive development; cohort; critical period; environmental chemical; experimental study; 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; neural circuit; neurocognitive test; neurogenesis; neuroimaging; novel strategies; novel therapeutic intervention; offspring; postnatal; prenatal; prenatal exposure; prenatal stress; psychosocial; psychosocial stressors; recruit; 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.

项目概要 由于以下原因，贫困城市社区的儿童认知迟缓的风险极高 生物和心理社会暴露。制定策略来支持这些弱势群体的认知发展 有能力的社区是一项紧迫的卫生优先事项，但由于缺乏有关机制的知识而受到阻碍 这些流行病学模式负有责任。我们的项目将通过关注两种类型的前任来解决这一差距 姿势（社会心理压力和环境污染物）和 2 种潜在的机制途径（炎症- 和肠道微生物组），这些都是潜在可改变的。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、 和功能性大脑网络的组装）并充当心理社会压力/en-之间的重要调解者 环境污染物暴露和认知发展。我们将通过 3 个具体目标来检验这一假设： (1) 确定社会心理压力（包括来自 COVID-19 大流行的压力）是否会影响认知发展 通过改变炎症特征和肠道微生物组发育模式来进行调节。 (2) 判断是否 接触环境污染物（重金属和多氯联苯）会影响认知发展 通过改变炎症特征和微生物组来调节。 (3) 识别参与这些机械的神经回路 通过 4 岁儿童最先进的多模态神经影像学研究无性通路。拟议的研究将 利用现有的基于概率的全州妊娠队列，最终将包括 1,100 名女性 和他们的后代。产前母亲压力和化学暴露的测量将通过父母获得 学习。我们还可以获得母体血清和尿液、胎盘、新生儿血斑、对蛾子的采访 3、9 和 24 个月时的健康和发育情况以及 3 个月的粪便样本。我们将招募300名孩子 在这项辅助研究中，添加了纵向粪便采样和神经认知测试（差异能力量表- II) 和 4 岁时的神经影像学检查。招募重点关注城市和郊区贫困家庭 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 母体血清和新生儿血斑中的标记物，对大约进行鸟枪法宏基因组测序 研究人员对 1000 份粪便样本进行了分析，并分析了 900 份母体尿液样本中的肾上腺素和去甲肾上腺素， 在怀孕期间的三个时间点进行选择，作为压力的客观衡量标准。成像将包括结构 MRI、扩散 离子张量成像 (DTI) 和静息态功能磁共振成像 (fMRI) 扫描。我们将生成皮质下结构的测量值 体积、整体和区域皮质厚度和表面积、白质微观结构和功能 大脑连接来实现我们的目标。这项多学科提案将产生积极影响，因为它将 极大地增进了我们对心理社会压力源和社会心理压力源的生物机制的理解。 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/或微生物组来减轻这些暴露的影响。