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 贫困城市社区的儿童由于两种原因， 生物学和心理社会学的暴露。制定战略，以支持认知发展，在这些vulner- 有能力的社区是一个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 造成了这些流行病模式。我们的项目将通过关注两种类型的前- 压力（心理社会压力和环境污染物）和2种潜在的机制途径（炎症- 信息和肠道微生物组），这是潜在的修改。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， 以及功能性大脑网络的组装），并在心理社会压力/en- 精神污染物暴露与认知发育。我们将通过三个具体目标来检验这一假设： (1)确定心理社会压力，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改善。(2)确定是否 暴露于环境污染物（重金属和多氯联苯）影响认知发育， 通过改变炎症特征和微生物组来进行调节。(3)找出这些机械的神经回路- 通过4岁儿童的最先进的多模态神经成像来观察anistic通路。拟定的研究将 利用现有的，基于概率的全州范围内的怀孕队列，最终将包括1,100名妇女 和他们的后代产前母亲压力和化学品接触的措施将通过父母提供 study.我们还能接触到母亲的血清和尿液，胎盘，新生儿的血斑，和飞蛾的谈话- 在3个月、9个月和24个月时对健康和发育进行评估，并采集3个月的粪便样本。我们将招募300名儿童 在这项辅助研究中，增加了纵向粪便取样和神经认知测试（能力差异量表- II）和4岁时的神经影像学检查。招募将集中在贫困的城市地区和郊区的家庭 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 标记在母体血清和新生儿血液斑点，进行鸟枪宏基因组测序的约， 收集1000份粪便样本，并分析900份孕妇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选择，作为压力的客观衡量标准。影像学检查将包括结构MRI、弥散- 锡永量成像（DTI）和静息状态fMRI扫描。我们将生成皮层下结构的测量结果 体积、整体和局部皮质厚度和表面积、白色物质显微结构和功能 大脑连接来实现我们的目标。这项多学科的建议将产生积极的影响，因为它将 大大推进我们对心理社会压力源和 环境化学物质影响认知发展，并为制定干预措施奠定基础 通过靶向炎症途径和/或微生物组来减轻这些暴露的影响。