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

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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.