Risk of Alzheimer's Disease and Related Dementias from Perinatal Lead Exposure: Brain Region and Cell Type Effects

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PROJECT SUMMARY The lifetime risk and population burden of Alzheimer’s disease and related dementias is high. Many dementias have a poorly characterized risk contribution from environmental factors. In longitudinal epidemiology studies, lead (Pb) exposure is linked to cognitive decline and Alzheimer’s disease. Despite public health efforts, Pb exposure remains widespread worldwide, with substantial exposure disparities. Early life is a particularly vulnerable exposure period. Using an established mouse model of perinatal Pb exposure, data from our research team suggests effects of Pb exposure persist into adulthood through epigenetic mechanisms, though epigenetic effects within brain regions over time have not been mapped. Brain region-specific analyses of genome-wide measures across multiple levels of the epigenome by perinatal Pb are critically needed. In addition, using single cell RNA-sequencing, our preliminary data demonstrate brain cell types have variable susceptibility to perinatal Pb exposure, specifically glial cells. Cell type-specific analyses of Pb exposure across time and brain region will establish cells particularly vulnerable to Pb exposure. We also showed Pb gene targets in the mouse overlap with key human dementia pathways. Further translation of toxicology to epidemiology findings is essential to maximize the advantages of both study designs. Together, our preliminary data support brain region and cell type specific alterations in epigenetic reprogramming and gene expression as likely targets of Pb exposure in the brain, which act on human relevant pathways, and highlight our team’s productivity and expertise in this area. The long-term goal of our research is to understand the sex-specific impacts of perinatal Pb exposure on brain composition and human dementia development. In a longitudinal study of mice perinatally exposed to Pb or control diet, we will test for Pb brain differences at multiple time points up to 18-months. We will 1) test how the effects of perinatal Pb exposure persist into adulthood by assaying pathological changes, behavior, RNA expression, DNA methylation, DNA hydroxymethylation, and chromatin conformation across three brain regions at three time points. We will 2) determine cell types in the brain most susceptible to the effects of Pb, using pathology and state-of-the-art ultrahigh resolution single cell spatial transcriptomics. We will 3) relate the molecular effects in mice from perinatal Pb exposure to existing data on human neurodegenerative disorders. This will be the first brain cell type specific map across multiple levels of the epigenome in response to a toxicant exposure. Using Pb as a model toxicant to identify molecular effects of perinatal exposure on brain regions and brain cell types, we will discover mechanistic insights into how environmental exposures drive dementia incidence with important toxicology, developmental biology, and public health implications.