Single-Nucleus Transcriptomics Reveals Prenatal and Postnatal Pb Exposure-Induced Cell-Specific Neurotoxicity and Dysregulated Microglia-Neuron Communication in Mice Brain

Lead (Pb) is an environmental pollutant that has lasting effects on neurodevelopment. Children exhibit heightened sensitivity to Pb exposure compared to adults, and prenatal Pb exposure can harm the developing fetal nervous system. However, the specific regulatory effects of Pb across various developmental stages are not well understood. This study employed single-nucleus RNA sequencing (snRNA-seq) to analyze mice brains at different ages (2 and 8 weeks) following prenatal and postnatal Pb exposure. Blood lead level in exposed mice is comparable to those detected in human samples, implying its environmental implication. A total of 43,303 brain cells were sequenced for cell-specific analysis. Pb exposure was found to elevate the proportion of immature neurons in the brains of 2 week-old mice and to perturb neurodevelopment- and neural structure-related pathways within neurons. In 8 week-old mice, Pb primarily influenced pathways implicated in synaptic transmission, signal transduction, and learning and memory in both neurons and glial cells. The communication involving neurotransmitters glutamate and γ-aminobutyric acid (GABA), along with their receptors, was disrupted between neuron and microglia. Through the application of snRNA-seq, this study has demonstrated that the Pb-induced neurotoxicity is characterized by cellular heterogeneity and the disruption of neurotransmitter-related communication between microglia and neurons could be a critical factor in Pb-induced neurotoxicity.