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.