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Single-Nucleus Transcriptomics Reveals Prenatal and Postnatal Pb Exposure-Induced Cell-Specific Neurotoxicity and
Xuting Liu1,2, Chunfeng Huang1,2, Mingyue Wang1,2
1State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
Insights
Lead (Pb) exposure harms neurodevelopment in mice, altering immature neurons and disrupting brain cell communication. This study reveals Pb-induced neurotoxicity involves cellular differences and neurotransmitter pathway disruptions.
Area of Science:
- Neuroscience
- Environmental Health
- Toxicology
Background:
- Lead (Pb) is a pervasive environmental pollutant with known neurodevelopmental impacts.
- Children are particularly vulnerable to lead's adverse effects on the developing brain.
- The precise mechanisms of lead's regulatory effects across different developmental stages remain unclear.
Purpose of the Study:
- To investigate the cell-specific effects of prenatal and postnatal lead exposure on mouse brain development.
- To elucidate the molecular pathways and cellular changes induced by lead at different ages.
- To identify critical disruptions in neural communication caused by lead toxicity.
Main Methods:
- Single-nucleus RNA sequencing (snRNA-seq) was utilized to analyze cellular heterogeneity in mouse brains.
- Brains from mice exposed to lead during prenatal and postnatal periods were analyzed at 2 and 8 weeks of age.
- Blood lead levels in exposed mice were validated to be comparable to human exposure levels.
Main Results:
- Lead exposure increased the proportion of immature neurons in 2-week-old mice, affecting neurodevelopment and neural structure pathways.
- In 8-week-old mice, lead impacted synaptic transmission, signal transduction, and learning/memory pathways in neurons and glial cells.
- Disruptions in communication involving glutamate and GABA neurotransmitters and their receptors were observed between neurons and microglia.
Conclusions:
- Lead-induced neurotoxicity exhibits significant cellular heterogeneity.
- Disrupted neurotransmitter communication between microglia and neurons is a critical factor in lead's neurotoxic effects.
- snRNA-seq provides a powerful tool for understanding lead's complex impact on the developing brain.
Abstract:
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.
