Prenatal exposure to particulate matter impairs offspring behavior via hippocampal NMDA receptor reduction: an in vivo and ex vivo study.

Accumulating epidemiological and experimental evidence implicates environmental particulate matter (PM) exposure as a risk factor for neurodevelopmental and neurodegenerative disorders. Because the developing brain is highly vulnerable to environmental toxicants, PM exposure during early pregnancy can exert disproportionate toxicity in offspring. However, systemic physiological effects of PM exposure can complicate the interpretation of neuron-specific susceptibility, and the susceptible brain cell types and molecular mechanisms underlying PM-induced neurotoxicity remain unclear. Here, we addressed this gap by investigating the neurotoxicity of PM exposure with a focus on specific brain cell populations. Prenatal intranasal administration of urban PM (200 and 400 μg/kg) induced abnormal offspring behaviors, including cognitive deficits, hyperactivity, and anxiety. Notably, exposure to 200 μg/kg PM elicited neurobehavioral abnormalities without affecting development or lung function. Transcriptomic analyses showed that PM altered hippocampal gene expression related to neuronal development and synaptic organization, potentially contributing to these behavioral deficits. Furthermore, PM reduced hippocampal expression of N-methyl-D-aspartate (NMDA) receptors, key glutamatergic receptors essential for neuronal development and function. Ex vivo hippocampal neuron cultures demonstrated that prenatal PM exposure (200 μg/kg) reduced NMDA receptor expression and disrupted spontaneous neuronal activity and synaptic networks, as revealed by imaging of pHluorin-tagged NMDA receptor subunits and electrophysiological recordings. By contrast, glial inflammatory responses remained unchanged. These adverse effects were recapitulated by prenatal exposure to benzo[a]pyrene (BaP), one of the most toxic polycyclic aromatic hydrocarbons in PM. Importantly, application of NMDA restored aberrant neuronal activity in PM- and BaP-exposed neurons. Our findings demonstrate the heightened vulnerability of the developing brain to PM exposure and underscore the need for effective strategies to mitigate PM-induced neurotoxicity.