Prenatal exposure to particulate matter impairs behavior in offspring by reduction of NMDA receptors in hippocampus: Evidence from in vivo and ex vivo studies

Accumulating evidences with epidemiological and experimental animal studies elicited concerns of environmental exposure to particulate matter (PM) as a risk of neurodevelopmental- and neurodegenerative disorders. Given that the susceptibility of developing brain to environmental pollutants and toxicants, exposure to PM during pregnancy cause more severe toxicity in the offspring. However, it is ambiguous whether the impairment in the brain is derived from direct or indirect effect from systemic toxicity. The deposition of PM and the subsequent activation of inflammatory responses and oxidative stress in various organs further complicate the identification of the specific toxic mechanisms of PM in the brain. This study aimed to uncover this uncertainty by investigating toxicity of PM exposure in the brain and other phenotypes. Prenatal exposure of PM (200 and 400 μg/kg) through intranasal respiration causes aberrant behaviors in offspring, including cognitive deficits, hyperactivity, and anxiety. However, exposure to 200 μg/kg of PM induces aberrant neurobehaviors, while lung functions remained unaffected. Transcriptomic analyses indicated PM dysregulate gene expression in the hippocampus related to neuronal activity and synaptic development, which may contribute to behavioral impairment in offspring. Additionally, we found that PM reduced the expression of N-methyl-D-aspartate (NMDA) receptors in the hippocampus, which are crucial glutamatergic receptors for neuronal development and activity. To further confirm the effect of PM on NMDA receptor expression, we examined the expression of NMDA receptor in ex vivo cultures of hippocampal neurons using pH-sensitive green fluorescence protein pHluorin fused to NMDA receptor subunit. Ex vivo cultures (200 μg/kg) showed that PM exposure decreased NMDA receptor expression and disrupted spontaneous neuronal activity and synaptic network, while inflammatory responses are unaffected in glial cells. Our results provide insights into the direct evidence by which vulnerability of developing brain to PM exposure and necessitate developing effective strategies for mitigating PM exposure.