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Background:

Exposure to ambient air pollution particulate matter (PM) is associated with increased risk of dementia and accelerated cognitive loss. Vascular contributions to cognitive impairment are well recognized. Chronic cerebral hypoperfusion (CCH) promotes neuroinflammation and blood–brain barrier weakening, which may augment neurotoxic effects of PM.

Objectives:

This study examined interactions of nanoscale particulate matter (nPM; fine particulate matter with aerodynamic diameter $\le 200\text{\hspace{0.17em}nm}$) and CCH secondary to bilateral carotid artery stenosis (BCAS) in a murine model to produce white matter injury. Based on other air pollution interactions, we predicted synergies of nPM with BCAS.

Methods:

nPM was collected using a particle sampler near a Los Angeles, California, freeway. Mice were exposed to 10 wk of reaerosolized nPM or filtered air (FA) for 150 h. CCH was induced by BCAS surgery. Mice (C57BL/6J males) were randomized to four exposure paradigms: a) FA, b) nPM, c) $\text{FA}\hspace{0.17em}+\hspace{0.17em}\text{BCAS}$, and d) $\text{nPM}\hspace{0.17em}+\hspace{0.17em}\text{BCAS}$. Behavioral outcomes, white matter injury, glial cell activation, inflammation, and oxidative stress were assessed.

Results:

The joint $\text{nPM}\hspace{0.17em}+\hspace{0.17em}\text{BCAS}$ group exhibited synergistic effects on white matter injury (2.3× the additive nPM and $\text{FA}\hspace{0.17em}+\hspace{0.17em}\text{BCAS}$ scores) with greater loss of corpus callosum volume on T2 magnetic resonance imaging (MRI) (30% smaller than FA group). Histochemical analyses suggested potential microglial-specific inflammatory responses with synergistic effects on corpus callosum C5 immunofluorescent density and whole brain nitrate concentrations (2.1× and 3.9× the additive nPM and $\text{FA}\hspace{0.17em}+\hspace{0.17em}\text{BCAS}$ effects, respectively) in the joint exposure group. Transcriptomic responses (RNA-Seq) showed greater impact of $\text{nPM}\hspace{0.17em}+\hspace{0.17em}\text{BCAS}$ than individual additive effects, consistent with changes in proinflammatory pathways. Although nPM exposure alone did not alter working memory, the $\text{nPM}\hspace{0.17em}+\hspace{0.17em}\text{BCAS}$ cohort demonstrated impaired working memory when compared to the $\text{FA}\hspace{0.17em}+\hspace{0.17em}\text{BCAS}$ group.

Discussion:

Our data suggest that nPM and CCH contribute to white matter injury in a synergistic manner in a mouse model. Adverse neurological effects may be aggravated in a susceptible population exposed to air pollution. https://doi.org/10.1289/EHP8792