Recovery After Acute Diesel Exhaust Inhalation Demonstrates Persistent Neuroinflammation and Sex-based Differences in Resolution of Neurotoxicity
Alexandra N. Demetriou1, Selena Chen1, Kristina Shkirkova1, Hongqiao Zhang2, Krista Lamorie-Foote1, Isaiah Becerra1, Lifu Zhao1, Max A. Thorwald2, Jose A. Godoy-Lugo2, Wendy J. Mack3, Constantinos Sioutas4, Caleb E. Finch2, Christian Pike2, William J. Mack1
1Keck School of Medicine, Department of Neurosurgery, 2Leonard Davis School of Gerontology, 3Keck School of Medicine, Department of Population and Public Health Sciences, 4Viterbi School of Engineering, University of Southern California
Objective:
To characterize the molecular underpinnings of recovery following acute diesel exhaust particle (DEP) exposure.
Background:
Traffic-associated air pollution harms neurologic health and may exacerbate pathologies such as stroke and dementia. Epidemiologic studies demonstrate that reductions in pollution exposure may slow cognitive decline and decrease dementia risk. The underlying mechanisms of neurologic recovery after pollution exposure are not defined.
Design/Methods:
Eight-week male and female C57BL/6 mice were exposed to five hours of filtered air (FA) or aerosolized DEP. One cohort (n = 32) of FA and DEP mice were promptly sacrificed while the other cohort (n =32) recovered in home cages for two weeks prior to euthanasia. Immunofluorescence was performed on corpus callosum samples to evaluate the presence of markers of oxidative stress (4-HNE and 8-OHdG), complement activity (C5 and C5a), white matter damage (dMBP), and microglial activation (Iba-1).
Results:
Acute DEP exposure caused elevations in 4-HNE, 8-OHdG, C5a, and Iba-1 (p < 0.05), but not in dMBP or C5. Two-week recovery allowed 4-HNE and 8-OHdG elevations to decline to near-control levels, whereas elevations in C5a and Iba-1 persisted. When analyzed by sex, female mice, but not males, exhibited persistent (yet down-trending) elevations in 4-HNE after recovery (p < 0.001). Females also demonstrated persistent Iba-1 elevations post-DEP recovery (p < 0.05), whereas males exhibited nonsignificant elevations.
Conclusions:
Five-hour DEP exposure causes persistent neuroinflammation after two-week recovery, though acute rises in oxidative stress markers generally resolve within this timeframe. Females exhibit more persistent oxidative stress and microglial activation than males, suggesting that the rate of recovery following pollution reduction may differ by sex in humans. These findings present, to our knowledge, the first molecular characterization of neurologic recovery following short-term pollution inhalation. The persistence of neuroinflammation observed after a single DEP exposure raises important clinical considerations regarding patient exposures to pollutants during recovery from neurologic insults.