Nanoparticulate matter exposure results in white matter damage and an inflammatory microglial response in an experimental murine model

Abstract

Exposure to ambient air pollution has been associated with white matter damage and neurocognitive decline. However, the mechanisms of this injury are not well understood and remain largely uncharacterized in experimental models. Prior studies have shown that exposure to particulate matter (PM), a sub-fraction of air pollution, results in neuroinflammation, specifically the upregulation of inflammatory microglia. This study examines white matter and axonal injury, and characterizes microglial reactivity in the corpus callosum of mice exposed to 10 weeks (150 hours) of PM. Nanoscale particulate matter (nPM, aerodynamic diameter ≤200 nm) consisting primarily of traffic-related emissions was collected from an urban area in Los Angeles. Male C57BL/6J mice were exposed to either re-aerosolized nPM or filtered air for 5 hours/day, 3 days/week, for 10 weeks (150 hours; n = 18/group). Microglia were characterized by immunohistochemical double staining of ionized calcium-binding protein-1 (Iba-1) with inducible nitric oxide synthase (iNOS) to identify pro-inflammatory cells, and Iba-1 with arginase-1 (Arg) to identify anti-inflammatory/ homeostatic cells. Myelin injury was assessed by degraded myelin basic protein (dMBP). Oligodendrocyte cell counts were evaluated by oligodendrocyte transcription factor 2 (Olig2). Axonal injury was assessed by axonal neurofilament marker SMI-312. iNOS-expressing microglia were significantly increased in the corpus callosum of mice exposed to nPM when compared to those exposed to filtered air (2.2 fold increase; p<0.05). This was accompanied by an increase in dMBP (1.4 fold increase; p<0.05) immunofluorescent density, a decrease in oligodendrocyte cell counts (1.16 fold decrease; p<0.05), and a decrease in neurofilament SMI-312 (1.13 fold decrease; p<0.05) immunofluorescent density. Exposure to nPM results in increased inflammatory microglia, white matter injury, and axonal degradation in the corpus callosum of adult male mice. iNOS-expressing microglia release cytokines and reactive oxygen/ nitrogen species which may further contribute to the white matter damage observed in this model.

Particulate matter exposure and chronic cerebral hypoperfusion promote oxidative stress and induce neuronal and oligodendrocyte apoptosis in male mice

“…However, the combined effect of nPM and BCAS induced a greater increase in oligodendrocyte apoptosis than neuronal apoptosis when compared to FA (700% vs. 200% increase). These data confirm and extend prior studies that demonstrated white matter damage secondary to nPM and increased effects of combined nPM + BCAS exposure on corpus callosum white matter injury (Connor et al, 2021; Liu et al, 2021).…”

“…Activated microglia upregulate iNOS and produce both NO and reactive oxygen species (ROS) (Kawabori & Yenari, 2015). Microglial activation has been previously demonstrated in the setting of nPM, BCAS, and joint nPM + BCAS exposures (Babadjouni et al, 2018; Connor et al, 2021; Liu et al, 2021). The current study demonstrates increased iNOS staining in the corpus callosum in each of these exposure groups (nPM, BCAS, and joint nPM + BCAS).…”

Cellular mechanisms of transcriptional regulation of human cell lines exposed to cadmium-based quantum dots

“…Here, the exposure to QDs is linked with an inflammatory response, as occurs following exposure to UFP. 49 For major details see S1.3 †…”

“…Looking at the analysis on mRNA and miRNA interactions, it could be hypothesized that the QDs, once inside THP-1 cells, determine the activation of the JAK/STAT and AKT signal cascades, resulting in the release of cytokines, including tumor necrosis factor α (TNFα), which is common to several inflammatory processes such as those consequent to exposure to environmental contaminants, 48 including nanoparticulates. 49 Indeed, since some of the physicochemical characteristics of nanomaterials and ultrafine particles (UFPs) can overlap, 50,51 such as size, exposure routes, and metal content, their toxicity mechanisms might also share common pathways and mechanisms. Here, the exposure to QDs is linked with an inflammatory response, as occurs following exposure to UFP.…”

“…Here, the exposure to QDs is linked with an inflammatory response, as occurs following exposure to UFP. 49 For major details see S1.3. † Most cytokines favor inflammation, while others are antiinflammatory.…”