The Neurological Impact of Ultrafine Particles in Air Pollution: A Comprehensive Exploration of Cellular and Molecular Mechanisms


Air pollution is a pervasive global health hazard, estimated to cause millions of deaths annually and diminish healthy life years (World Health Organization, 2021). The detrimental effects of air pollution on cardiovascular and respiratory systems are well-documented, primarily linked to exposure to particulate matter (PM) (Fuzzi et al., 2015).

However, an expanding body of evidence points to the neurological system’s vulnerability, particularly concerning smaller particle size fractions (Hahad et al., 2020). This article delves into the association between air pollution, cognitive decline, and other neurological effects, shedding light on the intricate interplay between ultrafine particles (UFPs) and the olfactory system.

Monitoring Air Quality:

Air quality assessment traditionally involves measuring various compounds and particles such as nitrogen oxides (NOx), sulfur dioxide (SO2), ozone (O3), and particulate matter with diameters smaller than 10 μm (PM10) and 2.5 μm (PM2.5) (Hahad et al., 2020; World Health Organization, 2021). While PM10 and PM2.5 have been extensively studied, ultrafine particles (UFPs), with a diameter of 0.1 μm or less, have received less attention (Cassee et al., 2019; Rönkkö and Timonen, 2019). The 2021 WHO Air Quality guideline report acknowledges UFPs but highlights the scarcity of epidemiological evidence, emphasizing the urgent need for more experimental and epidemiological studies on UFP exposure’s adverse effects.


ltrafine particles (UFPs) are tiny particles that are less than 0.1 micrometers in diameter. They are so small that they can easily be inhaled into the lungs and bloodstream. Studies have shown that exposure to UFPs can have a number of negative health effects, including:

  • Respiratory problems: UFPs can irritate the lungs and airways, and can cause inflammation and coughing. They can also trigger asthma attacks in people with asthma.
  • Cardiovascular problems: UFPs can damage the heart and blood vessels, and can increase the risk of heart disease and stroke.
  • Brain problems: UFPs can damage the brain and nervous system, and can increase the risk of dementia and Alzheimer’s disease.
  • Lifespan: Exposure to UFPs has been linked to a shorter lifespan.

The effects of UFPs on health can vary depending on a number of factors, including the concentration of UFPs in the air, the duration of exposure, and the individual’s age and health.

Here are some of the specific ways in which UFPs can harm the brain:

  • UFPs can cross the blood-brain barrier and enter the brain, where they can damage brain cells and disrupt brain function.
  • UFPs can trigger inflammation in the brain, which can lead to the death of brain cells.
  • UFPs can interfere with the production of important brain chemicals, such as dopamine and serotonin.
  • UFPs can damage the blood vessels in the brain, which can lead to strokes.

Exposure to UFPs is a major public health concern, especially in urban areas where air pollution levels are high. There are a number of things that can be done to reduce exposure to UFPs, including:

  • Reducing air pollution levels by reducing emissions from cars, trucks, and factories.
  • Using HEPA air filters in homes and offices.
  • Avoiding exposure to secondhand smoke.
  • Eating a healthy diet that is rich in antioxidants.

By taking steps to reduce exposure to UFPs, we can help to protect our health and the health of our loved ones.

Anthropogenic Sources of UFPs:

The major anthropogenic sources of UFPs in ambient air are combustion-based processes, utilizing fossil fuels and biofuels, including vehicle engine exhaust and biomass burning (Kwon et al., 2020; Rönkkö and Timonen, 2019; World Health Organization, 2021). While advances in exhaust aftertreatment technologies have mitigated solid particle emissions, gaseous compounds can still pass through filtration systems, potentially contributing to atmospheric UFP formation (Kwon et al., 2020).

Gateway to the Brain: Olfactory System:

Particles, including UFPs, can reach the brain either through the bloodstream or directly via the olfactory nerve, connected to the olfactory mucosa (OM) located at the nasal cavity’s rooftop (Costa et al., 2020; Jankowska-Kieltyka et al., 2021). The nasal cavity acts as an entrance hall, where inhaled air is processed and guided to the lungs for gas exchange (Freeman et al., 2021). The OM, consisting of epithelium, basement membrane, and lamina propria, specializes in odor perception, and increasing evidence suggests its involvement in neurodegenerative processes triggered by environmental exposures like air pollution (Kanninen et al., 2020).

Cellular and Molecular Mechanisms:

Despite the crucial role of the OM as a potential gateway for particles to the brain, detailed cellular and molecular mechanisms caused by UFPs remain largely unexplored. A primary human OM cell culture model has revealed mitochondrial dysfunction, inflammation, and apoptotic features upon exposure to PM from an urban environment in China (Chew et al., 2020). The heterogeneity of primary human OM cultures emphasizes the need for in-depth research into how environmental insults exploit this path to harm the brain (Lampinen et al., 2022).

Translational Research:

This article utilizes a highly translational primary cell model of the OM to investigate cellular and molecular mechanisms triggered by exposure to traffic-related UFPs (Lampinen et al., 2022). State-of-the-art methods for UFP characterization are combined with RNA-sequencing (RNA-Seq) to compare different aftertreatment systems and fuels on the transcriptomic level in OM cells. This groundbreaking approach aims to provide a comprehensive understanding of the intricate mechanisms underpinning the neurological impact of UFPs, offering valuable insights for future research and public health strategies.

Discussion: Unraveling the Impact of Exhaust Emissions on Human Olfactory Mucosa

The present study sought to deepen our understanding of the effects of exhaust emissions on the human olfactory mucosa, with a particular focus on the ultrafine particle (UFP) fraction. The investigation involved a comprehensive analysis of different fuels and engine technologies, shedding light on the intricate interplay between emissions and the cellular and molecular responses of the olfactory mucosa (OM).

Chemical Composition and Size Distribution of Emissions

An initial analysis of the emissions’ chemical composition and size distribution uncovered notable distinctions among the examined samples. The concentration of metals, particularly nickel, in A0 and A20 raised concerns given its potential link to olfactory impairment. The elevated levels of NOx, exceeding WHO guidelines, especially in A0 and A20, underscored the possible adverse health effects on OM cells.

Size distribution analyses revealed that UFPs constituted the majority of all samples, with A0 and A20 displaying higher concentrations of the smallest particles, emphasizing their potential harm to OM functions. Furthermore, the distinctive polycyclic aromatic hydrocarbon (PAH) profiles in A20 suggested differential toxicity compared to A0, reflecting the importance of fuel type in emission composition.

Cellular Responses and Viability

Exposure to A0 and A20 led to reduced metabolic activity in OM cells without significant cytotoxicity, with A20 exhibiting higher cytotoxicity potentially linked to increased phenanthrene levels. The clean Euro6 sample, equipped with selective catalytic reduction (SCR) technology, showcased lower NOx emissions and larger particle sizes, hinting at the efficacy of exhaust aftertreatment systems. The differential impact of fossil and renewable diesel on OM cells highlighted the importance of fuel composition in mitigating cellular disruption.

Transcriptomic Insights: Unraveling Cellular Mechanisms

Gene expression analysis revealed distinct trends in response to different samples. A20 induced the strongest transcriptional response, emphasizing its potential for cellular disruption. The acute response of A0, plateauing over time, suggested dynamic changes in chemical composition or cellular adaptation.

The identified differentially expressed genes (DEGs) implicated inflammatory responses, with CD7 upregulation associated with nasal mucosa inflammation. The role of PAHs, particularly in upregulating PPAR signaling, suggested intricate mechanisms governing inflammatory responses in OM cells.

Xenobiotic Metabolism and Impact on Olfactory Signaling

AHR-mediated upregulation of CYP enzymes, especially CYP1A1, highlighted the activation of xenobiotic metabolism pathways. Surprisingly, FMO1 and FMO2 downregulation contradicted expectations, hinting at suppressed N‑oxygenation pathways. The downregulation of odorant-metabolizing enzyme GSTA1 suggested impaired odor clearance and increased cellular stress.

Alterations in key genes associated with olfactory signaling, including KISS1 and LEP, raised concerns about potential disruptions in signaling from OM to the brain. The downregulation of LEP, known to inhibit neural activity in the olfactory bulb, hinted at possible impacts on odor discrimination.

Epithelial Barrier Integrity: A Multifaceted Challenge

Transcriptomic analyses unveiled UFP-induced compromises in olfactory epithelial barrier integrity. Downregulation of TJ-proteins (e.g., CLDN1, OCLN), genes related to epidermal barrier structure (FLG, keratins), and inhibited integrin signaling indicated multifaceted disruptions.

The inhibited pathways, including Actin Cytoskeleton Signaling and Signaling by Rho Family GTPases, suggested disturbances in ECM dynamics, actin cytoskeleton, and integrin-mediated adhesion. TEER measurements aligned with transcriptomic data, highlighting A20’s pronounced impact on epithelial integrity.

Limitations and Future Directions

While the study provides significant insights, certain limitations should be acknowledged. In vitro models may not fully replicate lifelong, low-level exposure scenarios. Multi-omics studies and further investigations into epigenetic and proteomic alterations are crucial for a comprehensive understanding of the identified DEGs and molecular mechanisms. Additionally, considering the heterogeneity of primary human cells, the observed variations may present challenges but also enhance the relevance of the findings.

Conclusion: A Holistic View of UFP Impact on Olfactory Mucosa

In conclusion, this study provides a holistic view of the impact of UFP emissions on the human olfactory mucosa. The intricate interplay between fuel composition, emission characteristics, and cellular responses underscores the complexity of air pollution effects on OM cells. The identified pathways and genes associated with inflammation, xenobiotic metabolism, olfactory signaling, and epithelial barrier integrity offer valuable insights for future research and potential interventions to mitigate the adverse health effects of air pollution on the olfactory system. As air quality continues to be a global concern, unraveling these mechanisms becomes paramount for safeguarding public health.

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