Particulate matter and ultrafine particles in urban air pollution and their effect on the nervous system

Abstract

According to the World Health Organization, both indoor and urban air pollution are responsible for the deaths of around 3.5 million people annually. During the last few decades, the interest in understanding the composition and health consequences of the complex mixture of polluted air has steadily increased. Today, after decades of detailed research, it is well-recognized that polluted air is a complex mixture containing not only gases (CO, NO_x, and SO₂) and volatile organic compounds but also suspended particles such as particulate matter (PM). PM comprises particles with sizes in the range of 30 to 2.5 μm (PM₃₀, PM₁₀, and PM_2.5) and ultrafine particles (UFPs) (less than 0.1 μm, including nanoparticles). All these constituents have different chemical compositions, origins and health consequences. It has been observed that the concentration of PM and UFPs is high in urban areas with moderate traffic and increases in heavy traffic areas. There is evidence that inhaling PM derived from fossil fuel combustion is associated with a wide variety of harmful effects on human health, which are not solely associated with the respiratory system. There is accumulating evidence that the brains of urban inhabitants contain high concentrations of nanoparticles derived from combustion and there is both epidemiological and experimental evidence that this is correlated with the appearance of neurodegenerative human diseases. Neurological disorders, such as Alzheimer's and Parkinson's disease, multiple sclerosis, and cerebrovascular accidents, are among the main debilitating disorders of our time and their epidemiology can be classified as a public health emergency. Therefore, it is crucial to understand the pathophysiology and molecular mechanisms related to PM exposure, specifically to UFPs, present as pollutants in air, as well as their correlation with the development of neurodegenerative diseases. Furthermore, PM can enhance the transmission of airborne diseases and trigger inflammatory and immune responses, increasing the risk of health complications and mortality. Therefore, understanding the different levels of this issue is important to create and promote preventive actions by both the government and civilians to construct a strategic plan to treat and cope with the current and future epidemic of these types of disorders on a global scale.

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Jessica Andrea Flood-Garibay

Jessica Flood studied her BSc in Chemistry at the University of the America's Puebla (UDLAP), and following this she studied the interaction of Ni and Zn with different proteins and enzymes pertinent to metal homeostasis in bacteria during her MSc in Chemistry with specialization in Biological Chemistry at the University of Toronto, Canada. After some time teaching at different academic levels, she worked on the synthesis, characterizations, and biological interactions of wrinkled mesoporous silica nanoparticles to be used as carriers of chemotherapy and possible theranostic applications during her doctoral studies in Molecular Biomedicine at UDLAP.

Aracely Angulo-Molina

Aracely Angulo-Molina is a Professor at the Department of Chemical and Biological Science/DIFUS of University of Sonora (Unison, Sonora, Mexico). She holds a Bachelor of Science Degree in Clinical Chemical Biology, Master's in Nutritional Biochemistry and PhD with a Major in Nanomedicine from the Center of Research in Food and Development (CIAD, Sonora, Mexico). Her research focuses on nanotechnology and medical biophysics applied to health, nutrition and cancer. Recently, she has been working on heath global problems and the effects of metal polluted urban dust. She is a Guest Professor at the University of Applied Sciences and Arts of Northwestern Switzerland (FHNW).

Miguel Ángel Méndez-Rojas

Miguel A. Méndez-Rojas, MRSC, is a Senior Professor of Chemistry and Nanotechnology at the Department of Chemical & Biological Sciences of Universidad de las Americas Puebla (UDLAP, Puebla, Mexico). He holds a Bachelor of Science Degree in Chemistry from UDLAP and a PhD in Chemistry from Texas Christian University (Forth Worth, Texas, USA). His research group is focused on the design, synthesis and characterization of nanomaterials for potential biomedical, environmental or energy storage applications, as well as the evaluation of their biological and toxicological impacts. He is also very interested in nanotechnology education from a chemical perspective and science outreach.

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Environmental significance

Air pollution kills around 3.5 million people per year. It is a complex mixture that includes gases such as NO₂ and O₃, together with particulate matter (PM), ultrafine particles (UFPs) and nanoparticles (NPs). There is evidence that inhaling PM is associated with harmful health effects. The brains of urban inhabitants contain high concentrations of NPs derived from pollution, and therefore it is crucial to understand the molecular mechanisms and pathophysiology related to exposure to PM in air and neurodegenerative diseases. PM may enhance the transmission of airborne diseases and trigger inflammatory and immune responses, increasing the risk of health complications and mortality. This understanding is important to promote preventive actions and design health policies to cope with the current and future potential environmental and health impacts.

Introduction

According to the World Health Organization (WHO), nearly 3.5 million people die annually from causes directly attributable to atmospheric pollutants; consequently, several efforts have been implemented to reduce air pollution on a global level.¹ More than 25% of premature deaths are linked to respiratory illnesses, such as chronic respiratory diseases and asthma, which are related to air pollution.² Among the more than 2800 different chemicals present in polluted air, nearly 189 of them have been identified as human carcinogens.^3,4 Polluted air is a complex mixture that varies in time and space, consisting of hundreds of compounds including include volatile organic compounds (VOCs), sulfur and nitrogen oxides, ozone (O₃) and particulate matter (PM) with diameters as large as 30 μm (PM₃₀) and as small as only a few nanometers (UFPs).^5,6 PM and UFPs are dispersed in air as a heterogeneous mixture of liquid droplets and particles, having multiple components (e.g., organics, acids, metals, and crystalline materials) and size fractions. The significant body of scientific knowledge developed for decades clearly demonstrates that both short- and long-term exposure to PM have significant effects on human health.^7,8 PM and UFPs are the main contributors to the global burden of disease due to their cardiovascular and respiratory effects, especially in developing countries, accounting for an estimated 4.5% of disability-adjusted life years.⁹ Recently, PM has also been designated as a human carcinogen and associated with the development of lung cancer.^10,11 In contrast, the understanding of the impact of ultrafine particles (UFPs) is insufficient. Among the different sources of pollution, traffic is one of the principal contributors to low the quality of breathable air in urban settlements worldwide. Car exhaust is one of the main contributors to smog in cities. In developing countries, where industry and power plants are often located within or very close to cities, this situation is aggravated. Black carbon (BC) is the most strongly light absorbing component of PM and UFPs, which is formed by the incomplete combustion of fossil fuels and is usually constituted by particles with sizes in the range of 2.5 to 0.1 μm.¹² There is abundant evidence regarding the adverse effects of chronic PM and UFP inhalation on the central nervous system (CNS). Emerging results from recent observational, clinical, epidemiological, and experimental studies imply that certain neurological diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), may be strongly associated with ambient air pollution. Recent studies have detected combustion-derived NPs (CDNP) in neurons, glia, the endothelium, the nasal and olfactory epithelium, and cerebrospinal fluid, and the presence of these particles has been related with accumulation and aggregation of unfolded proteins, mitochondrial dysfunction, and abnormal endosomal systems.¹³ Due to these findings, PM and UFPs in air pollution have been considered an important risk factor for neurodegenerative diseases such as Alzheimer's diseases (AD) and Parkinson's disease (PD), together with other types of neurodegenerative illness. It is important to consider that deaths from AD have increased by 89% since 2000 and the global burden of this type of dementia is estimated to be 1% ($605 billion) of the gross domestic product globally.¹⁴ The latter emphasizes the importance of understanding the impact of PM and UFPs in the etiology of these neurodegenerative diseases as well as the molecular mechanisms and neural circuitry that lead to the earliest cognitive and behavioral manifestations of AD and other dementias. In this review, we analyze our current knowledge on the impact of primary and anthropogenic PM and UFPs present in polluted air on the CNS, starting from how are they generated, followed by their most common entry routes in the body. Then, some of the most important effects of PM and UFPs on physiological and molecular processes related to the CNS will be discussed, together with some of the clinical and epidemiological evidence on neurodegeneration induced by particulate matter. Finally, as a perspective, some of the opportunities in this field will be highlighted, which will be helpful for a better understanding on the potential health risks associated with PM and UFP environmental exposition.

Air pollution and PM and UFPs

There has been growing interest in the study of the toxicology of PM and UFPs present in polluted air. These components may originate from natural processes and sources, as well as from anthropogenic-related activities. In toxicology, suspended particles are classified based on their size (Table 1). PM_30–10 is comprised of particles with a size in the range of 30 to 10 μm in diameter; PM_10–2.5 in the range of 10–2.5 μm (also called inhalable fraction); PM_2.5–0.1 is constituted of particles with a size of less than 2.5 μm but larger than 0.1 μm (or fine PM); and finally, PM_0.1 includes particles with a size of less than 0.1 μm in diameter (or ultrafine PM, UFPs) (Fig. 1). The definition of UFPs includes particles commonly described as NPs, which are particles dimensionally confined in the range of 1–100 nm (0.001 to 0.1 μm). Although both natural and anthropogenic sources of PM and UFPs are important, this work focuses on particles originating from primary (directly emitted) and anthropogenic sources. The primary sources of PM₁₀ are tire wear emissions, wind borne, road and agricultural dust, products of wood combustion, construction and demolition works, and mining operations. In the case of PM_2.5, it generally comes from power plants, oil refineries, tailpipe and brake emissions, metal processing facilities, residential fuel combustion, and wildfires.¹⁵ UFPs are mostly combustion-derived NPs, which can be produced by power plants, incinerators, internal combustion engines, and other sources of thermal degradation. However, biogenic secondary organic aerosols (SOA) are also a major component of fine particulate matter that has to be considered and atmospheric nucleation is also a major source of nanoparticles.^16,17 Nanotoxicology, an emerging branch of toxicology, is now starting to develop specific protocols and tools for the study of nanomaterials and their potential environmental and health hazards.^18,19 There is uncertainty on the environmental and health effects of UFPs or the correlation between their particle size and factors of penetration and transport, as well as that related to their increased surface area and reactivity. In this case, toxicity may not be present in large particulate matter, but it may occur at the nanoscale.

Table 1 PM and UFP size fractions

Designation	Fraction	Diameter (μm)	Primary sources	Constituents
				Major (>25%)^a	Minor (<25%)^a
a Parameters are general estimates determined by the University of Southern California for the city of Los Angeles; composition may vary considerably depending on location, atmospheric variables, and time.^20,21
PM10–2.5	Coarse PM	2.5–10	Tire wear emissions, road and agricultural dust, products of wood combustion, construction and demolition works, and mining operations	Inorganic ions & metals, organic matter	Black carbon, refractory elements
PM0.1–2.5	Fine PM	0.1–2.5	Wildfires, power plants, oil refineries, tailpipe and brake emissions, metal processing facilities, and residential fuel combustion	Inorganic ions	Organic matter & metals
PM0.1 (UFPs)	Ultrafine PM	≤0.1	Combustion-derived	Organic matter	Inorganic ions & metals

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Fig. 1 Relative scales, PM and UFP sources and range of their biodistribution into the body.

UFPs constitute the most abundant fraction (in number, not by mass) among particulate pollutants in urban/industrial areas, originating from several anthropogenic sources. Furthermore, the direct emissions of pollutant gases such as NO₂/NO_x, aromatic VOC and PAH are highly correlated with the direct emissions of UFPs. Thus, to differentiate the health impact of UFPs compared to other air pollution gases and their spatial distribution, new experimental approaches will be required to better understand the health impact of air pollution mixtures, instead of only focusing on single pollutant exposure.²² UFPs have been found to produce a critical deleterious effect in human health related to Alzheimer disease, cognitive impairment, and vascular dementia among other neurodegenerative diseases because they can enter the CNS via the olfactory epithelium, possessing higher toxic potential than larger PM.²³ However, UFPs are poorly studied in comparison to PM_2.5 and PM₁₀ particulates.²⁴ UFPs coming from urban air pollution (internal combustion engines, power plants, and incinerators), industrial manufacturing sites, and natural sources (volcanic eruptions, wildfires, soil erosion, etc.) are attracting research interest globally due to their notorious and evident impact on human health.^25–30 To determine their potential toxicological effects (genotoxicity and cytotoxicity), it is important to consider their characteristics such as shape, chemical composition, surface charge, surface functionalization, solubility, distribution of the particles in body fluids, internalization route, association with host carriers (example: red blood cells and plasma proteins), competition for receptors, tissue accumulation and clearance. A combination of these factors may influence the short and long-term effects in vital organs, including the brain.³¹

Although several nanomaterials have been explored for biomedical applications such as neuronal regeneration, CNS imaging and drug delivering systems, the UFPs found in the environment as pollutants may induce specific toxic effects of unknown consequences. Given that the olfactory bulb is exposed to direct interactions with many of the chemicals (molecular or PM) present in the environment through respiration, its role as part of the complex mechanism of the internalization of NPs in the brain, as an accessible entry door into the nervous system for several of these pollutants, needs to be clearly determined.³² Furthermore, the specific interactions that UFPs may have with the respiratory, gastrointestinal and cardiovascular systems are mostly unknown and have become a hot topic of biomedical research given that these interactions may trigger the development of several health issues.³³ It has been determined that UFPs can decrease cardiovascular function and induce respiratory malfunction due to oxidative stress and enhanced pro-inflammatory effects in airways. Several in vivo and in vitro studies have demonstrated that the toxicity of UFPs may be related to their ability to increase the concentration of intracellular reactive oxygen species (ROS), disrupting the homeostatic redox state and activating the transcription of pro-inflammatory genes such as TNFα (tumour necrosis factor α), interleukins (IL-1, IL-6, and IL-8), and NFκB (nuclear factor-κB).^34,35 The translocation of UFPs from the respiratory epithelium towards the circulatory system may induce toxicity in the vascular endothelium, changes in blood coagulation and alteration of cardiac frequency by triggering autonomic nervous system reflexes.²⁴ In a representative longitudinal survey performed in China, long-term cumulative and transitory exposure to pollutants in the air was associated with diminished cognitive performance in verbal and math tests at a national level.³⁶ The economical and health costs of air pollution, in particular for the elderly, are an important social issue, which will require the implementation of strict environmental laws to protect the general population. The effects of numerous nanomaterials currently used in several consumer products (such as carbon-based, iron, zinc, titanium oxides, silica NPs and asbestos) have been reviewed, given that the debate on their benefits versus their potential risks is still relevant.³⁷ However, the number and variety of studies that evaluate the environmental and health impact of nanomaterials (NMs) are still insufficient. Therefore, to understand and predict the potential effects of nanomaterials in the environment and in living organisms, the field of nanotoxicology will require an exponential increase in efforts.

PM and UFPs have also been correlated with negative outcomes on the reproductive system and offspring. Exposure to large concentrations of UFPs for prolonged periods has been linked to neurodevelopmental alterations in a mouse model for prenatal exposure to nanoparticulate matter.³⁸ Females are particularly vulnerable, influencing not only their reproductive capacity but also foetal development.³⁹ The translocation of NPs from the respiratory tract from maternal inhalation to the placenta and foetus may have effects in the offspring. Several specific brain responses such as alterations of neuronal glutamatergic functions, impaired differentiation of the cerebral cortex neurons and increased depression-like responses in adult males suggest that prenatal exposure to UFPs in urban air may alter neuronal differentiation in a gender-specific manner.⁴⁰

UFPs are more likely to be inhaled deeply into the lungs due to their size, affecting not only the respiratory tract but also increasing their chances to reach other organs by systemic translocation.⁴¹ However, once environmental UFPs access microcirculation, several biological barriers are still in place to avoid their dissemination through the body. For example, the endothelium helps to control the transfer of NPs between blood and the interstitial space, acting as a physiological barrier. The blood–brain barrier (BBB) plays a similar role, protecting the integrity of the central nervous system (CNS) by safeguarding the exchange between blood and the CNS. Nevertheless, the chemical modification of NPs may facilitate their crossing through the BBB.⁴² When thinking of the endothelium as a stage or combat area for the innate immune response, there are still several questions about the interactions of the endothelium and NPs that need to be studied to understand their potential toxic effects.⁴³ Although several factors may affect how metal NPs are distributed and assimilated in biological tissues (size, shape, and surface charge), there are several challenges that a nanomaterial must overcome to be able to translocate through the BBB and induce toxicity in the CNS.⁴⁴

It has been observed in animal models that after UFPs reach the brain, exposure to these particles lead to neurotoxicity; however, it is important to determine if there is a correlation. A series of major epidemiological and observational studies associated air pollution with diseases affecting the CNS such as stroke, Parkinson's and Alzheimer's diseases and different neurodevelopmental disorders.^45,46 It has been suggested that oxidative stress, cerebrovascular dysfunction, microglial activation, and neuroinflammation can be caused by pollutant NPs that translocate into the CNS, even impacting the BBB.^45,47 Borisova and co-workers (2018) reported that micro- and nano-sized particles reached the CNS after inhalation, avoiding the BBB, and then affecting synaptic neurotransmission among neurons.⁴⁸ If UFPs enter the organism through a different route, for example ingestion or dermal absorption, they can “grow” a corona when interacting with biomolecules (lipids, proteins) present in biological fluids, which act as surfactants. This type of surface modification facilitates their systemic mobility in the organism, avoiding clearance by the reticuloendothelial system (RES), and eventually enabling them able to reach the brain. Furthermore, the potential neurotoxicity of NPs depends on several factors (size, composition, stability, surface properties, shape, etc.), and thus to precisely evaluate their potential toxic effects on the brain, such as neuroinflammation, oxidative stress and gene expression, and prevent neurobehavioral disorders, the different types of NPs will require an extensive and complete physical characterization.⁴⁹ For example, recently, the neurotoxicity in mice with different age ranges exposed to ZnO NPs was evaluated.⁵⁰ Inflammatory responses induced by exposure to ZnO NPs increased oxidative stress, hippocampal pathological changes and impaired learning and memory skills dependent on aging. In a different study, the ability of another widely used nanostructured photoactive material, TiO₂, which can easily enter the body through inhalation, cross the BBB and accumulate in the brain (in particular in the cortex and hippocampus), was reviewed. The toxicity of nanostructured TiO₂ has been extensively studied, where it has been reported that nano-TiO₂ induces microglia activation, production of ROS, spatial recognition memory, locomotor activity impairment, neuroinflammatory processes and cell death, both in vivo and in vitro.⁵¹ In the case of silica (SiO₂) NPs administered into an animal model through intranasal instillation, an internalization process in the brain was reported, with the NPs accumulating into the striatum. The SiO₂ NPs induced oxidative damage and an increased inflammatory response, as well as depletion of dopamine in the striatum, showing a negative impact on dopaminergic neurons and a potential risk for triggering neurodegenerative diseases.⁵²

There is abundant evidence that inhaling PM derived from fossil fuel combustion is linked with a wide variety of harmful health effects not associated exclusively with respiratory diseases. Recently, Corona-Vázquez and co-workers reported that long-term exposure to air pollution in Mexico City was correlated with neurodegenerative diseases in the population, in particular multiple sclerosis.⁵³ Previous research has shown the presence of ash, soot, and solid particles of 10 nm or less in primary vehicle emissions, with variations depending on the characteristics of the fuel and lubricants, vehicle technology and driving conditions. The particles emitted from diesel engines (diesel exhaust particles or DEPs) are in the range of 20–130 nm, which were responsible for the emission of nearly 70% to 90% of the urban aerial UFPs, while that released from petroleum-based engines was in the range of 20–60 nm, generating less than 30% of UFPs. Recently, the presence of aerosol particles emitted by the exhaust of vehicles, with diameters between 1.3 and 3.0 nm, which are small enough to translocate to different organs easily after inhalation, was experimentally confirmed. DEPs have been studied as surrogate models of air pollution to demonstrate their association with increased mortality by cardiovascular and respiratory diseases.⁵⁴ Another important factor to consider is the interface between the pavement and the tires of trucks and automobiles. It has been reported that this interaction releases particles with diameters between 15 and 50 nm into the surrounding air.⁵⁵ Consequently, it has been found that urban areas of moderate traffic present large concentrations of UFPs, although they are several times higher in areas of heavy traffic such as tunnels and highways; in particular, it was observed that larger amounts of UFPs are produced by heavy duty vehicles than low duty vehicles.⁵⁶ Car exhaust increases the concentration of UFPs in urban areas by several orders of magnitude, while particulate matter only increases by 25–30% compared to clean controls.^5,57 UFP emissions, as well as excessive levels of NO₂/NO_x from road vehicles, are a dominant component of pollution at busy roadsides.^22,58

Recently, it has been found that DEPs and other UFPs present in diesel exhaust, such as metallic NPs, can translocate into the brain, causing neurodegenerative disorders such as AD, PD, and stroke.⁵⁹ These UFPs increase the oxidative stress and inflammatory events in the CNS and brain tissues, where they accumulate, activating the resident innate immune response, and therefore the pro-inflammatory factors that generate neurological conditions.⁶⁰ The neuroinflammatory response produced by low UFP exposure, using 20 nm NPs generated by combustion and collected from a diesel engine, was tested using a microglial in vitro biological sensor model. The results showed that the NPs promoted an inflammatory response, production of ROS and reduced in vitro neuronal survival rate.⁶¹ It has also been reported that when NPs reach the brain, they can become a potential reservoir of neurotoxic substances, which may be slowly released to their surroundings.⁶²

In recent years, studies have indicated that PM can be an important risk factor in different neurological diseases such as depression, dementia, and schizophrenia, besides PD and AD.^13,63,64 A neurodevelopmental disorder that is strongly correlated with exposure to PMs according to epidemiological studies is attention deficit and hyperactive disorder (ADHD), which affects between 5% to 10% of children worldwide, and its diagnosis has increased rapidly since the 1980s in industrialized countries, reporting that 65% of affected children continue to manifest symptoms as adults.⁶⁴ Additional effects of NPs present in polluted air are related with the hypothalamus, which plays an important role in the regulation of expenditure of energy through physical activity, exercise and food intake; there are reports about the effect of PM derived from the combustion of fossil fuels in hypothalamic cell death. It has been suggested that this chronic exposure can also affect the energy balance and influence obesity and metabolic syndrome. Similarly, hypothalamic dysfunction has also been reported in early onset AD and PD.⁶¹

Different types of nanomaterials (metallic NPs, quantum dots, and carbon nanotubes) have been studied in different animal models to determine their translocation and biodistribution after administration across different biological entries (skin, blood, and respiratory pathways). It was found that a very small fraction of nanomaterials can reach the blood, and from there different organs, including the CNS. Although there is evidence of the translocation of NPs into the brain, the present knowledge is insufficient to understand or predict their potential toxic effects.⁶⁵ In addition to these primary particles, several chemical species are also released in gaseous form due to the high working temperatures of the vehicle exhaust. These gases condense or even form nucleated particles immediately after they are released into the environment, which constitute what is termed as secondary particles.^6,66 Miller et al. followed the translocation of gold NPs in mice exposed to acute inhalation and found NPs in blood and urine samples after 24 h of exposure, which were still present even after 3 months.⁶⁷ The NPs accumulated preferentially in inflammation-rich vascular lesions, suggesting a link between cardiovascular disease and environmental exposition to NPs. However, the precise impact of UFP pollution on the CNS has been scarcely studied and it is a topic of particular importance for public health.³² It has been demonstrated in an anatomical model of the human nasal cavity that after nasal breathing, inhaled UFPs can be deposited in the olfactory epithelium, in a proportion that is dependent on their size. Subsequently, small NPs (1–7 nm) deposited in the olfactory bulb may migrate into the brain, participating in neurotoxic effects.⁶⁸ A study confirmed the importance of the nasal route for the entry of air pollutants into the CNS, where a decreasing gradient of deposition and accompanying tissue damage from the nose to the brain in the canine nervous system was reported.⁶⁹

In the last five years, it has been shown that the brains of urban dwellers contain high concentrations of NPs.^13,70 A study carried out in 2016 identified different types of metal oxide NPs, mainly magnetite (Fe²⁺/Fe³⁺ oxide mixture) using several histopathological and analytical techniques, finding that brain tissue samples from Manchester residents older than 65 years old contained high concentrations of magnetite NPs, especially samples from people with moderate and severe AD. Equivalent and greater concentrations of magnetite were found in young adults under 40 years living in Mexico City. Considering than less than 5% of AD cases are inherited, the rest of the cases could be related to nongenetic causes, such as environmental factors, which seem to play a major role in the beginning and development of the disease.⁷¹ High concentrations of UFPs are worrisome in terms of the CNS, given that they can easily cross biological barriers, including the vascular endothelium, epithelium, BBB, blood-cerebrospinal fluid barrier (BCFSB), olfactory barrier, and gastrointestinal barrier. Fig. 2 shows a schematic representation of the pathway that PM found in polluted air may follow, and the different entry points that may influence their translocation and the generation of diverse physiopathological effects.

Fig. 2 Schematic representation of PM and UFP entry doors and their physiological effects.

In the context of the COVID-19 pandemic, health complications related to urban pollution are a current concern that needs to be considered seriously to diminish potential complications and determine appropriate public health policies. Some of the more commonly reported symptoms include anosmia and ageusia, which are smell and taste sense disorders, in addition to intense headache. These conditions can be exacerbated by air pollution. There are several reports that recognize airborne transmission as an important route for the spread of airborne diseases.^70,72–74 Aerosols, which are small PM in the sub-micrometric range, may serve as nanocarriers, and depending on their composition, structure, shape, and size, they may stabilize microdroplets containing viable viral particles or bacteria long enough to facilitate their ability to move long distances and infect a host.⁷⁵ Several factors can affect the viability of airborne microorganisms such as temperature, humidity, radiation, and ventilation.⁷⁴ There is clear evidence between the presence of pollutants in the air and adverse effects in the respiratory system associated with human respiratory viruses.⁷⁶ Pollutants induce endothelial dysfunction, increasing the risk of infection, in addition to several of the health effects associated with exposure to PM previously stated, such as ROS generation, exacerbated inflammatory and immunological response. These processes are recognized as typical biological responses to viral disease. Considering all these effects in context of the present COVID-19 pandemic, it is straightforward to consider that patient prognosis can become much worse in areas with historical air pollution problems. In fact, long-term exposure to PM₁₀ and PM_2.5 in separate studies from Italy, China and the USA found a positive significant correlation between higher mortality due to COVID-19 and poor air quality.^77–79 Similarly, it has been reported that PM in alveolar cells produces high levels of pro-inflammatory IL6, which is the cytokine responsible for the inflammatory storm that occurs in serious COVID-19 cases.⁸⁰ Alternatively, it has been reported that exposure to PM_2.5 in a mouse model significantly increased the expression of ACE2 (angiotensin-converting enzyme 2) in lung tissue.⁸¹ Given that this is the receptor used by SARS-CoV-2 to enter human cells, it has been hypothesized that long-term exposure to PM in air pollution can increase the chances of COVID-19 infection.⁸² This suggests that some airborne infections may be more complicated to manage and may even become deadly for people living in highly polluted urban locations in contrast to those living in regions with better air quality.

Entry routes of UFPs and PM into the CNS

The main entry routes of UFPs and PM in the body are inhalation and ingestion. Intact skin is considered an efficient barrier, given that the mechanisms for nanoparticle diffusion are slow and complex.⁸³ The human gastrointestinal tract has approximately 200 m² of surface area, which represents a mucosal layer from which displacement to and through by UFPs can occur through different mechanisms.⁸⁴ Several inhaled particles can move through the trachea after which they can be swallowed, later interacting with the gastric and intestinal mucosa as well as with the microbiota of the digestive system. The target of the toxic effects of these particles is the intercellular junctions and the villi of enterocytes.⁸⁵ It has been observed that NPs with diameters smaller than 100 nm suffer endocytosis in epithelial cells of the stomach. In the intestine, they can cross the epithelium via transcytosis by uptake of M cells and through facilitated diffusion. Similarly, NPs can cross the intestinal villi through openings formed in their apical zone due to a process of dysfunction, which alters the epithelium morphology induced precisely by the same UFPs. There is an important relationship between the size of particles and their absorption by epithelial cells in the intestine, where 100 nm NPs are accumulated in the intestinal cells and their excretion is very low, while 50 nm NPs cross the apical side and are excreted towards the basolateral side where they can cross the plasma membrane. Finally, 15 nm NPs are absorbed by the intestinal epithelium and can rapidly spread to other epithelial cells. It has been determined that the junctions between cells can undergo an alteration that promotes the passage of NPs into the bloodstream, from where they can reach other organs, including the brain.^86,87 Similarly, it has been reported that the passage of NPs to the nervous system can also occur by direct distribution from the stomach and intestines directly to the vagus nerve,⁸⁵ which is part of the parasympathetic innervation through preganglionic motoneurons, providing vagal innervation that originates in the dorsal motor nucleus.⁸⁴ A schematic representation summarizing the different routes of exposure to NPs for humans, and their eventual mobility and translocation to different target organs is presented in Fig. 3.

Fig. 3 Most common access routes of PMs and UFPs into the human body.

In the respiratory system, the upper respiratory tract includes the nasal cavity, where the olfactory system originates with specialized olfactory neurons that are located inside the olfactory epithelium coating part of the nasal cavity.⁸⁴ The projections of the olfactory neurons form the olfactory nerve (cranial nerve I). The olfactory nerve roots are located anterior to the cerebral artery and superior to the origin of the optic nerve. The olfactory nerve finally ends in the olfactory bulb, after the nerve tracts pass through the skull. UFPs can enter the respiratory system through the pulmonary capillaries attached to the walls of the alveoli (systemic way) or through the nasal cavity (olfactory neurological pathway, olfactory epithelial pathway or trigeminal pathway). The largest inhaled particles from their deposition site in the respiratory tract are eliminated by phagocytosis of the macrophages in the alveoli and transported across the naso–oro-pharynx, and then through swallowing, until they reach the gastrointestinal tract. UFPs may have similar clearance, or they can relocate in the lymph or blood, encountering peripheral vegetative nerve fibres, and finally reaching the brain. Alternatively, bio-kinetic studies show that inhaled NPs can be transferred through the olfactory neurons from the nose to the CNS. There may be two absorption routes for NPs in the nasal cavity. Firstly, they can cross the respiratory epithelium, reaching the underlying blood vessels, or alternatively, the olfactory epithelium can absorb the NPs, and they can be transported along the olfactory bulb (approximately 11% of NPs deposited in the olfactory mucosa) and reach the brain. It is believed that the nasal olfactory pathway is key as a gateway entry because through it, inhaled NPs can reach the nerves of the trigeminal, brainstem and hippocampus.⁸⁸ Based on their size, the probability that NPs reach the alveoli is maximum at approximately 20 nm, while the probabilities of their deposition in the alveoli for smaller and larger NPs are reduced according to the classical model of the International Commission for Radiological Protection (ICRP). The olfactory nerve provides a route (nose to brain) for the transport of xenobiotics, including particles, to the CNS, which circumvents the protective BBB. It has been reported that some particles and antigens cross the synapses in the olfactory pathway and continue through secondary and tertiary neurons to reach distal sites within the brain.⁸⁹

From the alveoli, it is possible for NPs to enter the bloodstream from the lungs, and even travel to other organs.⁹⁰ Commonly, larger particles with a diameter in the range of 5–30 μm remain in the nasopharyngeal area, whereas smaller particles, with a size in the range of 1–5 μm, tend to be deposited in the tracheobronchial level. UFPs and PM (0.1–1 μm) can reach the alveolar region and suffer translocation to other interstitial sites. When this occurs in the deepest region of the respiratory system, by either Brownian diffusion or gravitational sedimentation, the burden on the lungs will be the harshest. From here, displacement to blood capillaries is easily achieved by PM with a diameter smaller than 0.5 μm,⁸⁶ which can facilitate the movement of these particles to other organs and the CNS.

The mechanisms of the cellular uptake of UFPs and PM has been explored extensively in recent years; however, little is known about their excretion from cells. After contact with biological fluids, the surfaces of NPs are coated by several biomolecules, including opsonizing proteins, forming the protein corona. Therefore, the cell interacts directly with the protein corona adsorbed on the surface of NPs instead of interacting with the actual surface of the particles. In general, foreign material (e.g., UFPs) use several well-recognized internalization mechanisms to reach the intercellular compartment, such as clathrin, caveolin, CDC42, RhoA, ARF6 and flotillin-mediated endocytosis. In early endosomes, part of the endocytosed materials is directed to the Golgi apparatus or can be recycled to the plasma membrane. The other materials remaining in early endosomes can move slowly along the microtubules, firstly to the cell interior, and then fuse with the late endosomes followed by the lysosomes. Alternatively, some of the endocytosed particles can escape from the vesicular systems to the cytosol. Additionally, some of the lysosomes may undergo exocytosis and discharge their undigested content after fusion with the plasma membrane. The composition of the protein corona can undergo significant changes in both the lysosome and Golgi apparatus. Therefore, after exocytosis, NPs may have the ability to cross critical barriers, such as the BBB barrier. Specific receptors in different cell types can recognize specific plasma proteins in the protein corona. After the absorption of NP and exocytosis, a different protein corona can result in recognition by other cell receptors. Different cell types can respond in a variety of ways to the same NPs with the same protein corona because at cellular level there are numerous detoxification strategies, that is, cells with different origin can respond to the same NPs in a plethora of ways. Therefore, the mechanisms of uptake and defence induced by NPs can be considerably different depending on the type of cell.⁹¹ It is important to mention that apart from the fact that endocytosis and exocytosis may be crucial for the transport of NPs in physiological fluids such as plasma and their distribution to other organs, recently extracellular vesicles (EV) including exosomes have emerged as a new form of cell communication. Previous studies have shown that exosomes of glial cells and neurons represent a new type of intercellular communication, which together with the secretion of soluble molecules used during the interaction and direct communication from cell to cell, play an important role in physiology and diseases of the CNS.⁹² The above-mentioned routes can be a key mechanism for the direct neurotoxicity of UFPs.

PM and UFPs in the CNS

The brain is normally protected against environmental factors, such as PM and hydrophilic or large molecules, by the BBB. However, as mentioned above, it has been reported that UFPs can encroach on the BBB and directly enter the CNS. Tight and adherent junctions join the capillary endothelial cells that form the BBB, which govern the exchange of compounds and bestow low paracellular permeability to the BBB.⁶⁰ The neurovascular unit (NVU) is comprised of neurons, myocytes, vascular cells (endothelium, pericytes and vascular smooth muscle cells (VSMC)), glial cells (astrocytes, microglia and oligodendroglia) and extracellular matrix components. In the NVU, the endothelial cells form a specialized membrane around the blood vessels. This membrane, underlying the BBB, limits the entry of plasma components, leukocytes, and red blood cells (RBCs) into the brain.⁹³ Only small lipophilic molecules, such as oxygen (O₂) and carbon dioxide (CO₂), diffuse freely through it, although other gases such as NO₂/NO_x, VOCs, O₃ and SO₂ can also reach the brain via diffusion through the lung epithelial and vascular endothelial layers, and neuronal olfactory nerve and disruption of the BBB by inducing oxidative stress and the expression of pro-inflammatory molecules.⁹⁴ These cells in the brain express transporter proteins to facilitate the transport of nutrients by their concentration gradients. The major pathways of vascular dysfunction that are related to neurodegenerative diseases include degradation of the BBB, hypoperfusion–hypoxia, and in more advanced cases, endothelial metabolic dysfunction. The interruption of tight and adherent junctions, increase in transcytosis of fluids at large volume scales and/or enzymatic degradation of the capillaries in the basement membrane leads to damage and physical breakdown of the BBB. It has been reported that the presence of NPs leads to the subexpression of proteins required in the tight junctions of endothelial cells in the BBB.^93,95 For example, the levels of many narrow-binding proteins, their adapter molecules and adherent binding proteins decrease in AD, dementia, and multiple sclerosis. This can be explained by the fact that the activity of the matrix metalloproteinase (MMP) associated with the vasculature increases in different neurodegenerative diseases and after an ischemic CNS injury, where tight junction proteins and extracellular proteins of the basement membrane are substrates for these enzymes. Similarly, some studies suggested that endogenous adsorbed or covalently linked proteins (such as transferrin and apolipoprotein E) or peptides (such as RVG2920 or Angiopeps21) on the surface of NPs can mediate uptake into the BBB. Some NPs, surface modified with polysaccharides, have demonstrated ability to cross a BBB model, which suggests that under certain conditions of in vivo surface chemical modification, NPs can cross the BBB.⁹⁶ It has been observed that most NPs do not pass the BBB even 48 h after exposure, but they do end up in intracellular organelles, especially in lysosomes. It is important to note that NPs can easily cross the BBB due to local imperfections in the barrier and that accumulation in the BBB itself can be considered a significant contributor that facilitates entry into the CNS.⁹³

Several potential mechanisms that may facilitate the crossing of NPs through the BBB have been proposed. They include passive processes such as the paracellular pathway, where the UFPs may cross the endothelial junctions, or transcellular diffusion where they pass through the cell membrane by slow diffusion, concentrating in different organelles, and finally moving to the other side. Active processes where the UFPs are internalized through the generation of exosomes and their eventual transport into the cell and release at the other side of the BBB or similar processes mediated by membrane receptors complete the potential particle crossing mechanisms (Fig. 4).

Fig. 4 Schematic representation of the different pathways followed by PM and UFPs to cross endothelial cells in the BBB.

UFPs that cross the BBB will immediately find astrocytes, where this cell type is the most abundant in the brain. These cells almost completely cover the capillaries of the brain with their endings in the form of feet. These cells play an essential role in the integrity of the BBB.⁹⁷ In addition, astrocytes have contact with neurons and other types of brain cells. Their strategic location in the brain allows the controlled transport of nutrients from the blood to the brain parenchyma and controlled elimination of brain waste products. Astrocytes have important functions in the detoxification of ROS and xenobiotics, as well as in the metabolism and homeostasis of iron and other metals in the brain. Because of this, they are key agents in the protection of other cells in the brain against metal toxicity. It has been reported that the exposure of cultured astrocytes to iron oxide NPs does not decrease cell viability but affects cell adhesion, where in the real brain microenvironment, this can disrupt their communication and behaviour, allowing the interaction of NPs with other cells of the brain. Likewise, it has been reported that astrocytes can accumulate NPs.⁹⁸ Astroglial activation occurs in response to CNS lesions caused by toxic materials. Reactive astrocytes show a broad and graduated spectrum of reactivity and are heterogeneous in morphological characteristics, gene expression and function. Glial fibrillary acidic protein (GFAP) has long been considered a standard marker of reactive astrocytes.⁹⁹ It has been reported that individuals that have been chronically exposed to high levels of air pollution over-express GFAP and present high levels of ROS in their brain tissue.^60,100 Similarly, it was recently reported that maternal exposure to NPs carries a potentially greater risk of age-related neurodegenerative diseases in the product due to the long-term activation of astrocytes, which results in an abnormal increase in astrocytes, homeostasis disruption in different metabolic processes and synapse upregulation due to NP neurotoxicity (Fig. 5).¹⁰⁰

Fig. 5 Potential biological pathways for nervous system effects following long-term PM exposure.

The resident innate immune cells of the brain, i.e., microglia, regulate synaptic communication and are the sentinels that inspect the environment of the CNS. They comprise approximately 12% of the cells in the brain. In addition to pre- and post-synaptic neurons, these cells actively contribute to neuronal excitability, neurotransmission, and various forms of synaptic plasticity. In the mature brain, microglia usually exist in a state of rest, which is recognized by their branched morphology. Once they are active, they undergo a dramatic transformation towards an amoeboid morphology and present a variety of surface molecules, such as molecules of the major histocompatibility complex (MHC), CD14 and chemokine receptors, among others. Activated microglia participate in the regulation of brain development through the programmed elimination of neuronal cells, as well as improving neuronal survival through the release of anti-inflammatory and trophic factors. In the adult brain, microglia are involved in the specific migration of stem cells to inflamed areas, which stimulate repair and may even be involved in neurogenesis. However, in adverse circumstances, microglia become over-activated and can induce strong neurotoxic effects due to the excess production of a wide variety of cytokines, including cytotoxic factors and TNFα. Microglial over-activation not only initiates additional neuronal losses, but can also amplify and promote neuronal damage, indicating that microglia, when affected by NPs can be crucial for the etiology and chronic nature of neurodegenerative diseases.¹⁰¹

It is believed that neuropathology and CNS disease occur when the pro-inflammatory response of the microglia is deregulated and exacerbated, which is related to microglial activation. Microglia have long been implicated in the neuronal damage that occurs in many diseases and conditions of the CNS, including AD, PD and autism, which supports the idea of a common neuroinflammatory mechanism.¹⁰² Microglia play a crucial role in the progression of AD disease because they are activated and recruited by the amyloid-β protein (Aβ). Once microglia are activated, their numbers increase in the sites of aggregated Aβ and they penetrate neuritic plaques, releasing neurotoxic factors such as NO (nitric oxide), TNFα and superoxide.¹⁰¹ AD is accompanied with severe neuronal cell death in the hippocampus (involved in memory formation, emotions and learning)-associated cortical areas, amygdala (a relay centre for visual inputs integrated with emotional experiences) and basal nucleus of Meynert (known as the nucleus basalis). It has been shown that apolipoprotein E (ApoE) is deeply involved in the pathogenesis of AD, which supports the transport of lipids and the repair of lesions in the brain and is an important carrier of cholesterol. ApoE has polymorphic alleles, and those carrying the e4 allele display a higher risk of severe AD compared to those carrying the most common e3 allele.¹⁰³ Conversely, α-synuclein, a component of Lewy bodies, which are typically found in PD, can damage dopaminergic neurons. PD is produced by neuronal degeneration, which results in a dopaminergic alteration in the striatum (crucial for the execution of movements and postural functions). Neuromelanin is an endogenous compound in the brain that forms protein aggregates, which accumulate during the beginning of PD, which are linked to the neurodegeneration of catecholaminergic neurons. Neuromelanin activates microglia via the up-regulation of TNF-α, which is dependent on NFκB and NO. In turn, matrix metalloproteinase 3 (MMP3), neuromelanin and α-synuclein are released by damaged dopaminergic neurons, and then overactivated microglia stimulate the production of ROS. It has been shown that exposure to PM derived from the combustion of fossil fuels causes a similar activation of microglia, which releases pro-inflammatory cytokines and NFκB, triggering chronic low-grade neuroinflammation and the dysregulation of brain function, leading to several subsequent health consequences, such as neurodegeneration, cognitive impairment, and neuronal death.⁶¹ Sequentially, the activated microglia engulf NPs and generate significantly high levels of NO and ROS, while decreasing the expression of TNF-α and overexpression of the COX-2 (cyclooxygenase-2) gene and release of interleukin-1β (IL-1β). The signalling cascade activated by IL-1β through mitogen-activated protein kinase (MAPK) is indispensable for synaptic plasticity control in the adult brain, which requires long-term potentiation (LTP) of the synapse under physiological conditions. However, high levels of IL-1β can impair LTP. AD and PD are characterized by abnormalities in the induction, maintenance and reversal of the main forms of neuroplasticity, affecting cognitive capacity and promoting neuroinflammation. The deleterious effect on neurons, similar to that seen in multiple sclerosis (MS), may be due to the mitochondrial lesions caused by the direct interaction with NPs or ROS produced by microglia and the consequent deficiency of ATP, leading to the proteolytic degeneration of cytoskeletal proteins and activation of calpains.^104,105

The process of neuroinflammation induced by UFPs is the product of the crosstalk between different cell types in the brain (Fig. 6). In normal circumstances, microglia have house-keeping tasks and an anti-inflammatory profile. In these circumstances, they release TNF-α, IL-1β, IFN, and BDNF, which contribute to homeostasis, plasticity, and cognition. UFPs cross the BBB through different mechanisms or macrophages with phagocytized UFPs in the blood pass through the BBB, releasing UFPs into the CNS. Commonly, these UFPs contain transition metals (e.g., Fe, Cu, Cr and Co), which can undergo Fenton-type reactions once inside microglia or neurons, mediating the formation of ROS. In the case of INOPs (iron oxide nanoparticles), they show peroxidase-like activity. These intracellular reactions affect neurons and microglia. Subsequently, microglia will be activated into a responsive pro-inflammatory state because of the internal damage and signals from damaged neurons nearby. When the pro-inflammatory profile is maintained for extended periods, pathological conditions such as toxicity, neuroinflammation, and neurodegeneration arise. Additionally, peripheral immune cells (such as CD4+ T cells) are recruited to the brain parenchyma, which further increase the proinflammatory environment.

Fig. 6 Neuroinflammation due to UFPs.

Molecular processes associated with PM and UFPs in the CNS

The molecular processes of the interaction among PM, UFPs and microglia are still not clear; however, it is very important to understand how these cells act in neurodegenerative processes, inflammation and interaction with pathogens because PM can stimulate innate immunity in the brain. Microglia express PRR (pattern recognition receptors) called Toll-like receptors (TLR) 1–9, which recognize PAMP (molecular patterns associated with pathogens) to initiate the innate immune response as a reply to different pathogens. It is known that TLR4 is positively regulated after cerebral inflammation occurs, and in addition to bacterial recognition, microglial TLR4 can recognize other additional ligands (yet to be identified) that contribute to the activation of microglia after neuronal damage. The activation of TLR4, TLR2 and TLR9 induces the microglial production of NO. Another class of receptors expressed by microglia are the seeking receptors (SRs), where the microglia in the brains of patients with AD have shown positive regulation of SR class A1 (SR-A1). These receptors are also positively regulated by microglia after injury and in response to cytokines. Activation of SRs may result in the internalization of the ligand and/or production of extracellular superoxide. Both SR-A1 and SR-B1 promote the adhesion and fibrillar Aβ endocytosis by microglia. Microglia also express RAGE (receptor for advanced glycation end products), which is positively regulated in AD and it has been reported that microglial RAGE mediates the proinflammatory effects of Aβ. The latter receptor may be responsible for both the internalization of harmful toxins into microglia and the generation of the proinflammatory response. Finally, NADPH oxidase is a fundamental transmembrane enzyme that catalyses the production of superoxide free radical from oxygen. It is associated with neuronal damage and neurodegenerative disorders. Studies have shown that it is activated in the brains of patients with AD.¹⁰¹

As mentioned above, two of the most common mechanisms presented by the cells in the body in the presence of UFPs from air pollution, and also gases such as NO₂/NO_x, VOCs, SO₂ and O₃, are oxidative stress and inflammation, which is why it is important to understand these processes and what they entail. Oxidative damage and health impacts associated with UFP exposure seem to be very similar to that caused by gaseous oxidants (NO₂/NO_x, and O₃). Although they present significative differences in their physical properties and the mechanisms used to diffuse and reach cells and tissues (in particular CNS and brain), it is important to understand the limitations of epidemiological cohort studies and controlled laboratory exposure evaluations to identify if some health impacts of air pollution oxidant gases have been masked by UFPs or vice versa.^106,107 Oxidative stress and inflammation are directly related, given that they interact with each other, promoting a positive feedback loop between them. Oxidative stress arises when the homeostasis between oxidant and antioxidant species is broken, which ultimately leads to the generation of ROS and reactive nitrogen species (RNS). ROS, including free radicals (superoxide anion (O²⁻), hydroxyl radical (˙OH) and hydrogen peroxide (H₂O₂)) and oxidants, are produced by all aerobic organisms during cellular respiration. Nevertheless, immune cells such as microglia, monocytes, mast cells, and neutrophils go through a respiratory explosion, which leads to the greater release of ROS and oxidative stress associated with the toxicity of UFPs.^85,108 ROS can damage key enzymatic systems and cellular components such as DNA, proteins, mitochondria, and lipids. Therefore, if the cell damage is exacerbated and the repair mechanisms of the cell cannot compensate, cell death can occur. Several studies have shown that UFPs induce necrotic cell effects.¹⁰⁸

Laboratory and epidemiological evidence of PM and UFPs in air pollution and neurodegeneration

Controlled laboratory studies that simulated the effect of air pollution with the use of DEPs found that neuroinflammation induced by air pollution may precede preclinical markers of neurodegenerative disease in the brain. The sub-chronic (6 months) exposure to DEPs in 5 brain regions has been previously reported including the olfactory bulb (a hypothetical brain entry point of PM and UFPs); the frontal lobe (which is damaged in AD and dementia in the frontal and temporal lobes); the temporal lobe (damaged in AD and dementia of the frontal and temporal lobes); the mesencephalon (damaged in PD); and the cerebellum (not associated with PD and AD). These studies showed that all regions, excluding the cerebellum, express high levels of the TNFα protein when exposed to the highest concentration of DEPs, 992 μg PM per m³.¹⁰⁹ Similarly, the Tau protein, which is expressed at high levels in most regions of the brain, has been studied because its aggregation into filaments is a major component of neurodegeneration, and neurofibrillary tangles (NFT) are found in the brains of patients with early AD. In some neurodegenerative diseases, Tau is hyperphosphorylated at several sites, and high levels of phosphorylation in the residue Ser199 (Tau [pS199]) has been specifically related to NFT. Importantly, Tau [pS199] hyperphosphorylation has also been shown to be involved as an early marker of Tau pathologies. Sub-chronic DEP exposure significantly increased the Tau [pS199] levels in the temporal and frontal lobe, confirming the induction of a pathology similar to early AD.¹⁰⁹ Similarly, Chuang and co-workers studied how PM of less than 2.5 μm was related to the reduction of white and grey matter in the brains of older women. They found that the large intraneuronal accumulation of Tau proteins (tauopathies) was associated with the development of neurodegenerative diseases and that an increased presence of Tau proteins was related to the PM present in polluted air, both in in vitro and in vivo experiments.¹¹⁰ They suggest that tau accumulation in the brain may be caused by dysfunction of autophagy, a degradative mechanism that is essential for maintaining good brain health. Autophagy, oxidative stress, and lysosome dysfunctions are some of the other possible mechanisms responsible for the potential toxicity of NPs in the brain.⁴² Another aspect observed was that sub-chronic exposure to DEPs resulted in the significant elevation of α-synuclein in the mesencephalon, demonstrating that high levels of air pollution increase pathology markers of early PD. Alternatively, it was found that sub-chronic exposure to DEPs promoted Aβ42 accumulation in the frontal lobe, indicating the elevation of a marker similar to AD and frontotemporal dementia (FTD). Finally, the evaluation of microglial markers after DEP exposure showed that the average brain expressed the highest levels of microglial activation markers, which are cells that are neurotoxic, especially towards dopaminergic neurons. In conclusion, it was found that the general proinflammatory response in the brain with sub-chronic DEPs exposure may be largely related to peripheral/systemic effects, which reach the entire brain (Table 2).^109,111

Table 2 Studies that provide evidence of the effects of PM on the nervous system^a

PM	Type of study	Species	Evidence	Reference
a BSID = Bayley scales of infant development; DDST = Denver developmental screening test II; MCDI = McArthur communicative development inventory; MIDI = Minnesota infant development inventory; mo = month(s); MSCA = McCarthy scales of children's abilities.
Brain inflammation and oxidative stress
UFPs	Multiple toxicological studies	Mouse	Indication of inflammation in whole brain, cortex, cerebral and hippocampus. Oxidative stress evidence in the cerebellum	112–117
PM10–2.5	Animal toxicological studies	Mouse	Immunohistochemistry of brain tissue and gene expression (Arc/Arg3.1; Rac1)	118
PM10–2.5	Animal toxicological studies	Mouse	DEP-induced oxidative stress and inflammation in the prefrontal cortex, cerebellum, temporal cortex, and striatum	119
PM10–2.5	Toxicological study	Human	Blood biomarkers indicative of changes in BBB integrity	120
PM	Epidemiological/toxicological study	Human	BBB damage and degeneration of cortical neurons and glia	85 and 121
Morphologic changes
UFPs	Animal toxicological studies	Mouse	Neurodegenerative alterations in hippocampus	122
			AD pathology in cerebral cortex (dependent on ApoE alleles)
PM2.5	Animal toxicological studies	Mouse	Hampered myelin repair, disruption of post-injury oligodendroglia differentiation and sustained astroglia and microglia reactivity	123
PM2.5	Epidemiologic evidence	Human	Decrease in white matter volume	124–126
PM2.5	Toxicological study	Human	Neurodegenerative changes in substantia nigra or hippocampus	127–129
Cognitive and behavioural effects
UFPs	Epidemiologic evidence	Human (children)	Decreased scores on memory tests and association with increased inattention	130
PM10–2.5	Epidemiologic evidence	Human (50–80 years old)	Association with mild cognitive impairment	131
PM2.5	Toxicological study	Mouse	Impaired learning and memory	128 and 129
PM2.5	Epidemiologic evidence	Human	Found increased risk of AD and/or PD per increase of PM2.5 over the follow-up period	132–135
PM2.5	Epidemiologic evidence	Human	Poor cognitive function	136
Neurodevelopmental effects
UFPs	Animal toxicological studies	Mouse	Modified neurotransmission	137–141
			Behavioural effects following prenatal and postnatal exposure
			Neuroinflammation and morphologic changes resulting from postnatal exposure
PM10–2.5	Epidemiologic evidence	Human (exposure during pregnancy at time of birth)	Cognitive and psychomotor development (MIDI, BSID, DDST, MCDI, and MSCA)	142
PM10–2.5	Epidemiologic evidence	Human (children)	Association with verbal cognitive development	143
PM2.5	Toxicological study	Mouse	Neuroinflammation and morphologic changes including ventriculomegaly following prenatal exposure	144

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The most recent epidemiological studies show that exposure to air pollutants is key in the development of severe cases of AD and other neurodegenerative diseases.^145,146 In a study comparing high versus low exposure to combustion-derived NPs (CDNP) through post-mortem neuropathology studies in children living in Mexico City with accidental deaths, it was shown that 40% of urban children exhibited frontal Tau hyper-phosphorylation with pre-tangled material and 51% had diffuse Aβ plaque in contrast with 0% in the controls, which is a distinctive signature of AD. The same group showed that residents of Mexico City highly exposed to CDNPs suffer an early brain imbalance of genes involved in immune responses, inflammation, and oxidative stress, and have high frontal concentrations of CDNPs, accumulation of hyperphosphorylated aggregates, high concentrations of α-synuclein, early extensive oxidative damage of DNA in axonal, dendritic and glial mitochondria, as well as molecular evidence of neuroinflammation and early PD. This group also found high levels of CDNPs in intramuscular nerve fibres, ganglionic neurons and in the vagus nerve.⁸⁵ Other findings observed in the residents of Mexico City included deregulated neuroinflammation, damage to the diffuse cerebral NVU and the accumulation of misfolded proteins. Most NPs present in key brain areas in Mexico City residents are CDNPs, especially high-temperature magnetic NPs, which have strong magnetic behaviour and contain transition metals including Co, Pt and Ni.¹²¹ It was found that NPs were broadly distributed in neuronal and glial organelles as well as in dendrites and axons together with important amounts in the nasal and olfactory epithelium, the olfactory bulb and the ganglia of the trigeminal. Interestingly, they also showed that the number of pinocytotic vesicles and the disassembly of the narrow inter-endothelial junctions substantially increased in the endothelium of the cerebral capillaries in the residents of Mexico City compared to the normal controls. White matter lesions, changes in volume in specific areas of the brain and cognitive deficits accompanied the neuropathological findings made by Calderón-Garcidueñas and group. These brains of young urbanites showing the first characteristics of AD showed particularly severe cognitive deficits in overweight adolescents who carry the APOE4 allele. In conclusion, they found that 99.5% of young urbanites have AD that begins in the brainstem, which is a sign of a clear and serious health crisis.^85,121,147Fig. 7 summarizes some of the most common pathologies of the CNS that have been associated with PM and UFP exposure in urban polluted environments.

Fig. 7 Schematic representation of CNS pathologies triggered by particulate matter exposure in urban polluted environments.

Perspectives

Worldwide there is a speedy rise in the number of people living with AD and other related types of dementia, where an estimated 44 million people of all ages have AD globally. Deaths from this disease have increased by 89% since 2000. These numbers are projected to increase to 82 million by 2030, partially due to the increase in ageing population.¹⁴⁸ It is important to highlight that 9% of cases is attributed to young onset dementia, which is defined as the beginning of symptoms before the age of 65. In 2018, the total lifetime cost of care for someone with dementia was estimated to be $250 174.¹⁴⁹ The global cost of AD and dementia is expected to be 1% ($605 billion) of the gross domestic product globally.¹⁴ As has been described in this review, CNS effects can be chronic and with the increasing exposure to PM in early childhood and damage can accumulate with age and add to the already aging population, which will result in an increase in the number of dementia cases and related diseases. In this case, it has been reported that chronic exposure to PM in early childhood leads to cognition deficits. By the time individuals reach the stage of young adults, when they are supposed to build skills and acquire knowledge in the academic and work setting, they progress to AD scores, further contributing to the economic burden of the disease and affecting local and global economic development.¹⁵⁰ Although epidemiological data links an increased risk for AD, MS, and PD to exposure to PM in air pollution, additional experimental and mechanistic studies seeking the relationship between specific types of PM in air pollution and the development of CNS diseases are important for the upcoming worldwide emergency caused by the increase in these diseases.

Currently, there are different hypotheses and models explaining the effects of air pollution on the brain. It has been proposed that peripheral signals traveling in the blood (e.g., lipids, circulating cytokines and modified proteins), neuronal signals from the periphery, passage of the particle components from atmospheric pollution to the brain and the transfer of the adsorbed chemical components in PM (e.g., polyaromatic hydrocarbons) into the brain can regulate the way in which neuroinflammation and neuropathology occur. Therefore, side effects in the CNS may be related to the production of inflammatory mediators from the primary entry organs and from the secondary deposition sites. Consequently, we must consider these processes as a primary and direct effect, in addition to these secondary mechanisms. However, it has been clearly demonstrated that air pollution promotes oxidative stress in the CNS, neuroinflammation, neuronal damage, activation of glia, increase in abnormal filamentous proteins, alterations in the BBB, blood vessels and blood supply damage, linking the pathways through which air pollution affects the pathology of CNS disease. As mentioned above, uncontrolled neuroinflammation and chronic increase in ROS in the CNS can develop into severe neurodegenerative disorders, such as AD. In addition, exposure to UFPs in air pollution may aggravate neuroinflammation in patients with one of several brain diseases with activation of underlying microglia, such as AD, PD, and ME. Due to the serious environmental problem of air pollution in most of the major cities on Earth and the prevalence of UFPs, an urgent health emergency has to be recognized and serious and systematic studies need to be performed to understand the molecular mechanisms and pathophysiology related to the problem. Furthermore, although the impact of UFPs and relevant oxidant gases may not be separable in field studies, the specific health impact of classical air pollutants (NO₂/NO_x, O₃, SO₂, and VOCs) and their interactions with UFPs and PMs will require new experimental designs and transdisciplinary effort to differentiate their differential contributions. Health impact assessments rely on cohort studies but the complexity of the problem may require new approaches to better understand how complex air pollution mixtures behave and impact human health.

Alternatively, given the multi-variable response involved in the brain's answer to air pollution, it is vital that researchers realize that comparison of brain effects should not be based solely on the PM concentration. Moreover, complex mixtures of polluted air are poorly understood and need further controlled toxicological studies in human cohorts to adequately understand the possible additive, synergistic, and enhanced effects between different types of PM and other components of air pollution. In this case, the scientific community is in dire need of the development of new detection methods for exposure assessment that tackle problems such as epidemiological studies with well validated outcomes, quantitative descriptions of real-world exposure conditions, dosimetry, and standardization.^151–153 To simplify toxicity screening in human studies, the search for biomarkers using genomics and proteomics will be beneficial moving forward.^152,154 The interactions among environmental, nutritional, metabolic and genetic risk factors and their association with air pollution and CNS damage should be explored in the future via the use of gene–environment interaction studies to delve into the mechanism and the importance of molecular pathways, which will account for genetic susceptibility.¹⁵⁵ Recent epidemiological studies suggest that iron-rich combustion- and friction-derived nanoparticles impair brain chromatin silencing, an epigenetic marker described in both AD patients and animal models.¹⁵⁶ In this regard, epigenetic mechanisms that can contribute to CNS damage due to interaction with the PM in air pollution should also be further explored.^157,158 Physiological responses and the changes and damage to cellular and molecular mechanisms due to interaction with airborne PM can also be aided by the development and application of biomimetic organ-on-a-chip technology. This technology allows the construction of models of different genders, regions, ages, and diseases to minutely minor physiological differences to integrate microenvironment and personalization parameters (e.g., breathing pattern, heart rate, and substance abuse), thus promoting the development of precision models that can even include multi-organ systems.¹⁵⁹

Alternatively, the reported measurements of PM_2.5 concentrations in Metropolitan Mexico City since 2004 to date have remained practically the same,¹⁵⁰ exceeding the health limits stated by the EPA air quality standards and the WHO guidelines.^160,161 Similar statistics can be found in many other metropolitan areas worldwide, especially in developing countries.¹⁶² Furthermore, measurements in metropolitan areas like these usually are limited to PM₁₀ and PM_2.5. Currently, UFPs are not being monitored in most urban areas and are not even accounted for in the WHO air quality guidelines¹⁶¹ or any country-specific guidelines. Because of this, the further understanding of PM in air pollution and their health effects will be useful to set regulations for controlling their use, release and recovery or inactivation to avoid potentially harmful exposure, evaluate risk assessment and the elaboration of recommendations regarding methods for personal protection.^163–165 It is important to develop preventive strategies, promote actions from both the government and society and construct strategic plans to address and cope with the current and future epidemic of neurodegenerative diseases. Furthermore, the potential facilitation of PM and UFPs for transmitting airborne diseases requires urgent actions and the involvement of different research and governmental institutions to understand and prevent their potential negative impact in human health.

Conflicts of interest

There are no conflicts to declare.

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