Air Pollution and Its Adverse Effects on the Central Nervous System

Air pollution is recognized as a significant public health problem and is associated with illnesses of the central nervous system (CNS) as well as neuroinflammation and neuropathology. Air pollution may cause chronic brain inflammation, white matter abnormalities, and microglia activation, which increases the risk of autism spectrum disorders, neurodegenerative disorders, stroke, and multiple sclerosis (MS). Methods: A literature review was done on “PubMed, EMBASE and Web of Science” on the relationship of air pollution with MS and stroke, using the keywords “air pollution” OR “pollution”; “ambient air pollution,” “particulate matter, ozone, black carbon” AND “stroke” OR “cerebrovascular diseases,” “multiple sclerosis,” “neuroinflammation,” or “neurodegeneration.” Results: We first identified 128 articles and their related websites, of which 44 articles were further selected for analysis mainly based on study relevance, study quality and reliability, and date of publication. Further studies on air pollution and its adverse effects on the CNS are needed. The findings of such studies will support the development of appropriate preventive measures in the future.


Introduction And Background
The World Health Organization (WHO) estimates that ambient and indoor air pollution cause over 4.2 and 3.8 million deaths each year, respectively [1]. It is well documented that air pollution increases adverse health effects related to cardiovascular and respiratory diseases [2,3]. Recently, growing evidence has linked air pollution to illnesses of the central nervous system (CNS) as well as to neuroinflammation and neuropathology [2][3][4].
Air pollution can be defined as any process that introduces particles into the atmosphere that can cause harm to living organisms and the environment [5]. Common forms of air pollution consist of components derived from various natural and anthropogenic sources, including carbon monoxide (CO); sulfur oxides (SOx); particulate matter (PM); nitrogen oxides (NOx); ozone (O3); methane; and other gases, metals, and volatile organic compounds [3].

Method
A literature review was conducted using PubMed, EMBASE, and Web of Science. A search was conducted for articles published on the relationship of air pollution with MS and stroke, using the keywords "air pollution" OR "pollution"; "ambient air pollution," "particulate matter, ozone, black carbon" AND "stroke" OR "cerebrovascular diseases," "multiple sclerosis," "neuroinflammation," or "neurodegeneration." A total of 44 articles  were collected for the analysis based on study type, abstract, quality, reliability, and publication date ( Table 1).

Multiple Sclerosis
MS is a chronic inflammatory autoimmune neurological disorder that impacts the CNS [6]. In recent decades, the prevalence of MS has increased; today, around 2.2 million individuals suffer from MS worldwide [7]. Air pollution has been implicated as a chronic environmental cause of neuroinflammation, reactive oxygen species (ROS), and neuropathology, all of which can contribute to CNS disorders [2,4]. Older and very young individuals seem to be particularly susceptible to neurotoxicity induced by air pollution. Exposure during the prenatal or postnatal period may contribute to behavioral abnormalities and developmental disabilities, while older people may develop neurodegenerative diseases due to exposure to air pollution [4]. Heydarpour et al. suggest that long-term exposure to air pollutants may be a risk factor for MS; this conclusion is due to an observed significant difference between the exposure of MS patients and controls to NO2, NOx, PM10, and SO2 [8]. A case-control study of the association between air pollutants and pediatric MS found that higher exposure to air pollutants (CO, SO2, and lead) was significantly associated with a higher risk of MS in pediatric patients [9].
Several studies of adult MS have found that an increase in PM10 exposure is associated with an increased risk of MS in adults [8,10,11], active MS inflammatory lesions detected by magnetic resonance imaging (MRI), and MS relapse [11][12][13][14][15][16]. A strong association has been observed between active MS inflammatory lesions (shown in an MRI) and a higher concentration of PM10; for every increase of PM10 by an increment of 30 µg/m 3 , the risk of an inflammatory lesion increases by 86% [12].
A deeper investigation of various air pollutants revealed that the risk of MS relapse increased following exposure to NO2 and PM10 during cold seasons and that exposure to O3 increases the risk of relapse during hot seasons [17]. Vojinović et al. found a significant negative correlation between seasonal vitamin D levels (which are higher from July to October in the northern hemisphere and MS relapse). The findings of this fiveyear observational study confirmed the influence of seasonal conditions and air pollution on MS relapse risk [17,18]. Air pollution has also been found to correlate with poorer scores on the MS expanded disability status scale (EDSS), lower rates of MS remission, higher MS severity, and poorer recovery from the first MS event [18].
An Italian study in the northeastern province of Padua (Veneto region) found a higher prevalence of MS in urban areas, which have higher PM2.5 levels than rural areas [19]. Similarly, Bergamaschi et al. suggest that the risk of developing MS is reduced as air pollution reduces [20]. A recent study in Turkey found that MS is more than twice as prevalent in regions near steel and iron factories than in rural areas [21]. These findings support the hypothesis that air pollution may play a role in the etiology of MS.
However, the results of several other studies are inconsistent with this hypothesis. A recent study in Canada found no association between air pollutants and MS incidence [22]. Other studies have found no link between MS risk and PM2.5 [9,22,23], PM10 [9,24], NO2, or O3 [23]. Chen et al. also found no association between living close to heavy traffic and MS incidence [25].
Several theories have been proposed regarding the impact of air pollutants on the CNS and MS risk. First, respiratory exposure to air pollutants may trigger oxidative stress and increase the permeability of the epithelial wall, resulting in the release of pro-inflammatory cytokines and provoking an immune response by activating the aggressive auto-reactive T cells and enhancing their migration to the CNS through the blood-brain barrier (BBB) [12,21,26,27]. PM10, in particular, may play a pro-inflammatory role by upregulating the expression of C-C chemokine receptors 6 (CCR6) on circulating cluster of differentiation four (CD4+) T cells and provoking the production of T helper 17 cells (Th17) polarizing cytokines in cells that regulate innate immunity [27]. A second theory proposes that inhaled particles may be translocated to the CNS through the olfactory system [26]. A third explanation is that exposure to air pollutants, along with lifestyle changes, may interrupt the normal balance between self-tolerance (the unresponsiveness state of the immune system to self-antigens [28]) and immunity [18]. Other probable mechanisms include insufficient vitamin D, which may be an indirect effect of exposure to air pollution [12,18]. MS risk could also be related to genetics, particularly epigenetic modifications, and, more specifically, DNA methylation alterations [26].

Stroke
A stroke is an acute disturbance of cerebral circulation caused by arterial stenosis, blockage, or rupture in patients with cerebrovascular disease; it may occur due to a variety of inducing factors [29]. It is the second leading cause of death globally and a significant cause of hospitalization, long-term disability, and high medical costs [30]. The global burden of stroke is enormous and growing, especially in developing countries [30].

Particulate Matter and Stroke
Several studies have found an association between PM and stroke. Long-term exposure to PM10 from local traffic was associated with the incidence of stroke in a region with comparatively low air pollution levels [31]. Another study found a borderline significant association between same-day and previous-day exposure to PM2.5 exposure and the risk of stroke or transient ischemic attack (TIA) [32]. Elevated PM10 and PM2.5 levels have also been positively associated with an increase in hospital admissions due to TIA [33]. Another study found that PM2.5 was associated with a higher incidence of hospitalization due to stroke; this association was stronger for ischemic than hemorrhagic stroke. Moreover, individuals with lower incomes had a higher risk of stroke after exposure to PM2.5 [34]. Yet another study showed a positive association between long-term PM2.5 exposure and stroke incidence, particularly ischemic stroke [35].
In one study, every 10μg/m 3 increase in PM2.5 was associated with an increase of 0.69% in stroke morbidity. This changes to an increase of 0.80% in the risk of stroke morbidity for females and to an increase of 0.78% in the risk of stroke morbidity for individuals over 65 years old. No association was between stroke and PM10 or PMc [36]. Another study found that each 10 μg/m 3 increase in PM2.5 was associated with a 20% increase in the incidence of ischemic stroke and a 12% increase in the incidence of hemorrhagic stroke. Ischemic stroke is more common in elderly people and people with normal weight [37]. One study also found a significant association between PM10 exposure and ischemic but not hemorrhagic stroke [38]. Similarly, another study showed that a 10 μg/m 3 increase in PM2.5 was positively associated with an increase of 0.23% in mortality due to ischemic stroke and an increase of 0.37% in mortality due to hemorrhagic stroke. The same study found that exposure to PM10 increased the risk of mortality due to ischemic stroke by 0.16% but did not impact the risk of mortality due to hemorrhagic stroke [39].
Another study found that PM2.5 exposure increased the risk of stroke onset, particularly 12 to 14 hours after exposure. In that study, patients experienced ischemic stroke due to large artery atherosclerosis or small vessel occlusion rather than cardioembolism [40]. In another study, long-term exposure to PM2.5 was also associated with a higher incidence of ischemic and unspecified stroke; this association was strongest in older people, those with lower levels of education, and men who smoked. The association with hemorrhagic stroke was less clear [41]. In contrast, another study found that PM10, PM2.5, and PM1 were associated with hemorrhagic stroke but not ischemic stroke. That study also found an association between stroke mortality and secondary aerosol components of PM2.5, including sulfate, nitrate, and ammonium [42].
However, other studies have found no association between PM and stroke. For example, two studies found no association between stroke and PM2.5 and PM10 [43,44]. Another study found no association between initial stroke severity and long-term residential PM2.5 exposure [45]. Yet another found no evidence of an association between short-term PM2.5 exposure and the onset of stroke symptoms, including ischemic stroke, in the 72 hours following exposure [46]. Interestingly, another study showed that PM10 was linked to a lower incidence of ischemic stroke and a higher incidence of intracerebral hemorrhage; this risk increased for every 10 mg/m 3 increase in PM10. However, after controlling for other variables, these relationships were found to be insignificant [47].

Ozone and Stroke
O3 is a strong oxidant that can affect the oxidant-antioxidant balance in the body, thereby contributing to ischemic cerebrovascular diseases [48]. In one study, a 10 μg/m 3 increase in O3 was associated with emergency outpatient stroke in Chongqing City. This association was particularly strong for males, for whom the risk increased by 0.77% more than it did for females; the risk for individuals over 60 years old increased by 1.14%, and the risk for individuals with pre-existing hypertension increased by 0.26% [48].
Another study showed a significant association between O3 levels and ischemic stroke in men over 40 years old; this association was weaker in women [49]. A 10 µg/m 3 increase in O3 was associated with an approximately 12% increase in the risk of stroke subtypes for recurrent stroke and with an approximately 8% increase in the risk of large artery stroke [50].
Another study demonstrated a borderline significant association between O3 exposure and ischemic stroke or TIA [32]. A higher incidence of stroke hospitalization was associated with O3 exposure; this was particularly true for ischemic stroke, and the association was stronger in older age groups [34]. One study found that ambient O3 had different effects in different seasons: It had a positive association with hospital admission for stroke during warm seasons and a negative association during cold seasons [37]. In twopollutant models, a combination of O3 and a 10 μg/m 3 increase in NO2 led to a 0.22% increase in the risk of emergency stroke [48]. After other pollutants were included in the model, particularly PM10, the effect of O3 on stroke risk in men remained significant [49].
Interestingly, another study showed that O3 could have a protective effect on stroke patients with coronary atherosclerosis [51].

Black Carbon and Stroke
A number of studies have evaluated the relationship between black carbon (BC) and stroke. One found that BC exposure from local traffic sources was positively associated with stroke incidence. However, no association was found between stroke and BC exposure from residential heating sources [43]. Another study found a significant association between stroke risk and BC exposure due to traffic pollution [40]. However, yet another study found no increased risk of ischemic stroke of any etiology in the 72 hours following exposure to BC. A stratified analysis found an increased risk of ischemic stroke arising from large artery atherosclerosis at two-time points: 24 to 47 hours and 48 to 72 hours after exposure to BC [49].

NO2, NOx, SO2, and Stroke
There may be a significant association between NO2 exposure due to traffic pollution and the risk of stroke [34,40]. One study found a borderline significant relationship between NO2 and the incidence of stroke, specifically ischemic and unspecified stroke; however, the same study found that NO2 exposure was negatively associated with hemorrhagic stroke. That study also found that 10 years of education significantly attenuated the negative impacts of NO2 exposure [52].
One study found a positive association between hospital admission for stroke and exposure to NO2 or SO2; this association was strongest during warm seasons and in individuals over 65 years old. A stratified analysis by season showed that both NO2 and SO2 have stronger associations with stroke admission during warm seasons than cold seasons [53]. Another study found that, during warm seasons, stroke admissions increased on the same day, the previous day, and for a three-day moving average following exposure to NO2; however, during cold seasons, this positive association was only observed on the same day as exposure [53]. NOx from local road traffic is associated with stroke incidence in areas with comparatively low air pollution levels [31]. NO2 and NOX exposure in the previous three days was also found to have a significant association with a higher risk of hemorrhagic stroke in a large cohort of postmenopausal women. This effect was more pronounced in non-obese participants than in obese participants [44].

Conclusions
Based on the findings of the studies included in this literature review, air pollution is a real global threat. In previous decades, concerns about air pollution were limited to its relationship with cardiovascular and respiratory disorders. Today, however, there is accumulating evidence that there is a strong association between air pollution and CNS disorders. The neurotoxicity of air pollution may impact neuroinflammation, oxidative stress, and cerebral vascular damage through several mechanisms. However, further studies on air pollution and its adverse effects on the CNS are needed. The findings of such studies will support the development of appropriate preventive measures in the future.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.