Neurotoxicity Induced by Atmospheric Fine Particulate Matters and the Underlying Molecular Mechanism

Yuzhu Zhang; Jing Zhan; Qian Liu; Qunfang Zhou; Guibin Jiang

doi:10.7536/PC210102

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (5) : 713-725 DOI: 10.7536/PC210102

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Neurotoxicity Induced by Atmospheric Fine Particulate Matters and the Underlying Molecular Mechanism

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Abstract

The health effect of atmospheric fine particulate matters(PMs) is now being increasingly concerned, and a growing number of epidemiological studies have reported the adverse impacts of PMs on the respiratory system, cardiovascular system, etc. However, whether PMs can enter the brain and cause neurotoxicities or not remains unknown, which has been an important research direction for the health risk evaluation of atmospheric smog in recent years. Based on the relevant epidemiological studies and experimental evidences in vitro and in vivo, this paper summarizes the potential pathways regulating the neurotoxicity of atmospheric PMs, their detrimental effects on the adult, elderly, and developmental nervous systems, as well as the underlying molecular mechanisms. Atmospheric PMs were reported to affect the nervous system through the blood-brain barrier pathway, the olfactory nerve pathway, the microbiota-gut-brain axis, etc. Herein, oxidative stress, mitochondrial damage, inflammation, DNA damage, epigenetic regulation, hematological homeostasis, and several key signaling pathways were found to be involved in the observed neurotoxicities caused by atmospheric PM exposure. This review aims to reveal the neurotoxicities of atmospheric PMs, especially their neurodevelopmental effects on special populations such as children. On this basis, this article points out the future research directions in this field, providing a theoretical basis for the evaluation of neurotoxicities and public health hazards of atmospheric PMs.

Contents

1 Introduction

2 Epidemiological studies on neurological diseases induced by PM exposure

2.1 Developmental nervous system

2.2 Adult nervous system

2.3 Elderly nervous system

3 Pathways by which PMs affect the nervous system

3.1 The blood-brain barrier pathway

3.2 The olfactory nerve pathway

3.3 Other pathways

4 Experimental findings on neurotoxic effects of PMs

4.1 In vitro experiments

4.2 In vivo experiments

5 Molecular mechanisms underlying the neurotoxicities of PMs

5.1 Oxidative stress and mitochondrial damage

5.2 Inflammation

5.3 Key signaling pathways regulating the neurotoxicities of PMs

5.4 DNA damage and epigenetic regulation

5.5 Effects on hematological homeostasis

6 Prospects and research points

Graphical abstract

Keywords

atmospheric fine particulate matters / neurotoxicity / epidemiological study / molecular mechanism

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Yuzhu Zhang, Jing Zhan, Qian Liu, Qunfang Zhou, Guibin Jiang. Neurotoxicity Induced by Atmospheric Fine Particulate Matters and the Underlying Molecular Mechanism. Progress in Chemistry, 2021, 33(5): 713-725 DOI:10.7536/PC210102

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1 Introduction

In recent decades, air pollution caused by human activities and the resulting health risks have become an important issue of global concern^[1]. Air pollutants are a complex mixture, including a variety of Atmospheric particulate matters (PMs), organic components, metals and gases (such as nitrogen oxides, sulfur oxides and ozone)^[2]. Among them, PMs are the most complex and harmful pollutants in the atmospheric environment. They are solid or liquid particles suspended in the air. Because of their harm to organisms and human health, PMs have become one of the main harmful factors affecting the quality of the atmospheric environment and human health^[3].

Studies have shown that PMs concentrations in most Chinese cities are much higher than the average levels surveyed in the World Health Organization's air quality guidelines^[4]. Studies on the characteristics of PMs pollution show that PMs fall slowly, spread widely and far, are more serious in winter than in summer, and are more serious in heating period than in non-heating period. At the same time, the toxic components of PMs with different particle sizes and their corresponding health hazards are different in different regions^[5]. According to the aerodynamic size, PMs can be divided into particles entering the lungs PM₁₀(≤10μm), coarse particles PM_2.5-10(2.5~10μm) and fine particles PM_2.5(≤2.5μm). particles with aerodynamic size less than or equal to 0.1 μm are called Ultrafine particles (UFP)^[6]. The health effects of fine particulate air pollutants (< 10 μm in diameter) are particularly significant because, once inhaled, the particles may enter the circulatory system and eventually cause damage to multiple organs, such as the heart, lungs and brain^[7]. PM_2.5 is an important component of PMs, which mainly comes from the combustion of wood, coal, fuel oil and other fuels, as well as vehicle exhaust emissions^[8]. Many studies have confirmed that PM_2.5 is the most relevant component of air pollution to cognitive function^{[9⇓⇓⇓⇓⇓~15]}. The composition of PM_2.5 is very complex and related to regional, seasonal, source and other factors^[8]. Polycyclic aromatic hydrocarbons (PAHs) and organic carbon (OC) loadings in the PM_2.5 were most strongly associated with neuronal damage, and PAHs-laden particles from traffic sources were strongly associated with cognitive decline^[8]^[13]. Heavy metals, such as Fe, Zn and Cu, loaded in PM can induce oxidative stress in mitochondria and cause body damage^[16]. Diesel exhaust fumes (DEP), one of the main sources of primary particulate UFP, are thought to have the potential to enter the brain^[17]. Therefore, the potential brain neurotoxicological effects of PMs have attracted wide attention.

In recent decades, studies in the field of environmental epidemiology have shown that exposure to PMs may lead to increased mortality and affect the incidence of cardiovascular and respiratory diseases. Inflammation and oxidative stress have been considered as the main potential mechanisms of cardiovascular and respiratory damage caused by air pollution^[18,19]^[20]^[21]^[22]. In contrast, there is only some preliminary evidence of the effects of air pollution on the brain, and the mechanism of action is not yet clear. Oberd Oberdörster et al. First proposed that UFP may act on the brain, and then epidemiological studies showed that exposure to PMs had adverse effects on human cognitive function^[23]^[13,24]. At the same time, in vitro studies have shown that PMs can be carried by the systemic circulation through the damaged Blood brain barrier (BBB) into the brain, or through the nasal mucosa through the olfactory nerve directly to the olfactory bulb of the brain, further leading to central nervous system abnormalities^[23]. PMs entering the brain can directly act on nerve cells and produce harmful effects, and PMs entering the body can also indirectly affect the neuroimmune system by affecting the microbial composition of the gastrointestinal tract and regulating the "gut-brain axis" signal^[25]^[26]. Epidemiological data have shown that PMs exposure may be related to some central nervous system diseases, such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and other neurodegenerative diseases^[27]^[28]^[29]. Air pollution is also associated with the occurrence of stroke and depression in adults. Affected by air pollution, the body can have obvious systemic inflammation, imbalance of neuroimmune regulation in brain tissue, neuroinflammation and oxidative stress in brain^[30,31]^[17,32]. For some sensitive populations, such as children, there is evidence that PMs exposure is associated with autism, attention deficit and hyperactivity disorders, suggesting that PMs exposure may lead to neurodevelopmental disorders in children^[2]. Laboratory studies based on ex vivo or in vivo studies have also provided substantial evidence to reveal the neurotoxicity of PMs. For example, exposure to PMs can shorten the neurite length of neural stem cells, release inflammatory factors from astrocytes, and induce neuroinflammation and neurodegeneration. PMs exposure can cause the decline of learning and memory in experimental animals, and show abnormal neurobehavior in water maze experiments^[33,34]. There are many studies on the mechanism of PMs' neural injury, which is related to oxidative stress and inflammatory response^[35]^[15]. In addition, studies have shown that PMs can lead to neurotoxicity by mediating epigenetic changes^[36,37]. Nuclear transcription factors (such as NF-κB) signaling pathway, mitogen-activated protein kinases (MAPKs) signaling pathway and Notch signaling pathway play important regulatory roles in PMs-induced neurotoxicological effects^[38]^[39]^[40].

The neurotoxicological effects of PMs are an important aspect of health risk assessment. Based on the current research progress of neurotoxicology of PMs, this paper comprehensively reviews the neurotoxic effects of atmospheric particulate matter from the aspects of epidemiological data, the pathway of PMs entering the nervous system, the results of laboratory studies on neurotoxicological effects of PMs, and the mechanism of neurotoxicity caused by PMs.Taking the physiological stage as a sensitive indicator of the neurotoxicological effects of PMs, the neurotoxic effects and mechanisms of PMs were discussed in depth at multiple levels, and the scientific issues that need to be focused on in future research were put forward.

2 Epidemiological study on neurologic diseases induced by exposure to atmospheric particulate matter

In the past decade, the incidence of neurological diseases has increased year by year, especially neurodevelopmental disorders in children and neurodegenerative diseases in the elderly^[41]^[42]. There is growing evidence that air pollution may also be detrimental to brain health and function, and that exposure to PMs can adversely affect neurobehavioral and functional outcomes in children and adults^[43]^[2]. The cumulative risk assessment of 40 environmental hazardous air pollutants (HAPs) using the toxicology database showed that among the 17 health hazards analyzed, nervous system damage ranked second only to respiratory diseases, mainly due to the vigorous metabolism of the nervous system, especially the central nervous system, which may be more vulnerable to oxidative stress^[44]. In addition, people at different physiological stages have different sensitivities to PMs exposure. For example, the blood-brain barrier of infants and young children is still in the development period, and the development time window is wide, which may lead to their central nervous system being more vulnerable to air pollution exposure. There is evidence that exposure to pollutants early in life can have an impact on the development of neurodegenerative diseases later in life^[45]. At present, some preliminary progress has been made in the epidemiological study of neurologic diseases induced by PMs exposure in development, adulthood and old age.

2.1 Developmental nervous system

PMs exposure is associated with a variety of adverse pregnancy outcomes, and current epidemiological cohort and model studies have shown that prenatal air pollution exposure is associated with low birth weight, preterm birth, intrauterine growth retardation, and birth defects^[46]^[47,48]^[49]^[50]. Therefore, the adverse effects of prenatal PMs exposure on the developing nervous system have attracted wide attention. In addition, epidemiological studies have shown that air pollution can cause an increase in brain inflammation in children, which can further lead to changes in brain structure, brain development disorders and cognitive impairment in childhood^[41]. Studies on neurologic impairment caused by PMs exposure during pregnancy and early life have focused on cognitive dysfunction, neurodevelopmental disorders, and neuropsychology, such as autism and attention deficit hyperactivity disorder^{[51⇓⇓~54]}^[2].

Compared with adults, fetuses and children are more vulnerable to various environmental pollutants because of the imperfect development of the barrier to protect the central nervous system^[55]. Several studies have shown that prenatal exposure to PMs may cause irreversible neurological damage to the developing fetus, leading to a variety of neurodevelopmental defects^[56,57]. A study using spatio-temporally resolved predictive models to analyze individuals' prenatal exposure to PM_2.5 and test neurodevelopmental levels in children (6.5 ± 0.98 years) suggested that increased exposure to PM_2.5 in a specific prenatal time window was associated with poorer memory and attention in childhood^[51]. Another study examined the relationship between prenatal exposure to PMs and other outdoor air pollutants and behavioral developmental delays in children, and showed a positive association between air pollution and neurodevelopmental delays^[52]. Epidemiological cohort designs have been used to explore the effects of prenatal PMs exposure on children's cognitive function. A cohort of 719 newborns recorded in the 2003-2004 GASPII project in Rome found that prenatal PMs exposure was inversely related to verbal IQ and verbal comprehension indices^[53]. A study in the United States used a spatio-temporal LUR model to estimate the level of PM_2.5 exposure during pregnancy and childhood in 1109 pairs of mothers and children, and analyzed the association between PM_2.5 exposure and children's cognitive level based on cohort studies. The results of linear regression analysis showed that prenatal exposure to PM_2.5 might lead to the decrease of some cognitive abilities of children, including non-verbal intelligence, verbal intelligence and visual level, and children with higher prenatal exposure level showed greater neurologic impairment effects. The study also found that exposure to PM_2.5 in the second trimester of pregnancy was not associated with reduced cognitive performance in childhood^[54].

There has been considerable evidence of the potential effects of PMs exposure on neurodevelopmental disorders in children, such as autism and attention deficit and hyperactivity disorder, and the results are of great concern^[2]. In order to explore the impact of PM₁₀ exposure on autism, Kalkbrenner et al. Used statistical interpolation to monitor the PM₁₀ exposure levels of 979 autistic children from North Carolina and San Francisco Bay Area, California.Exposure to PM₁₀ in the third trimester of pregnancy was associated with the development of childhood autism when compared with a random sample of children from the same place and year of birth^[58]. Studies of PM_2.5 have also consistently concluded that prenatal and early life exposure to PM_2.5 is significantly and positively associated with an increased risk of autism^[59]. A study of 245 children with autism and 1522 normal controls compared the incidence of autism in the offspring of pregnant women exposed to PMs with that of healthy pregnant women, using a validated spatiotemporal model to estimate exposure to PM_2.5 and PM_2.5-10. The study found that exposure to PM_2.5 during pregnancy was associated with an increased incidence of autism in children^[60]. Attention-deficit/hyperactivity disorder (ADHD) is the most common cause of cognitive and behavioral disorders in children, with a prevalence of about 5% worldwide. Many studies have confirmed that there is a positive correlation between PMs exposure and ADHD^[61]^[62]. For example, a prospective study of 2715 children (aged 7-10) in 39 schools in Barcelona found that children attending schools with higher levels of traffic-related air pollution made slower progress in cognitive development^[63].

Most of the existing studies on the neurodevelopmental regulation of PMs rely on statistical data, and the main limitations of this method are that there are errors in the assessment of PMs exposure levels and the influence of genetic factors is ignored.In the future, more accurate and objective assessment of the neurodevelopmental toxicological effects of PMs should be carried out in combination with biomarkers and other indicators.

2.2 Adult nervous system

In the adult nervous system, PMs exposure is closely associated with brain inflammation, which may further induce neurodegenerative diseases, cerebrovascular diseases, synaptic dysfunction, cognitive impairment or decline and other adverse neurological health outcomes^[64].

A study of the association between exposure to airborne PMs and Multiple sclerosis (MS) hospitalizations in Italy from 2002 to 2009. A total of 8287 MS-related hospitalizations were obtained from discharge records. Air pollutant exposure levels were estimated based on air monitoring station data, and the risk of MS was found to be associated with PM₁₀ exposure by Poisson regression analysis^[65]. Another study assessed the relationship between baseline cognition and the most recent 7-14 years of exposure to PMs using a spatiotemporal smoothing model and the US EPA Air Quality Monitoring System. After adjusting for important covariates in the generalized estimating equation regression model, it was found that cognitive decline was faster in people exposed to long-term PM_2.5-10 and PM_2.5^[66]. Population studies have also found that young people in heavily polluted areas have higher levels of AD-related biomarkers in cerebrospinal fluid samples, suggesting that the risk of AD in this population is of concern^[29]. Overall, the current epidemiological evidence for neurological damage in adulthood from PMs is still very limited.

2.3 Senile nervous system

Previous studies have shown that the elderly are particularly vulnerable to the adverse effects of PMs pollution^[67,68]. Studies in both animals and humans have found an association between exposure to high concentrations of PMs and increased inflammation in the brain and the accumulation of beta-amyloid, a marker of neuronal dysfunction^[64,69,70]. Individuals who experience air pollution-induced inflammation and neurodegenerative disease are more likely to have cognitive deficits and are at greater risk of developing neurodegenerative diseases such as AD in the future^[71].

Due to the convenience of research design and methodology, many cohort studies have been carried out around the neuropsychological effects of PMs exposure. These studies have shown that higher levels of air pollution exposure can affect the performance of older people in neuropsychological tests, such as the decline in memory^[14,72]. A cohort study that assessed cognitive function in 19 409 older women (70 to 81 years of age) further confirmed that long-term exposure to PM_2.5-10 can lead to cognitive decline^[13]. In addition, cohort studies have further demonstrated the association between air pollution and AD. The first cohort study in an Asian population collected and analyzed information on 95,690 people over 65 years of age between 2001 and 2010. The results suggest that long-term exposure to O₃ and PM_2.5 above the US EPA air quality standards increases the risk of AD^[66,73]. Cross-sectional studies on the relationship between residential particulate matter concentration and cognitive function in the elderly confirm that long-term living in a high concentration of PM_2.5 environment (≥15μg/m³) is more likely to lead to cognitive decline in the elderly^[14].

Although more and more studies have been devoted to revealing the relationship between PMs exposure and the development of neurological diseases, the results are still limited and inconsistent. Current epidemiological studies are difficult to obtain accurate evaluation results due to large differences in methods used, difficulty in accurately judging the actual exposure level of PMs in the population, and insufficient control of confounding factors.Therefore, it is still a challenge to establish a more reliable and representative epidemiological evaluation method system for the neurotoxicological effects of PMs^[2].

3 Pathways of atmospheric particulate matter affecting nervous system

Previous studies have shown that PMs are closely related to the occurrence of neuroinflammation, so many studies have been devoted to explaining the pathway by which PMs enter the central nervous system and induce inflammation. Inhaled PMs are transported to the central nervous system (CNS) by two main routes: the first is that PMs are precipitated in the respiratory tract and transported to the blood circulation system, and then penetrate the blood-brain barrier into the CNS; The other is that PMs deposit on the nasal mucosa and reach the olfactory nerve and enter the central nervous system through the olfactory bulb^[23]. In addition, a small number of small particles may enter the human body through the digestive tract and skin, penetrate the barrier between different tissues, eventually reach the capillaries, transfer through the circulatory system and deposit in multiple organs, including the brain, but the contribution of these pathways to the neurotoxic effects of PMs remains to be determined^[75]. A series of previous studies have tentatively explored the role of the blood-brain barrier, olfactory nerves, and other pathways in PMs-induced central nervous system injury^[27].

3.1 Blood-brain barrier pathway

Blood-brain barrier (BBB) is mainly composed of brain microvascular endothelial cells and glial cells, which is not only a highly selective semi-permeable membrane, but also a dynamic structure with both chemical and physical barrier functions. BBB can strictly restrict the penetration of substances, resist various toxic substances and protect the life center^[76]^[77]. Due to the small particle size of PMs, especially UFP, many studies suggest that PMs can penetrate and/or destroy the integrity of the blood-brain barrier, and then reach the central nervous system^[23]. There is also evidence that PMs exposure can induce the production of inflammatory factors in peripheral blood, and whether these inflammatory factors can enter the brain and affect the function of the central nervous system depends on the permeability of the blood-brain barrier^[27].

Based on animal models and epidemiological studies, it has been found that PM_2.5 exposure can induce the decrease of tight junction protein expression in endothelial cells, lead to the increase of blood-brain barrier permeability and the decrease of integrity, and is related to the occurrence of central nervous system related diseases, including stroke and AD^[27]. Exposure to high concentrations of air pollutants, especially PMs, may be one of the important factors leading to blood-brain barrier damage. The possible mechanism of PMs mediating neurotoxic effects through the blood-brain barrier pathway is that :PM_2.5 enter the brain by destroying the integrity of the blood-brain barrier, further causing neuroinflammation and neurodegeneration, and at the same time, peripheral inflammatory factors mediated by PM_2.5 are more likely to enter the brain and cause injurious effects.

3.2 Olfactory nerve pathway

Studies based on animal models have found that PMs can enter the brain through the nose^[78]. Among them, the olfactory nerve pathway is an important pathway for the exposure of PMs to the central nervous system after inhalation, and it has been confirmed that PMs are transported to the central nervous system more effectively through the olfactory nerve than through the blood circulation and blood-brain barrier in non-human primates^[27]^[78]. In some studies, rats were exposed to synthetic ultrafine particles containing elemental ¹³C to simulate the olfactory nerve uptake pathway of PMs, and the concentration of ¹³C in the olfactory bulb of rats was observed to increase significantly by isotope ratio mass spectrometry, suggesting that PMs can deposit in the olfactory mucosa of the respiratory tract and nasopharynx and transmit through olfactory nerves^[23]. In addition, some studies have found that the dendrites of olfactory neurons in mice exposed to PM_2.5 degenerate, and severe air pollution exposure can lead to olfactory bulb inflammation and increased levels of tumor necrosis factor-α (TNF-α) in the brain^[79]^[79]. Considering that the levels of cytokines such as TNF-α in the brain are closely related to the function of glutamate receptors in the hippocampus and cerebral cortex, PMs may increase the expression of inflammatory factors in the brain through olfactory neural pathways, resulting in cognitive deficits consistent with epidemiological studies of air pollutants^[80]^[79].

3.3 Other ways

In addition to entering the nervous system through the respiratory tract, PMs can also act on the central nervous system through other pathways. PMs may enter the digestive tract through diet or blood circulation. Studies have shown that inhalation of PM_2.5 can change the intestinal microbiome and affect intestinal microecology^[25]. Intestinal microorganisms regulate the body's physiological functions and maintain normal metabolism in a variety of ways. They are easily regulated by the internal and external environment of the body. Intestinal microecological imbalance can induce the occurrence of a variety of diseases^[81]. Intestinal microflora is involved in regulating the physiological function of the brain.Intestinal microecological imbalance and intestinal cell damage can lead to systemic inflammation and immune activation, further induce the production of cytokines such as TNF-α, interfere with the "gut-brain axis" signaling pathway, and lead to neuroimmune abnormalities^[26,82]^[27]. PM_2.5 are usually loaded with lipopolysaccharide (LPS), and studies with a single intraperitoneal injection of LPS into mice have shown that the levels of pro-inflammatory cytokines TNF-α, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) in the serum and brain of experimental animals increase in a dose- and time-dependent manner^[83]^[84]. In addition, the exposure of Reactive oxygen species to colonic epithelial cells can trigger the production of Reactive oxygen species (ROS) and inflammatory cytokines in mitochondria, and induce apoptosis of colonic epithelial cells, which may be transferred from peripheral blood to the central nervous system through the damaged intestinal barrier^[85]. These results provide indirect evidence for the involvement of gut microbes in neurodegenerative diseases caused by PMs.

4 Experimental study on neurotoxicological effects of atmospheric particulate matter

Epidemiological surveys and clinical studies have confirmed that PMs exposure is associated with adverse health outcomes in the nervous system, but the underlying molecular mechanism is not yet clear. At present, it is not feasible to conduct large-scale brain histological studies at the population level, and the results of existing epidemiological studies are limited by the problem of small sample size. Experimental studies have been used as a tool to explore the neurotoxicological effects and mechanisms of PMs. There are two main methods: one is to evaluate the toxicological effects of PMs and the underlying molecular mechanisms based on a variety of neural cell models in vitro; The other is to use wild-type animal models to evaluate the damage effects of PMs on the nervous system, and to explore the underlying molecular mechanisms by genetic engineering^[88].

4.1 In vitro experiment

Primary neural cells cultured in vitro can better simulate the physiological state of target cells in vivo, and can be used to evaluate the response of target tissues to neurotoxic substances at the cellular and molecular levels^[87]. For example, some studies have induced the activation of rat astrocytes in vitro, and found that astrocytes are involved in the signaling pathways mediating nerve injury^[86]. Primary neural cells are usually prepared from brain tissues of embryos (preparation of cerebral cortical neurons, hippocampal neurons, etc.) Or experimental animals of several days of age (preparation of astrocytes, oligodendrocytes, microglia, etc.). At that end of the PMs exposure,Cytotoxicity of PMs was evaluated by relevant molecular biological indicators, including changes in cell morphology, lactate dehydrogenase release (indicating cell necrosis), nuclear fragmentation (indicating cell apoptosis), changes in neurotransmitter uptake or release (indicating changes in nerve conduction), cytokine and chemokine secretion (indicating neuroinflammation) and ROS formation (indicating oxidative damage). For example, neuron-based studies have found that PM_2.5 can enhance excitatory synaptic transmission regulated by cyclooxygenase 2 (COX2) through ROS-NF-κB pathway^[38]. Studies based on glial cells have found that PMs can induce microglia to activate and release inflammatory cytokines (such as TNF-α), which can further inhibit synaptic growth or cause neuronal damage.Considering that neurodegenerative diseases are associated with changes in neuronal synaptic function and nervous system inflammation, these results suggest that inflammatory cytokines derived from glial cells may be involved in mediating the occurrence of neurodegenerative diseases associated with air pollution^[33,89]^[33].

Human neuroblastoma cells (SH-SY5Y and SK-N-SH), rat adrenal pheochromocytoma cells (PC12), immortalized BV2 microglial cells, C6 astrocyte cell line, etc. Are commonly used models to study the neurotoxicological effects of PMs. For example, studies based on human neuroblastoma cells SH-SY5Y have found that diesel exhaust particles can induce neuronal gluconeogenesis, accompanied by oxidative stress and cell injury, suggesting that PMs may mediate neuronal glucose metabolism disorders and lead to cerebrovascular injury^[90]. Another study based on SH-SY5Y cells also found that oxidative stress and DNA hydroxymethylation play a role in regulating the neurotoxicity of PM_2.5^[91]. In studies based on immortalized BV2 microglia, samples of PM_2.5 collected in the morning (AM-PM_2.5) showed greater pro-inflammatory activity than samples of PM_2.5 collected in the afternoon (PM-PM_2.5), and up-regulation of nitric oxide (NO) and the pro-inflammatory cytokines interleukin-1β (IL-1β), IL-6, and chemokine ligand-1 (CCL-1) was observed in BV2 cells^[30].

4.2 In Vivo Experiment

The association between PMs exposure and adverse health outcomes in the central nervous system can be validated under controlled experimental conditions^[7]. A large number of neurotoxicological experiments based on wild-type experimental animals and gene knockout models have explored the neurotoxic effects and mechanisms of PMs. Commonly used wild-type experimental animals include C57BL/6 mouse model, SD rat model, etc. Gene knockout experimental animals include Nrf2 knockout mouse model (Nrf2^-/-), apolipoprotein E knockout mouse model (ApoE^-/-), etc.

The results based on wild-type C57BL/6J mice showed that exposure to PM_2.5, SO₂ and NO₂ could impair the spatial learning and memory ability of mice, and lead to abnormal expression of apoptosis-related genes such as p53, bax and bcl-2. This study suggests that mitochondrial dysfunction caused by air pollution is related to the above neuropathic dysfunction^[40]. A study on male SD rats found that PM_2.5 exposure significantly reduced the cognitive and learning abilities of rats, and increased the levels of lead, manganese, aluminum and glutamate in the hippocampus of experimental animals after exposure.The decreased expression of ionotropic glutamate receptor N-methyl-D-aspartate receptor (NMDA receptor) and the increased expression of metabotropic glutamate receptor 1 suggest that the impairment of learning and memory caused by PM_2.5 may be related to the structural changes in the hippocampus and the abnormal expression of neurotransmitters and their receptors^[93].

Nrf2 is a key factor in regulating oxidative stress and energy metabolism, which is highly expressed in tissues with vigorous metabolism and detoxification function. Nrf2^-/- mice can be used for pathological and toxicological studies related to neurodegeneration, ischemic injury and nervous system tumors^[94,95]. Studies have explored the role of Nrf2 and NF-κB signaling pathway in metabolic disorders and nervous system inflammation induced by PM_2.5 based on Nrf2^-/- mice, and the results show that Nrf2 deficiency can increase the activation of NF-κB signaling pathway in astrocytes induced by PM_2.5, and aggravate the nerve damage caused by PM_2.5^[96]. Apolipoprotein E (ApoE) plays an important role in lipid metabolism, and its abnormal function is considered to be related to AD and cardiovascular and cerebrovascular diseases^[97,98]. ApoE is mainly synthesized and secreted by astrocytes in the central nervous system, which can transport cholesterol to neurons through the corresponding receptors, and participate in the maintenance of synaptic plasticity and the repair of damaged nerve cells. The mouse model of ApoE^-/- has a higher baseline level of oxidative stress and an increased susceptibility to external stimuli. Morphometric analysis of the central nervous system of ApoE^-/- mice exposed to PMs showed that the brain was the key target of PMs exposure, and suggested that oxidative stress was an important inducer of neurodegenerative diseases caused by PMs^[7]. In another study, a mouse model of ApoE^-/- was used to explore the effects of long-term exposure to low-dose PMs on cardiovascular and cerebrovascular diseases. After exposure, the expression of oxidative stress markers and vascular inflammation in the vascular wall of experimental animals was observed to be upregulated, suggesting that PMs exposure may further aggravate atherosclerosis and increase the potential risk of cardiovascular and cerebrovascular diseases^[99].

The in vivo and in vitro experimental methods have the advantages of short cycle and controllable conditions. However, when exploring the neurotoxicological effects and mechanisms of PMs, the current experimental studies also have some limitations: for example, many in vivo experimental exposure methods are difficult to simulate the real exposure situation of human body.Different experimental conditions may lead to different research conclusions, such as the lack of consideration of the interaction between different cells in vitro experimental design, the lack of analysis of PMs effect components, and so on.

5 Molecular Mechanism of Neurotoxicity of Atmospheric Particulate Matter

PMs-induced neurotoxicity is thought to be related to oxidative stress and inflammation^[102]. Studies have shown that PMs can not only cause systemic inflammatory response, but also interact with glial cells (such as microglia and astrocytes) and neurons in brain tissue, inducing oxidative stress and inflammatory response in the central nervous system, resulting in neurotoxicity^[86]. In addition, PMs may also aggravate nervous system injury by affecting blood homeostasis, destroying the tight junction between brain microvascular endothelial cells, and increasing the permeability of blood-brain barrier. The key signaling pathways involved in the regulation of PMs neurotoxicity include NF-κB signaling pathway, MAPKs signaling pathway and Notch signaling pathway.DNA damage and epigenetic regulation as a new mechanism of PMs neurotoxicological effects have gradually attracted attention.

5.1 Oxidative stress and mitochondrial damage

Oxidative stress is considered to be one of the important mechanisms by which PMs induce inflammatory response and exert neurotoxicological effects^[7]. PMs are loaded with a variety of components, such as environmentally persistent free radicals, peroxides, aromatic compounds and soluble metals, which can produce reactive oxygen species (ROS) in vivo. It has been shown that water-soluble extracts, organic extracts and carbon core components of PM_2.5 can differentially induce oxidative stress, thereby enhancing inflammation and possibly leading to cell death^[91]^[35]. For example, studies based on human neuroblastoma cells SK-N-SH have found that aromatic compounds trigger intracellular ROS production, leading to the activation of apoptotic signaling pathways^[103]. Mitochondria is the main site of ROS production and one of the cellular targets of PMs destruction, which plays a key role in PMs-induced body damage^[35,16]. For example, studies based on SH-SY5Y cells have shown that PM_2.5 can cause mitochondrial swelling, opening of mitochondrial permeability transition pore (MPTP), and decrease of ATP level, mitochondrial membrane potential and mitochondrial DNA copy number in SH-SY5Y cells, suggesting that mitochondrial dysfunction is a potential mechanism of brain nerve cell damage caused by PM_2.5^[104]. In addition, PMs can also interact with enzymes that catalyze the generation of ROS. For example, PMs can directly induce the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which leads to the formation of ROS near the plasma membrane and ultimately causes oxidative damage to brain tissue^[105,106]. PMs can also exacerbate oxidative damage by disrupting antioxidant defense systems. SD Rats were injected intraperitoneally with PM_2.5 once every 7 days, and the brain oxidative stress response was examined after 3, 6 and 12 months of exposure. Superoxide dismutase (SOD), which is related to the elimination of

O 2 -

(·), was observed.The activity of Glutathione peroxidase (GSH-Px) showed the same decreasing trend as that of superoxide dismutase (SOD)^[107].

5.2 Inflammatory reaction

Recent studies have shown that PMs can change the state of oxidative stress and the level of inflammation in the circulatory system, and then promote the expression of inflammatory cytokines, chemokines and adhesion molecules, and ultimately cause systemic inflammatory response. These pro-inflammatory factors can enter the central nervous system through blood circulation and produce toxic effects on various tissues and organs, including the nervous system^[86]. In addition, PMs can also induce the activation of glial cells, leading to inflammatory response, and further damage the function of the nervous system. Exposure to PMs can promote microglia to secrete a variety of inflammatory mediators such as TNF-α and IL-1β, which can act on astrocytes and induce secondary inflammatory responses^[108]. Microglia and astrocytes activated by PMs produce ROS and NO, which destroy myelin sheath and neuronal structure and further cause nerve damage^[109]. Animal experiments have shown that the continuous activation of microglia and astrocytes accelerates the development of neurodegenerative diseases, including AD, PD, ALS and MS^[109]. Epidemiological studies have found that the expression level of COX2 in brain tissue samples of urban residents in areas with serious air pollution is significantly increased, and the accumulation level of beta-amyloid protein in neurons and astrocytes is relatively high^[64].

5.3 Key Signaling Pathways Regulating PMs Neurotoxicity

Studies have shown that PMs exposure can activate a variety of signaling pathways, such as NF-κB signaling pathway, Notch signaling pathway and MAPKs signaling pathway, which are involved in the process of PMs-regulated nerve injury^[38,110]. The neurotoxicological effects of PMs are closely related to the inflammatory response, and the up-regulation of nuclear transcription factor NF-κB can induce the release of pro-inflammatory factors^[111]. Exposure of microglia to nanoparticles resulted in increased gene expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1), as well as increased secretion of TNF-α, IL-1β, interleukin-4 (IL-4), and IL-6, which was accompanied by activation of the nuclear transcription factor NF-κB^[89]. In vivo studies have shown that PM_2.5 can activate NF-κB signaling pathway in astrocytes of Nrf2^-/- mice, resulting in toxic phenotypes such as dysplasia, peripheral inflammation, nerve damage and hypothalamic oxidative stress^[96]. At the same time, the antioxidant function of Nrf2 signaling pathway can alleviate the neurotoxicity induced by PM^[112]. Notch signaling pathway plays an important role in controlling neuronal morphology and astrocyte fate, and astrocytes can respond to lipopolysaccharide stimulation through NF-κB regulated Notch signaling pathway^[39]. Tumor suppressor gene p53 is a pro-apoptotic factor. As a member of MAPKs signaling pathway, it plays an important role in the regulation of neuronal apoptosis^[110]. Studies have shown that the combined exposure of PM_2.5, SO₂ and NO₂ can mediate neuronal apoptosis through the activation of p53 signaling pathway^[40].

5.4 DNA Damage and Epigenetic Regulation

Many pollutants and their metabolites carried by PMs have certain cytotoxicity, some of which can destroy DNA structure and block cell cycle in G1 or S phase, thus affecting cell proliferation and increasing the probability of mutation^[113]. DNA damage induced by PMs exposure includes DNA breakage and oxidative DNA damage^[114]. The results showed that the organic extracts of PM_2.5 could cause DNA fragmentation and micronucleus formation, microtubule disruption and chromosome breakage were observed in mitotic cells, and DNA damage could lead to the activation of protein kinases such as ATM, which further mediated p53 phosphorylation and apoptosis^[115]^[114]^[113]. In addition, PMs can also induce epigenetic changes^[37]. DNA hydroxymethylation refers to the process that the 5 'carbon atom of DNA cytosine is modified by hydroxymethylation under the action of TET enzyme without changing the DNA sequence^[116]. DNA hydroxymethylation can affect gene transcription and neural differentiation, and thus participate in the regulation of many physiological and pathological processes^[117]. PM_2.5 and its organic extracts can lead to neurodevelopmental disorders by increasing the level of neuronal DNA hydroxymethylation, which is manifested by the decrease of neuronal axon length and the decrease of mRNA expression of neuronal and synaptic markers^[91]. In addition, PM_2.5 exposure can also change the DNA methylation pattern in the promoter region of target genes, which further leads to the abnormal expression of autism and synapse-related gene mRNA^[118]. It is of great significance for the discovery of PMs neurotoxicological biomarkers to clarify the epigenetic changes in the nervous system caused by PMs pollution and the downstream effects mediated by PMs pollution.

5.5 Affect blood homeostasis

Previous studies have suggested that ultrafine particulate matter can penetrate the alveoli and enter the human blood circulation system, and the discovery of exogenous ultrafine particulate matter in the blood and pleural effusion of the general population provides direct evidence for this hypothesis^[119]. PMs entering the blood circulation system may interact with blood components, and their potential effects on the nervous system by regulating blood homeostasis deserve attention. For example, PMs can interfere with the coagulation cascade by activating the kallikrein-kinin system (KKS), leading to upregulation of thrombin levels^[120]. Thrombin can bind to the corresponding receptors of astrocytes (such as PAR1 receptor), induce astrocyte activation and up-regulate the secretion of inflammatory factors, and further affect the central nervous system^[121]. On the other hand, the activation of plasma key proenzymes (such as KKS) can regulate the permeability of vascular endothelial cells, which may lead to changes in the permeability of the blood-brain barrier and provide a possibility for atmospheric fine particles to enter the central nervous system through the blood-brain barrier^[122]^[123].

In general, the current studies on the molecular mechanisms of PMs neurotoxicity are mostly focused on oxidative stress and inflammatory response, lacking the initial molecular events and key toxic pathways.

6 Conclusion and prospect

In recent years, great progress has been made in the prevention and control of air pollution in China, but the situation of air pollution, especially atmospheric particulate matter pollution, is still grim. There has been a large body of research evidence suggesting a correlation between environmental exposure to PMs and adverse health outcomes in the nervous system. Considering that the central nervous system is responsible for regulating many physiological functions of the body, the neurotoxicological effects of PMs will have a profound impact on human health. However, the current understanding of PMs exposure and adverse health outcomes in the nervous system is still very limited, and the study of neurotoxicity of exposure to atmospheric particulate matter pollution will continue to be an important aspect of PMs health effect evaluation.

(1) At present, there are some limitations in epidemiological studies on neurologic diseases induced by atmospheric particulate matter exposure, such as small sample size, insufficient representativeness, incomplete cohort design and lack of individual exposure level data. In order to scientifically explain the health effects of environmental exposure to PMs, it is urgent to establish a scientific standard research method system and carry out prospective cohort studies with large samples combined with biomarkers and other indicators.

(2) The sources and causes of atmospheric particulate matter are complex, and the composition of PMs is different in different regions and seasons, and the components of PMs inducing specific neurotoxicological effects are not clear enough, so the identification of effect components is of great guiding significance for air pollution prevention and control. At the same time, the multi-omics study of PMs and their specific components will help to fully explain the neurotoxicological mechanism of atmospheric particulate matter.

(3) Cells cultured in vitro often lack the interaction between different kinds of cells in the body, and the establishment of co-culture system of nerve cells in vitro is the trend of neurotoxicological effects and mechanisms of PMs in the future. In addition, considering the effects of PMs exposure mode, dose and frequency on the neurotoxicological phenotype of experimental animals, in order to restore the real human exposure to the maximum extent, more and more studies use real-time online systemic inhalation exposure system to carry out in vivo experiments.

(4) In practical studies, the differences in sampling methods, exposure modes, model selection and detection indicators often make it difficult to integrate different studies into a systematic conclusion, so it is urgent to establish a standard method for the evaluation of neurotoxicological effects of atmospheric particulate matter.

(5) The mechanism of neurotoxicity of atmospheric particulate matter is still unclear, and most of the current studies focus on oxidative stress and inflammatory response, so it is necessary to strengthen the exploration of toxic initiation molecular events and specific pathways in the future.

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