Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: Neurochem Int. 2019 Oct 15;131:104580. doi: 10.1016/j.neuint.2019.104580

Developmental impact of air pollution on brain function

Lucio G Costa 1,2, Toby B Cole 1,3, Khoi Dao 1, Yu-Chi Chang 1,a, Jacqueline M Garrick 1
PMCID: PMC6892600  NIHMSID: NIHMS1543979  PMID: 31626830

Abstract

Air pollution is an important contributor to the global burden of disease, particularly to respiratory and cardiovascular diseases. In recent years, evidence is accumulating that air pollution may adversely affect the nervous system as shown by human epidemiological studies and by animal models. Age appears to play a relevant role in air pollution-induced neurotoxicity, with growing evidence suggesting that air pollution may contribute to neurodevelopmental and neurodegenerative diseases. Traffic-related air pollution (e.g. diesel exhaust) is an important contributor to urban air pollution, and fine and ultrafine particulate matter (PM) may possibly be its more relevant component. Air pollution is associated with increased oxidative stress and inflammation both in the periphery and in the nervous system, and fine and ultrafine PM can directly access the central nervous system. This short review focuses on the adverse effects of air pollution on the developing brain; it discusses some characteristics that make the developing brain more susceptible to toxic effects, and summarizes the animal and human evidence suggesting that exposure to elevated air pollution is associated with a number of behavioral and biochemical adverse effects. It also discusses more in detail the emerging evidence of an association between perinatal exposure to air pollution and increased risk of autism spectrum disorder. Some of the common mechanisms that may underlie the neurotoxicity and developmental neurotoxicity of air pollution are also discussed. Considering the evidence presented in this review, any policy and legislative effort aimed at reducing air pollution would be protective of children’s well-being.

Keywords: Air pollution, Diesel exhaust (DE), Particulate matter (PM), Developmental neurotoxicity, Autism spectrum disorder, Oxidative stress, Neuroinflammation

Air pollution

In December 1952, a dense smog containing sulfur dioxide and smoke particulate (from coals burning and industrial activities) descended upon London, resulting in a very high morbidity and mortality (Bell and Davis, 2001; Anderson et al. 2012). This episode, and various others, prompted awareness that quality of air is an important determinant of human health. In 1970 regulation was enacted in the U.S. (the Clean Air Act), and limits were set for six primary air pollutants, carbon monoxide, lead, nitrogen dioxide, ozone, sulfur dioxide, and particulate matter (PM). Sources of these compounds are motor vehicles, construction equipment, electric utilities, and industrial facilities. Ozone is formed when nitrogen oxides react with volatile organic carbons and oxygen in the presence of heat and light, while sulfur dioxide is formed when sulfur-containing fuel is burned. PM is a complex mixture of acids, organic chemicals, metals and soil or dust particles (Anderson et al. 2012) which can be of natural sources (e.g. volcanoes, fires) or of man-made sources (e.g. tobacco smoke, vehicle emissions) (Anderson et al. 2012). PM is defined by its aerodynamic equivalent diameter, with particles with the same diameter tending to have similar settling velocity; PM10 is comprised of particles <10 μm in diameter, while PM2.5 represents particles <2.5 μm in diameter (fine PM). Also, of relevance (particularly regarding neurotoxicity) is ultrafine PM (UFPM or PM0.1, with diameter <100 nm).

Ambient air pollution is continuously monitored by regulatory agencies in various countries, and most particulate information is available for PM2.5. The Air Quality Index provides information on levels of air pollutants, and in some cases on their potential adverse effects. Its specific definition varies among countries but in general it varies between 0 and 500, with values below 50 considered acceptable and values over 150–200 considered to be unhealthy. In some urban areas (e.g. large cities in India, China or Mexico) the Air Quality Index may remain above 200 for several days and even exceed it. Traffic-related air pollution (TRAP) is a major contributor to global air pollution, of which diesel exhaust (DE) is an important component (Ghio et al. 2012). In New Delhi, it is estimated that traffic may contribute to up to 72% of air pollution (Goyal et al. 2006). DE is a major constituent of ambient PM, particularly PM2.5 and UFPM (USEPA, 2002), and DE exposure is often utilized as a measure of traffic-related air pollution. In addition to PM, DE contains more than forty toxic air pollutants, including nitrogen and sulfur oxides, carbon monoxide, hydrocarbons, volatile organic compounds, metals, organic and elemental carbon, and its makeup varies by engine load conditions and fuel composition (Cooney and Hickey, 2008; Lim et al. 2009). In recent years, improved diesel engine technology and the use of specialized catalytic converters have changed the composition of DE, resulting in an output lower in concentration of PM, nitrogen oxides, volatile organic compounds, sulfur oxide and carbon monoxide (Su et al. 2008).

Inhalation is the main exposure route for air pollutants. While PM10 is filtered out by the nose and upper airways, PM2.5 is deposited in the lungs or ingested (Forman and Finch, 2018). PM2.5 can enter the olfactory epithelium and be transported in the olfactory bulb, and then further to the olfactory cortex and other brain regions (Ajimani et al. 2016). Oberdoerster and his colleagues (Oberdoerster and Utell, 2002; Oberdoerster et al., 2004) have shown that UFPM enters the brain through the olfactory nerves and distribute to other regions such as the cerebral cortex and the cerebellum. Once PM reaches the lung, it can translocate to the blood and from there to the brain (Forman and Finch, 2018). The first and most studied target for air pollution toxicity are the airways; nose and throat irritation, bronchoconstriction and dyspnea are observed, particularly in individuals with pre-existing respiratory conditions (Kampa and Castanas, 2008). PM that penetrates the alveolar epithelium and ozone are responsible for lung inflammation and, together with metals, may also induce emphysema and lung cancer (Pope and Dockery, 2006). The cardiovascular system has also emerged in the past two decades as an important target for air pollution toxicity (Brook and Rajagopalan, 2007; Brook et al. 2010), as systemic inflammatory changes caused by air pollution affect blood coagulation, atherosclerosis progression, and are associated with consistent increased risk for cardiovascular events (Pope and Dockery, 2006; Brook and Rajagopalan, 2007; Brook et al. 2010).

Neurotoxicity of air pollution

In recent years mounting evidence indicates the central nervous system (CNS) as a primary important target of air pollution. As indicated before, inhaled UFPM may enter the CNS either by way of the olfactory nerve, or through the endothelial junctions that comprise the vascular interface of the blood-brain barrier, rendered more permeable by higher levels of peripheral oxidative stress and inflammation (Lochhead et al. 2010). As discussed in several reviews, human epidemiological and animal studies suggest that air pollution may negatively affect the CNS and contribute to CNS diseases (Calderon-Garciduenas et al. 2002; Block and Calderon-Garciduenas, 2009; Genc et al. 2012; Block et al. 2012; Costa et al. 2014; 2017a; Sram et al. 2017; Russ et al. 2019). Decreases in cognitive and olfactory functions, auditory deficits, depressive symptoms and other adverse neuropsychological effects have been reported in children, adults and the elderly (Ranft et al. 2009; Freire et al. 2010; Calderon-Garciduenas et al. 2010; 2011; 2019; Fonken et al. 2011; Guxens and Sunyer, 2012; Lee et al. 2019), where increased markers of oxidative stress and neuroinflammation have been found in postmortem investigations (Calderon-Garciduenas et al. 2008; 2011; 2012; Levesque et al. 2011a). Animal studies are supportive of the human observations (Costa et al. 2014). For example, dogs exposed to heavy air pollution had signs of neuroinflammation and neurodegeneration in various brain regions (Calderon-Garciduenas et al. 2002; 2003), and mice exposed to traffic in a highway tunnel had higher levels of pro-inflammatory cytokines in the brain (Bos et al. 2012). Controlled exposure to DE has been reported to alter motor activity, spatial learning and memory, novel object recognition ability, and emotional behavior, and to cause microglia activation, oxidative stress and neuro-inflammation in the CNS (MohanKumar et al. 2008; Gerlofs-Nijland et al. 2010; Win-Shwe and Fujimaki, 2011; Levesque et al. 2011b; Ehsanifar et al. 2019; Cole et al. 2016). Evidence accumulated so far strongly indicates that air pollution negatively affects the CNS, and of much interest is whether it may be causally associated with neurological or neuropsychiatric disorders, particularly neurodevelopmental and neurodegenerative diseases. Several epidemiological studies identifying adverse effects of air pollution on behavior, particularly cognitive behavior, have identified significant effects in the elderly (Ranft et al. 2009; Power et al. 2011; Weuve et al. 2012; Chen et al. 2015). Aging is often associated with a wide variety of clinical and pathological conditions which can be generally classified as neurodegenerative diseases (e.g. Alzheimer’s disease (AD), or Parkinson’s disease (PD)). There is only limited evidence from epidemiological studies suggesting that air pollution may be associated with PD, though observations in humans and in controlled animal studies suggest that air pollution may increase the expression of the PD marker α-synuclein (Costa, 2017). In contrast, evidence is stronger for an association between elevated air pollution and AD, as indicated by epidemiological and experimental studies (Power et al. 2016; Costa, 2017). As age appears to represent a significant determinant of air pollution neurotoxicity, several investigators have focused on effects of perinatal (pre- and post-natal) air pollution exposure on brain development and on possible associations with neurodevelopmental disorders. The following sections will discuss the general characteristics that render the developing brain extremely sensitive to external insult, and the current knowledge on the effect of air pollution on brain development, with a focus on a major neurodevelopmental disorder, autism spectrum disorder (ASD). This is not a systematic review and does not include evaluation of the risk of bias or quantitative evaluation of the evidence.

The sensitivity of the developing central nervous system to environmental insult

Several lines of evidence suggest that the developing nervous system may be more susceptible, and/or differentially susceptible, to toxic insult than the adult nervous system. Different parts of the CNS develop at different stages; cell proliferation, migration and differentiation contribute to the formation of definite brain structures, in which the correct number of cells in the proper location is necessary for proper function (Bayer et al., 1993; Rodier, 1994). Even within a single brain region, subpopulations of neurons may have different rates of development; for example, in the cerebellum, Purkinje cells develop early (embryonic days 13–15 in the rat, corresponding to gestational weeks 5–7 in humans), while granule cells are generated much later (postnatal days 4–19 in the rat, corresponding to gestational weeks 24–36) (Bayer et al. 1993). Failure in cell proliferation or cell migration because of exposure to toxic insults has profound deleterious effects on the developing brain (Costa et al. 2004). Though neurons maintain the ability to make new synapses throughout life, the period of brain development when synaptogenesis occurs is critical for the formation of the basic circuitry of the nervous system (Rodier, 1995). Furthermore, in the developing nervous system, neurotransmitters may have functions other than neurotransmission, such as modulation of cell proliferation, survival, and differentiation (Nguyen et al. 2001), and toxicants that interfere with neurotransmission during development may cause permanent defects in the CNS. Developmental neurogenesis produces more neurons than those found in the mature nervous system, and excess neurons are pruned by finely regulated apoptotic processes at different developmental times (Johnson and Deckwerth, 1993). Any chemical interfering with apoptotic processes may trigger degeneration of neurons that would not otherwise have been deleted or may promote survival of unnecessary cells (Ikonomidou et al. 2001). In addition, pruning, defined as loss of synapses, also occurs physiologically in the developing brain, and chemicals interfering with this process (which is longer lasting than neuronal loss due to apoptosis) would have the most significant adverse effects on brain functions (Webb et al. 2001). It has become apparent that glial cells (astrocytes, oligodendrocytes and microglia) also play a relevant role in brain development and may be the target of toxic action (Aschner and Costa, 2004), and several chemicals exert profound neurotoxic effects when exposure occurs during the brain growth spurt, characterized by extensive glial cell proliferation and maturation. In addition to all sensitive processes described, the developing brain is distinguished by the absence of a blood-brain barrier. The development of this barrier is a gradual process, beginning in utero and reaching completion around postnatal month six in humans (Rodier, 1995). The incomplete development of the blood-brain barrier allows endogenous and exogenous chemicals, normally excluded from the brain, to freely enter the developing brain.

Of the approximately 200 chemicals which have been found to be neurotoxic in humans, a great number are developmental neurotoxicants (Grandjean and Landrigan, 2006). As the developing brain is often more sensitive than the adult brain to toxic insult, neurotoxicity may be observed at lower exposure levels, or be different from those observed in adult, upon similar exposure. In some cases, developmental exposure to neurotoxicants results in morphological alteration of the CNS, with accompanying changes in functions. However, in several instances, functional changes may be the result of more subtle biochemical and molecular alterations without major structural abnormalities. Exposure to chemicals which may adversely affect the nervous system has been suggested to be associated with a number of developmental disabilities (learning disabilities, attention-deficit hyperactivity disorder, dyslexia, sensory deficits, mental retardation, autism spectrum disorders) which are diagnosed in children at an alarmingly increasing rate (Miodovnik, 2011).

Neurodevelopmental effects of air pollution: animal studies

The increasing evidence that elevated air pollution may adversely affect the development of the nervous system, and thereby cause significant behavioral deficits in children, has been recently underlined (Kicinski and Nawrot, 2015; D’Angiulli, 2018; Payne-Sturges et al. 2019; Sunjer and Dadvand, 2019). Indeed, epidemiological and animal studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity (Calderon-Garciduenas et al. 2008; 2011; 2012; Freire et al. 2010; Guxens and Sunjer, 2012; Guxens et al. 2014), with experimental studies supporting observations in humans and vice versa. Regarding controlled animal studies, it has been reported that in utero exposure to high levels of DE (1.0 mg/m3) caused alterations in motor activity, motor coordination and impulsive behavior in male mice (Yokota et al. 2009; 2013; Suzuki et al. 2010). Early postnatal exposure of mice (PND 4–7 and 10–13) to concentrated ambient PM (308.5 μg/kg) was reported to cause behavioral changes (enhanced bias towards immediate rewards), as well as long-term impairment of short-term memory and impulsivity-like behavior (Allen et al. 2013; 2014a). Additional studies in mice showed that post-natal administration of DE-PM caused changes in GFAP expression in various brain regions (Morris-Shaffer et al. 2019), while a similar exposure to low level ultrafine particles caused male-specific learning and memory dysfunctions (Cory-Slechta et al. 2018). Depression-like responses were found in mice exposed prenatally to urban air nanoparticles (350 μg/m3) (Davis et al. 2013). Other studies in mice have shown that developmental DE exposure alters motor activity, spatial learning and memory, and novel object recognition ability, and causes changes in gene expression, neuroinflammation, and oxidative damage (Hougaard et al. 2008; 2009; Tsukue et al. 2009; Win-Shwe et al. 2008; 2014). A recent study in mice (Ehsanifar et al. 2019) reported that pre-natal exposure to DE particles (350 μg/m3) caused anxiety, spatial memory disorders and altered expression of hippocampal pro-inflammatory cytokines (e.g. IL-6) and NMDA receptor subunit in the hippocampus of adult offspring. Zhang et al. (2018) found that maternal exposure of mice to PM2.5 (75–1000 μg/m3) altered the development of the cerebral cortex and induced significant apoptosis in the offspring. Yet another recent study (Cui et al. 2019) found that pre-natal exposure of mice to PM2.5 (400 μg/m3) enhanced spontaneous locomotion and exploratory behaviors and altered dopamine and glycine pathways in the brain. While all these studies were carried out in mice, evidence of developmental neurotoxicity of air pollution in other animal species also exists. For example, rats were exposed to UFPM during gestation and until 25 weeks of age; male rats exhibited activated microglia, impaired hippocampal neurogenesis, alteration of the blood-brain-barrier, together with behavioral symptoms of depression and deficits in contextual memory (Woodward et al. 2018). In yet another animal species, the rabbit, Bernal-Melendez et al. (2019) found that prenatal exposure to DE (1 mg/m3) from gestational day 3 to 27, caused changes in olfactory bulb morphology and in olfactory-based behaviors in the offspring, together with alterations in monoaminergic neurotransmission.

Neurodevelopmental effects of air pollution: human studies

Human epidemiological studies support the above experimental findings demonstrating that pre- and/or post-natal exposure to elevated air pollution is associated with behavioral alterations in children (Kicinski and Nawrot, 2015; D’Angiulli, 2018; Payne-Sturges et al. 2019; Sunjer and Dadvand, 2019). Studies in Mexico City have shown elevated levels of neuroinflammatory markers in brains of children exposed to high air pollution, as well as cognitive deficits (Calderon-Garciduenas et al. 2008; 2011; 2013). Newman et al. (2013) reported hyperactivity in 7-year old children associated with early life exposure to traffic-related air pollution. A retrospective cohort study in Catalonia, Spain, also found an association between air pollution and incidence of attention deficit hyperactivity disorder (ADHD) (Saez et al. 2018). In contrast, a very large study with eight European population-based birth/child cohorts reported no association between air pollution exposure and ADHD (Forns et al. 2018). In six European cohorts, exposure to air pollution during pregnancy was found to be associated with delayed psychomotor development (Guxens et al. 2014). A recent study reported that exposure to traffic-related air pollution is inversely associated with sustained attention in adolescents (Kicinski et al. 2015), and to lower cognitive development in primary school children (Sunyer et al. 2015). The BREATHE project in Catalonia, Spain, found that exposure to TRAP was associated with behavioral problems in children, including cognitive development (Forns et al. 2016; 2017), and that the APOEε4 genotype represented a risk factor for some of them (Alemany et al. 2018). In the same population, Rivas et al. (2019) found working memory and attention deficits in boys. Another recent study in the U.K. reported that children with intellectual disabilities were found to be significantly more likely to live in areas with high levels of DE-PM, NO2 and CO (Emerson et al. 2018).

Altogether, human and animal findings indicate that exposure to air pollution may damage the developing brain and perhaps contribute to neurodevelopmental disorders A major neurodevelopmental disorder is autism spectrum disorder, and as evidence from human epidemiological and from controlled animal studies suggests that air pollution may be associated with its etiology, these studies are discussed in more detail.

Developmental exposure to air pollution and autism spectrum disorder

Autism is a neurodevelopmental disorder characterized by marked reduction of social and communicative skills, and by the presence of stereotyped behaviors (Levy et al. 2009). Currently, the term autism spectrum disorder (ASD) is utilized to include autism and a range of similar disorders, such as Asperger’s syndrome. The symptoms of ASD are typically present before the age of three, and are often accompanied by abnormalities of cognitive functioning, learning, attention, and sensory processing. The incidence of ASD appears to have increased in the past few decades, and it is now estimated at about 7–9/1000, though certain studies have identified up to 27/1000 children affected by ASD (Wingate et al. 2012). ASD is more common in males than in females, and represents an important societal problem, as the economic burden of caring for an individual with ASD and intellectual disability during his/her lifespan has been estimated at $2.4 million (Schaafsma and Pfaff, 2014; Buescher et al. 2014). Children diagnosed with ASD present several morphological abnormalities in the brain (Wegiel et al. 2010; Stoner et al. 2014), higher levels of oxidative stress (Frustaci et al. 2012), neuroinflammation and increased systemic inflammation (El-Ansary and Al-Ayadhi, 2012; Depino, 2013).

Susceptibility to ASD is attributable to both genetic and environmental factors (Levy et al. 2009; Landrigan, 2010; Kalkbrenner et al. 2014; Pelch et al. 2019). Though candidate susceptibility genes for ASD have been identified, no single anomaly predominates, and the fraction of ASD attributable to genetic inheritance may be only about 30–50% (Sandin et al. 2014). DNA methylation is also altered in ASD, suggesting that epigenetic dysregulation may contribute to these disorders (Nardone et al. 2014; Ladd-Acosta et al. 2019). Thus, ASD may result from the complex interactions between genes conferring vulnerability and diverse environmental factors. In addition to air pollution (particularly traffic-related), which is discussed in the next section, several other chemicals have been studied in this regard including metals, pesticides and other industrial chemicals (Pelch et al. 2019). A strong association between an environmental factor and ASD has been found with maternal infection (Patterson, 2011). Studies in humans and in various animal species have demonstrated that maternal immune activation (MIA), due to viral or bacterial infection, increases neuroinflammation in the placenta and in the fetal brain, leading to offspring that display ASD-like behaviors (Malkova et al. 2012; Xuan and Hampson, 2014; Estes and McAllister, 2016). Several effects seen in MIA are also found upon developmental exposure to air pollution.

Epidemiological studies have found associations between exposures to traffic-related air pollution and ASD and such findings are supported by a few animal experiments (Costa et al. 2017b). Volk et al. (2011; 2013) and Becerra et al. (2013) found that in California residential proximity to freeways and gestational and early-life exposure to traffic-related air pollution were associated with autism. Another study (Roberts et al. 2013) found that perinatal exposure to DE was significantly associated with ASD, particularly in boys, while two studies in Taiwan and in Pennsylvania, respectively, reported an increased risk of ASD associated with PM (Jung et al. 2013; Talbott et al. 2015). A similar study in two cohorts (North Carolina and California) also reported an association between PM exposure and ASD, particularly when exposure occurred in the third trimester of pregnancy (Kalkbrenner et al. 2015). The latter finding was also reported by Raz et al. (2015) in the Nurses’ Health Study II cohort. Additional studies population-based in Vancouver, British Columbia (Pagalan et al. 2019) and in Cincinnati, OH (Kaufman et al. 2019) reported an association between exposure to nitric oxide and ASD, and between ozone and PM2.5 and ASD, respectively. A recent study in Shanghai, China found that exposure to PM2.5, and PM10 during the first three years of life significantly increased the risk of ASD (Chen et al. 2019). Similarly, a study in Denmark reported an association between postnatal exposure to air pollution (particularly PM2.5 and sulfur dioxide) and ASD (Ritz et al. 2019).

Though these epidemiological studies show moderate to strong associations between exposure to air pollution in utero and/or early in life and risk of ASD, they have been criticized because of the exposure matrix and multiple confounding factors (Fordyce et al. 2018). However, animal studies generally agree with the positive human observations (Costa et al. 2014; 2017a; 2017b). Developmental exposure of mice to DE is associated with behaviors like those present in humans with ASD, including higher motor activity, increased self-grooming, and rearing (Thirtamara Rajamani et al. 2013). Postnatal exposure to concentrated ambient ultrafine particles (on PND 4–7 and 10–13) caused persistent glial cell activation, ventriculomegaly (lateral ventricular dilation), and changes in cytokines and neurotransmitters which occurred preferentially in male mice (Allen et al. 2014a; 2014b). These investigators also reported male-specific alterations in social novelty preferences (an indication of low sociability) and a reduction in testosterone levels (Sobolewski et al. 2018). In another study, prenatal exposure to UFPM was found to cause hypermyelination of the cerebellum in male mice only, together with ultrastructural abnormalities and increase in iron content (Klocke et al. 2018), as also seen in ASD (Fatemi et al. 2012). Chang et al. (2018) found that perinatal exposure of mice to DE at environmentally relevant concentrations (250–300 μg/m3, from GD 0 to PND 21) caused significant behavioral deficits in the domains of persistent/repetitive behaviors (T-maze and marble burial tests), communication (isolation-induced ultrasonic vocalization and responses to social odors), and social interactions (reciprocal interaction and social novelty tests). Similarly, Church et al (2018) found that exposure of mice to PM2.5 (138 μg/m3) throughout gestation and until PND 10, decreased sociability, reduced social interactions, and increased grooming behavior, particularly in males. Chang et al. (2019) also reported neuroinflammation (increase in IL-6) and reduced expression of reelin in the cerebral cortex of DE-exposed mice, together with subtle alterations in cortical layering, as also found in ASD (Stoner et al. 2014). A study in rats also reported that postnatal exposure to PM2.5 caused communication deficits, poor social interactions, and novelty avoidance, together with microglia activation and increases in pro-inflammatory cytokines (Li et al. 2018). In summary, there is suggestive evidence from human epidemiological studies that in utero and early-life exposure to air pollution and to TRAP is associated with an increased risk of ASD. Controlled animal studies also indicate that developmental exposure to TRAP induces behavioral, biochemical, and morphological effects also seen in ASD.

Mechanistic considerations of air pollution-induced developmental neurotoxicity

Oxidative stress and inflammation are believed to the most important contributors to the adverse effects of air pollution on the respiratory and cardiovascular systems (Møller et al. 2014). While the precise mechanisms or air pollution developmental neurotoxicity are still elusive, oxidative stress and neuroinflammation appear to play important roles. Indeed, the fact that air pollution causes systemic inflammation, microglia activation, oxidative stress, and neuro-inflammation provides biological plausibility and potential underlying mechanisms for the observed association between exposures and ensuing risk of neurodegenerative and neurodevelopmental diseases (Kraft and Harry, 2011). Such oxidative and neuroinflammatory processes may be caused in situ, for example by PM that find access to the brain, but the potential contribution of peripheral inflammation to neuro-inflammation should also be considered (Hopkins, 2007; Mumaw et al. 2016). In the CNS, activation of microglia causes an increase in oxidative stress and in pro-inflammatory cytokines. Oxidative stress and neuroinflammation are believed to play a role in PD (Qian et al. 2010; Hirsch et al. 2012) and in AD (Heneka et al. 2015; Huang et al. 2016) pathogenesis. Additional mechanisms (e.g. impairment of adult neurogenesis, alterations of microRNAs, changes in excitatory or inhibitory neurotransmission) potentially involved in air pollution-associated neurodegeneration are discussed by Costa (2017).

Activation of microglia and subsequent oxidative stress and neuroinflammation caused by air pollution may also explain the effects seen following developmental air pollution exposure. For example, microglia-generated pro-inflammatory cytokines could lead to the observed hypomyelination and ventriculomegaly via toxicity to oligodendrocytes (Allen et al. 2017). Microglia activation and neuroinflammation may also play a role in the ASD-like effects observed in mice developmentally exposed to DE (Chang et al. 2018; 2019); an initial increase in IL-6 would lead to an epigenetic-mediated decrease in reelin expression causing alterations in cortical layering (Chang et al. 2019).

Conclusions and future perspectives

During the past several years evidence has been accumulating providing strong support to the fact that high level of air pollution may be associated with neurotoxicity. Epidemiological studies in human populations and experimental studies in animals, as well as in vitro observations, provide substantial evidence of the ability of air pollution to adversely affect the CNS (Costa et al. 2014; 2017). Of note is the fact that age appears to represent a significant susceptibility factor, with the very young and the elderly being more affected, and there is increasing evidence that air pollution may play an etiological role in neurodevelopmental diseases and in neurodegenerative disorders. Regarding the former, most attention has been given to the association of air pollution with ASD, observed in humans and supported by animal studies. However, one should also consider other developmental disorders such as attention deficit hyperactivity disorder or early onset schizophrenia.

Several questions remain to further our understanding of the effects of air pollution on the developing brain. For example, epidemiological studies are not always consistent regarding which component(s) of air pollution may be more strongly associated with a certain outcome. Additionally, it would be important to carry out studies in population with chronic high- level air pollution, such as in certain urban areas of India or China. A better understanding of the cellular and molecular mechanisms responsible for the developmental effects of air pollution is also needed, as it may lead to specific therapeutic interventions (targeting, for example, microglia activation). Additional important issue would be those of potential gender differences in susceptibility and of possible gene-environment interactions. Furthermore, longitudinal studies investigating whether developmental exposure to elevated air pollution may lead to accelerated aging or to an increased incidence of neurodegenerative disorders would also be of much interest considering the ever-increasing interest in fetal or early-life origin of diseases. Needless to say, that any effort at diminishing emissions and thereby increasing air quality would be warranted.

Highlights.

  • In addition to its known targets (the respiratory and cardiovascular systems) air pollution can also adversely affect the central nervous system

  • The developing nervous system is particularly susceptible to toxic insult by chemicals including air pollution, as evidenced by epidemiological and animal studies

  • Air pollution may contribute to the etiology of neurodevelopmental diseases such as autism spectrum disorder

Funding

Research by the authors is supported by the grants from NIEHS (R01ES022949, R01ES028273, P30ES07033, P42ES04696, T32ES007032) and NICHD (U54HD08091).

Footnotes

Conflict of Interest Statement

The authors declare that they have no conflicts of interest.

References

  1. Ajmani GS, Suh HH, Pinto JM 2016. Effects of ambient air pollution exposure on olfaction: a review. Environ. Health Perspect 124, 1683–1693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alemany S, Vilor-Tejedor N, Garcia-Esteban R, Bustamante M, Dadvand P et al. 2018. Traffic-related air pollution, APOEe4 status, and neurodevelopmental outcomes among children enrolled in the BREATHE project (Catalonia, Spain). Environ. Health Perspect 126 (8), 087001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Allen JL, Conrad K, Oberdoerster G, Johnston CJ, Sleezer B et al. 2013. Developmental exposure to concentrated ambient particles and preference for immediate reward in mice. Environ. Health Perspect 121, 32–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Allen JL, Liu X, Weston D, Prince L, Oberdörster G et al. 2014a. Developmental exposure to concentrated ambient ultrafine particulate matter air pollution in mice results in persistent and sex dependent behavioral neurotoxicity and glial activation. Toxicol. Sci 140, 160–178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Allen JL, Oberdoerster G, Morris-Schaffer K, Wong C, Klocke C et al. 2017. Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders. Neurotoxicology 59, 140–154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Anderson JO, Thundiyil JG, Stolbach A 2012. Clearing the air: a review of the effects of particulate matter air pollution on human health. J. Med. Toxicol 8, 166–175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Aschner M, Costa LG (Eds.) 2004. The Role of Glia in Neurotoxicity, 2nd Ed., CRC Press, Boca Raton, pp. 456. [Google Scholar]
  8. Bayer SA, Altman J, Russo RJ, Zhang X 1993. Timetables of neurogenesis in the human brain based on experimentally detremined patterns in the rat. Neurotoxicology 14, 83–144. [PubMed] [Google Scholar]
  9. Becerra TA, Wilhelm M, Olsen J, Cockburn M, Ritz B 2013. Ambient air pollution and autism in Los Angeles County, California. Environ. Health Perspect 121, 380–386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bell ML, Davis DL 2001. Reassessment of the lethal London fog of 1952: novel indicators of acute and chronic consequences of acute exposure to air pollution. Environ. Health Perspect 109 (Suppl. 3), 389–394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bernal-Melendez E, Lacroix MC, Bouillaud P, Callebert J, Olivier B et al. 2019. Repeated gestational exposure to diesel exhaust affects the fetal olfactory system and alters olfactory-based behavior in rabbit offspring. Particle Fiber Toxicol. 16, 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Block ML, Calderon-Garciduenas L 2009. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci. 32, 506–516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Block ML, Elder A, Auten RL, Bilbo SD, Chen H et al. 2012. The outdoor pollution and brain health workshop. Neurotoxicology 33, 972–984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Bos I, DeBoever P, Emmerechts J, Buekers J, Vanoirbeek J et al. 2012. Changed gene expression in brains of mice exposed to traffic in a highway tunnel. Inhal. Toxicol 24, 676–686. [DOI] [PubMed] [Google Scholar]
  15. Brook RD, Rajagopalan S 2007. Air pollution and cardiovascular events. New Engl. J. Med 356, 2104–2105. [DOI] [PubMed] [Google Scholar]
  16. Brook RD, Rajagopalan S, Pope A, Brook JR, Bhatnagar A et al. 2010. Particulate matter air pollution and cardiovascular disease. An update to the scientific statement from the American Heart Association. Circulation 121, 2331–2378. [DOI] [PubMed] [Google Scholar]
  17. Buescher AV, Cidav Z, Knapp M, Mandell DS 2014. Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr. 168, 721–728. [DOI] [PubMed] [Google Scholar]
  18. Calderon-Garciduenas L, Azzarelli B, Acuna H, Garcia R, Gambling TM et al. 2002. Air pollution and brain damage. Toxicol. Pathol 30, 373–389. [DOI] [PubMed] [Google Scholar]
  19. Calderon-Garciduenas L, Maronpot RR, Torres-Jardon R, Henriquez-Roldan C, Schoonhoven R et al. 2003. DNA Damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration. Toxicol. Pathol 31, 524–538. [DOI] [PubMed] [Google Scholar]
  20. Calderon-Garciduenas L, Solt AC, Henriquez-Roldan C, Torres-Jardon R, Nuse B et al. 2008. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha -synuclein in children and young adults. Toxicol. Pathol 36, 289–310. [DOI] [PubMed] [Google Scholar]
  21. Calderon-Garciduenas L, Franco-Lira M, Henriquez-Roldan C, Osnaya N, Gomzalez-Maciel A et al. 2010. Urban air pollution: influences on olfactory function and pathology in exposed children and young adults. Exp. Toxicol. Pathol 62, 91–102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Calderon-Garciduenas L, Engle R, Mora-Tiscareno A, Styner M, Gomez-Garza G et al. 2011. Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children. Brain Cognition 77, 345–355. [DOI] [PubMed] [Google Scholar]
  23. Calderon-Garciduenas L, Kavanaugh M, Block M, D’Angiulli A, Delgado-Chavez R et al. 2012. Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. J. Alzheim. Dis 28, 93–107. [DOI] [PubMed] [Google Scholar]
  24. Calderon-Garciduenas L, Cross JV, Franco-Lira M, Aragon-Flores M, Kavanaugh M et al. 2013. Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrPC), interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and serum interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution. Front. Neurosci 7, 183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Chang YC, Cole TB, Costa LG 2018. Prenatal and early-life diesel exhaust exposure causes autism-like behavioral changes in mice. Part. Fibre Toxicol 15, 18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Chang YC, Daza R, Hevner R, Costa LG, Cole TB 2019. Prenatal and early life diesel exhaust exposure disrupts cortical lamina organization: evidence for a reelin-related pathogenic pathway induced by interleukin-6. Brain Behav. Immun 78, 105–115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Chen JC, Wang X, Wellenius GA, Serre ML, Driscoll I et al. 2015. Ambient air pollution and neurotoxicity on brain structure: evidence from women’s health initiative memory study. Ann. Neurol 78, 466–476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Chen G, Jin Z, Li S, Jin X, Tong S et al. 2019. Early life exposure to particulate matter air pollution (PM1, PM2.5 and PM10) and autism in Shanghai, China: a case control study. Environ. Int 121, 1121–1127. [DOI] [PubMed] [Google Scholar]
  29. Church JS, Tijerina PB, Emerson FJ, Coburn MA, Blum JL et al. 2018. Perinatal exposure to concentrated ambient particulates results in autism-like behavioral deficits in adult mice. Neurotoxicology 65, 231–240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Cole TB, Coburn J, Dao K, Roque P, Kalia V et al. 2016. Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain. Toxicology 374, 1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Cooney DJ, Hickey AJ 2008. The generation of diesel exhaust particle aerosols from a bulk source in an aerodynamic size range similar to atmospheric particles. Int. J. Nanomed 3, 435–439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Cory-Slechta DA, Allen JL, Conrad K, Marvin E, Sobolewski M 2018. Developmental exposure to low level ambient ultrafine particle air pollution and cognitive dysfunction. Neurotoxicology 69, 217–231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Costa LG 2017. Traffic-related air pollution and neurodegenerative diseases: epidemiological and experimental evidence IN: Advances in Neurotoxicology, Vol. 1, Aschner M, Costa LG, eds., Elsevier, New York, pp. 1–47. [Google Scholar]
  34. Costa LG, Aschner M, Vitalone A, Syversen T, Porat Soldin O 2004. Developmental neuropathology of environmental agents. Annu. Rev. Pharmacol. Toxicol 44, 87–110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Costa LG, Cole TB, Coburn J, Chang YC, Dao K et al. 2014. Neurotoxicants are in the air: convergence of human, animal and in vitro studies on the effects of air pollution on the brain. BioMed. Res. Int. ID 736385, 8 p. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Costa LG, Cole TB, Coburn J, Chang YC, Dao K et al. 2017a. Neurotoxicity of traffic-related air pollution. Neurotoxicology 59, 133–139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Costa LG, Chang YC, Cole TB 2017b. Developmental neurotoxicity of traffic-related air pollution: focus on autism. Curr. Envir. Health Rep 4, 156–165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Cui J, Fu Y, Lu R, Bi Y, Zhang L et al. 2019. Metabolomics analysis explores the rescue to neurobehavioral disorder induced by maternal PM2.5 exposure in mice. Ecotoxicol. Environ. Safety 169, 687–695. [DOI] [PubMed] [Google Scholar]
  39. D’Angiulli A 2018. Severe urban outdoor air pollution and children’s structural and functional brain development, from evidence to precautionary action. Front. Publ. Health 6, art. 95 (7 pg.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Davis DA, Bortolato M, Godar SC, Sander TK, Iwata N et al. 2013. Prenatal exposure to urban air nanoparticles in mice causes altered neuronal differentiation and depression like responses. PLoS ONE 8, e64128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Depino AM 2013. Peripheral and central inflammation in autism spectrum disorders. Mol. Cell. Neurosci 53, 69–76. [DOI] [PubMed] [Google Scholar]
  42. Ehsanifar M, Jafari AJ, Nikzad H, Zavareh MS, Atlasi MA et al. 2019. Prenatal exposure to diesel exhaust particles causes anxiety, spatial memory disorders with altered expression of hippocampal pro-inflammatory cytokines and NMDA receptor subunits in adult male mice offspring. Ecotoxicol. Environ. Safety 176, 34–41. [DOI] [PubMed] [Google Scholar]
  43. El-Ansary A, Al-Ayadhi L 2012. Neuroinflammation in autism spectrum disorders. J. Neuroinflammat 9, 265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Emerson E, Robertson J, Hatton C, Baines S 2018. Risk of exposure to air pollution among British children with and without intellectual disabilities. J. Intel. Disab. Res 63, 161–167. [DOI] [PubMed] [Google Scholar]
  45. Estes ML, McAllister AK 2016. Maternal immune activation: implications for neuropsychiatric disorders. Science 353, 772–776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Fatemi SH, Aldinger KA, Ashwood P, Bauman ML, Blaha CD et al. 2012. Consensus paper: pathological role of the cerebellum in autism. Cerebellum 11, 777–807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Fonken LK, Xu X, Weil ZM, Chen G, Sun Q et al. 2011. Air pollution impairs cognition, provokes depressive-like behaviors and alters hippocampal cytokine expression and morphology. Mol. Psych 16, 987–995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Fordyce TA, Leonhard MJ, Chang ET 2018. A critical review of developmental exposure to particulate matter, autism spectrum disorder, and attention deficit hyperactivity disorder. J. Environ. Sci. Health A Tox. Hazard. Subst. Environ. Eng 53, 14–204. [DOI] [PubMed] [Google Scholar]
  49. Forman HJ, Finch CE 2018. A critical review of assays for hazardous components of air pollution. Free Rad. Biol. Med 117, 202–217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Forns J, Dadvand P, Foraster M, Alvarez-Pedrerol M, Rivas I et al. 2016. Traffic-related air pollution, noise at school, and behavioral problems in Barcelona schoolchildren: a cross-sectional study. Environ. Health Perspect 124, 529–535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Forns J, Dadvand P, Esnaola M, Alvarez-Pedrerol M, Lopez-Vicente M et al. 2017. Longitudinal association between air pollution exposure at school and cognitive development in school children over a period of 3.5 years. Environ. Res 159, 416–421. [DOI] [PubMed] [Google Scholar]
  52. Forns J, Sunyer J, Garcia-Esteban R, Porta D, Ghassabian A et al. 2018. Air pollution exposure during pregnancy and symptoms of attention deficit and hyperactivity disorder in children in Europe. Epidemiology 29, 618–626. [DOI] [PubMed] [Google Scholar]
  53. Freire C, Ramos R, Puertas R, Lopez-Espinosa MJ, Julvez J et al. 2010. Association of traffic-related air pollution with cognitive development in children. J. Epidemiol. Comm. Health 64, 223–228. [DOI] [PubMed] [Google Scholar]
  54. Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Della Bernardina B, Bonassi S 2012. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Rad. Biol. Med 52, 2128–2141. [DOI] [PubMed] [Google Scholar]
  55. Genc S, Zadeoglulari Z, Fuss SH, Genc K 2012. The adverse effects of air pollution on the nervous system. J. Toxicol 2012, ID 782462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Gerlofs-Nijland ME, van Berlo D, Cassee FR, Schins RPF, Wang K et al. 2010. Effect of prolonged exposure to diesel engine exhaust on proinflammatory markers in different regions of the rat brain. Particle Fibre Toxicol 7, 12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Ghio AJ, Smith CB, Madden MC 2012. Diesel exhaust particles and airway inflammation. Curr. Op. Pulm. Med 18, 144–150. [DOI] [PubMed] [Google Scholar]
  58. Goyal SK, Ghatge SV, Nema P, Tamhane MS 2006. Understanding urban vehicular pollution problem vis-à-vis ambient air quality – a case study of a megacity (Delhi, India). Environ. Monit. Assess 119, 557–569. [DOI] [PubMed] [Google Scholar]
  59. Grandjean P, Landrigan PJ 2006. Developmental neurotoxicity of industrial chemicals. Lancet 368, 167–178. [DOI] [PubMed] [Google Scholar]
  60. Guxens M, Sunyer J 2012. A review of epidemiological studies on neuropsychological effects of air pollution. Swiss Med. Wkly 141, w13322. [DOI] [PubMed] [Google Scholar]
  61. Guxens M, Garcia-Esteban R, Giorgis-Allemand L, Forns J, Badaloni C et al. 2014. Air pollution during pregnancy and childhood cognitive and psychomotor development. Epidemiology 25, 636–647. [DOI] [PubMed] [Google Scholar]
  62. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F et al. 2015. Neuroinflammation in Alzheimer’s disease. Lancet 14, 388–405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Hirsch EC, Vyas S, Hunot S 2012. Neuroinflammation in Parkinson’s disease. Parkins. Rel. Disord 18 S1, S210–S212. [DOI] [PubMed] [Google Scholar]
  64. Hopkins SJ 2007. Central nervous system recognition of peripheral inflammation: a neural, hormonal collaboration. Acta Biomed. 78 (Suppl. 1), 231–247. [PubMed] [Google Scholar]
  65. Hougard KS, Jensen KA, Nordly P, Taxvig C, Vogel U et al. 2008. Effects of prenatal exposure to diesel exhaust particles on postnatal development, behavior, genotoxicity and inflammation in mice. Particle Fibre Toxicol. 5, 3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Hougaard KS, Saber AT, Jensen KA, Vogel U, Wallin H 2009. Diesel exhaust particles: effects on neurofunction in female mice. Basic Clin. Pharmacol. Toxicol 105, 139–143. [DOI] [PubMed] [Google Scholar]
  67. Huang WJ, Zhang X, Chen WW 2016. Role of oxidative stress in Alzheimer’s disease (Review). Biomed. Rep 4, 519–522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Ikonomidou C, Bittigau P, Koch C, Genz K, Hoester F et al. 2001. Neurotransmitters and apoptosis in the developing brain. Biochem. Pharmacol 62, 401–405. [DOI] [PubMed] [Google Scholar]
  69. Johnson EM, Deckwerth TL 1993. Molecular mechanisms of developmental neuronal death. Annu. Rev. Neurosci 16, 31–46. [DOI] [PubMed] [Google Scholar]
  70. Jung CR, Lin YT, Hwang BF 2013. Air pollution and newly diagnostic autism spectrum disorders: a population-based cohort study in Taiwan. Plos ONE 8, e75510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Kalkbrenner AE, Schmidt RJ, Penlesky AC 2014. Environmental chemical exposures and autism spectrum disorders: a review of epidemiological evidence. Curr. Probl. Pediatr. Adolesc. Health Care 44, 277–318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Kalkbrenner AE, Windham GC, Serre ML, Akita Y, Wang X et al. 2015. Particulate matter exposure, prenatal and postnatal windows of susceptibility, and autism spectrum disorders. Epidemiology 26, 30–42. [DOI] [PubMed] [Google Scholar]
  73. Kampa M, Castanas E 2008. Human health effects of air pollution. Environ. Pollut 151, 362–367. [DOI] [PubMed] [Google Scholar]
  74. Kaufman JA, Wright JM, Rice G, Connolly N, Bowers K et al. 2019. Ambient air and fine particulate matter exposures and autism spectrum disorder in metropolitan Cincinnati, Ohio. Environ. Res 171, 218–227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Kicinski M, Nawrot TS 2015. Neurobehavioral effects of air pollution in children, in: Aschner M, Costa LG (Eds.), Environmental Factors in Neurodevelopmental and Neurodegenerative Disorders. Academic Press, New York, pp. 89–105. [Google Scholar]
  76. Kicinski M, Vermeir G, Van Larebeke N, Den Hond E, Schoeters G et al. 2015. Neurobehavioral performance in adolescents is inversely associated with traffic exposure. Environ. Int 75, 136–143. [DOI] [PubMed] [Google Scholar]
  77. Klocke C, Sherina V, Graham UM, Gundersson J, Allen JL et al. 2018. Enhanced cerebellar myelination with concomitant iron elevation and ultrastructural irregularities following prenatal exposures to ambient particulate matter in the mouse. Inhal. Toxicol 30, 381–396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Kraft AD, Harry GJ 2011. Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. Int. J. Environ. Res. Public Health 8, 2980–3018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Ladd-Acosta C, Feinberg JI, Brown SC, Lurmann FW, Croen LA, Hetz-Picciotto I, Newschaffer CJ, Feinberg AP, Fallin MD, Volk HE 2019. Epigenetic marks of prenatal air pollution exposure found in multiple tissues relevant for child health. Environ. Int 126, 363–376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Landrigan PJ 2010. What causes autism? Exploring the environmental contribution. Curr. Op. Pediatr 22, 219–225. [DOI] [PubMed] [Google Scholar]
  81. Lee S, Lee W, Kim D, Kim E, Myung W et al. 2019. Short-term PM2.5 exposure and emergency hospital admissions for mental disease. Environ. Res 171, 313–320. [DOI] [PubMed] [Google Scholar]
  82. Levesque S, Surace MJ, McDonald J, Block ML 2011a. Air pollution & the brain: subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease. J. Neuroinflam 8, 105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Levesque S, Taetzsch T, Lull ME, Kodavanti U, Stadler K et al. 2011b. Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity. Environ. Health Perspect 119, 1149–1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Levy SE, Mandell DS, Schultz RT 2009. Autism. Lancet 374, 1627–1638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Li K, Li L, Cui B, Gai Z, Li Q et al. 2018. Early postnatal exposure to airborne fine particulate matter induces autism-like phenotypes in male rats. Toxicol. Sci 162, 189–199. [DOI] [PubMed] [Google Scholar]
  86. Lim J, Lim C, Yu LE 2009. Composition and size distribution of metals in diesel exhaust particulates. J. Environ. Monit 11, 1614–1621. [DOI] [PubMed] [Google Scholar]
  87. Lochhead JJ, McCaffrey G, Quigley CE, Finch J, DeMarco KM et al. 2010. Oxidative stress increases blood-brain barrier permeability and induces alterations in occluding during hypoxiareoxygenation. J. Cereb. Blood Flow Metab 30, 1625–1636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH 2012. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav. Immun 26, 607–616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Miodovnik A 2011. Environmental neurotoxicants and developing brain. Mt. Sinai J. Med 78, 58–77. [DOI] [PubMed] [Google Scholar]
  90. MohanKumar SMJ, Campbell A, Block ML & Veronesi B 2008. Particulate matter, oxidative stress and neurotoxicity. Neurotoxicology 29, 479–488. [DOI] [PubMed] [Google Scholar]
  91. Møller P, Danielsen PH, Karottki DG, Jantzen K, Rousgaard M et al. 2014. Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles. Mutat. Res 762, 133–166. [DOI] [PubMed] [Google Scholar]
  92. Morris-Schaffer K, Merrill AK, Wong C, Jew K, Sobolewski M et al. 2019. Limited developmental neurotoxicity from neonatal inhalation exposure to diesel exhaust particles in C57BL/6 mice. Particle Fiber Toxicol. 16, 1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Mumaw CL, Levesque S, McGraw C, Robertson S, Lucas S et al. 2006. Microglial priming through the lung-brain axis: the role of air pollution-induced circulating factors. FASEB J. 30, 1880–1891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Nardone S, Sams D, Reuveni E, Getselter D, Oron O et al. 2014. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Trans. Psychiat 4, e433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Newman NC, Ryan P, LeMasters G, Levin L, Bernstein D et al. 2013. Traffic-related air pollution exposure in the first year of life and behavioral scores at 7 years of age. Environ. Health Perspect 121, 731–736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Nguyen L, Rigo JM, Rocher V, Belachew B, Malgrange B et al. 2001. Neurotransmitters as early signals for central nervous system development. Cell Tissue Res. 305, 187–202. [DOI] [PubMed] [Google Scholar]
  97. Oberdoerster G, Utell MJ 2002. Ultrafine particles in the urban air: to the respiratory tract – and beyond? Environ. Health. Perspect 110, A440–A441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Oberdoerster G, Sharp Z, Atudorei V, Elder A, Gelein R et al. 2004. Translocation of inhaled ultrafine particles to the brain. Inhal. Toxicol 16, 437–445. [DOI] [PubMed] [Google Scholar]
  99. Pagalan L, Bickford C, Weikum W, Lanphear B, Brauer M et al. 2019. Association of prenatal exposure to air pollution with autism spectrum disorder. JAMA Pediatrics 173, 86–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Patterson PH 2011. Maternal infection and immune involvement in autism. Trends Mol. Med 17, 389–394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Payne-Sturges DC, Marty MA, Perera F, Miller MD, Swanson M et al. 2019. Healthy air, healthy brains: advancing air pollution policy to protect children’s health. Am. J. Public Health 109, 550–554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Pelch KE, Bolden AL, Kwiatkowski CF 2019. Environmental chemicals and autism: a scoping review of the human and animal research. Environ. Health Perspect 127 (4), 1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Pope CA, Dockery DW 2006. Health effects of fine particulate air pollution: lines that connect. Air Waste Manage. Assoc 56, 709–742. [DOI] [PubMed] [Google Scholar]
  104. Power MC, Weisskopf MG, Alexeeff SE, Coull BA, Spiro III A et al. 2011. Traffic-related air pollution and cognitive function in a cohort of older men. Environ. Health Perspect 119, 682–687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Power MC, Adar SD, Yanosky JD, Weuve J, 2016. Exposure to air pollution as a potential contributor to cognitive function, cognitive decline, brain imaging, and dementia: a systematic review of epidemiologic research. Neurotoxicology 56, 235–253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Qian L, Flood PM, Hong JS 2010. Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J. Neural Transm 117, 971–979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Ranft U, Schikowski T, Sugiri D, Krutmann J, Kramer U 2009. Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly. Environ. Res 109, 1004–1011. [DOI] [PubMed] [Google Scholar]
  108. Raz R, Roberts AL, Lyall K, Hart JE, Just AC et al. 2015. Autism spectrum disorder and particulate matter air pollution before, during and after pregnancy: a nested case-control analysis within the nurses’ health study II cohort. Environ. Health Perspect 123, 264–270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Ritz B, Liew Z, Yan Q, Cui Q, Virk J et al. 2019. Air pollution and autism in Denmark. Environ. Epidemiol 2 (4z), e28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Rivas I, Basagana X, Cirach M, Lopez-Vicente M, Suades-Gonzalez E et al. 2019. Association between early life exposure to air pollution and working memory and attention. Environ. Health Perspect 127 (5), 57002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Roberts AL, Lyall K, Hart JE, Laden F, Just AC et al. 2013. Perinatal air pollutant exposures and autism spectrum disorder in the Children of Nurses’s Health Study II participants. Environ. Health Perspect 121, 978–984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Rodier PM 1994. Vulnerable periods and processes during central nervous system development. Environ. Health Perspect 102 (Suppl. 2), 121–124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Rodier PM 1995. Developing brain as a target for toxicity. Environ. Health Perspect 103 (Suppl. 6), 73–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Russ TC, Reis S, van Tongeren M 2019. Air pollution and brain health: defining the research agenda. Curr. Op. Psychiatr 32, 97–104. [DOI] [PubMed] [Google Scholar]
  115. Saez M, Barcelo MA, Farrerons M, Lopez-Casasnovas G 2018. The association between exposure to environmental factors and the occurrence of attention-deficit/hyperactivity disorder (ADHD). A population-based retrospective cohort study. Environ. Res 156, 2015–214. [DOI] [PubMed] [Google Scholar]
  116. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A 2014. The familial risk of autism. JAMA 311, 1770–1777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Schaafsma SM, Pfaff DW 2014. Etiologies underlying sex differences in autism spectrum disorders. Front. Neuroendocrinol 35, 255–271. [DOI] [PubMed] [Google Scholar]
  118. Sobolewski M, Anderson T, Conrad K, Marvin E, Klocke C et al. 2018. Developmental exposures to ultrafine particle air pollution reduces early testosterone levels and adult male social novelty preference: risk for children’s sex-biased neurobehavioral disorders. Neurotoxicology 68, 203–211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Sram RJ, Veleminsky M, Veleminsky M, Stejskalova J 2017. The impact of air pollution to central nervous system in children and adults. Neuroendocrinol. Lett 38, 389–396. [PubMed] [Google Scholar]
  120. Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A, Colamarino SA, Lein ES, Courchesne E 2014. Patches of disorganization in the neocortex of children with autism. New Engl. J. Med 370, 1209–1219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Su D, Serafino A, Müller JO, Jentoft R, Schlögl R et al. 2008. Cytotoxicity and inflammatory potential of soot particles of low-emission diesel engines. Environ. Sci. Technol 42, 1761–1765. [DOI] [PubMed] [Google Scholar]
  122. Sunyer J, Dadvand P 2019. Pre-natal brain development as a target for urban air pollution. Basic Clin. Pharmacol. Toxicol 125 (Suppl. 3), 81–88. [DOI] [PubMed] [Google Scholar]
  123. Sunyer J, Esnaola M, Alvarez-Pedrerol M, Forns J, Rivas I et al. 2015. Association between traffic-related air pollution in schools and cognitive development in primary school children: a prospective cohort study. PLoS Med. 12, e1001792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Suzuki T, Oshio S, Iwata M, Saburi H, Odagiri T et al. 2010. In utero exposure to a low concentration of diesel exhaust affects spontaneous locomotor activity and monoaminergic system in male mice. Particle Fibre Toxicol. 7, 7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  125. Talbott EO, Arena VC, Rager JR, Clougherty JE, Michanowicz DR et al. 2015. Fine particulate matter and the risk of autism spectrum disorders. Environ. Res 140, 414–420. [DOI] [PubMed] [Google Scholar]
  126. Thirtamara Rajamani K, Doherty-Lyons S, Bolden C, Willis D, Hoffman C et al. 2013. Prenatal and early life exposure to high level diesel exhaust particles leads to increased locomotor activity and repetitive behaviors in mice. Autism Res. 6, 248–257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Tsukue N, Watanabe M, Kumamoto T, Takano H, Takeda K 2009. Perinatal exposure to diesel exhaust affects gene expression in mouse cerebrum. Arch. Toxicol 83, 985–1000. [DOI] [PubMed] [Google Scholar]
  128. USEPA (United States Environmental Protection Agency). 2002. Health Assessment Document for Diesel Engine Exhaust National Center for Environmental Assessment, USEPA, Washington, DC, pp. 669. [Google Scholar]
  129. Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R 2011. Residential proximity to freeways and autism in the CHARGE study. Environ. Health Perspect 119, 873–877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  130. Volk HE, Lurmann F, Penfold B, Hertz-Picciotto I, McConnell R 2013. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiat. 70, 71–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. Webb SJ, Monk CS, Nelson CA 2001. Mechanisms of postnatal neurobiological development: implications for human development. Develop. Neuropsychol 19, 147–171. [DOI] [PubMed] [Google Scholar]
  132. Wegiel J, Kuchna I, Nowicki K, Imaki H, Wegiel J et al. 2010The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol. 119, 755–770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  133. Weuve J, Puett RC, Schwartz J, Yanosky JD, Laden F et al. 2012. Exposure to particulate air pollution and cognitive decline in older women. Arch. Int. Med 172, 219–227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  134. Wingate M, Mulvihill B, Kirby RS, Pettygrove S, Cunniff C et al. 2012. Prevalence of autism spectrum disorders-Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill. Summ 61, 1–19. [PubMed] [Google Scholar]
  135. Win-Shwe TT, Fujimaki H 2011. Nanoparticles and neurotoxicity. Int. J. Mol. Sci 12, 6267–6280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  136. Win-Shwe TT, Yamamoto S, Fujitani Y, Hirano S, Fujimaki H 2008. Spatial learning and memory function-related gene expression in the hippocampus of mouse exposed to nanoparticles-rich diesel exhaust. Neurotoxicology 29, 940–947. [DOI] [PubMed] [Google Scholar]
  137. Win-Shwe TT, Fujitani Y, Kyi-Tha-Thu C, Furuyama A, Michikawa T et al. 2014. Effects of diesel engine exhaust origin secondary organic aerosols on novel object recognition ability and maternal behavior in BALB/C mice. Int. J. Environ. Res. Public Health 11, 11286–11307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  138. Woodward NC, Haghani A, Johnson RG, Hsu TM, Saffari A et al. 2018. Prenatal and early life exposure to air pollution induced hippocampal vascular leakage and impaired neurogenesis in association with behavioral deficits. Translat. Psychiatr 8, 261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  139. Xuan ICY, Hampson DR 2014. Gender-dependent effects of maternal immune activation on the behavior of mouse offspring. PLOSOne 9 (8), e104433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  140. Yokota S, Mizuo K, Moriya N, Oshio S, Sugawara I et al. 2009. Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Neurosci. Lett 449, 38–41. [DOI] [PubMed] [Google Scholar]
  141. Yokota S, Moriya N, Iwata M, Umezawa M, Oshio S et al. 2013. Exposure to diesel exhaust during fetal period affects behavior and neurotransmitters in male offspring mice. J. Toxicol. Sci 38, 13–23. [DOI] [PubMed] [Google Scholar]
  142. Zhang T, Zheng X, Wang X, Zhao H, Wang T et al. 2018. Maternal exposure to PM2.5 during pregnancy induces impaired development of cerebral cortex in mice offspring. Int. J. Mol. Sci 19, 257. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES