How air pollution alters brain development: the role of neuroinflammation

Animal models of air pollutants and brain development

There is a convergence of human, animal, and in vitro studies on the effects of air pollution on the brain. Animal models exposed to air pollutant components such as ozone, PM, diesel nanoparticles (NP), endotoxins, etc., have contributed to our understanding of the potential mechanisms acting upon the CNS. Depending on the pollutant component, doses, exposure protocol, age and gender, health status, etc., a wide, complex range of effects have been discovered including formation of free radicals and oxidative stress, dopaminergic neuronal damage, RNA, DNA damage, and identification of early hallmarks of Alzheimer’s and Parkinson’s diseases [8-13]. Notably, diesel exhaust particles (DEP), a major component of urban air pollution, have been linked in mice to neuroinflammation and the accumulation of Aß_1-42, tau (linked to Alzheimer’s disease), along with α-synuclein, microglial activation and Parkinson’s disease-like pathology [8, 9]. Inhalation exposure to traffic-generated air pollutants promotes increased activity of powerful matrix metalloproteinases and degradation of tight junction proteins in the cerebral microvasculature resulting in altered brain-blood-barrier permeability and expression of neuroinflammatory markers [13].

Oxidative stress caused by low doses of ozone results in dysregulation of inflammatory responses, progressive neurodegeneration, altered brain repair in the hippocampus, and brain plasticity changes in the rat analogous to those seen in Alzheimer’s disease [14]. In rats, cigarette smoking a powerful source of oxidative stress and particles reduces the expression of pre-synaptic proteins, impairs axonal transport and produces neurodegenerative changes as those seen in Alzheimer’s disease [15]. In animal models, prenatal exposure to either one or a combination of criteria pollutants causes permanent changes in neurotransmitters and alters brain development, most commonly resulting in long-term deficits in functions associated with one or more memory systems [10,16-18].

The effects of air pollution on children’s brain

In spiteof thecomplexity of action and effects, the evidence shows that developmental detrimental effects in animals are analogous to the effects that are observed in children [19]. Children are among those most vulnerable to suffering adverse health effects due to exposure to high levels of air pollution. Due to their higher breathing rate to body size ratio, and less developed natural barriers in the lungs warding against inhaled particles children are subject to heightened sensitivity to airborne pollutants in the their environment [20]. The healthy development of natural barriers such as the blood-brain barrier, nasal, gut and lung epitheliums are of crucial importance for a child’s healthy developmental outcome. These barriers have been shown to be compromised in young urbanites exposed to air pollution [21], thus reducing the brain’s capacity to protect itself against potentially dangerous toxicants/ particles. Children also consume more air and water per unit of body size when compared to adults [22], and also spend a significant amount of time outdoors. This factor in particular elevates a child’s risk exposure to air pollution, especially when considering that not only are a child’s organs developing but also his/her sanitary behaviors respective to his/her environment. A child may not be aware of a potentially hazardous environment, and increased frequency of contact between the hands, face and mouth may elevate risk for ingesting/inhaling environmental toxicants.

When air pollutants enter the body, an innate immune response is generated. Such a response is observable by assessing blood and cerebrospinal fluid levels of small proteins, termed cytokines, such interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). These cytokines are prominent inflammatory signaling mediators, promoting the swelling of tissue, the release of cytotoxic species by immune cells, and further pro-inflammatory signaling to additional cytokines. These actions contribute to widespread neuroinflammation in the brain, leading to the damage and diffuse loss of neural tissue in various areas of the brain. Affected structures include the prefrontal and frontal cortices and olfactory bulb (Fig. 1B), as well as midbrain structures such as the hippocampus [23]. These brain structures are critical to healthy cognitive function, and given the physiological changes observed in children as a result of chronic exposure to high levels of air pollution, present as tangible evidence for public health intervention.

The human brain contains receptors specific to Il-1 β, IL-6 and TNF-α.These proteins may also cross the blood-brain barrier, gaining ready access to developing regions of the brain. Once inside the brain these inflammatory molecules may signal to neurons and associated immune cells promoting inflammation. Exposure of elevated levels of air pollution results in high bodily concentrations of these inflammatory mediators [21], subsequently increasing their concentration in the CNS. White matter hyperintensities (WMH), or areas of demyelinated neurons resulting from reduced blood flow visible using magnetic resonance imaging (MRI), have been observed in children exposed to high levels of air pollution [24]. The presence of WMH has a negative impact on a neuron’s ability to synapse successfully, impairing its ability to communicate. WMH have been consistently associated with global cognitive deficits [25, 26]. In the context of children exposed to air pollution, WMH have been associated with inflammatory mechanisms, such as the presence TNF-α [24] in Mexico City urban adolescents. These findings suggest that exposure to air pollution may have deleterious effects on the myelination and thus function of neurons within the CNS, as well as a measureable increase in pro-inflammatory mediators contributing to neuroinflammation and cell loss. Taken together, these aspects of exposure to air pollution ultimately contribute to cognitive deficits, observable in clinically healthy children. Elevated levels of endothelin-1 (ET-1), a protein important for the constriction of blood vessels, has been associated with PM exposure [27]. Constriction of blood vessels will result in reduced blood flow to the affected area, negatively impacting the integrity of local cells/neurons (Harper et al., 1998). Disruptions in blood flow resulting from high ET-1 concentrations have been observed to negatively impact the circulatory architecture of the brain [27]. In children, these disruptions may contribute to a higher blood pressure, which has been associated with the development of respiratory disease [28], as well potentially damaging developing brain regions due to restricted blood flow and thus, less oxygen. Another finding in children exposed to high levels of air pollution is the presence of proteins characteristic of Alzheimer’s disease pathology. Two critical proteins in development of Alzheimier’s disease include hyperphosphorylated tau protein and the accumulation of Aβ_1-42 plaques in and around neurons [29]. Neuropathology studies in children with accidental deaths and having been exposed to air pollution showed both hyperphosphorylation of tau protein and diffuse Aβ plaques in the frontal cortex of brains, compared to 0% in controls [30]. Of utmost importance for this review was the finding that children carrying the apolipoprotein E gene (APOE) allele ∊4 (well-known genetic risk factor for Alzheimer’s disease) displayed a greater number of these two marker proteins when compared to the more common APOE allele ∊3 carriers [30]. This finding suggests that genetic factors could make a significant portion of children exposed to air pollution more prone to developing Alzheimer’s disease later in life. The presence of such plaques also indicate an acceleration of Alzheimer’s disease pathology, and contribute to increased neuroinflammation and loss of communication between neurons. In Alzheimer’s disease patients, the presence and amount of both tau tangles and Aβ are a marker of disease progression, and the subsequent decline in cognitive function that is characteristic of the disease. The abnormal levels and diffuse presence of these protein complexes in clinically healthy children chronically exposed to airborne pollutants are disturbing at the very least, and may have a significant impact on cognitive outcome and neurodevelopment given their inherent and well-documented pathological nature.

Chronic damage to the lungs in response to prolonged inhaling of large amounts of PM is inevitable, and this is indeed the case with children [31]. This has been reported in Mexico City Metropolitan Area (MCMA) children, with boys being more affected than girls, likely due to longer daily outdoor activities and thus longer time of exposure [32]. Due to importance of physical activity in child’s development and the benefits of associated outdoor spaces [33], elevated levels of air pollution present a direct challenge to maintaining both cardiovascular and healthy neurodevelopment of children, by allowing them to play outside and engage in physical activities otherwise beneficial for their health and development [34].

Clinically healthy children from MCMA selected by stringent criteria including the absence of known risk factors for cognitive or neurological deficits, exhibited structural, neurophysiological and cognitive detrimental effects compared to low pollution exposed children matched for SES, gender, age and mother’s IQ [1, 35]. The cognitive deficits in MCMA children were associated with MRI volumetric alterations in their right parietal and bilateral temporal areas [24]. Dynamic changes of inflammatory mediators influence children’s CNS structural and volumetric MRI responses and cognitive correlates resulting from environmental pollution exposures. MCMA children performed more poorly across a variety of cognitive tests, compared to control children [1, 24, 35]. This is indicative of high air pollution contributing to a negative environment for healthy brain development and cognitive improvement.

Recent epidemiologic studies in cities across the world provide convergent confirmatory evidence of the link between exposure to similar air pollution components, and neurobehavioral outcomes similar to those observed in MCMA children [36]. In particular, vehicular emissions which are one important source of particulate pollution, have been associated with higher prevalence of frontal executive function deficits of preschool (2 to 5 year olds) and school aged children (6 to 14 year olds) in India [37], Boston [38], Cincinnati [39], New York City [40, 41], China [42], Barcelona [43] and Japan [44].

The reviewed evidence strongly suggests that air pollution exposed children experience a chronic intense state of environmental stress and exhibit an early brain imbalance in genes involved in inflammation, immune responses to their environment, cell integrity and neural communication [23, 24, 30]. Neuroinflammation, changes in endothelial barriers, alterations in blood vessel arrangement and the widespread blood-brain barrier breakdown contribute to cognitive impairment and pathogenesis and pathophysiology of neurodegenerative states [45, 46]. By its very nature, a mechanistic pathway (Fig. 1A) involving inflammation, the breakdown of the epithelial and the blood-brain barriers, and restricted blood flow has the potential to negatively impact cortical structures and the subsequent child’s development of brain regions central to behavior and cognitive performance. This collection of findings lies at the core of the pathology in exposed children, and structural changes are significant in areas of the prefrontal cortex, but have also been observed throughout the brain, including the brainstem (Fig. 1B)[35]. The blood-brain barrier in children has been observed to be more permeable during development than later in life [21], increasing the likelihood of ingested and inhaled pollutants entering the brain, causing inflammation of tissue and further damaging vulnerable brain regions. Taken together, the collected evidence gives weight to the importance of structured intervention strategies for children chronically exposed to air pollution. Children are amongst those individuals possessing the highest level of risk exposure, have underdeveloped natural defense mechanisms and consistently display a disturbing variety of physiological alterations associated with environmental imbalance with the potential to negatively affect neural and thus behavioral development.

From data to action: future directions

Air pollution effects on the developing brain may vary along a continuum from minor, subtle subclinical deficits in cognitive functioning to significant cognitive deficits that are identified readily by parents and/or teachers. The detrimental effects may also worsen with the age of the child, thus selected neurocognitive tools/screening ought to be useful for longitudinal studies, across educational backgrounds and expecting overlaps in the functional areas and tests affected. Complex cognitive responses that may be affected include: attention and short-term memory, information processing speed and executive function, verbal abstraction, and visuospatial and motor skills. Further refining the cognitive processes, as well as brain structures involved in/affected by exposure to air pollution would serve to broaden the current understanding of environment-mediated neurodevelopmental deficits. The inclusion of longitudinal and follow-ups to clinical studies is also of crucial importance.

Regarding the role of a mechanistic pathway (Fig. 1), one gap in our knowledge concerns the understanding of multiple concurrent underlying systemic mechanisms by which several observed developmental health effects and disease processes arise as a result of exposure to air pollution. In this context, particularly relevant is current evidence that air pollutants have an influence at the epigenetic levels [47]. The most recent and comprehensive reviews show that the majority of the findings to date reveal that polycyclic aromatic hydrocarbon (PAH) and PM₂.₅ may have modest effects on methylation levels of certain CpG (cytosine being 5’ to the guanine base) dinucleotide sites within candidate genes linked with cancer, cardiovascular and respiratory diseases [48, 49]. However, the data are too scarce and the methods too heterogeneous to afford conclusions with regard to effects directly related to the CNS and neuroinflammation. The latter aspects, in particular, would include investigation into complex brain-immune interactions resulting from exposure to air pollution, as well as genetic/epigenetic studies looking at changes in the expression of inflammatory genes. For instance, a very recent cross-sectional study [50] has indicated that exposure to short-term single (i.e., sulfate, black carbon) or combined air pollution components is associated with epigenetic alterations of mitogen-activated protein kinase (MAPK) pathway genes. Such epigenetic alterations are still not well understood since their effects on the biological pathways are too complex to be easily predicted on the basis of the current conceptual models. Future studies need to be designed so that this limitation can be overcome.

Related to the domain of epigenetics (see [51]), an increasing amount of studies suggests links between maternal, prenatal and early air pollution exposure, neuroinflammation and autism spectrum disorder (ASD) (for example, [52-54]). Findings have some degree of consistency, with associations seen with different components, including hazardous air toxics, ozone, particulate, and traffic-related pollution. However, very few studies are immune from residual confounds linked with multiple exposure, socioeconomic status and residential area. Among the exceptions are, notably, two large-scale US studies [55, 56] which found a specific association with air pollution exposure during the 3rd, but not the 1st, trimester, when both trimesters were modeled simultaneously and many key confounds were accounted for.

Furthermore, the generalizability of the available findings represents a further challenge given the variability of the diagnostic criteria across studies. For example, a study based on data from four large European population-based birth/child cohorts [57] squarely contradicts the US studies, by finding that prenatal exposure to NO2 and PM was not associated with autistic traits in children from 4 to 10 years of age. Analogously to the broader epigenetic effects discussed earlier, the available evidence requires complex models to decode the critical component(s) and causal pathway(s). The future generation of studies will need to address not only methodological discrepancies but also theoretical challenges. As a step towards this objectives, Weisskopf, Kioumourtzoglou, and Roberts [58] have illustrated the usefulness of directed acyclic graphs analysis to test models that differentiate the role of time-specific windows of susceptibility, with significant impact, from time-invariant confounds that have no effects. The latter is a good example of the type of work that will be necessary to advance knowledge about the nuanced, multi-level relationships between air pollution exposure, neuroinflammation mechanisms and neurodevelopmental processes, which although progressively gaining more clarity at the moment are at the level of sparse and isolated associations in the literature.

While our knowledge-base and understanding continue to grow, intervention strategies, such as the neuropsychological screening described above, being targeted at geographically defined populations should seek to not only gain an accurate assessment of current health and risk factors present, but also facilitate communication between health professionals, affected children/parents/ families, teachers and researchers in a reciprocal fashion. Further research inspired by the effectiveness of such programs, the usefulness of the information garnered by them and the logistical limitations of such tools should be prioritized. These research efforts would allow for the interplay between developmental researchers and the environment they are investigating, leading to context-dependent research investigating context-specific factors affecting populations at risk of high exposure to air pollution. Further refining definitions of high vs. low pollution, and establishing reliable proxies for air pollution exposure may render these applications more effective and clarify research regarding concentrations of specific pollutants.

The widespread nature of inflammation within the brain and the neuronal changes observed in exposed children suggests not to rely on a single study or measure but rather to employ a weight of evidence approach incorporating current clinical, neurophysiological, radiological and epidemiological research regarding exposure to single or mixtures of pollutants. Changes in immune system activity play a key role in the identification of children with structural changes and cognitive responses to their lifelong pollutant exposures [35, 36] and since inflammation of the brain/vascular damage/loss of neurons go hand in hand [23, 24], definition of biomarkers associated with immunological and cellular changes in the CNS establishing an observable relationship between brain development and behavioral/psychological outcomes in children are urgently needed. Identification of such biomarkers would allow for screening tools to non-invasively and accurately assess the presence of damage resulting from their exposure to air pollution, and provide health practitioners, educational professionals and families with empirical feedback regarding the need for intervention or therapy. Such a practice has its roots in preventative medical approaches [59], and would aid in further directing some of the applied developmental science research specializing on social justice [60] towards the issues of children’s outcomes and health behaviors in polluted environments.