Pregnant women exposed to higher levels of air pollutants had children with lower IQs


A new study found that pregnant women exposed to higher levels of air pollutants had children with lower IQs, compared to the children of women exposed to lower levels.

The study, led by researchers at the University of Washington and UCSF as part of the ECHO PATHWAYS consortium, will be published in the September issue of Environmental Research and is currently available online.

Researchers looked at 1,005 pregnant women participating in the Conditions Affecting Neurodevelopment and Learning study, set in Shelby County, Tenn., and assessed the IQs of their offspring between the ages of 4 and 6.

They found that exposure to PM10 – pollutant particles with a diameter of one-seventh the width of a human hair that are produced by industry, power plants, cars, air traffic and railways – was negatively associated with IQ.

Children whose mothers were in the highest 10 percent of exposure had IQ scores that were 2.5 points lower than those in the lower 10 percent.

When the researchers looked at plasma levels of maternal folate, which is found naturally in leafy vegetables, beans and citrus fruit, and is recommended for all pregnant women in its synthetic form as folic acid, they found that the difference between offspring IQs in the highest and lowest PM10-exposed groups had widened to 6.8 points among those whose mothers had the lowest levels (bottom 25 percent) of folate.

PM10 exposure had no impact on IQ if maternal levels of folate were higher, the researchers found.

While the study underlines the importance of folic acid in pregnancy, there may be such a thing as too much folic acid supplementation, said first author Christine Loftus, an epidemiologist from the UW’s Department of Environmental & Occupational Health Sciences.

“Although supplementation has been shown to be protective against neural tube defects, which are devastating birth defects of the central nervous system, recent research suggests that too much prenatal folic acid may impair healthy fetal neurodevelopment,” Loftus said.

“The dose of folic acid is something that pregnant women should discuss with their doctors.”

Long-term exposure to PM10 has been linked to reduced lung function and the development of cardiovascular and respiratory diseases.

In this study, other pollutants, including nitrogen dioxide, which is a marker for high-concentration motor traffic, were not found to impact IQ.

The authors said that they could not explain the mechanism by which PM10 exposure contributed to lower IQ, but said that animal studies indicated that air pollution exposure increased maternal inflammation and oxidative stress.

“This could result in placental inflammation and may interfere with placental or fetal epigenetic programming,” said senior author Kaja LeWinn, ScD, associate professor of psychiatry at the UCSF School of Medicine.

“While it’s beyond the scope of our paper to understand how folate might alter this association, it is possible that higher folate levels increase the antioxidant capability of the diet, buffering oxidative stress associated with PM10 exposure,” said LeWinn.

“It may also be that folate itself is protective, since it plays an important role in healthy neurodevelopment, regardless of air pollution exposure.”

Clean air is critical for children′s health and well-being.

Megacities around the world exceed the standards for air pollutants and many samples from children populations are showing an array of adverse short and long-term health outcomes, which include some of the most detrimental effects on brain development [13].

However, for the most part, current research and policy efforts link air pollution to respiratory and cardiovascular disease [4], and the effects on children’s central nervous system (CNS) are still not broadly recognized.

As a result, wide reaching public health initiatives targeting pediatric populations are still considered premature or unwarranted.

One of the goals of this review is to show that contrary to a hesitant approach, there is enough evidence supporting the perspective that air pollution brain effects on children should be one of the main public health targets linked with policies that are in the purview of the broader issue of global climate change.

In this paper, we briefly review current air pollutant standards, followed by experimental, clinical, epidemiologic and pathology studies associating air pollution exposures with children′s brain effects.

This overview puts forward common denominators for the biological pathways linking air pollution to negative effects on the developing brain (Fig. 1).

Then, we turn to outstanding challenges facing the development of dynamic and reciprocal intervention strategies aimed at children exposed to high levels of air pollution.

Such challenges include the issues of how to establish links with the current mainstream concepts of cognition and neurodevelopment with the systemic biological and anatomical effects of air pollution, as well as the issues surrounding the formulation of strategies to study seemingly clinically healthy children exposed to air pollutants.

Our goal is to provide sufficient evidence to justify the proposal of structured intervention strategies protecting exposed children from further damage due to air pollution.

Our pediatric studies contrast age, gender, socio-economic status (SES), diets and physical activities matched children residents in extremes of low vs high air pollution (as defined below).

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Figure 1.
A. Hypothesized progression by which air pollution may negatively impact the central nervous system, regarding the interaction of compromised epithelial barriers, normally protective against such pollutants, and a pro-inflammatory state of the body’s immune system. B. Sagittal view of magnetic resonance image of neuroinflammation in cortical structures in a male Mexico City resident aged 10 (Courtesy of Professor Lilian Calderón-Garcidueñas). Yellow = prefrontal cortex; Blue = olfactory bulb; Green = brainstem. Red arrows indicate plausible vectors by which airborne pollutants may enter the central nervous system and contribute to neuroinflammation/ cell loss. PM = particulate matter, BBB = blood-brain barrier.

tervention strategies based on reciprocal interactions between multidisciplinary teams of researchers addressing the cognitive and developmental health effects of air pollution on children, and the public response to such initiatives, are of critical importance.

Through further refining the context in which urban children and adolescents should become the primary target of multidisciplinary intervention strategies, the deleterious effects of exposure to air pollution may at the same time be more rigorously defined at a systemic developmental level, and lead to a more thorough understanding of the roles needed to protect exposed children.

The perspective guiding the present review indicates the need of a multidisciplinary approach; not only to address the issue’s complexity and challenges but also to make developmental, behavioral and clinical researchers and practitioners (in neuroscience and allied disciplines) aware of the wide spectrum of air pollution effects and the potential impact on their daily practice.

Through the integration of various fields of research and expertise, informed and clear presentation of current air pollution research and dynamically structured intervention strategies, the negative impact of exposure to airborne pollutants on child development could be alleviated.

Air pollutants

Air quality is often defined by various indices reflecting the concentrations of six criteria air pollutants: particulate matter (PM), ozone (O3), carbon monoxide (CO), sulfur dioxide (SO2), nitrogen oxide (NO), and lead (Pb).

These pollutants have been identified by the Environmental Protection Agency (EPA) to be hazardous to human health.

The Air Quality Index (AQI) set standard values as a function of the characteristics and potential health/welfare impacts pollutants possess at varying concentrations.

While the AQI values range from country to country, it is generally depicted as an open-ended scale ranging from 0 to 500+.

Low values are typically color-coded green and represent minimal impact on health/welfare, whereas higher values are shown in orange-red and represent hazardous levels of pollution.

Within the context of this review, exposure to PM (both fine and ultrafine), is particularly relevant. For instance, in the US alone, more than 103 million people are exposed to PM concentrations above the standards, while 123 million are exposed to ozone (a respiratory toxin).

The two fractions of PM predominantly implicated in CNS effects are PM2.5 (particles with a diameter < 2.5 μm) and ultrafine PM (UFPM) (particles with a diameter < 100 nm). Outdoor PM2.5, mostly comes from tailpipe and brake emissions from mobile sources, residential fuel combustion, power plants, wildfires, oil refineries, and metal processing facilities. The primary contributors to UFPM are tailpipe emissions from mobile sources.

Indoor air pollutants, including tobacco smoke, emissions from cook stoves, mold, plasticizers, flame retardants, and pesticides also represent a major source of harmful substances.

Indoor air quality in schools is a major issue, the presence of mold, poor air quality, close proximity to major highways, and contaminated playgrounds can result in serious health problems [5,6].

Moreover, there are major disparities in indoor air pollution exposures related to SES: the lower the SES, the higher indoor exposures [7].

Effects of air pollution on the developing brain

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 [813].

Notably, diesel exhaust particles (DEP), a major component of urban air pollution, have been linked in mice to neuroinflammation and the accumulation of Aß1-42, tau (linked to Alzheimer’s disease), along with α-synuclein, microglial activation and Parkinson’s disease-like pathology [89].

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 [10,1618].

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 childs 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 [2526].

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 Aβ1-42 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 [135].

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 [12435].

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 [4041], 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 [232430].

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 [4546].

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.

More information: Christine T. Loftus et al. Prenatal air pollution and childhood IQ: Preliminary evidence of effect modification by folate, Environmental Research (2019). DOI: 10.1016/j.envres.2019.05.036

Journal information: Environmental Research
Provided by University of Washington


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