Air pollution, a rising environmental risk factor for cognition, neuroinflammation and neurodegeneration: The clinical impact on children and beyond

International audienceAir pollution (indoors and outdoors) is a major issue in public health as epidemiological studies have highlighted its numerous detrimental health consequences (notably, respiratory and cardiovascular pathological conditions). Over the past 15 years, air pollution has also been considered a potent environmental risk factor for neurological diseases and neuropathology. This review examines the impact of air pollution on children's brain development and the clinical, cognitive, brain structural and metabolic consequences. Long-term potential consequences for adults’ brains and the effects on multiple sclerosis (MS) are also discussed. One challenge is to assess the effects of lifetime exposures to outdoor and indoor environmental pollutants, including occupational exposures: how much, for how long and what type. Diffuse neuroinflammation, damage to the neurovascular unit, and the production of autoantibodies to neural and tight-junction proteins are worrisome findings in children chronically exposed to concentrations above the current standards for ozone and fine particulate matter (PM2.5), and may constitute significant risk factors for the development of Alzheimer's disease later in life. Finally, data supporting the role of air pollution as a risk factor for MS are reviewed, focusing on the effects of PM10 and nitrogen oxide

Desarrollo y evaluación de un dispositivo electrónico de peso ligero para el muestreo de compuestos orgánicos volátiles en la vertical acoplado a un globo meteorológico cautivo

An understanding of the vertical profile of the composition of volatile organic compounds (VOCs) in polluted urban areas can help to better understand the impact of these compounds on air quality and in the development of better control strategies. To facilitate these types of measurements and they have the necessary reliability, a programmable, lightweight and lowcost VOCs miniaturized sampling device was designed and integrated, that allows to anchor several of them at different heights in the string of a captive instrumented meteorological balloon and also a start/stop control of the samplers that can be operated from the ground. Simultaneous sampling ensures that the vertical profile of the captured VOCs, represents with better certainty the expected differences in the concentration of these compounds due to the influence of the urban canopy layer and urban activity. Each sampling device consists of an electronic circuit that receives the start or stop signal of the air suction mini-pump from a master control system that is on the surface and that allows radio frequency operation. The capture of VOCs is carried out by packed cartridges with an appropriated adsorbent medium for this purpose. The feasibility of the miniaturized system was demonstrated in a short sampling campaign at the levels 0 m, 50 m, and 100 m above ground at a site southwest of the Metropolitan Area of Mexico City during April 2017. The profiles of the determined VOCs concentrations were compared with previous records obtained at the surface level and in vertical profiles using less dynamic sampling methods, demonstrating the benefit of knowing the concentration at different heights in the interpretation of atmospheric chemistry associated with these profiles.El conocimiento del perfil vertical de la composición de los compuestos orgánicos volátiles (COVs) en áreas urbanas contaminadas puede ayudar a un mejor entendimiento del impacto de estos compuestos en la calidad del aire y en el desarrollo de mejores estrategias de control. Con el fin facilitar este tipo de mediciones y de que éstas tengan la confiabilidad necesaria, se diseñó e integró un dispositivo de muestreo miniaturizado programable de COVs ligero de bajo costo, que permite el anclaje de varios de ellos a diversos niveles de altura en el cordel de un globo meteorológico cautivo instrumentado, y cuyo arranque y paro de los muestreadores es controlado desde superficie. El muestreo simultáneo asegura que el perfil vertical de los COVs capturados representen con mejor certeza las diferencias esperadas en la concentración de estos compuestos debido a la influencia del dosel urbano y de la actividad urbana. Cada dispositivo de muestreo consiste en un circuito electrónico que recibe la señal de arranque y/o paro de la minibomba de succión de aire de un sistema maestro de control que se ubica en superficie y que comanda la operación por radiofrecuencia. La captura de los COVs es realizada por medio de un cartucho empacado con un medio adsorbente apropiado para este objeto. La aplicabilidad del sistema miniaturizado fue demostrada en una campaña corta de muestreos a los niveles 0 m, 50 m, y 100 m sobre la superficie en un sitio al suroeste de la Zona Metropolitana de la Ciudad de México durante abril de 2017. Los perfiles de las concentraciones de COVs determinadas fueron comparados tanto con registros previos obtenidos a nivel superficie como en perfiles verticales utilizando métodos de muestreo menos dinámicos demostrando así el beneficio de conocer la concentración a diferentes alturas en la interpretación de la química atmosférica asociada a estos perfiles

Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal

Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases (AD,PD). AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)–rich nanoparticles (NP), matching air pollution combustion- and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29 ± 11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al- and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM are associated with metal-rich NPs including exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry. Thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breathe,what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical. © 2020 Elsevier Inc

Air pollution and detrimental effects on children's brain. The need for a multidisciplinary approach to the issue complexity and challenges

Millions of children in polluted cities are showing brain detrimental effects. Urban children exhibit brain structural and volumetric abnormalities, systemic inflammation, olfactory, auditory, vestibular and cognitive deficits v low-pollution controls. Neuroinflammation and blood-brain-barrier (BBB) breakdown target the olfactory bulb, prefrontal cortex and brainstem, but are diffusely present throughout the brain. Urban adolescent Apolipoprotein E4 carriers significantly accelerate Alzheimer pathology. Neurocognitive effects of air pollution are substantial, apparent across all populations, and potentially clinically relevant as early evidence of evolving neurodegenerative changes. The diffuse nature of the neuroinflammation and neurodegeneration forces to employ a weight of evidence approach incorporating current clinical, cognitive, neurophysiological, radiological and epidemiological research. Pediatric air pollution research requires extensive multidisciplinary collaborations to accomplish a critical goal: to protect exposed children through multidimensional interventions having both broad impact and reach. Protecting children and teens from neural effects of air pollution should be of pressing importance for public health

Combustion- and friction-derived magnetic air pollution nanoparticles in human hearts

Air pollution is a risk factor for cardiovascular and Alzheimer's disease (AD). Iron-rich, strongly magnetic, combustion- and friction-derived nanoparticles (CFDNPs) are abundant in particulate air pollution. Metropolitan Mexico City (MMC) young residents have abundant brain CFDNPs associated with AD pathology. We aimed to identify if magnetic CFDNPs are present in urbanites' hearts and associated with cell damage. We used magnetic analysis and transmission electron microscopy (TEM) to identify heart CFDNPs and measured oxidative stress (cellular prion protein, PrPC), and endoplasmic reticulum (ER) stress (glucose regulated protein, GRP78) in 72 subjects age 23.8 ± 9.4y: 63 MMC residents, with Alzheimer Continuum vs 9 controls. Magnetite/maghemite nanoparticles displaying the typical rounded crystal morphologies and fused surface textures of CFDNPs were more abundant in MMC residents' hearts. NPs, ∼2–10 × more abundant in exposed vs controls, were present inside mitochondria in ventricular cardiomyocytes, in ER, at mitochondria-ER contact sites (MERCs), intercalated disks, endothelial and mast cells. Erythrocytes were identified transferring ‘hitchhiking’ NPs to activated endothelium. Magnetic CFDNP concentrations and particle numbers ranged from 0.2 to 1.7 μg/g and ∼2 to 22 × 109/g, respectively. Co-occurring with cardiomyocyte NPs were abnormal mitochondria and MERCs, dilated ER, and lipofuscin. MMC residents had strong left ventricular PrPC and bi-ventricular GRP78 up-regulation. The health impact of up to ∼22 billion magnetic NPs/g of ventricular tissue are likely reflecting the combination of surface charge, ferrimagnetism, and redox activity, and includes their potential for disruption of the heart's electrical impulse pathways, hyperthermia and alignment and/or rotation in response to magnetic fields. Exposure to solid NPs appears to be directly associated with early and significant cardiac damage. Identification of strongly magnetic CFDNPs in the hearts of children and young adults provides an important novel layer of information for understanding CVD pathogenesis emphasizing the urgent need for prioritization of particulate air pollution control

Elevated Plasma Endothelin-1 and Pulmonary Arterial Pressure in Children Exposed to Air Pollution

BackgroundControlled exposures of animals and humans to particulate matter (PM) or ozone air pollution cause an increase in plasma levels of endothelin-1, a potent vasoconstrictor that regulates pulmonary arterial pressure.ObjectivesThe primary objective of this field study was to determine whether Mexico City children, who are chronically exposed to levels of PM and O3 that exceed the United States air quality standards, have elevated plasma endothelin-1 levels and pulmonary arterial pressures.MethodsWe conducted a study of 81 children, 7.9 ± 1.3 years of age, lifelong residents of either northeast (n = 19) or southwest (n = 40) Mexico City or Polotitlán (n = 22), a control city with PM and O3 levels below the U.S. air quality standards. Clinical histories, physical examinations, and complete blood counts were done. Plasma endothelin-1 concentrations were determined by immunoassay, and pulmonary arterial pressures were measured by Doppler echocardiography.ResultsMexico City children had higher plasma endothelin-1 concentrations compared with controls (p < 0.001). Mean pulmonary arterial pressure was elevated in children from both northeast (p < 0.001) and southwest (p < 0.05) Mexico City compared with controls. Endothelin-1 levels in Mexico City children were positively correlated with daily outdoor hours (p = 0.012), and 7-day cumulative levels of PM air pollution < 2.5 μm in aerodynamic diameter (PM2.5) before endothelin-1 measurement (p = 0.03).ConclusionsChronic exposure of children to PM2.5 is associated with increased levels of circulating endothelin-1 and elevated mean pulmonary arterial pressure

The impact of environmental metals in young urbanites’ brains

Air pollution exposures are linked to cognitive and olfaction deficits, oxidative stress, neuroinflammation and neurodegeneration including frontal hyperphosphorilated tau and diffuse amyloid plaques in Mexico City children and young adults. Mexico City residents are chronically exposed to fine particulate matter (PM2.5) concentrations (containing toxic combustion and industrial metals) above the annual standard (15 μg/m3) and to contaminated water and soil. Here, we sought to address the brain-region-specific effects of metals and key neuroinflammatory and DNA repair responses in two air pollution targets: frontal lobe and olfactory bulb from 12 controls v 47 Mexico City children and young adults average age 33.06 ± 4.8 SE years. Inductively coupled plasma mass spectrometry (metal analysis) and real time PCR (for COX2, IL1β and DNA repair genes) in target tissues. Mexico City residents had higher concentrations of metals associated with PM: manganese (p=0.003), nickel and chromium (p=0.02) along with higher frontal COX2 mRNA (p=0.008) and IL1β (p=0.0002) and COX2 (p=0.005) olfactory bulb indicating neuroinflammation. Frontal metals correlated with olfactory bulb DNA repair genes and with frontal and hippocampal inflammatory genes. Frontal manganese, cobalt and selenium increased with age in exposed subjects

Iron-rich air pollution nanoparticles:An unrecognised environmental risk factor for myocardial mitochondrial dysfunction and cardiac oxidative stress

Exposure to particulate air pollution is a major environmental risk factor for cardiovascular mortality and morbidity, on a global scale. Both acute and chronic cardiovascular impacts have so far been attributed to particulate-mediated oxidative stress in the lung and/or via 'secondary' pathways, including endothelial dysfunction, and inflammation. However, increasing evidence indicates the translocation of inhaled nanoparticles to major organs via the circulation. It is essential to identify the composition and intracellular targets of such particles, since these are likely to determine their toxicity and consequent health impacts. Of potential major concern is the abundant presence of iron-rich air pollution nanoparticles, emitted from a range of industry and traffic-related sources. Bioreactive iron can catalyse formation of damaging reactive oxygen species, leading to oxidative stress and cell damage or death. Here, we identify for the first time, in situ, that exogenous nanoparticles (~15-40 nm diameter) within myocardial mitochondria of young, highly-exposed subjects are dominantly iron-rich, and co-associated with other reactive metals including aluminium and titanium. These rounded, electrodense nanoparticles (up to ~ 10 x more abundant than in lower-pollution controls) are located within abnormal myocardial mitochondria (e.g. deformed cristae; ruptured membranes). Measurements of an oxidative stress marker, PrP C and an endoplasmic reticulum stress marker, GRP78, identify significant ventricular up-regulation in the highly-exposed vs lower-pollution controls. In shape/size/composition, the within-mitochondrial particles are indistinguishable from the iron-rich, combustion- and friction-derived nanoparticles prolific in roadside/urban environments, emitted from traffic/industrial sources. Incursion of myocardial mitochondria by inhaled iron-rich air pollution nanoparticles thus appears associated with mitochondrial dysfunction, and excess formation of reactive oxygen species through the iron-catalyzed Fenton reaction. Ventricular oxidative stress, as indicated by PrP C and GRP78 up-regulation, is evident even in children/young adults with minimal risk factors and no co-morbidities. These new findings indicate that myocardial iron overload resulting from inhalation of airborne, metal-rich nanoparticles is a plausible and modifiable environmental risk factor for cardiac oxidative stress and cardiovascular disease, on an international scale

Magnetite pollution nanoparticles in the human brain

Biologically formed nanoparticles of the strongly magnetic mineral, magnetite, were first detected in the human brain over 20 y ago [Kirschvink JL, Kobayashi-Kirschvink A, Woodford BJ (1992) Proc Natl Acad Sci USA 89(16):7683-7687]. Magnetite can have potentially large impacts on the brain due to its unique combination of redox activity, surface charge, and strongly magnetic behavior. We used magnetic analyses and electron microscopy to identify the abundant presence in the brain of magnetite nanoparticles that are consistent with high-temperature formation, suggesting, therefore, an external, not internal, source. Comprising a separate nanoparticle population from the euhedral particles ascribed to endogenous sources, these brain magnetites are often found with other transition metal nanoparticles, and they display rounded crystal morphologies and fused surface textures, reflecting crystallization upon cooling from an initially heated, iron-bearing source material. Such high-temperature magnetite nanospheres are ubiquitous and abundant in airborne particulate matter pollution. They arise as combustion-derived, iron-rich particles, often associated with other transition metal particles, which condense and/ or oxidize upon airborne release. Those magnetite pollutant particles which are &lt;sim;200 nm in diameter can enter the brain directly via the olfactory bulb. Their presence proves that externally sourced iron-bearing nanoparticles, rather than their soluble compounds, can be transported directly into the brain, where they may pose hazard to human health.</enty

Decreases in Short Term Memory, IQ, and Altered Brain Metabolic Ratios in Urban Apolipoprotein ε4 Children Exposed to Air Pollution

Children's urban air pollution exposures result in systemic and brain inflammation and the early hallmarks of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most prevalent genetic risk for AD. We assessed whether APOE in healthy children modulates cognition, olfaction, and metabolic brain indices. The Wechsler Intelligence Scale for Children (WISC-R) and the University of Pennsylvania Smell Identification Test were administered to 50 Mexico City Metropolitan Area children (13.4 ± 4.8 years, 28 APOE ε3 and 22 APOE ε4). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (mI)/Cr, and NAA/mI were calculated using proton magnetic resonance spectroscopy in the white matter of the frontal and parietal lobes, hippocampus, and pons. APOE ε4 versus ε3 children had a reduced NAA/Cr ratio in the right frontal white matter and decrements on attention, short-term memory, and below-average scores in Verbal and Full Scale IQ (>10 points). APOE modulated the group effects between WISC-R and left frontal and parietal white matter, and hippocampus metabolites. Soap was the predominantly failed odor in urban children and, in APOE ε4 versus ε3 carriers, strongly correlated with left hippocampus mI/Cr ratio. APOE modulates responses to air pollution in the developing brain. APOE ε4 carriers could have a higher risk of developing early AD if they reside in a polluted environment. APOE, cognition, and olfaction testing and targeted magnetic resonance spectroscopy may contribute to the assessment of urban children and their results could provide new paths toward the unprecedented opportunity for early neuroprotection and AD prevention