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

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

8-hydroxy-2'-deoxyguanosine, a major mutagenic oxidative DNA lesion, and DNA strand breaks in nasal respiratory epithelium of children exposed to urban pollution.

Southwest metropolitan Mexico City children are repeatedly exposed to high levels of a complex mixture of air pollutants, including ozone, particulate matter, aldehydes, metals, and nitrogen oxides. We explored nasal cell 8-hydroxy-2'-deoxyguanosine (8-OHdG), a major mutagenic lesion producing G-->T transversion mutations, using an immunohistochemical method, and DNA single strand breaks (ssb) using the single cell gel electrophoresis assay as biomarkers of oxidant exposure. Nasal biopsies from the posterior inferior turbinate were examined in children in grades one through five, including 12 controls from a low-polluted coastal town and 87 Mexico City children. Each biopsy was divided for the 8-OHdG and DNA ssb assays. There was an age-dependent increase in the percentage of nasal cells with DNA tails > 10 microm in Mexico City children: 19 +/- 9% for control cells, and 43 +/- 4, 50 +/- 16, 56 +/- 17, 60 +/- 17 and 73 +/- 14%, respectively, for first through fifth graders (p < 0.05). Nasal ssb were significantly higher in fifth graders than in first graders (p < 0.05). Higher levels (2.3- to 3-fold) of specific nuclear staining for 8-OHdG were observed in exposed children as compared to controls (p < 0.05). These results suggest that DNA damage is present in nasal epithelial cells in Mexico City children. Persistent oxidative DNA damage may ultimately result in a selective growth of pr eneoplastic nasal initiated cells in this population and the potential for nasal neoplasms may increase with age. The combination of 8-OHdG and DNA ssb should be useful for monitoring oxidative damage in people exposed to polluted atmospheres

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

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

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

Beyond cardiovascular medicine: potential future uses of icosapent ethyl

The REDUCE-IT trial demonstrated that icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), reduced cardiovascular events in an at-risk population by a substantial degree. While the cardiovascular protective properties of this compound are now proven, several other potential uses are being actively explored in clinical studies. These areas of investigation include cancer, inflammatory bowel disease, infections, Alzheimer’s disease, dementia, and depression. The next decade promises to deepen our understanding of the beneficial effects that EPA may offer beyond cardiovascular risk reduction