Influence of biomass burning on ozone levels in the Megalopolis of Central Mexico during the COVID-19 lockdown.

The massive reductions in anthropogenic emissions resulting from the COVID-19 lockdown provided a unique opportunity to evaluate the effect of mitigation measures aiming to abate air pollution. In Mexico, the total lockdown period took place during the dry-hot season when biomass burning activity is enhanced. Here, we investigate the role of biomass burning emissions on regional ozone levels in the Megalopolis of Central Mexico. The studied period covers the lockdown phases 2 and 3, and the first month of the New Normal. We applied a factor separation technique and process analysis to estimate the pure and synergistic contributions of emission reductions under lockdown and that from biomass burning to daily ozone maximum concentrations in 7 metropolitan areas of different states in the Megalopolis. The results revealed that biomass burning plumes likely masked the effect of massive reductions from mobile emissions, impacted the PBL development during phase 3 and favored transition and mixed NOx-limited and VOC-limited regional regimes. This contributed to increased ozone production in the middle to lower PBL by changing the regional background levels which potentially could bias high ozone production efficiency estimations. Given the Megalopolis contribution to economic and societal development at national scale, our study suggests that ozone mitigation measures during the dry-hot season targeting mainly mobile emissions will likely be offset by biomass burning plumes. A regional and synergic policy aiming to control biomass burning would help to reduce the occurrence of high ozone levels in Central Mexico with the co-benefit of tackling short-lived climate pollutants.

Evaluating pollution-related damage and restoration success in urban forests with participatory monitoring and digital tools.

Peri-urban forest monitoring requires indicators of vegetation damage. An example is the sacred fir (Abies religiosa) forests surrounding Mexico City, which have been heavily exposed to tropospheric ozone, a harmful pollutant, for over 4 decades. We developed a participatory monitoring system with which local community members and scientists generated data on ozone tree damage. Santa Rosa Xochiac rangers (13) used the digital tool KoboToolBox to record ozone damage to trees, tree height, tree ages, tree condition, tree position, and whether the tree had been planted. Thirty-five percent of the trees (n = 1765) had ozone damage. Younger trees had a lower percentage of foliage damaged by ozone than older trees (p < 0.0001), and asymptomatic trees tended to be younger (p < 0.0001). Symptomatic trees were taller than asymptomatic trees of the same age (R2 c  = 0.43, R2 m  = 0.27). Involving local communities facilitated forest monitoring and using digital technology improved data quality. This participatory system can be used to monitor forest condition change over time and thus aids restoration efforts driven by government or local communities' interests, facilitating local decision-making.

Evaluación del daño relacionado a la contaminación y del éxito de la restauración de los bosques urbanos con un monitoreo participativo y herramientas digitales Resumen El monitoreo de los bosques periurbanos requiere indicadores de daños en la vegetación. Un ejemplo son los bosques de abeto (Abies religiosa) que rodean la Ciudad de México, pues desde hace más de 4 décadas han estado expuestos al ozono troposférico, un contaminante nocivo. Desarrollamos un sistema de monitoreo participativo con el que miembros de la comunidad local y científicos generaron datos sobre los daños causados por el ozono en los árboles. Los guardabosques de Santa Rosa Xochiac (133) utilizaron la herramienta digital KoboToolBox para registrar los daños causados por el ozono en los árboles, su altura, edad, estado, posición y si eran árboles plantados. El 35% de los árboles (n = 1,765) presentó daños por ozono. Los árboles más jóvenes tenían un menor porcentaje de follaje dañado por el ozono que los árboles más viejos (p<0.0001), y los árboles asintomáticos tendían a ser más jóvenes (p<0.0001). Los árboles sintomáticos eran más altos que los asintomáticos de la misma edad (R2 c = 0.43, R2 m = 0.27). La participación de las comunidades locales facilitó el monitoreo forestal y el uso de tecnología digital mejoró la calidad de los datos. Este sistema participativo puede utilizarse para monitorear los cambios en el estado de los bosques a lo largo del tiempo y contribuir a los esfuerzos de restauración impulsados por el gobierno o las comunidades locales, facilitando la toma de decisiones a nivel local.

Alzheimer disease starts in childhood in polluted Metropolitan Mexico City. A major health crisis in progress.

Exposures to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards are associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) youth have life time exposures to PM2.5 and O3 above standards. We focused on MMC residents ≤30 years and reviewed 134 consecutive autopsies of subjects age 20.03 ± 6.38 y (range 11 months to 30 y), the staging of Htau and ß amyloid, the lifetime cumulative PM2.5 (CPM 2.5) and the impact of the Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD. We also reviewed the results of the Montreal Cognitive Assessment (MoCA) and the brainstem auditory evoked potentials (BAEPs) in clinically healthy young cohorts. Mobile sources, particularly from non-regulated diesel vehicles dominate the MMC pollutant emissions exposing the population to PM2.5 concentrations above WHO and EPA standards. Iron-rich,magnetic, highly oxidative, combustion and friction-derived nanoparticles (CFDNPs) are measured in the brain of every MMC resident. Progressive development of Alzheimer starts in childhood and in 99.25% of 134 consecutive autopsies ≤30 years we can stage the disease and its progression; 66% of ≤30 years urbanites have cognitive impairment and involvement of the brainstem is reflected by auditory central dysfunction in every subject studied. The average age for dementia using MoCA is 20.6 ± 3.4 y. APOE4 vs 3 carriers have 1.26 higher odds of committing suicide. PM2.5 and CFDNPs play a key role in the development of neuroinflammation and neurodegeneration in young urbanites. A serious health crisis is in progress with social, educational, judicial, economic and overall negative health impact for 25 million residents. Understanding the neural circuitry associated with the earliest cognitive and behavioral manifestations of AD is needed. Air pollution control should be prioritised-including the regulation of diesel vehicles- and the first two decades of life ought to be targeted for neuroprotective interventions. Defining paediatric environmental, nutritional, metabolic and genetic risk factor interactions is a multidisciplinary task of paramount importance to prevent Alzheimer's disease. Current and future generations are at risk.

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.

Gait and balance disturbances are common in young urbanites and associated with cognitive impairment. Air pollution and the historical development of Alzheimer's disease in the young.

To determine whether gait and balance dysfunction are present in young urbanites exposed to fine particular matter PM2.5 ≥ annual USEPA standard, we tested gait and balance with Tinetti and Berg tests in 575 clinically healthy subjects, age 21.0 ±â€¯5.7 y who were residents in Metropolitan Mexico City, Villahermosa and Reynosa. The Montreal Cognitive Assessment was also applied to an independent cohort n:76, age 23.3 ±â€¯9.1 y. In the 575 cohort, 75.4% and 34.4% had abnormal total Tinetti and Berg scores and high risk of falls in 17.2% and 5.7% respectively. BMI impacted negatively Tinetti and Berg performance. Gait dysfunction worsen with age and males performed worse than females. Gait and balance dysfunction were associated with mild cognitive impairment MCI (19.73%) and dementia (55.26%) in 57/76 and 19 cognitively intact subjects had gait and balance dysfunction. Seventy-five percent of urbanites exposed to PM2.5 had gait and balance dysfunction. For MMC residents-with historical documented Alzheimer disease (AD) and CSF abnormalities, these findings suggest Alzheimer Continuum is in progress. Early development of a Motoric Cognitive Risk Syndrome ought to be considered in city dwellers with normal cognition and gait dysfunction. The AD research frame in PM2.5 exposed young urbanites should include gait and balance measurements. Multicity teens and young adult cohorts are warranted for quantitative gait and balance measurements and neuropsychological and brain imaging studies in high vs low PM2.5 exposures. Early identification of gait and balance impairment in young air pollution-exposed urbanites would facilitate multidisciplinary prevention efforts for modifying the course of AD.

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 ±â€¯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.

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 <∼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.

Alzheimer's disease and alpha-synuclein pathology in the olfactory bulbs of infants, children, teens and adults ≤ 40 years in Metropolitan Mexico City. APOE4 carriers at higher risk of suicide accelerate their olfactory bulb pathology.

There is growing evidence that air pollution is a risk factor for a number of neurodegenerative diseases, most notably Alzheimer's (AD) and Parkinson's (PD). It is generally assumed that the pathology of these diseases arises only later in life and commonly begins within olfactory eloquent pathways prior to the onset of the classical clinical symptoms. The present study demonstrates that chronic exposure to high levels of air pollution results in AD- and PD-related pathology within the olfactory bulbs of children and relatively young adults ages 11 months to 40 years. The olfactory bulbs (OBs) of 179 residents of highly polluted Metropolitan Mexico City (MMC) were evaluated for AD- and alpha-synuclein-related pathology. Even in toddlers, hyperphosphorylated tau (hTau) and Lewy neurites (LN) were identified in the OBs. By the second decade, 84% of the bulbs exhibited hTau (48/57), 68% LNs and vascular amyloid (39/57) and 36% (21/57) diffuse amyloid plaques. OB active endothelial phagocytosis of red blood cell fragments containing combustion-derived nanoparticles (CDNPs) and the neurovascular unit damage were associated with myelinated and unmyelinated axonal damage. OB hTau neurites were associated mostly with pretangle stages 1a and 1b in subjects ≤ 20 years of age, strongly suggesting olfactory deficits could potentially be an early guide of AD pretangle subcortical and cortical hTau. APOE4 versus APOE3 carriers were 6-13 times more likely to exhibit OB vascular amyloid, neuronal amyloid accumulation, alpha-synuclein aggregates, hTau neurofibrillary tangles, and neurites. Remarkably, APOE4 carriers were 4.57 times more likely than non-carriers to die by suicide. The present findings, along with previous data that over a third of clinically healthy MMC teens and young adults exhibit low scores on an odor identification test, support the concept that olfactory testing may aid in identifying young people at high risk for neurodegenerative diseases. Moreover, results strongly support early neuroprotective interventions in fine particulate matter (PM2.5) and CDNP's exposed individuals ≤ 20 years of age, and the critical need for air pollution control.

Hallmarks of Alzheimer disease are evolving relentlessly in Metropolitan Mexico City infants, children and young adults. APOE4 carriers have higher suicide risk and higher odds of reaching NFT stage V at ≤ 40 years of age.

Exposures to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards are associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) residents have life time exposures to PM2.5 and O3 above USEPA standards. We investigated AD intra and extracellular protein aggregates and ultrastructural neurovascular pathology in 203 MMC residents age 25.36 ±â€¯9.23 y. Immunohistochemical methods were used to identify AT8 hyperphosphorilated tau (Htau) and 4G8 (amyloid ß 17-24). Primary outcomes: staging of Htau and amyloid, per decade and cumulative PM2.5 (CPM2.5) above standard. Apolipoprotein E allele 4 (APOE4), age and cause of death were secondary outcomes. Subcortical pretangle stage b was identified in an 11month old baby. Cortical tau pre-tangles, neurofibrillary tangles (NFT) Stages I-II, amyloid phases 1-2, Htau in substantia nigrae, auditory, oculomotor, trigeminal and autonomic systems were identified by the 2nd decade. Progression to NFT stages III-V was present in 24.8% of 30-40 y old subjects. APOE4 carriers have 4.92 times higher suicide odds (p = 0.0006), and 23.6 times higher odds of NFT V (p < 0.0001) v APOE4 non-carriers having similar CPM2.5 exposure and age. Age (p = 0.0062) and CPM2.5 (p = 0.0178) were significant for developing NFT V. Combustion-derived nanoparticles were associated with early and progressive damage to the neurovascular unit. Alzheimer's disease starting in the brainstem of young children and affecting 99.5% of young urbanites is a serious health crisis. Air pollution control should be prioritised. Childhood relentless Htau makes a fundamental target for neuroprotective interventions and the first two decades are critical. We recommend the concept of preclinical AD be revised and emphasize the need to define paediatric environmental, nutritional, metabolic and genetic risk factor interactions of paramount importance to prevent AD. AD evolving from childhood is threating the wellbeing of our children and future generations.

Exposures to fine particulate matter (PM2.5) and ozone above USA standards are associated with auditory brainstem dysmorphology and abnormal auditory brainstem evoked potentials in healthy young dogs.

BACKGROUND: Delayed central conduction times in the auditory brainstem have been observed in Mexico City (MC) healthy children exposed to fine particulate matter (PM2.5) and ozone (O3) above the current United States Environmental Protection Agency (US-EPA) standards. MC children have α synuclein brainstem accumulation and medial superior olivary complex (MSO) dysmorphology. The present study used a dog model to investigate the potential effects of air pollution on the function and morphology of the auditory brainstem. METHODOLOGY: Twenty-four dogs living in clean air v MC, average age 37.1 ± 26.3 months, underwent brainstem auditory evoked potential (BAEP) measurements. Eight dogs (4 MC, 4 Controls) were analysed for auditory brainstem morphology and histopathology. RESULTS: MC dogs showed ventral cochlear nuclei hypotrophy and MSO dysmorphology with a significant decrease in cell body size, decreased neuronal packing density with regions in the nucleus devoid of neurons and marked gliosis. MC dogs showed significant delayed BAEP absolute wave I, III and V latencies compared to controls. CONCLUSIONS: MC dogs show auditory nuclei dysmorphology and BAEPs consistent with an alteration of the generator sites of the auditory brainstem response waveform. This study puts forward the usefulness of BAEPs to study auditory brainstem neurodegenerative changes associated with air pollution in dogs. Recognition of the role of non-invasive BAEPs in urban dogs is warranted to elucidate novel neurodegenerative pathways link to air pollution and a promising early diagnostic strategy for Alzheimer's Disease.

Prefrontal white matter pathology in air pollution exposed Mexico City young urbanites and their potential impact on neurovascular unit dysfunction and the development of Alzheimer's disease.

Millions of urban children are chronically exposed to high concentrations of air pollutants, i.e., fine particulate matter (PM2.5) and ozone, associated with increased risk for Alzheimer's disease. Compared with children living with clear air those in Mexico City (MC) exhibit systemic, brain and intrathecal inflammation, low CSF Aß42, breakdown of the BBB, attention and short-term memory deficits, prefrontal white matter hyperintensities, damage to epithelial and endothelial barriers, tight junction and neural autoantibodies, and Alzheimer and Parkinson's hallmarks. The prefrontal white matter is a target of air pollution. We examined by light and electron microscopy the prefrontal white matter of MC dogs (n: 15, age 3.17±0.74 years), children and teens (n: 34, age: 12.64±4.2 years) versus controls. Major findings in MC residents included leaking capillaries and small arterioles with extravascular lipids and erythrocytes, lipofuscin in pericytes, smooth muscle and endothelial cells (EC), thickening of cerebrovascular basement membranes with small deposits of amyloid, patchy absence of the perivascular glial sheet, enlarged Virchow-Robin spaces and nanosize particles (20-48nm) in EC, basement membranes, axons and dendrites. Tight junctions, a key component of the neurovascular unit (NVU) were abnormal in MC versus control dogs (χ(2)<0.0001), and white matter perivascular damage was significantly worse in MC dogs (p=0.002). The integrity of the NVU, an interactive network of vascular, glial and neuronal cells is compromised in MC young residents. Characterizing the early NVU damage and identifying biomarkers of neurovascular dysfunction may provide a fresh insight into Alzheimer pathogenesis and open opportunities for pediatric neuroprotection.

Interactive and additive influences of Gender, BMI and Apolipoprotein 4 on cognition in children chronically exposed to high concentrations of PM2.5 and ozone. APOE 4 females are at highest risk in Mexico City.

Children's air pollution exposures are associated with systemic and brain inflammation and the early hallmarks of Alzheimer's disease (AD). The Apolipoprotein E (APOE) 4 allele is the most prevalent genetic risk for AD, with higher risk for women. We assessed whether gender, BMI, APOE and metabolic variables in healthy children with high exposures to ozone and fine particulate matter (PM2.5) influence cognition. The Wechsler Intelligence Scale for Children (WISC-R) was administered to 105 Mexico City children (12.32±5.4 years, 69 APOE 3/3 and 36 APOE 3/4). APOE 4v 3 children showed decrements on attention and short-term memory subscales, and below-average scores in Verbal, Performance and Full Scale IQ. APOE 4 females had higher BMI and females with normal BMI between 75-94% percentiles had the highest deficits in Total IQ, Performance IQ, Digit Span, Picture Arrangement, Block Design and Object Assembly. Fasting glucose was significantly higher in APOE 4 children p=0.006, while Gender was the main variable accounting for the difference in insulin, HOMA-IR and leptin (p<.05). Gender, BMI and APOE influence children's cognitive responses to air pollution and glucose is likely a key player. APOE 4 heterozygous females with >75% to <94% BMI percentiles are at the highest risk of severe cognitive deficits (1.5-2SD from average IQ). Young female results highlight the urgent need for gender-targeted health programmes to improve cognitive responses. Multidisciplinary intervention strategies could provide paths for prevention or amelioration of female air pollution targeted cognitive deficits and possible long-term AD progression.

Megacities air pollution problems: Mexico City Metropolitan Area critical issues on the central nervous system pediatric impact.

The chronic health effects associated with sustained exposures to high concentrations of air pollutants are an important issue for millions of megacity residents and millions more living in smaller urban and rural areas. Particulate matter (PM) and ozone (O3) concentrations close or above their respective air quality standards during the last 20 years affect 24 million people living in the Mexico City Metropolitan Area (MCMA). Herein we discuss PM and O3 trends in MCMA and their possible association with the observed central nervous system (CNS) effects in clinically healthy children. We argue that prenatal and postnatal sustained exposures to a natural environmental exposure chamber contribute to detrimental neural responses. The emerging picture for MCMA children shows systemic inflammation, immunodysregulation at both systemic and brain levels, oxidative stress, neuroinflammation, small blood vessel pathology, and an intrathecal inflammatory process, along with the early neuropathological hallmarks for Alzheimer and Parkinson's diseases. Exposed brains are briskly responding to their harmful environment and setting the bases for structural and volumetric changes, cognitive, olfactory, auditory and vestibular deficits and long term neurodegenerative consequences. We need to improve our understanding of the PM pediatric short and long term CNS impact through multidisciplinary research. Public health benefit can be achieved by integrating interventions that reduce fine PM levels and pediatric exposures and establishing preventative screening programs targeting pediatric populations that are most at risk. We fully expect that the health of 24 million residents is important and blocking pediatric air pollution research and hiding critical information that ought to be available to our population, health, education and social workers is not in the best interest of our children.

Mexico City normal weight children exposed to high concentrations of ambient PM2.5 show high blood leptin and endothelin-1, vitamin D deficiency, and food reward hormone dysregulation versus low pollution controls. Relevance for obesity and Alzheimer disease.

Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease.

Histologic, metabolomic, and transcriptomic differences in fir trees from a peri-urban forest under chronic ozone exposure.

Urbanization modifies ecosystem conditions and evolutionary processes. This includes air pollution, mostly as tropospheric ozone (O3), which contributes to the decline of urban and peri-urban forests. A notable case are fir (Abies religiosa) forests in the peripheral mountains southwest of Mexico City, which have been severely affected by O3 pollution since the 1970s. Interestingly, some young individuals exhibiting minimal O3-related damage have been observed within a zone of significant O3 exposure. Using this setting as a natural experiment, we compared asymptomatic and symptomatic individuals of similar age (≤15 years old; n = 10) using histologic, metabolomic, and transcriptomic approaches. Plants were sampled during days of high (170 ppb) and moderate (87 ppb) O3 concentration. Given that there have been reforestation efforts in the region, with plants from different source populations, we first confirmed that all analyzed individuals clustered within the local genetic group when compared to a species-wide panel (Admixture analysis with ~1.5K SNPs). We observed thicker epidermis and more collapsed cells in the palisade parenchyma of needles from symptomatic individuals than from their asymptomatic counterparts, with differences increasing with needle age. Furthermore, symptomatic individuals exhibited lower concentrations of various terpenes (ß-pinene, ß-caryophylene oxide, α-caryophylene, and ß-α-cubebene) than asymptomatic trees, as evidenced through GC-MS. Finally, transcriptomic analyses revealed differential expression for 13 genes related to carbohydrate metabolism, plant defense, and gene regulation. Our results indicate a rapid and contrasting phenotypic response among trees, likely influenced by standing genetic variation and/or plastic mechanisms. They open the door to future evolutionary studies for understanding how O3 tolerance develops in urban environments, and how this knowledge could contribute to forest restoration.

La urbanización altera tanto las condiciones del ecosistema como los procesos evolutivos, siendo la contaminación del aire, principalmente el ozono troposférico (O3), un factor que contribuye al declive de los bosques urbanos y periurbanos. Un ejemplo destacado son los bosques de oyamel (Abies religiosa) en las montañas periféricas al suroeste de la Ciudad de México, que han sufrido graves afectaciones por la contaminación de O3 desde la década de 1970. Resulta curioso observar que algunos individuos jóvenes presentan un daño mínimo relacionado con el O3 dentro de zonas con una exposición significativa a este contaminante. Aprovechando este entorno como un experimento natural, hemos comparado individuos asintomáticos y sintomáticos de edad similar (≤15 años; n = 10) mediante enfoques histológicos, metabolómicos y transcriptómicos. Las muestras de plantas se recolectaron durante días con concentraciones altas (170 ppb) y moderadas (87 ppb) de O3. Dado que se han llevado a cabo esfuerzos de reforestación en la región con plantas de diferentes poblaciones, primero confirmamos que todos los individuos analizados se organizaron dentro del grupo genético local en comparación con un amplio panel poblacional de esta misma especie (Análisis de Admixture con ~1.5 K SNPs). Observamos una epidermis más gruesa y más células colapsadas en el parénquima en empalizada de las agujas de los individuos sintomáticos que de sus contrapartes asintomáticas, y estas diferencias aumentaban con la edad de la aguja. Además, los individuos sintomáticos exhibieron concentraciones más bajas de varios terpenos (ß­pineno, óxido de ß­cariofileno, α­cariofileno y ß­α­cubebeno) que los árboles asintomáticos, según se evidenció mediante GC­MS. Por último, los análisis transcriptómicos revelaron una expresión diferencial para trece genes relacionados con el metabolismo de carbohidratos, la defensa de plantas y la regulación génica. Nuestros resultados indican una respuesta fenotípica rápida y contrastante entre los árboles, probablemente influenciada por la variación genética presente y/o mecanismos plásticos. Estos hallazgos abren la puerta a futuros estudios evolutivos para comprender cómo se desarrolla la tolerancia al O3 en entornos urbanos y cómo este conocimiento podría contribuir a la restauración forestal.

Up-regulation of mRNA ventricular PRNP prion protein gene expression in air pollution highly exposed young urbanites: endoplasmic reticulum stress, glucose regulated protein 78, and nanosized particles.

Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role.

APOE Peripheral and Brain Impact: APOE4 Carriers Accelerate Their Alzheimer Continuum and Have a High Risk of Suicide in PM2.5 Polluted Cities.

This Review emphasizes the impact of APOE4-the most significant genetic risk factor for Alzheimer's disease (AD)-on peripheral and neural effects starting in childhood. We discuss major mechanistic players associated with the APOE alleles' effects in humans to understand their impact from conception through all life stages and the importance of detrimental, synergistic environmental exposures. APOE4 influences AD pathogenesis, and exposure to fine particulate matter (PM2.5), manufactured nanoparticles (NPs), and ultrafine particles (UFPs) associated with combustion and friction processes appear to be major contributors to cerebrovascular dysfunction, neuroinflammation, and oxidative stress. In the context of outdoor and indoor PM pollution burden-as well as Fe, Ti, and Al alloys; Hg, Cu, Ca, Sn, and Si UFPs/NPs-in placenta and fetal brain tissues, urban APOE3 and APOE4 carriers are developing AD biological disease hallmarks (hyperphosphorylated-tau (P-tau) and amyloid beta 42 plaques (Aß42)). Strikingly, for Metropolitan Mexico City (MMC) young residents ≤ 40 y, APOE4 carriers have 4.92 times higher suicide odds and 23.6 times higher odds of reaching Braak NFT V stage versus APOE4 non-carriers. The National Institute on Aging and Alzheimer's Association (NIA-AA) framework could serve to test the hypothesis that UFPs and NPs are key players for oxidative stress, neuroinflammation, protein aggregation and misfolding, faulty complex protein quality control, and early damage to cell membranes and organelles of neural and vascular cells. Noninvasive biomarkers indicative of the P-tau and Aß42 abnormal protein deposits are needed across the disease continuum starting in childhood. Among the 21.8 million MMC residents, we have potentially 4 million APOE4 carriers at accelerated AD progression. These APOE4 individuals are prime candidates for early neuroprotective interventional trials. APOE4 is key in the development of AD evolving from childhood in highly polluted urban centers dominated by anthropogenic and industrial sources of pollution. APOE4 subjects are at higher early risk of AD development, and neuroprotection ought to be implemented. Effective reductions of PM2.5, UFP, and NP emissions from all sources are urgently needed. Alzheimer's Disease prevention ought to be at the core of the public health response and physicians-scientist minority research be supported.

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders-Denial is not an option.

Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aß1 - 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority.

Alzheimer and Parkinson diseases, frontotemporal lobar degeneration and amyotrophic lateral sclerosis overlapping neuropathology start in the first two decades of life in pollution exposed urbanites and brain ultrafine particulate matter and industrial nanoparticles, including Fe, Ti, Al, V, Ni, Hg, Co, Cu, Zn, Ag, Pt, Ce, La, Pr and W are key players. Metropolitan Mexico City health crisis is in progress.

The neuropathological hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are present in urban children exposed to fine particulate matter (PM2.5), combustion and friction ultrafine PM (UFPM), and industrial nanoparticles (NPs). Metropolitan Mexico City (MMC) forensic autopsies strongly suggest that anthropogenic UFPM and industrial NPs reach the brain through the nasal/olfactory, lung, gastrointestinal tract, skin, and placental barriers. Diesel-heavy unregulated vehicles are a key UFPM source for 21.8 million MMC residents. We found that hyperphosphorylated tau, beta amyloid1-42, α-synuclein, and TAR DNA-binding protein-43 were associated with NPs in 186 forensic autopsies (mean age 27.45 ± 11.89 years). The neurovascular unit is an early NPs anatomical target, and the first two decades of life are critical: 100% of 57 children aged 14.8 ± 5.2 years had AD pathology; 25 (43.9%) AD+TDP-43; 11 (19.3%) AD + PD + TDP-43; and 2 (3.56%) AD +PD. Fe, Ti, Hg, Ni, Co, Cu, Zn, Cd, Al, Mg, Ag, Ce, La, Pr, W, Ca, Cl, K, Si, S, Na, and C NPs are seen in frontal and temporal lobes, olfactory bulb, caudate, substantia nigra, locus coeruleus, medulla, cerebellum, and/or motor cortical and spinal regions. Endothelial, neuronal, and glial damages are extensive, with NPs in mitochondria, rough endoplasmic reticulum, the Golgi apparatus, and lysosomes. Autophagy, cell and nuclear membrane damage, disruption of nuclear pores and heterochromatin, and cell death are present. Metals associated with abrasion and deterioration of automobile catalysts and electronic waste and rare earth elements, i.e., lanthanum, cerium, and praseodymium, are entering young brains. Exposure to environmental UFPM and industrial NPs in the first two decades of life are prime candidates for initiating the early stages of fatal neurodegenerative diseases. MMC children and young adults-surrogates for children in polluted areas around the world-exhibit early AD, PD, FTLD, and ALS neuropathological hallmarks forecasting serious health, social, economic, academic, and judicial societal detrimental impact. Neurodegeneration prevention should be a public health priority as the problem of human exposure to particle pollution is solvable. We are knowledgeable of the main emission sources and the technological options to control them. What are we waiting for?

Fall Risk, Sleep Behavior, and Sleep-Related Movement Disorders in Young Urbanites Exposed to Air Pollution.

BACKGROUND: Quadruple aberrant hyperphosphorylated tau, amyloid-ß, α-synuclein, and TDP-43 pathology had been documented in 202/203 forensic autopsies in Metropolitan Mexico City ≤40-year-olds with high exposures to ultrafine particulate matter and engineered nanoparticles. Cognition deficits, gait, equilibrium abnormalities, and MRI frontal, temporal, caudate, and cerebellar atrophy are documented in young adults. OBJECTIVE: This study aimed to identify an association between falls, probable Rapid Eye Movement Sleep Behavior Disorder (pRBD), restless leg syndrome (RLS), and insomnia in 2,466 Mexican, college-educated volunteers (32.5±12.4 years). METHODS: The anonymous, online study applied the pRBD and RLS Single-Questions and self-reported night-time sleep duration, excessive daytime sleepiness, insomnia, and falls. RESULTS: Fall risk was strongly associated with pRBD and RLS. Subjects who fell at least once in the last year have an OR = 1.8137 [1.5352, 2.1426] of answering yes to pRBD and/or RLS questions, documented in 29% and 24% of volunteers, respectively. Subjects fell mostly outdoors (12:01 pm to 6:00 pm), 43% complained of early wake up hours, and 35% complained of sleep onset insomnia (EOI). EOI individuals have an OR of 2.5971 [2.1408, 3.1506] of answering yes to the RLS question. CONCLUSION: There is a robust association between falls, pRBD, and RLS, strongly suggesting misfolded proteinopathies involving critical brainstem arousal and motor hubs might play a crucial role. Nanoparticles are likely a significant risk for falls, sleep disorders, insomnia, and neurodegenerative lethal diseases, thus characterizing air particulate pollutants' chemical composition, emission sources, and cumulative exposure concentrations are strongly recommended.