Environmental Contamination and Autism: Special Report from UPHE
Last spring, leading scientists in pediatrics and public health warned of a “silent pandemic,” of brain disorders citing strong evidence that “children worldwide are being exposed to unrecognized toxic chemicals that are silently eroding intelligence, disrupting behaviors, truncating future achievements and damaging societies (1).”
These toxins—heavy metals, fluoride, chemicals like PCBs, toluene, solvents, flame retardants, BPA, phalates, pesticides, and PAHs (polycyclic aromatic hydrocarbons)—are found in the air you breathe, the food you eat, the water you drink, and the grass your kids play soccer on. Dramatically escalating rates of autism are part of this “silent pandemic.” Autism rates have climbed another 30% just since the last survey of two years ago, with Utah having the second highest rates of autism in the country, double the national average. As of 2012, one in every 32 Utah boys had autism. This “silent pandemic” warning should be a real wake up call for Utah physicians and policy makers.
Evidence is mounting that autism is likely caused by environmental exposures in genetically susceptible individuals (2, 3). Supporting an environmental/genetic tag team are other studies showing autistic children and their mothers have a high rate of a genetic deficiency in the production of glutathione, an antioxidant and the body’s primary means of detoxifying heavy metals. High levels of toxic metals in children are strongly correlated with the severity of autism. Low levels of glutathione, coupled with high production of homocysteine, increase the chance of a mother having an autistic child to one in three. That autism is four to five times more common among boys than girls is likely related to a defect in the single male X chromosome contributing to antioxidant deficiency. But there is no such thing as a genetic disease epidemic because genes don’t change that quickly, so the alarming rise in autism must be the result of increased environmental exposures that exploit these genetic defects.
While numerous environmental exposures have been implicated, including pharmaceuticals like anti-depressants, in the last few years a growing body of epidemiological studies (4,5,6,7,8, 59) have been published linking autism to air pollution, including a highly regarded one from the Harvard School of Public Health just last month (9) that showed a strong correlation between prenatal air pollution, especially in the third trimester, and autism. Correlation does not automatically mean causation however, so is there a plausible pathophysiologic explanation for an air pollution/autism connection?
Let’s address that question from the larger context of the relevant microbiology. Air pollution is merely a delivery mechanism for toxic particles and chemicals. Nano particles (NP), 100 nanometers in diameter and smaller, are now well understood to be the most dangerous subset of particulate air pollution. Not only are they the most likely to be inhaled, but they are also the most likely to cross the alveolar-capillary barrier in the lungs where they can then become systemically distributed. The ability of NPs to cross this barrier and create downstream toxicity is well documented and influenced by a number of factors that include the size of the particles, their charge, their chemical composition as well as their propensity to form aggregates (10).
A generalized inflammatory process first triggered by air pollution’s contact with the lung is then distributed throughout the body via damaging chemical mediators like cytokines, as well as distribution of the NP particles themselves. The physiologic response is often vasoconstriction of the microvascular network.
Like all other organs, the placenta is vulnerable to the systemic vascular inflammatory process triggered by air pollution and constriction has been demonstrated on the maternal side of the placenta with compensatory dilatation on the fetal side (11, 12, 13). This morphologic change has the potential to compromise fetal blood supply.
Furthermore, the placenta is not the noble barrier protecting the fetus against hazardous substances that was once assumed. In fact, regrettably, babies are born essentially “pre-polluted” with literally hundreds of chemicals perusing umbilical cord blood at the time of birth (16, 17, 52). One study detected 287 chemicals in umbilical cord blood, 217 of which are known to be toxic to the brain and nervous system (53). Essentially, the greater the contamination of our environment, including the air we breathe, the greater will be the risk of irreversible harm to a developing embryonic brain.
The brain is the primary fat reservoir of a developing fetus. Because many of the most toxic components of particulate air pollution are lipophilic, like dioxins, PAHs and heavy metals, once they cross the placenta and the fetal BBB, they end up disproportionately in the brain.
During the first three months of gestation, a human embryo adds 250,000 brain cells per minute, reaching 200 billion by the fifth month. But more than just rapid cellular proliferation, this is an extremely complicated process that involves neuronal migration from their place of origin to their final location, and the establishment of specific connections between neurons and target tissues. And during the entire process the timing and sequence of these developments must be precise (14). This exquisitely delicate process can be adversely influenced by environmental conditions. Air pollutants can affect the brain at any age, but the fetal brain is particularly vulnerable because of its high neuronal proliferation and differentiation rates, its immature metabolism and imperfect BBB (15). Likewise reduced cerebral blood flow from inflammatory vascular constriction would be expected to have consequences at any age, but during fetal development the consequences are undoubtedly much greater.
The well established disturbances of developmental processes in the brain by these toxic substances can lead to permanent cognitive and behavioral abnormalities. Numerous epidemiologic and clinical studies show prenatal and early life exposure to high concentrations of PAHs and other air pollution components are associated with impaired mental development in childhood (18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). Many of these studies showed cognitive impairment from levels of air pollution typical of urban areas to be substantial, 4-9 IQ points. Non-cognitive areas of the brain can be affected as well. Prenatal ozone exposure leads to permanent damage of the cerebellum and disruption of the cerebellar monoaminergic system (31, 32).
Clinical studies show a strong correlation with childhood anxiety, attention deficit, motor and behavioral disorders with prenatal PAH air pollution exposure of the mother (34, 35, 36, 37). Prenatal PAH exposure is even associated with smaller head circumference, which in turn correlates with overall intelligence (38).
After birth the brain becomes vulnerable to air pollution in new ways. Inhaled and vascularly distributed NP can specifically disrupt the blood brain barrier leading to neuroinflammation, oxidative stress, glial activation, and cerebrovascular damage that either directly impair brain tissue or leave a predisposition to multiple neurodegenerative diseases. Ultimately some NP can cross cell membranes, ending up intracellularly, where they can penetrate sub cellular structures like the mitochondria and nucleus of cells like erthrocytes and neurons (39, 40).
Mice exposed to air pollution levels realistic to congested freeways or a residence that regularly burns wood, for a period that corresponds to the first month of human life, show significant brain architectural changes (persistent ventriculomegaly), neurochemical disruption, and glial activation–that are comparable to changes found in humans with autism, schizophrenia, and other forms of poor neurodevelopment (41). This finding was almost exclusively in male mice, similar to the strong male predominance of human autism. The authors analyzed their findings this way. “When we looked closely at the ventricles, we could see that the white matter that normally surrounds them hadn’t fully developed. It appears that inflammation had damaged those brain cells and prevented that region of the brain from developing, and the ventricles simply expanded to fill the space.” The anatomic changes were permanent.
The interaction of NP with intracellular proteins can also result in protein degradation and denaturation, loss of enzyme activity and formation of autoantigens. Air pollution damages endothelial and epithelial barriers in the brain just like it does in the GI and respiratory tracts. Other researchers have found significantly higher levels of autoantibodies against brain blood vessels and proteins in serum and cerebrospinal fluid among children and adolescents exposed to the air pollution of Mexico City (42). Even NP that do not enter cells directly can still interact with surface proteins and change cellular signaling and behavior. Air pollution-induced loss of neurons is a consistent finding in postmortem and experimental studies.
During air pollution exposure reactive oxygen species (ROS) levels can increase dramatically throughout the body resulting in significant damage to cellular components, including proteins, lipids, and DNA. The brain is especially vulnerable to oxidative stress from ROS because of its high metabolic activity, its low activity of antioxidant enzymes (superoxide dismutase and catalase), its low concentrations of endogenous radical scavengers, its high cellular content of lipids and proteins, and its high amounts of redox metals such as iron and copper which can act as a potent catalyst for ROS production (43). Metals, pesticides, and air pollutants, all of which have been associated with neurodegeneration share a common toxic denominator, i.e. their increased production of reactive oxygen and nitrogen species.
The postnatal brain is unique among organs because pollution exposure can also occur from secondary routes, not dependent upon the lungs or vascular system. An accessory, more direct route is translocation from the nasal mucosa, allowing NP to enter the nervous system from environmental air. Even short term air pollution exposure, i.e. two days, can cause breakdown of the normal nasal mucosa, facilitating NP penetration. Once pollution NP penetrate the nasal mucosa, they can attach themselves to trigeminal and olfactory neurons, then move by slow axonal transport along the axons to the olfactory bulb (44). From there, pollutants can migrate further into the CNS along mitral cell axons that project from the olfactory bulb to multiple brain regions, including the olfactory cortex, the anterior olfactory nucleus, the piriform cortex, the amygdale, and the hypothalamus.
By this mechanism chronic air pollution exposure interferes with, among many other brain functions, our sense of smell (58), which happens to be one of the earliest and most consistent features of Alzheimer’s and Parkinson’s diseases.
Additional direct neuronal entry routes for NPs have been described that involve the retrograde and anterograde transport in axons and dendrites originating in sensory nerve fibers that innervate the airway epithelia (45). Almost certainly there exist some excretory pathways for NP to leave the CNS, but these have been less well defined. Chronic, or critically timed acute exposure can likely overwhelm excretory pathways.
Physicians are well aware of how smokers’ and coal miners’ lungs appear at autopsy. But it may be an entirely new thought process for physicians and the public to realize that these nano particles can also end up lodged permanently throughout the body, including in the brain itself. That air pollution can cause “brain pollution” is true in the most literal sense. Air-borne particulate matter has been identified both in human brain capillaries and in the brain parenchyma (46).
Brain tissue samples from individuals residing in highly polluted areas show an increase in the number of infiltrating monocytes or activated microglia, increased expression of interleukin-1beta, BBB damage, small blood vessel pathology, perivascular infiltrates, intrathecal inflammation, and brain lesions in the prefrontal lobe that are the neuropathologic hallmarks for Alzheimer and Parkinson’s diseases. In children it is especially disturbing that air pollution exposure is associated with brain structural and volumetric changes, cognitive, olfactory, auditory and vestibular deficits, all of which also have long term neurodegenerative consequences (47, 48).
Animals from polluted areas exhibited brain deposits of diffuse amyloid plaques a decade earlier than control animals from less-polluted regions (49, 50). Brains of young people chronically exposed to air pollution show an accumulation of alpha-synuclein, a major component of Lewy bodies, a pathologic hallmark of Parkinson’s Disease (51), amyloid, and hyperphosphorilated tau, hallmarks of Alzheimer’s disease. Brain autopsies of children and young adults from highly polluted Mexico City showed a startling 15 fold down regulation of the prion-related protein (PrPC). Down-regulation of the PrPC is a critical finding given its important role in neuroprotection, neurodegeneration, and mood disorders (54).
Specialized neurons in the brain stem that allow individuals to localizes sound sources, are smaller and show distinct anatomic abnormalities in children exposed to high air pollution. This is similar to the anatomic changes of these neurons found in children with autism (55, 56). Brainstem auditory-evoked potentials (BAEPs) were compared across children from cities of high and low pollution levels. Children from the highly polluted environments displayed significant delays in the central conduction time of BAEPs, suggesting that exposure to air pollution may be a risk for auditory and vestibular impairment (33).
Multiple studies suggest genetic variability in disease susceptibility to the physiologic consequences of air pollution, including the brain pathologic consequences, are consistent with the known genetic variability in susceptibility to autism (57).
Many physicians and even more policy makers may want to think it’s too early to say that air pollution causes autism. Fair enough, but evidence is mounting that it is very likely one of many environmental exposures that likely plays a contributing role. But in a larger context, evidence is already overwhelming that air pollution causes and contributes to a broad spectrum of neurologic diseases and brain dysfunction that is “eroding intelligence, disrupting behaviors, truncating future achievements and damaging societies.”
We made tragic mistakes as a society, not following the precautionary principle, waiting for more “proof” that asbestos, lead, mercury, tobacco, radiation, and PCBs were serious health hazards even though the research had been solid for decades prior to government action. We should not make the same mistake again about air pollution’s role in the “silent pandemic” of brain pathology.
1. Grandjean P, Landrigan P. Neurobehavioural effects of developmental toxicity. LancetNeurology Volume 13, No. 3, p330–338, March 201
2. Andrey Rzhetsky, Steven C. Bagley, Kanix Wang, Christopher S. Lyttle, Edwin H. Cook, Russ B. Altman, Robert D. Gibbons. Environmental and State-Level Regulatory Factors Affect the Incidence of Autism and Intellectual Disability. PLoS Computational Biology, 2014; 10 (3): e1003518 DOI: 10.1371/journal.pcbi.1003518
3. Hallmayer J, Cleveland S, Torres A, et al. Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Arch Gen Psychiatry. 2011;68(11):1095-1102. doi:10.1001/archgenpsychiatry.2011.76
4. Windham GC, Zhang L, Gunier R, Croen LA, Grether JK. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay area. Environmental Health Perspectives. 2006;114(9):1438–1444
5. Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R. Residential proximity to freeways and autism in the CHARGE study. Environmental Health Perspectives. 2011;119(6):873–877
6. Jung CR, Lin YT, Hwang BF. Air Pollution and Newly Diagnostic Autism Spectrum Disorders: A Population-Based Cohort StPLoS One. 2013 Sep 25;8(9):e75510.
udy in Taiwan.
7. Becerra T, Wilhelm M, Olsen J, Cockburn M, Ritz B. Ambient Air Pollution and Autism in Los Angeles County, California. Environ Health Perspect 121:380–386 (2013). http://dx.doi.org/10.1289/ehp.1205827 [Online 18 December 2012]
8. von Ehrenstein OS, Aralis H, Cockburn M, Ritz B. In Utero Exposure to Toxic Air Pollutants and Risk of Childhood Autism. Epidemiology. 2014 Jul 21. [Epub ahead of print]
9. Raz R, Roberts AL, Lyall K, Hart JE, Just AC, Laden F, Weisskopf MG. Autism Spectrum Disorder and Particulate Matter Air Pollution before, during, and after Pregnancy: A Nested Case-Control Analysis within the Nurses’ Health Study II Cohort. Environ Health Perspect. 2014 Dec 18. [Epub ahead of print]
10. Genc S, Zadeoglulari Z, Fuss S, Genc K. The Adverse Effects of Air Pollution on the Nervous System. J Toxicol. 2012; 2012: 782462. Published online Feb 19, 2012. doi: 10.1155/2012/782462
11. Veras, M., Damaceno-Rodrigues, N., Caldini, E. et al. Particulate Urban Air Pollution 12. Affects the Functional Morphology of Mouse Placenta. Biology of Reproduction September 1, 2008 vol. 79 no. 3 578-584
12. Rennie M, et al. Vessel tortuousity and reduced vascularization in the fetoplacental arterial tree after maternal exposure to polycyclic aromatic hydrocarbons. American Journal of Physiology – Heart and Circulatory PhysiologyPublished 1 February 2011Vol. 300no. 2, H675-H684DOI: 10.1152/ajpheart.00510.2010
13. Akbuluta, M., et al. Chorangiosis: The potential role of smoking and air pollution. Pathology – Research and Practice. Volume 205, Issue 2, 15 February 2009, Pages 75–81
14. Grandjean PJ, Landrigan P. Developmental neurotoxicity of industrial chemicals. The Lancet. 2006;368(9553):2167–2178.
15. Sunyer J. The neurological effects of air pollution in children. European Respiratory Journal. 2008;32(3):535–537
16. Sexton, K. et al. Polycyclic Aromatic Hydrocarbons in Maternal and Umbilical Cord Blood from Pregnant Hispanic Women Living in Brownsville, Texas. Int J Environ Res Public Health. Aug 2011; 8(8): 3365–3379. Published online Aug 17, 2011. doi: 10.3390/ijerph8083365
17. Wick P, Malek A, Manser P, et al. Barrier capacity of human placenta for nanosized materials. Environmental Health Perspectives. 2010;118(3):432–436
18. Yokota S, Mizuo K, Moriya N, Oshio S, Sugawara I, Takeda K. Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Neuroscience Letters. 2009;449(1):38–41.
19. Suzuki T, Oshio S, Iwata M, et al. In utero exposure to a low concentration of diesel exhaust affects spontaneous locomotor activity and monoaminergic system in male mice. Particle and Fibre Toxicology. 2010;7, article 7
20. Calderón-Garcidueñas L, Franco-Lira M, Torres-Jardón R, et al. Pediatric respiratory and systemic effects of chronic air pollution exposure: nose, lung, heart, and brain pathology. Toxicologic Pathology. 2007;35(1):154–162.
21. Calderón-Garcidueñas L, Solt AC, Henríquez-Roldán C, et al. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid β-42 and α-synuclein in children and young adults. Toxicologic Pathology. 2008;36(2):289–310
22. Calderón-Garcidueñas L, Mora-Tiscareño A, Ontiveros E, et al. Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs. Brain and Cognition. 2008;68(2):117–127
23. Perera FP, Rauh V, Whyatt RM, et al. Effect of prenatal exposure to airborne polycyclic aromatic hydocarbons on neurodevelopment in the first 3 years of life among inner-city children. Environmental Health Perspectives. 2006;114(8):1287–1292
24. Suglia SF, et al. Association of Black Carbon with Cognition among Children in a Prospective Birth Cohort Study Am J Epidemiology 2008 167:280-286.
25. Edwards SC, Jedrychowski W, Butscher M, Camann D, Kieltyka A, Mroz E, et al. 2010. Prenatal Exposure to Airborne Polycyclic Aromatic Hydrocarbons and Children’s Intelligence at Age 5 in a Prospective Cohort Study in Poland. Environ Health Perspect :-. doi:10.1289/ehp.0901070
26. Freire,C., Ramos,R., Puertas,R., et al. Association of traffic-related air pollution with cognitive development in children. J Epidemiol Community Health 2010;64:223-228
27. Vrihheid, M, D Martinez, I Aguilera, M Bustamante, F Ballester, M Estarlich, A Fernandez-Somoano, M Guxens, N Lertxundi, MD Martinez, A Tardon, J Sunyer; on behalf of the INMA Project. 2011. Indoor air pollution from gas cooking and infant neurodevelopment. Epidemiology http://dx.doi.org/10.1097/EDE.0b013e31823a4023.
28. Morales, E., Julvez, J., Torrent, M., et al. Association of Early-life Exposure to Household Gas Appliances and Indoor Nitrogen Dioxide With Cognition and Attention Behavior in Preschoolers. American Journal of Epidemiology 2009 169(11):1327-1336;
29. Jedrychowski WA, Perera FP, Camann D, Spengler J, Butscher M, Mroz E, Majewska R, Flak E, Jacek R, Sowa A. Prenatal exposure to polycyclic aromatic hydrocarbons and cognitive dysfunction in children. Environ Sci Pollut Res Int. 2014 Sep 26. [Epub ahead of print]
30. Tang D, Lee J, Muirhead L, Li TY, Qu L, Yu J, Perera F. Molecular and neurodevelopmental benefits to children of closure of a coal burning power plant in china. PLoS One. 2014 Mar 19;9(3):e91966. doi: 10.1371/journal.pone.0091966. eCollection 2014.
31. Rivas-Manzano P, Paz C. Cerebellar morphological alterations in rats induced by prenatal ozone exposure. Neuroscience Letters. 1999;276(1):37–40.
32. Gonzalez-Pina R, Escalante-Membrillo C, Alfaro-Rodriguez A, Gonzalez-Maciel A. Prenatal exposure to ozone disrupts cerebellar monoamine contents in newborn rats. Neurochemical Research. 2008;33(5):912–918
33. Calderón-Garcidueñas L, D’Angiulli A, Kulesza RJ, et al. Air pollution is associated with brainstem auditory nuclei pathology and delayed brainstem auditory evoked potentials. International Journal of Developmental Neuroscience. 2011;29(4):365–375
34. Frederica P. Perera, Deliang Tang, Shuang Wang, Julia Vishnevetsky, Bingzhi Zhang, Diurka Diaz, David Camann, Virginia Rauh. Prenatal Polycyclic Aromatic Hydrocarbon (PAH) Exposure and Child Behavior at age 6-7. Environmental Health Perspectives, 2012; DOI: 10.1289/ehp.1104315
35. Perera FP, Chang H-w, Tang D, Roen EL, Herbstman J, et al. (2014) Early-Life Exposure to Polycyclic Aromatic Hydrocarbons and ADHD Behavior Problems. PLoS ONE 9(11): e111670. doi:10.1371/journal.pone.0111670
36. Guxens M, Garcia-Esteban R, Giorgis-Allemand L, Forns J, Badaloni C, Ballester F, Beelen R, Cesaroni G, Chatzi L, de Agostini M, de Nazelle A, Eeftens M, Fernandez MF, Fernández-Somoano A, Forastiere F, Gehring U, Ghassabian A, Heude B, Jaddoe VW, Klümper C, Kogevinas M, Krämer U, Larroque B, Lertxundi A, Lertxuni N, Murcia M, Navel V, Nieuwenhuijsen M, Porta D, Ramos R, Roumeliotaki T, Slama R, Sørensen M, Stephanou EG, Sugiri D, Tardón A, Tiemeier H, Tiesler CM, Verhulst FC, Vrijkotte T, Wilhelm M, Brunekreef B, Pershagen G, Sunyer J. Air Pollution During Pregnancy and Childhood Cognitive and Psychomotor Development: Six European Birth Cohorts. Epidemiology. 2014 Jul 16. [Epub ahead of print]
37. Freire,C., Ramos,R., Puertas,R., et al. Association of traffic-related air pollution with cognitive development in children. J Epidemiol Community Health 2010;64:223-228
38. Tanga D, et al. Air pollution effects on fetal and child development: A cohort comparison in China. Environmental Pollution. Volume 185, February 2014, Pages 90–96
39. Block ML, Calderón-Garcidueñas L. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends in Neurosciences. 2009;32(9):506–516.
40. Valavanidis A, Fiotakis K, Vlachogianni T. Airborne particulate matter and human health: toxicological assessment and importance of size and composition of particles for oxidative damage and carcinogenic mechanisms. Journal of Environmental Science and Health C. 2008;26(4):339–362
41. Allen JL, Liu X, Pelkowski S, Palmer B, Conrad K, Oberdörster G, Weston D, Mayer-Pröschel M, Cory-Slechta DA. Early postnatal exposure to ultrafine particulate matter air pollution: persistent ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice. Environ Health Perspect. 2014 Sep;122(9):939-45. doi: 10.1289/ehp.1307984. Epub 2014 May 22.
42. Lilian Calderón-Garcidueñas1, Aristo Vojdani2, Eleonore Blaurock-Busch3, Yvette Busch3, Albrecht Friedle3, Maricela Franco-Lira4, Partha Sarathi-Mukherjee5, Su-Bin Park6, Ricardo Torres-Jardón7, Amedeo D’Angiulli6Air Pollution and Children: Neural and Tight Junction Antibodies and Combustion Metals, the Role of Barrier Breakdown and Brain Immunity in Neurodegeneration Journal of Alzheimer’s Disease. 10.3233/JAD-141365
43. Migliore L, Coppedè F. Environmental-induced oxidative stress in neurodegenerative disorders and aging. Mutation Research. 2009;674(1-2):73–84
44. Lewis J, Bench G, Myers O, Tinner B, Staines W, Barr E, Divine KK, Barrington W, Karlsson J (2005) Trigeminal uptake and clearance of inhaled manganese chloride in rats and mice. Neurotoxicology 26:113–23.
45. Oberdörster G, Elder A, Rinderknecht A. Nanoparticles and the brain: cause for concern? Journal of Nanoscience and Nanotechnology. 2009;9(8):4996–5007
46. Calderon-Garciduenas L, Solt AC, Henriquez-Roldan C, Torres-Jardon R, Nuse B, Herritt L, et al. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicol Pathol. 2008b;36:289–310
47. Calderón-Garcidueñasa L, et al. Megacities air pollution problems: Mexico City Metropolitan Area critical issues on the central nervous system pediatric impact. Environmental Research. Volume 137, February 2015, Pages 157–169
48. CAdar SD, Klein R, Klein BE, Szpiro AA, Cotch MF, Wong TY, O’Neill MS, Shrager S, Barr RG, Siscovick DS, Daviglus ML, Sampson PD, Kaufman JD. Air Pollution and the Microvasculature: A Cross-Sectional Assessment of In Vivo Retinal Images in the Population-Based Multi-Ethnic Study of Atherosclerosis (MESA). PLoS Med. 2010 Nov 30;7(11):e1000372
49. Calderón-Garcidueñas L, Maronpot RR, Torres-Jardon R, et al. DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration. Toxicologic Pathology. 2003;31(5):524–538
50. Calderón-Garcidueñas L, Azzarelli B, Acuna H, et al. Air pollution and brain damage. Toxicologic Pathology. 2002;30(3):373–389
51. Calderón-Garcidueñas L, Solt AC, Henríquez-Roldán C, et al. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid β-42 and α-synuclein in children and young adults. Toxicologic Pathology. 2008;36(2):289–310.
54. Calderón-Garcidueñas, L., Kavanaugh, M., Block, M.L., D’Angiulli, A., Delgado-Chá- vez, R., Torres-Jardón, R., González-Maciel, A., Reynoso-Robles, R., Osnaya, N., Villarreal-Calderon, R., Guo, R., Hua, Z., Zhu, H., Perry, G., Diaz, P., 2012a. Neu- roinflammation, hyperphosphorilated tau, diffuse amyloid plaques and down- regulation of the cellular prion protein in air pollution exposed children and adults. J. Alzheimer Dis. 28, 93–107.
55. Kulesza, R.J., Mangunay, K., 2008. Morphological features of the medial superior olive in autism. Brain Res. 1200, 132–137.
56. Kulesza Jr, R.J., Lukose, R., Stevens, L.V., 2011. Malformation of the human superior olive in autistic spectrum disorders. Brain Res. 1367, 360–371.
57. Calderón-Garcidueñas, L., Mora-Tiscareño, A., Franco-Lira, M., Zhu, H., Lu, Z., Solorio, E., Torres-Jardón, R., D’Angiulli, A., 2015. Urban apolipoproteinε4 healthy children have short term memory deficits, a decrease of >10 points in Verbal and Full Scale IQ and altered brain metabolic ratios v APOE 3 carriers. APOE modulates children’s brain air pollution responses. J. Alzheimer Dis., in press.
58. Calderón-Garcidueñas, L., Franco-Lira, M., Henríquez-Roldán, C., González-Maciel, A., Reynoso-Robles, R., Villarreal-Calderon, R., Herritt, L., Brooks, D., Keefe, S., Palacios- Moreno, J., Villarreal-Calderon, R., Torres-Jardón, R., Medina-Cortina, H., Delgado-Chávez, R., Aiello-Mora, M., Maronpot, R.R., Doty, R.L., 2010. Urban air pollution: influences on olfactory function and pathology in exposed chil- dren and young adults. Exp. Toxicol. Pathol. 62, 91–102.
59. Talbott E, et al. Fine particulate matter and the risk of autism spectrum disorder. Environmental Research. Volume 140, July 2015, Pages 414–420