Exposure To Urban Air Pollution Nanoparticles and CNS Disease Volume 5 - Issue 5

Mojtaba Ehsanifar^1,2*, Seyyed Shahabeddin Banihashemian³ and Farzaneh Farokhmanesh⁴

• ¹Department of environmental health engineering, School of public health, Iran University of medical sciences, Tehran, Iran
• ²Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran
• ³AJA University of Medical Sciences, Tehran, Iran
• ⁴M.A in Psychology in Clinical psychology at the University of Al-Zahra (SA), Tehran, Iran

Received:June 24, 2021   Published:July 7, 2021

Corresponding author:Mojtaba Ehsanifar, Department of environmental health engineering, School of public health Iran University of medical sciences, Iran

DOI: 10.32474/OJNBD.2021.05.000223

Abstract PDF

Exposure to urban air pollutants has been established as a source of oxidative stress and neuroinflammation that causes central nervous system (CNS) disease. Nitrogen oxides, particulate matter (PM), including fine particles (PM with aerodynamic diameters ≤ 2.5μm, PM 2.5) and ultra-fine particles (UFPs, PM <0.1μm, PM 0.1), transition metals, and ozone are potent or oxidant capable of producing reactive oxygen species (ROS). While the mechanisms underlying CNS pathology due to air pollution are not well understood, recent findings suggest that changes in the blood brain barrier (BBB) and or leakage and transmission along the olfactory nerve into the olfactory bulb (OB) and microglial activation are the key factors of CNS damage following air pollution exposure. The incidence of stroke and the pathology of Parkinson’s (PD) and Alzheimer’s disease (AD) are associated with air pollution exposure. Some of the recent research shows that air pollutants reach the brain and in addition to cardiovascular and lung diseases, affect the health of the CNS too. This review cites evidence that exposure to air pollution fine particles is one of the causes of CNS disease.

Keywords: Air pollution exposure; Nanoparticles; Airborne particulate matter; CNS disease

Recent studies report that the CNS may be a vital target for exposure to air pollutants, and especially for traffic air pollutants, of which diesel exhaust particles (DEPs) are common sources. As said earlier, there is a strong convergence between experimental animal studies and human epidemiological studies concerning the ultimate biochemical and behavioral considerations that are affected by air pollution exposure [1]. Furthermore, in vitro researches support the in vivo findings that exposure to DEPs activates microglia and stimulates neuroinflammation and oxidative stress [2-4]. The effects of air pollutants pass from periphery to the brain through systemic inflammation and the movement of UFPs into brain, where both physical properties of its particles and toxic compounds adsorbed on the PM can cause damage. Brain capillaries, astroglia, and especially microglia, respond to air pollution components by chronic activation, oxidative stress, and inflammation. Exposure to a high concentration of urban air pollutants is problematic given the proposed associations between exposure to air pollution and neurodegenerative diseases such as autism spectrum disorders (ASD) or dementia. Furthermore, given that even short-term exposure can cause biochemical changes associated with such diseases, air pollutants exposure in work places are commonly low but is also of very concern. Generally, other studies aimed at better describing the effects of traffic air pollutants exposure on the CNS, its role and its underlying mechanisms in the cause of neurodegenerative and neurodevelopmental diseases are indispensable. Especially, given the greater prevalence of neurodevelopmental (such as ASD) and neurological disorders neurodegenerative (such as PD) in males, gender may be affected by air pollution exposure [5].

Air Pollution Exposure and Developmental Neurotoxicity

Animal surveys and epidemiological surveys suggest that young people may be particularly vulnerable to the neurotoxicity of exposure to air pollution [6-11]. Hyperactivity in 7-yearolds is associated with air pollutants exposure early in life [12]. Research findings in Mexico City show that in addition to cognitive deficits due to exposure to air pollution, there is a high level of inflammatory markers in children’s brains [6, 7, 13]. Prenatal exposure to air pollution, in six groups, was related to delayed psychomotor development [11]. Some studies show that exposure to DEPs may cause neurotoxicity [14-16]. Research findings also show that exposure to urban air pollutants is inversely related to sustained attention in adolescents [17], and to reduce cognitive development in preschool children [18]. Prenatal exposure to the high concentration of DEPs (1.0 mg / m3) causes changes in locomotor activity, impulsive behavior, and motor coordination in male mice [19, 20]. Behavioral alteration (enhanced bias toward immediate rewards), impulsivity-like behavior, and also long term impairment of short term memory, was reported following early postnatal ambient PM exposure in mice [16, 21, 22]. Exposure to UFPs in pregnancy causes depression-like responses in mice [23,24]. Experimental studies show that long term DEPs exposure in mice causes changes in motor activity, spatial memory and learning, and the ability to detect new objects, resulting in oxidative damage, neurodegeneration, and alterations in gene expression [25-28].

Autism is a type of neurodevelopmental disorder that characterized by a significant decrease in social and communication skills and presence of the stereotyped behaviors [29], and term of ASD is commonly utilized, include the autism and a range of the similar disorders. Much attention has been paid to autism among the neurological disorders that may be associated with exposure to air pollutants, and some of the recent research has found associations between exposure to urban air pollutants and autism. Symptoms of the ASD often present before age of three and usually accompanied by the abnormalities of attention, learning, cognitive function, and sensory processing [29]. ASD in the males is common 4 to 12 times more than females [30], and incidence of the ASD appears to be have increased over past few decades, that is now estimated to be around 7-9/1000 [31,32]. Findings indicate the higher levels of oxidative stress in the children with ASD [33, 34], also higher neuroinflammation, increased systemic inflammation, and microglia activation [35-38]. Studies showed that residential proximity to the freeways and prenatal and early-life urban air pollutants exposure was associated with autism [39,40]. Another study also showed a related between exposure to PM and ASD, especially when exposure to PM occurred in third trimester of pregnancy [41]. Another epidemiological study had also similar results [42] and the other study showed that maternal DE exposure was significantly related to ASD, especially in boys [43]. Also, a cohort study evidenced the higher susceptibility following exposure in the third trimester [44]. The results of some animal studies are consistent with human observations [1]. Reported that postnatal exposure to a high level of urban air pollution PM in male mice causes persistent various neurochemical changes, glial cell activation, and ventriculomegaly [45]. While has been shown that prenatal DEPs exposure, to disrupt DNA methylation in the brain, especially affecting genes involved in neurogenesis and neuronal differentiation in mice [46]. Prenatal exposure to DEPs at urban air pollution relevant concentrations (350–400 μg/m3) causes a behavioral alteration in adult male mice [23]. Human studies showed that when exposure occurs in the third trimester of the pregnancy, association between ASD and PM exposure is stronger [41, 44], which is the equivalent to the first few of postnatal weeks in rats or mice [47]. As said, our studies in the behavioral alterations of exposure to DEPs encompassing both prenatal and the postnatal periods in the mice will be continues.

Air Pollution Exposure and Neurodegeneration

Many epidemiological studies that identify the effects of exposure to air pollutants on behavior, especially cognitive behavior, have shown significant effects also in the elderly. So, in addition to the susceptibility of developing the brain, also aging brain may be especially sensitive to the neurotoxicity caused by air pollution [48-51]. As mentioned, the primary mechanisms of the harmful effects of air pollutants exposure on the CNS appear to be related to neuroinflammation and oxidative stress [52-55]. There are amples evidence that neuroinflammatory and oxidative processes occur in the various neurodegenerative diseases [56, 57]. Air pollutants are the CNS inflammatory stimulants which have been largely overlooked as a risk factor for the neurogenic diseases. Furthermore, millions are exposed to the air pollutants in job disasters such as fires, war, and terrorist attacks [58]. Diseases that are likely to be affected by exposure to air pollutants, including PD and AD, are also widespread [59]. PD is a devastating motor disorder and the second most common neurological disorder affecting 23- 1% of the population over 50 years. Given these statistics, there is considerable concern that the recent findings link exposure to air pollutants to neurodegenerative and neuropathological conditions associated with AD and PD. The earliest studies of this transplant were performed on populations of wild animals naturally exposed to contaminated urban environments [60].

The other of the important early symptom of the neurodegenerative diseases and particularly of PD is olfactory dysfunction [61], in which, actually precedes neuropathology in motor areas such as striatum and substantianigra, the OB is damaged [62]; in people exposed to high-level of air pollution, olfaction problems have also been reported [63]. Wild dogs living in areas of high contamination show enhanced oxidative damage, prepuberty sporadic maturation, and the significant increase in DNA damage (apurinic /apyrimidinic sites) in OB, hippocampus (HI) and frontal cortex. Besides, dogs exposed to a high level of urban contamination exhibit accumulated metals (vanadium and nickel) and tissue damage in the target regions of the brain by gradient method (olfactory mucosa>OB > frontal cortex) and indicate Enter the nasal route as a key portal [60]. In striking similarity, both PD and AD share primary pathology in OB, nuclei, and related pathways, with olfactory deficiency being one of the first findings in both diseases [64]. This work established the first link between air pollution exposure and accelerating the pathology of neurological disease.

Recently, these findings have been extended and confirmed in animal models and humans. Brain tissue from highly infected individuals showed increased CD-68, CD-163, and HLA-DR-positive cells (a marker of infiltrating monocytes or activation of resident microglia), increased pro-inflammatory markers, increased deposition of Ab42 (characteristic of AD protein), endothelial cell activation, BBB, [6] and brain lesions in frontal lobe [65]. The rearrangement of pro-inflammatory markers such as interleukin-1b (IL1-b) and cyclooxygenase 2 (COX2) as well as the CD-14 marker have been localized for innate immune cells in the frontal cortex, Niger essence, and vagal nerves [6]. In addition, animal studies have shown that exposure to air pollutants induces cytokine production [66, 67], increased MAP kinase signaling through JNK [67], lipid peroxidation, enhanced NFkb expression [66] neurochemical changes [68], and behavioral alteration [69] Taken together, these studies show that exposure to air pollutants has effects on CNS [70]. While there is no survey yet to find a direct effect of air pollutants on defined levy bodies (a pathological feature of PD) or beta-amyloid plaques (Ab) (a pathological feature of AD), urban air pollution exposure causes neurological inflammation [6]. For example, exposure to high dose of air pollutants in dogs, exhibits scattered amyloid plaque deposits a decade earlier than their fresh air exposure counterparts [60, 71].

In addition, accumulation of Ab42 and a-synuclein in early childhood begins [6] after high level of air pollutant exposure, from the view that exposure to air pollutants may cause premature aging in brain and/or stimulate disease progression. One of the plausible mechanisms is that nanoparticles [72-74] and oxidative stress [75- 77] alter the accumulation and rate of protein fibrosis, potentially affecting the AB solution and a-synuclein. Changes in protein accumulation associated with exposure to air pollutants may be the primary pathology in neurodegenerative processes. Ambient toxins may exert their effects at various points throughout human development leading to CNS disease, a theory called the “multiimpact hypothesis” [78]. According to this assumption, studies show that PM affects the CNS at an early age [65]. For example, MRI analysis revealed structural damage (white matter lesions) in the frontal cortex in children exposed to high levels of air pollutants, potentially related to cognitive impairment [65]. Interestingly, air pollution exposure in the same condition in dogs also show vascular/endothelial pathology and neurogenesis of frontal lesions [65]. Therefore, the inflammatory effects of air pollution exposure may be harmful to humans and young animals, and these effects may accumulate throughout one’s lifetime. Whereas ischemic stroke [79, 80], multiple sclerosis (exposure to secondhand smoke increases risk) [81], and PD (airborne manganese content is associated with increased risk) [82] Currently, only CNS diseases are epidemiologically based. Many other unexplained diseases are likely to be air pollution exposed. These risks may be distributed between individual differences in population sensitivity, as genetic prediction may be vulnerable to CNS effects of air pollutant exposure, such as in inherited APOE4 allelic vectors [6] in humans apoE and knockout mice [83]. Due to the high prevalence of PD and AD, the association between neurodegeneration and the pathogenesis of PD/AD, CNS pathology induced by air pollutants and the high prevalence of air pollution exposure, the expansion of mechanical studies and epidemiological follow-up is needed.

Air Pollution Exposure and Ischemic Stroke

Human epidemiological studies and animal experimental surveys in recent years, suggesting that air pollutants may adversely affect to CNS and cause disease [84-86]. The impact of urban air pollutants on brain was first reported as an increase in the ischemic stroke in persons was internal coal smoke exposed. While it is clear that air pollution exposure can affect human health through respiratory, cardiovascular, and mortality complications, recently it has been shown also to have a detrimental effect on the brain [87, 88]. Whereas data on the association between ambient air pollution and cerebrovascular disease is limited, various air pollutants exposure (e.g., carbon monoxide, ozone, nitrogen dioxide, and particles) is epidemiologically at increased risk. It is associated with ischemic cerebrovascular events [79, 80, 89-91]. Indeed, current reports indicate that the risk of ischemic stroke is associated with exposure to air pollutants, even in relatively low pollutant communities [88, 89, 92]. Ozone and particles rapidly modulate the expression of genes involved in the major pathways of cerebrovascular vascularization, while pathological mechanisms are still unknown [91,93]. Current findings also show that effects of exposure to air pollutants invade brain parenchyma and cause pathological signs of neurological disease.

In conclusion, air pollutants are a mixture combination of ambient toxins that invade the CNS through several molecular and cellular pathways and cause disease. The effects of CNS are chronic, start in childhood, and may require time (years) to accumulate in the pathology. Particularly, exposure to air pollutants causes neuritis, oxidative stress, brain injury, and neuropathology. Either way, based on recent findings, the more emission from diesel engines than mentioned above has created a major concern that needs to be addressed with further studies into the health effects of UFPs exposure thus further experimental and epidemiological surveys of the association between UFPs and CNS disease are of particular importance.

This work was supported by Dr. Ehsanifar research Lab, Tehran, Iran.

All authors contributed to the study conception and design. The first draft of the manuscript was written by Mojtaba Ehsanifar and also he read and approved the final submitted manuscript.

1. Costa LG, Toby B Cole , Jacki Coburn, Yu-Chi Chang , Khoi Dao, et al. (2014) Neurotoxicants are in the air: Convergence of human, animal, and in vitro studies on the effects of air pollution on the brain. BioMed research international.
2. Block M, X Wu, Z Pei, G Li, T Wang, et al. (2004) Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: The role of microglia, phagocytosis, and NADPH oxidase. The FASEB Journal 18(13): 1618-1620.
3. Roque P, Khoi Dao, Lucio G Costa (2015) Microglia mediate diesel exhaust particle-induced cerebellar neuronal death. Toxicologist 453: 2109.
4. Ehsanifar M, Ahmad Jonidi Jafari, Zeinab Montazeri, Roshanak Rezaei Kalnari, Mitra Gholami, et al. (2021) Learning and memory disorders related to hippocampal inflammation following exposure to air pollution. Journal of Environmental Health Science and Engineering.
5. Clougherty JE (2010) A growing role for gender analysis in air pollution epidemiology. Environmental health perspectives 118(2): 167-176.
6. Calderón Garcidueñas, Anna C Solt, Carlos Henríquez Roldán, Ricardo Torres Jardón, Bryan Nuse, L et al. (2008) 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 36(2): 289-310.
7. Calderón Garcidueñas L, Randall Engle, Antonieta Mora Tiscareño, Martin Styner, Gilberto Gómez Garza, et al. (2011) Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children. Brain and cognition 77(3): 345-355.
8. Calderón Garcidueñas L, Michael Kavanaugh, Michelle Block, Amedeo D Angiulli, Ricardo Delgado Chávez, et al. (2012) Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. Journal of Alzheimer's disease 28(1): 93-107.
9. Freire C, Rosa Ramos, Raquel Puertas, Maria Jose Lopez Espinosa, Jordi Julvez, et al. (2010) Association of traffic-related air pollution with cognitive development in children. Journal of Epidemiology & Community Health 64(3): 223-228.
10. Guxens M, J Sunyer (2012) A review of epidemiological studies on neuropsychological effects of air pollution. Swiss Medical Weekly 141(0102).
11. Guxens M, Raquel Garcia Esteban, Lise Giorgis Allemand, Joan Forns, Chiara Badaloni, et al. (2014) Air pollution during pregnancy and childhood cognitive and psychomotor development: Six European birth cohorts. Epidemiology 25(5) 636-647.
12. Newman NC, Patrick Ryan, Grace Lemasters, Linda Levin, David Bernstein, et al. (2013) Traffic-related air pollution exposure in the first year of life and behavioral scores at 7 years of age. Environmental health perspectives 121(6): 731-736.
13. Calderon Garciduenas L, Janet V Cross, Maricela Franco-Lira, Mariana Aragón-Flores, Michael Kavanaugh, et al. (2013) Brain immune interactions and air pollution: Macrophage inhibitory factor (MIF), prion cellular protein (PrPC), Interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution. Frontiers in Neuroscience7: 183.
14. Ema M, Masato Naya, Masao Horimoto, Haruhisa Kato (2013) Developmental toxicity of diesel exhaust: A review of studies in experimental animals. Reproductive toxicology 42: 1-17.
15. Ehsanifar M, Abolfazl Azami Tameh , Mahdi Farzadkia, Roshanak Rezaei Kalantari , Mahmood Salami Zavareh , Hossein Nikzaad et al. (2019) Exposure to nanoscale diesel exhaust particles: Oxidative stress, neuroinflammation, anxiety and depression on adult male mice. Ecotoxicology and Environmental Safety 168: 338-347.
16. Mojtaba Ehsanifar, Zeinab Yavari , Mohammad Karimian, Marjan Behdarvandi (2020) Anxiety and Depression Following Diesel Exhaust Nano-Particles Exposure in Male and Female Mice. Journal of Neurophysiology and Neurological Disorders 6(101): 1-8.
17. Kicinski M, Griet Vermeir, Nicolas Van Larebeke, Elly Den Hond, Greet Schoeters, et al. (2015) Neurobehavioral performance in adolescents is inversely associated with traffic exposure. Environment international 75: 136-143.
18. Sunyer J, Mikel Esnaola, Mar Alvarez Pedrerol, Joan Forns , Ioar Rivas, et al. (2015) Association between traffic-related air pollution in schools and cognitive development in primary school children: A prospective cohort study. PLoS Med 12(3): 1001792.
19. Yokota S, KeisukeMizuo, NozomuMoriya, ShigeruOshio, IsamuSugawara, et al. (2009) Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Neuroscience letters 449(1): 38-41.
20. Suzuki T, Shigeru Oshio, Mari Iwata, Hisayo Saburi, Takashi Odagiri, et al. (2010) 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(1): 7.
21. Allen JL, Katherine Conrad, Günter Oberdörster, Carl J Johnston, Brianna Sleezer, et al. (2013) Developmental exposure to concentrated ambient particles and preference for immediate reward in mice. Environmental health perspectives 121(1): 32-38.
22. Allen JL, Xiufang Liu, Douglas Weston, Lisa Prince, Günter Oberdörster, et al. (2014) Developmental exposure to concentrated ambient ultrafine particulate matter air pollution in mice results in persistent and sex-dependent behavioral neurotoxicity and glial activation. Toxicological Sciences 140(1): 160-178.
23. Ehsanifar M, Ahmad Jonidi Jafari , Hossein Nikzad , Mahmoud Salami Zavareh, Mohammad Ali Atlasi, et al. (2019) Prenatal exposure to diesel exhaust particles causes anxiety, spatial memory disorders with alters expression of hippocampal pro-inflammatory cytokines and NMDA receptor subunits in adult male mice offspring. Ecotoxicology and Environmental Safety 176: 34-41.
24. Davis DA, Marco Bortolato, Sean C Godar, Thomas K Sander, Nahoko Iwata, et al. (2013) Prenatal exposure to urban air nanoparticles in mice causes altered neuronal differentiation and depression-like responses. PloS one 8(5): 64128.
25. Hougaard KS, Keld A Jensen, Pernille Nordly, Camilla Taxvig, Ulla Vogel, et al. (2008) Effects of prenatal exposure to diesel exhaust particles on postnatal development, behavior, genotoxicity and inflammation in mice. Particle and fibre toxicology 5(1): 3.
26. Hougaard KS, Anne Thoustrup Saber, Keld Alstrup Jensen, Ulla Vogel, Håkan Wallin (2009) Diesel exhaust particles: Effects on neurofunction in female mice. Basic & clinical pharmacology & toxicology 105(2): 139-143.
27. Tsukue N, Manabu Watanabe, Takayuki Kumamoto, Hirohisa Takano, Ken Takeda (2009) Perinatal exposure to diesel exhaust affects gene expression in mouse cerebrum. Archives of toxicology 83(11): 985-1000.
28. Win Shwe TT, Yuji Fujitani, Chaw Kyi Tha Thu, Akiko Furuyama, Takehiro Michikawa, et al. (2014) Effects of diesel engine exhaust origin secondary organic aerosols on novel object recognition ability and maternal behavior in BALB/c mice. International journal of environmental research and public health 11(11): 11286-11307.
29. Susan E Levy , David S Mandell, Robert T Schultz (2009) Autism. Lancet 374(9701): 1627-1638.
30. Schaafsma SM, DW Pfaff (2014) Etiologies underlying sex differences in autism spectrum disorders. Frontiers in neuroendocrinology 35(3): 255-271.
31. Boyle CA, Sheree Boulet, Laura A Schieve, Robin A Cohen, Stephen J Blumberg, et al. (2011) Trends in the prevalence of developmental disabilities in US children, 1997–2008. Pediatrics 127(6): 1034-1042.
32. Martha Wingate, Beverly Mulvihill, Russell S Kirby, Sydney Pettygrove, Chris Cunniff, et al. (2012) Prevalence of autism spectrum disorders-Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ 61(3): 1-19.
33. Rose S, S Melnyk, O Pavliv, S Bai, T G Nick, et al. (2012) Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Translational psychiatry 2(7): 134-134.
34. Frustaci A, Monica Neri, Alfredo Cesario, James B Adams, Enrico Domenici, et al. (2012) Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radical Biology and Medicine 52(10): 2128-2141.
35. Morgan JT, Gursharan Chana, Carlos A Pardo, Cristian Achim, Katerina Semendeferi, et al. (2010) Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biological psychiatry 68(4): 368-376.
36. El Ansary A, L Al Ayadhi (2012) Neuroinflammation in autism spectrum disorders. Journal of neuroinflammation 9(1): 265.
37. Depino AM (2013) Peripheral and central inflammation in autism spectrum disorders. Molecular and Cellular Neuroscience 53: 69-76.
38. Suzuki K, Genichi Sugihara, Yasuomi Ouchi, Kazuhiko Nakamura, Masami Futatsubashi, et al. (2013) Microglial activation in young adults with autism spectrum disorder. JAMA psychiatry 70(1): 49-58.
39. Volk HE, Irva Hertz Picciotto, Lora Delwiche, Fred Lurmann, Rob McConnell (2011) Residential proximity to freeways and autism in the CHARGE study. Environmental health perspectives 119(6): 873-877.
40. Volk HE, Fred Lurmann, Bryan Penfold, Irva Hertz Picciotto, Rob McConnell (2013) Traffic-related air pollution, particulate matter, and autism. JAMA psychiatry 70(1): 71-77.
41. Kalkbrenner AE, Gayle C Windham, Marc L Serre, Yasuyuki Akita, Xuexia Wang, et al. (2015) Particulate matter exposure, prenatal and postnatal windows of susceptibility, and autism spectrum disorders. Epidemiology 26(1): 30-42.
42. Becerra TA, Michelle Wilhelm, Jørn Olsen, Myles Cockburn, Beate Ritz (2013) Ambient air pollution and autism in Los Angeles County, California. Environmental health perspectives 121(3): 380-386.
43. Roberts AL, Kristen Lyall, Jaime E Hart, Francine Laden, Allan C Just, et al. (2013) Perinatal air pollutant exposures and autism spectrum disorder in the children of Nurses’ Health Study II participants. Environmental health perspectives 121(8): 978-984.
44. Raz R, Andrea L Roberts, Kristen Lyall, Jaime E Hart, Allan C Just, et al. (2015) 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. Environmental health perspectives 123(3): 264-270.
45. Allen JL, Xiufang Liu, Sean Pelkowski, Brian Palmer, Katherine Conrad, et al. (2014) Early postnatal exposure to ultrafine particulate matter air pollution: Persistent ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice. Environmental health perspectives, 2014. 122(9): p. 939-945.
46. Tachibana K, Kohei Takayanagi, Ayame Akimoto, Kouji Ueda, Yusuke Shinkai, et al. (2015) Prenatal diesel exhaust exposure disrupts the DNA methylation profile in the brain of mouse offspring. The Journal of toxicological sciences 40(1): 1-11.
47. Bayer SA, J Altman, R J Russo, X Zhang (1993) Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. Neurotoxicology (Park Forest South) 14(1): 83-144.
48. Ranft U, Tamara Schikowski, Dorothee Sugiri, Jean Krutmann, Ursula Krämer (2009) Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly. Environmental research 109(8): 1004-1011.
49. Power MC, Marc G Weisskopf, Stacey E Alexeeff, Brent A Coull, Avron Spiro, et al. (2011) Traffic-related air pollution and cognitive function in a cohort of older men. Environmental health perspectives 119(5): 682-687.
50. Weuve J, Robin C Puett, Joel Schwartz, Jeff D Yanosky, Francine Laden, et al. (2012) Exposure to particulate air pollution and cognitive decline in older women. Archives of internal medicine 172(3): 219-227.
51. Chen JC, Xinhui Wang, Gregory A Wellenius , Marc L Serre, Ira Driscoll , et al. (2015) Ambient air pollution and neurotoxicity on brain structure: Evidence from women's health initiative memory study. Annals of neurology 78(3): 466-476.
52. Teeling JL, VH Perry (2009) Systemic infection and inflammation in acute CNS injury and chronic neurodegeneration: Underlying mechanisms. Neuroscience 158(3): 1062-1073.
53. Lee YJ, Sang Bae Han, Sang-Yoon Nam, Ki-Wan Oh, Jin Tae Hong (2010) Inflammation and Alzheimer’s disease. Archives of pharmacal research 33(10): 1539-1556.
54. Qian L, PM Flood, JS Hong (2010) Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. Journal of neural transmission 117(8): 971-979.
55. Russ TC, S Reis, M van Tongeren (2019) Air pollution and brain health: Defining the research agenda. Current Opinion in Psychiatry 32(2): 97-104.
56. Butterfield DA, B Halliwell (2019) Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nature Reviews Neuroscience 20(3): 148-160.
57. Heneka MT, RM McManus, E Latz (2018) Inflammasome signalling in brain function and neurodegenerative disease. Nature Reviews Neuroscience 19(10): 610-621.
58. Seagrave J, Jacob D McDonald, Edward Bedrick, Eric S Edgerton, Andrew P Gigliotti, et al. (2006) Lung toxicity of ambient particulate matter from southeastern US sites with different contributing sources: Relationships between composition and effects. Environmental health perspectives 114(9): 1387-1393.
59. Hirtz D, D J Thurman, K Gwinn Hardy, M Mohamed, A R Chaudhuri, et al. (2007) How common are the “common” neurologic disorders? Neurology 68(5): 326-337.
60. Calderón Garcidueñas L, Biagio Azzarelli, Hilda Acuna, Raquel Garcia, Todd M Gambling, et al. (2002) Air pollution and brain damage. Toxicologic pathology 30(3): 373-389.
61. Doty RL (2012) Olfaction in Parkinson's disease and related disorders. Neurobiology of disease. 46(3): 527-552.
62. Braak H, Estifanos Ghebremedhin, Udo Rüb, Hansjürgen Bratzke, Kelly Del Tredici (2004) Stages in the development of Parkinson’s disease-related pathology. Cell and tissue research 318(1): 121-134.
63. Calderón Garcidueñas L, Maricela Franco Lira, Carlos Henríquez Roldán, Norma Osnaya, Angelica González Maciel, et al. (2010) Urban air pollution: Influences on olfactory function and pathology in exposed children and young adults. Experimental and Toxicologic Pathology 62(1): 91-102.
64. Doty RL, (2008) The olfactory vector hypothesis of neurodegenerative disease: Is it viable? Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 63(1): 7-15.
65. Calderon Garcidueñas L, Antonieta Mora Tiscareño, Esperanza Ontiveros, Gilberto Gómez Garza, Gerardo Barragán Mejía, et al. (2008) Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs. Brain and cognition 68(2): 117-127.
66. Campbell A, M Oldham, A Becaria, SC Bondy, D Meacher, et al. (200) Particulate matter in polluted air may increase biomarkers of inflammation in mouse brain. Neurotoxicology 26(1): 133-140.
67. Kleinman M, JA Araujo, A Nel, C Sioutas, A Campbell, P Q Cong, et al. (2008) Inhaled ultrafine particulate matter affects CNS inflammatory processes and may act via MAP kinase signaling pathways. Toxicology letters 178(2): 127-130.
68. Sirivelu MP, Sheba M J MohanKumar, James G Wagner, Jack R Harkema, Puliyur S MohanKumar (2006) Activation of the stress axis and neurochemical alterations in specific brain areas by concentrated ambient particle exposure with concomitant allergic airway disease. Environmental health perspectives 114(6): 870-874.
69. Zanchi AC, Carina Duarte Venturini, Mitiko Saiki, Paulo Hilario Nascimento Saldiva, Helena Maria Tannhauser Barros, et al. (2008) Chronic nasal instillation of residual-oil fly ash (ROFA) induces brain lipid peroxidation and behavioral changes in rats. Inhalation toxicology 20(9): 795-800.
70. Block ML, L Zecca, JS Hong (2007) Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nature Reviews Neuroscience 8(1): 57.
71. Calderon Garciduenas L, Robert R Maronpot, Ricardo Torres Jardon, Carlos Henríquez Roldán, Robert Schoonhoven, et al. (2003) 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 31(5): 524-538.
72. Colvin VL, KM Kulinowski (2007) Nanoparticles as catalysts for protein fibrillation. Proceedings of the National Academy of Sciences 104(21): 8679-8680.
73. Cedervall T, Iseult Lynch, Stina Lindman, Tord Berggård, Eva Thulin, et al. (2007) Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proceedings of the National Academy of Sciences104(7): 2050-2055.
74. Lynch I, Tommy Cedervall, Martin Lundqvist, Celia Cabaleiro Lago, Sara Linse, et al. (2007) The nanoparticle protein complex as a biological entity; a complex fluids and surface science challenge for the 21^st Advances in colloid and interface science 134: 167-174.
75. Liu L, Hiroaki Komatsu, Ian V J Murray, Paul H Axelsen (2008) Promotion of amyloid β protein misfolding and fibrillogenesis by a lipid oxidation product. Journal of molecular biology 377(4): 1236-1250.
76. Qin Z, Dongmei Hu, Shubo Han, Stephen H Reaney, Donato A Di Monte, et al. (2007) Effect of 4-hydroxy-2-nonenal modification on α-synuclein aggregation. Journal of Biological Chemistry 282(8): 5862-5870.
77. Leni Z, L Künzi, M Geiser (2020) Air pollution causing oxidative stress. Current Opinion in Toxicology 20: 1-8.
78. Carvey PM, A Punati, MB Newman (2006) Progressive dopamine neuron loss in Parkinson's disease: the multiple hit hypothesis. Cell transplantation 15(3): 239-250.
79. Lokken RP, Gregory A Wellenius, Brent A Coull, Mary R Burger, Gottfried Schlaug, et al. (2009) Air pollution and risk of stroke: Underestimation of effect due to misclassification of time of event onset. Epidemiology (Cambridge, Mass.) 20(1): 137.
80. Hong YC Jong Tae Lee, Ho Kim, Ho Jang Kwon (2002) Air pollution: A new risk factor in ischemic stroke mortality. Stroke 33(9): 2165-2169.
81. Mikaeloff Y, Guillaume Caridade, Marc Tardieu, Samy Suissa, KIDSEP study group (2007) Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain 130(10): 2589-2595.
82. Finkelstein MM, M Jerrett (2007) A study of the relationships between Parkinson's disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. Environmental research 104(3): 420-432.
83. Veronesi B, Om Makwana, Melanie Pooler, Lung Chi Chen (2005) Effects of Subchronic Exposures to Concentrated Ambient Particles: VII. Degeneration of Dopaminergic Neurons in Apo E−/− Mice. Inhalation Toxicology 17(4-5): 235-241.
84. Block ML, L Calderon Garcidueñas (2009) Air pollution: Mechanisms of neuroinflammation and CNS disease. Trends in neurosciences 32(9): 506-516.
85. Block ML, Alison Elder, Richard L Auten, Staci D Bilbo, Honglei Chen, et al. (2012) The outdoor air pollution and brain health workshop. Neurotoxicology 33(5): 972-984.
86. Genc S, Zeynep Zadeoglulari, Stefan H Fuss, Kursad Genc (2012) The adverse effects of air pollution on the nervous system. Journal of toxicology 782462.
87. Zhang ZF, SZ, Yu, GD Zhou (1988) Indoor air pollution of coal fumes as a risk factor of stroke, Shanghai. American journal of public health 78(8): 975-977.
88. Kuan Ken Lee, Mark R Miller , Anoop S V Shah (2018) Air pollution and stroke. Journal of stroke 20(1): 2-11.
89. Lisabeth LD, James D Escobar, J Timothy Dvonch, Brisa N Sánchez, Jennifer J Majersik, et al. (2008) Ambient air pollution and risk for ischemic stroke and transient ischemic attack. Annals of neurology: Official journal of the American neurological association and the Child neurology society 64(1):53-59.
90. Dong H, Yongquan Yu, Shen Yao, Yan Lu, Zhiyong Chen, et al. (2018) Acute effects of air pollution on ischaemic stroke onset and deaths: A time-series study in Changzhou, China. BMJ open 8(7): 020425.
91. Fiorito G, Jelle Vlaanderen, Silvia Polidoro , John Gulliver , Claudia Galassi, Andrea Ranzi, et al. (2018) Oxidative stress and inflammation mediate the effect of air pollution on cardio‐and cerebrovascular disease: A prospective study in nonsmokers. Environmental and molecular mutagenesis 59(3): 234-246.
92. Kettunen J, Jaana Kettunen , Timo Lanki, Pekka Tiittanen, Pasi P Aalto, Tarja Koskentalo, et al. (2007) Associations of fine and ultrafine particulate air pollution with stroke mortality in an area of low air pollution levels. Stroke 38(3): 918-922.
93. Thomson EM, Prem Kumarathasa, Lilian Calderón Garcidueñas Renaud Vincent (2007) Air pollution alters brain and pituitary endothelin-1 and inducible nitric oxide synthase gene expression. Environmental research 105(2): 224-233.