Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism

Abstract

Purpose of Review

Epidemiological and animal studies suggest that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component.

Recent Findings

Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which are characterized by impairment in socialization and in communication and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals.

Summary

Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. Gene-environment interactions may play a relevant role in determining individual susceptibility to air pollution developmental neurotoxicity. Given the worldwide presence of elevated air pollution, studies on its effects and mechanisms on the developing brain, genetic susceptibility, role in neurodevelopmental disorders, and possible therapeutic interventions are certainly warranted.

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References

Papers of particular interest, published recently, have been highlighted as: •Of importance •• Of outstanding importance

  1. 1.

    Møller P, Jacobsen NR, Folkmann JK, Danielsen PH, Mikkelsen L, Hemmingsen JG, Vesterdal LK, Forchhammer L, Wallin H, Loft S. Role of oxidative damage in toxicity of particulates. Free Rad Res. 2010;44:1–46.

    Article  CAS  Google Scholar 

  2. 2.

    Costa LG, Cole TB, Coburn J, Chang YC, Dao K, Roque P. Neurotoxicants are in the air: convergence of human and in vitro studies on the effects of air pollution on the brain. BioMed Res Int. 2014. ID 736385, 8 p.

  3. 3.

    Brook RD, Rajagopalan S, Pope A, Brook JR, Bhatnagar A, Diez-Roux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, Peters A, Siscovick D, Smith SC, Whitesel L, Kaufman JD, on behalf of the American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease. An update to the scientific statement from the American Heart Association. Circulation. 2010;121:2331–78.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    • Van Donkelaar A, Martin RV, Brauer M, Boys BL. Use of satellite observations for long-term exposure of global concentrations of fine particulate matter. Environ Health Perspect. 2015;123:135–43. This study provides useful information on the global burden of PM.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Ghio AJ, Smith CB, Madden MC. Diesel exhaust particles and airway inflammation. Curr Op Pulm Med. 2012;18:144–50.

    CAS  Article  Google Scholar 

  6. 6.

    USEPA (United States Environmental Protection Agency). Health assessment document for diesel engine exhaust. Washington, DC: National Center for Environmental Assessment, USEPA; 2002. p. 669.

    Google Scholar 

  7. 7.

    Brook RD, Rajagopalan S. Air pollution and cardiovascular events. New Engl. J. Med. 2007;356:2104–5.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Gill EA, Curl CL, Adar SD, Allen RW, Auchincloss AH, O’Neill MS, Park SK, Ven Hee VC, Diez Roux AV, Kaufman JD. Air pollution and cardiovascular disease in the multi-ethnic study of atherosclerosis. Progr Cardiovasc Res. 2011;53:353–60.

    Article  Google Scholar 

  9. 9.

    Møller P, Danielsen PH, Karottki DG, Jantzen K, Rousgaard M, Klingberg H, Jensen DM, Christophersen DV, Hemmingsen JG, Cao Y, Loft S. Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles. Mutat Res. 2014;762:133–66.

    Article  CAS  Google Scholar 

  10. 10.

    Calderon-Garciduenas L, Azzarelli B, Acuna H, Garcia R, Gambling TM, Osnaya N, Monroy S, Del Rosario TM, Carson JL, Villareal-Calderon A, Rewcastle B. Air pollution and brain damage. Toxicol Pathol. 2002;30:373–89.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Block ML, Calderon-Garciduenas L. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci. 2009;32:506–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Genc S, Zadeoglulari Z, Fuss SH, Genc K. The adverse effects of air pollution on the nervous system. J Toxicol. 2012. ID 782462, (23pp.).

  13. 13.

    Block ML, Elder A, Auten RL, Bilbo SD, Chen H, Chen JC, Cory-Slechta DA, Costa D, et al. The outdoor air pollution and brain health workshop. Neurotoxicology. 2012;33:972–84.

    PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Chen JC, Wang X, Wellenius GA, Serre ML, Driscoll I, Casanova R, McArdle JJ, Manson JE, Chui HC, Espeland MA. Ambient air pollution and neurotoxicity on brain structure: evidence from women’s health initiative memory study. Ann Neurol. 2015;78:466–76.

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Kioumourtzoglou MA, Schwartz JD, Weisskopf MG, Melly SJ, Wang Y, Dominici F, Zanobetti A. Long-term PM2.5 exposure and neurological hospital admissions in the northeastern United States. Environ Helath Perspect. 2016;124:23–9.

    Google Scholar 

  16. 16.

    Oberdoerster G, Utell MJ. Ultrafine particles in the urban air: to the respiratory tract—and beyond? Environ Health Perspect. 2002;110:A440–1.

    Article  Google Scholar 

  17. 17.

    Oberdoerster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol. 2004;16:437–45.

    CAS  Article  Google Scholar 

  18. 18.

    Peters A, Veronesi B, Calderon-Garciduenas L, Gehr P, Chen LC, Geiser M, Reed W, Rothen-Rutishauser B, Schurch S, Schulz H. Translocation and potential neurological effects of fine and ultrafine particles a critical update. Particle Fibre Toxicol. 2006;3:13.

    Article  CAS  Google Scholar 

  19. 19.

    Lucchini RG, Dorman DC, Elder A, Veronesi B. Neurological impacts from inhalation of pollutants and the nose-brain connection. Neurotoxicology. 2012;33:838–41.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Garcia GJM, Schroeter JD, Kimbell JS. Olfactory deposition of inhaled nanoparticles in humans. Inhal Toxicol. 2015;27:394–403.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Ranft U, Schikowski T, Sugiri D, Krutmann J, Kramer U. Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly. Environ Res. 2009;109:1004–11.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Freire C, Ramos R, Puertas R, Lopez-Espinosa MJ, Julvez J, Aguilera I, Cruz F, Fernandez MF, Sunyer J, Olea N. Association of traffic-related air pollution with cognitive development in children. J Epidemiol Comm Health. 2010;64:223–8.

    Article  Google Scholar 

  23. 23.

    Calderon-Garciduenas L, Franco-Lira M, Henriquez-Roldan C, Osnaya N, Gomzalez-Maciel A, Reynoso-Robles R, Villareal-Calderon R, Herritt L, Brooks D, Keefe S, Palacios-Moreno J, Villareal-Calderon R, Torres-Jardon R, Medina-Cortina H, Delgado-Chavez R, Aiello-Mora M, Maronpot RR, Doty RL. Urban air pollution: influences on olfactory function and pathology in exposed children and young adults. Exp Toxicol Pathol. 2010;62:91–102.

    PubMed  Article  Google Scholar 

  24. 24.

    Calderon-Garciduenas L, Engle R, Mora-Tiscareno A, Styner M, Gomez-Garza G, Zhu H, Jewells V, Torres-Jardon R, Romero L, Monroy-Acosta ME, Bryant C, Gonzalez-Gonzalez LO, Median-Cortina H, D’Angiulli A. Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children. Brain Cognition. 2011;77:345–55.

    PubMed  Article  Google Scholar 

  25. 25.

    Fonken LK, Xu X, Weil ZM, Chen G, Sun Q, Rajagopalan S, Nelson RJ. Air pollution impairs cognition, provokes depressive-like behaviors and alters hippocampal cytokine expression and morphology. Mol Psych. 2011;16:987–95.

    CAS  Article  Google Scholar 

  26. 26.

    Guxens M, Sunyer J. A review of epidemiological studies on neuropsychological effects of air pollution. Swiss Med Wkly. 2012;141:w13322.

    PubMed  Google Scholar 

  27. 27.

    Calderon-Garciduenas L, Solt AC, Henriquez-Roldan C, Torres-Jardon R, Nuse B, Herritt L, Villareal-Calderon R, Osnaya N, Stone I, Garcia R, Brooks DM, 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. 2008;36:289–310.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Calderon-Garciduenas L, Kavanaugh M, Block M, D’Angiulli A, Delgado-Chavez R, Torres-Jardon R, Gonzales-Maciel A, et al. Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. J Alzheim Dis. 2012;28:93–107.

    CAS  Google Scholar 

  29. 29.

    Levesque S, Surace MJ, McDonald J, Block ML. Air pollution and the brain: subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease. J. Neuroinflammat. 2011a;8:105.

    CAS  Article  Google Scholar 

  30. 30.

    Costa LG, Cole TB, Coburn J, Chang YC, Dao K, Roque P. Neurotoxicity of traffic-related air pollution. Neurotoxicology. 2016.

  31. 31.

    Calderon-Garciduenas L, Maronpot RR, Torres Jardon R, Henriquez-Roldan C, Schoonhoven R, Acuna-Ayala H, Villareal-Calderon A, Nakamura J, Fernando R, Reed W, Azzarelli B, Swenberg JA. DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration. Toxicol Pathol. 2003;31:524–38.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Bos I, DeBoever P, Emmerechts J, Buekers J, Vanoirbeek J, Meeusen R, Van Poppel M, Nemry B, Nawrot T, Panis LI. Changed gene expression in brains of mice exposed to traffic in a highway tunnel. Inhal Toxicol. 2012;24:676–86.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Win-Shwe TT, Yamamoto S, Fujitani Y, Hirano S, Fujimaki H. Spatial learning and memory function-related gene expression in the hippocampus of mouse exposed to nanoparticles-rich diesel exhaust. Neurotoxicology. 2008;29:940–7.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Yokota S, Moriya N, Iwata M, Umezawa M, Oshio S, Takeda K. Exposure to diesel exhaust during fetal period affects behavior and neurotransmitters in male offspring mice. J Toxicol Sci. 2013;38:13–23.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    MohanKumar SMJ, Campbell A, Block M, Veronesi B. Particulate matter, oxidative stress and neurotoxicity. Neurotoxicology. 2008;29:479–88.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Gerlofs-Nijland ME, van Berlo D, Cassee FR, Schins RPF, Wang K, Campbell A. Effect of prolonged exposure to diesel engine exhaust on proinflammatory markers in different regions of the rat brain. Particle Fibre Toxicol. 2010;7:12.

    Article  CAS  Google Scholar 

  37. 37.

    Win-Shwe TT, Fujimaki H. Nanoparticles and neurotoxicity. Int J Mol Sci. 2011;12:6267–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Levesque S, Taetzsch T, Lull ME, Kodavanti U, Stadler K, Wagner A, Johnson JA, Duke L, Kodavanti P, Surace MJ, Block ML. Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity. Environ Health Perspect. 2011b;119:1149–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Cole TB, Coburn J, Dao K, Roqué P, Kalia V, Guilarte T, Diedzic J, Costa LG. Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain. Toxicology. 2016;374:1–9.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Durga M, Devasena T, Rajasekar A. Determination of LC50 and sub-chronic neurotoxicity of diesel exhaust nanoparticles. Environ Toxicol Pharmacol. 2015;40:615–25.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Calderon-Garciduenas L, Torres-Jardon R, Kulesza RJ, Park SB, D’Angiulli A. Air pollution and detrimental effects on children’s brain. The need for a multidisciplinary approach to the issue complexity and challenges. Front. Human Neurosci. 8: Art. 613, 2014.

  42. 42.

    Calderon-Garciduenas L, Kulesza RJ, Doty RL, D’Angiulli A, Torres-Jardon R. Megacities air pollution problems: Mexico City metropolitan area critical issues on the central nervous system pediatric impact. Environ Res. 2015;137:157–69.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Guxens M, Garcia-Esteban R, Giorgis-Allemand L, Forns J, Badaloni C, Ballester F, Cesaroni G, Chatzi L, et al. Air pollution during pregnancy and childhood cognitive and psychomotor development. Epidemiology. 2014;25:636–47.

    PubMed  Article  Google Scholar 

  44. 44.

    Suades-Gonzalez E, Gascon M, Guxens M, Sunyer J. Air pollution and neuropsychological development: a review of the latest evidence. Endocrinology. 2015;156:3473–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Vrijheid M, Casas M, Gascon M, Valvi D, Nieuwenhuijsen M. Environmental pollutants and child health—a review of recent concerns. Int J Hyg Environ Health. 2016.

  46. 46.

    Calderon-Garciduenas L, Cross JV, Franco-Lira M, Aragon-flores M, Kavanaugh M, Torres-Jardon R, et al. 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 serum interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution. Front Neurosci. 2013;7:183. doi:10.3389/fnins.2013.00183.

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Saenen ND, Plusquin M, Bijnens E, Jansen BG, Gyselaers W, Cox B, Fierens F, Molenberghs G, Penders J, Vrijens K, De Boever P, Nawrot TS. In utero fine particle air pollution and placental expression of genes in the brain-derived neurotrophic factor signaling pathway; an ENVIRONAGE birth cohort study. Environ Health Perspect. 2015;123:834–40.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Newman NC, Ryan P, LeMasters G, Levin L, Bernstein D, Khurana Hershey GK, Lockey JE, et al. Traffic-related air pollution exposure in the first year of life and behavioral scores at 7 years of age. Environ Health Perspect. 2013;121:731–6.

    PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Yorifuji T, Kashima S, Higa Diez M, Kado Y, Sanada S, Doi H. Prenatal exposure to traffic-related air pollution and child behavioral development milestone delays in Japan. Epidemiology. 2016;27:57–65.

    PubMed  Article  Google Scholar 

  50. 50.

    Kicinski M, Vermeir G, Van Larebeke N, Den Hond E, Schoeters G, Bruckers L, Sioen I, et al. Neurobehavioral performance in adolescents is inversely associated with traffic exposure. Environ Int. 2015;75:136–43.

    PubMed  Article  Google Scholar 

  51. 51.

    Sunyer J, Esnaola M, Alvarez-Pedrerol M, Forns J, Rivas I, Lopez-Vicente M, Suades-Gonzales E, Foraster M, Garcia-Esteban R, et al. Association between traffic-related air pollution in schools and cognitive development in primary school children: a prospective cohort study. PLoS Med. 2015;12:e1001792. doi:10.1371/journal.pmed.1001792.

    PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    • Basagaña X, Esnaola M,Rivas I, Amato F, Alvarez-Pedrerol M, Forns J, Lopez-Vicente M, Pujol J, Nieuwenhuijsen M, Querol X, Sunyer J. Neurodevelopmental deceleration by urban fine particles from different emission sources: a longitudinal observational study. Environ Health Perspect. 2016. This is an example of recent studies investigating the behavioral effects of air pollution in children.

  53. 53.

    Harris MH, Gold DR, Rifas-Shiman SL, Melly SJ, Zanobetti A, Coull BA, Schwartz JD, Gryparis A, Kloog I, Koutrakis P, Bellinger DC, Belfort MB, Webster TF, White RF, Sagiv SK, Oken E. Prenatal and childhood traffic-related air pollution exposure and childhood executive function and behavior. Neurotoxicol Teratol. 2016.

  54. 54.

    Chiu YHM, Hsu HHL, Coull BA, Bellinger DC, Kloog I, Schwartz J, Wright RO, Wright RJ. Prenatal particulate air pollution and neurodevelopment in urban children: examining sensitive windows and sex-specific associations. Environ Int. 2016;87:56–65.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Xu X, Uyen Ha S, Basnet R. A review of epidemiological research on adverse neurological effects of exposure to ambient air pollution. Front Public Health. 2016;4:Art. 157. 31 p.

    Article  Google Scholar 

  56. 56.

    Ema M, Naya M, Horimoto M, Kato H. Developmental toxicity of diesel exhaust: a review of studies in experimental animals. Reprod Toxicol. 2013;42:1–17.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Yokota S, Mizuo K, Moriya N, Oshio S, Sugawara I, Takeda K. Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Neurosci Lett. 2009;449:38–41.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Suzuki T, Oshio S, Iwata M, Saburi H, Odagiri T, Udagawa T, Sugawara I, Umezawa M, Takeda K. In utero exposure to a low concentration of diesel exhaust affects spontaneous locomotor activity and monoaminergic system in male mice. Particle Fibre Toxicol. 2010;7:7.

    CAS  Article  Google Scholar 

  59. 59.

    Davis DA, Bortolato M, Godar SC, Sander TK, Iwata N, Pakbin P, Shih JC, Berhane K, McConnell R, et al. Prenatal exposure to urban air nanoparticles in mice causes altered neuronal differentiation and depression like responses. PLoS One. 2013;8(5):e64128. doi:10.1371/journal.pone.0064128.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Hougard KS, Jensen KA, Nordly P, Taxvig C, Vogel U, Saber AT, Wallin H. Effects of prenatal exposure to diesel exhaust particles on postnatal development, behavior, genotoxicity and inflammation in mice. Particle Fibre Toxicol. 2008;5:3. doi:10.1186/1743-8977-5-3.

    Article  CAS  Google Scholar 

  61. 61.

    Hougaard KS, Saber AT, Jensen KA, Vogel U, Wallin H. Diesel exhaust particles: effects on neurofunction in female mice. Basic Clin Pharmacol Toxicol. 2009;105:139–43.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Tsukue N, Watanabe M, Kumamoto T, Takano H, Takeda K. Perinatal exposure to diesel exhaust affects gene expression in mouse cerebrum. Arch Toxicol. 2009;83:985–1000.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Win-Shwe TT, Fujitani Y, Kyi-Tha-Thu C, Furuyama A, Michikawa T, Tsukahara S, Nitta H, Hirano S. Effects of diesel engine exhaust origin secondary organic aerosols on novel object recognition ability and maternal behavior in BALB/C mice. Int J Environ Res Public Health. 2014;11:11286–307.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Yokota S, Sato A, Umezawa M, Oshio S, Takeda K. In utero exposure of mice to diesel exhaust particles affects spatial learning and memory with reduced N-methyl-D-aspartate receptor expression in the hippocampus of male offspring. Neurotoxicology. 2015;50:108–15.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Yokota S, Oshio S, Moriya N, Takeda K. Social isolation-induced territorial aggression in male offspring is enhanced by exposure to diesel exhaust during pregnancy. PLoS One. 2016;11(2):e0149737. doi:10.1371/journal.pone.0149737.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66.

    Allen JL, Conrad K, Oberdorster G, Johnston CJ, Sleezer B, Cory-Slechta DA. Developmental exposure to concentrated ambient particles and preference for immediate reward in mice. Environ Health Perspect. 2013;121:32–8.

    PubMed  Article  Google Scholar 

  67. 67.

    Allen JL, Liu X, Weston D, Prince L, Oberdörster G, Finkelstein JN, Johnston CJ, Cory-Slechta DA. Developmental exposure to concentrated ambient ultrafine particulate matter air pollution in mice results in persistent and sex dependent behavioral neurotoxicity and glial activation. Toxicol Sci. 2014a;140:160–78.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Levy SE, Mandell DS, Schultz RT. Autism. Lancet. 2009;374:1627–38.

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Boyle CA, Boulet S, Schieve LA, Cohen RA, Blumberg SJ, Yeargin-Allsopp M, Visser S, Kogan MD. Trends in the prevalence of developmental disabilities in US children, 1997-2008. Pediatrics. 2011a;127:1034–42.

    PubMed  Article  Google Scholar 

  70. 70.

    Wingate M, Mulvihill B, Kirby RS, Pettygrove S, Cunniff C, Meaney F, et al. Prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill Summ. 2012;61:1–19.

    Google Scholar 

  71. 71.

    Schaafsma SM, Pfaff DW. Etiologies underlying sex differences in autism spectrum disorders. Front Neuroendocrinol. 2014;35:255–71.

    PubMed  Article  Google Scholar 

  72. 72.

    Buescher AV, Cidav Z, Knapp M, Mandell DS. Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr. 2014;168:721–8.

    PubMed  Article  Google Scholar 

  73. 73.

    Wegiel J, Kuchna I, Nowicki K, Imaki H, Wegiel J, Marchi E, Ma SY, Chauhan A, Chauhan V, Wierzba Bobrowicz T, de Leaon M, Saint Louis LA, Cohen IL, London E, Brown WT, Wisniewski T. The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuroptahol. 2010;119:755–70.

    Article  Google Scholar 

  74. 74.

    Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A, Colamarino SA, Lein ES, Courchesne E. Patches of disorganization in the neocortex of children with autism. New Engl J Med. 2014;370:1209–19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Lam KS, Aman MG, Arnold LE. Neurochemical correlates of autistic disorder. A review of the literature Rev Dev Disab. 2006;27:254–89.

    Google Scholar 

  76. 76.

    Rose S, Melnyk S, Pavliv O, Bai S, Nick TG, Frye RE, James SJ. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry. 2012;2:e134.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Della Bernardina B, Bonassi S. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Rad. Biol. Med. 2012;52:2128–41.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Napoli E, Wong S, Giulivi C. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA damage in children with typical autism. Mol Autism. 2013;4:2.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007;36:361–5.

    PubMed  Article  Google Scholar 

  80. 80.

    Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011;25:40–5.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    El-Ansary A, Al-Ayadhi L. Neuroinflammation in autism spectrum disorders. J. Neuroinflammat. 2012;9:265.

    CAS  Google Scholar 

  82. 82.

    Theoharides TC, Asadi S, Patel AB. Focal brain inflammation and autism. J. Neuroinflammat. 2013;10:46.

    CAS  Article  Google Scholar 

  83. 83.

    Depino AM. Peripheral and central inflammation in autism spectrum disorders. Mol Cell Neurosci. 2013;53:69–76.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miler J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiat. 2011;68:1095–102.

    PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, Buxbaum JD. Most genetic risk for autism resides in common variation. Nature Genet. 2014;46:881–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Landrigan PJ. What causes autism? Exploring the environmental contribution Curr Op Pediatr. 2010;22:219–25.

    Article  Google Scholar 

  87. 87.

    Kalkbrenner AE, Schmidt RJ, Penlesky AC. Environmental chemical exposures and autism spectrum disorders: a review of epidemiological evidence. Curr Probl Pediatr Adolesc Health Care. 2014;44:277–318.

    PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Rossignol DA, Genuis SJ, Frye RE. Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiat. 2014;4:e360.

    CAS  Article  Google Scholar 

  89. 89.

    Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014;311:1770–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Nardone S, Sams D, Reuveni E, Getselter D, Oron O, Karpuj, Elliott E. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Trans Psychiat. 2014;4:e433.

    CAS  Article  Google Scholar 

  91. 91.

    Berko ER, Greally JM. How might epigenetic dysregulation in early embryonic life contribute to autism spectrum disorder? Epigenomics. 2015;7:1–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Lyall K, Schmidt RJ, Hertz-Picciotto I. Maternal lifestyle and environmental risk factors for autism spectrum disorders. Int J Epidemiol. 2014;43:443–64.

    PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Lyall K, Croen LA, Sjodin A. Yoshida CK, Zerbo O, Kharrazi M, Windham GC. Polychlorinated biphenyl and organochlorine pesticide concentrations in mid-pregnancy serum analysis: association with autism spectrum disorder and intellectual disability. Environ Health Perspect. 2016.

  94. 94.

    Patterson PH. Maternal infection and immune involvement in autism. Trends Mol Med. 2011;17:389–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 26: 607–616, 2012.

  96. 96.

    Bauman MD, Iosif AM, Smith SEP, Bregere C, Amaral DG, Patterson PH. Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol Psychiatry. 2014;75:332–41.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    •• Estes ML, McAllister AK. Maternal immune activation: implications for neuropsychiatric disorders. Science. 2016;353:772–7. This review highlights the importance of maternal immune activation in numerous CNS disorders.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, DeLorenze GN, Kharrazi M, Yolken R, Ashwood P, Van de Water J. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psych. 2016.

  99. 99.

    Wong CT, Wais J, Crawford DA. Prenatal exposure to common environmental factors affects brain lipids and increases risk of developing autism spectrum disorders. Eur J Neurosci. 2015;42:2742–60.

    PubMed  Article  Google Scholar 

  100. 100.

    Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect. 2011;119:873–7.

    PubMed  Article  Google Scholar 

  101. 101.

    Volk HE, Lurmann F, Penfold B, Hertz-Picciotto I, McConnell R. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiat. 2013;70:71–7.

    Article  Google Scholar 

  102. 102.

    Becerra TA, Wilhelm M, Olsen J, Cockburn M, Ritz B. Ambient air pollution and autism in Los Angeles County. California Environ Health Perspect. 2013;121:380–6.

    PubMed  Google Scholar 

  103. 103.

    Roberts AL, Lyall K, Hart JE, Laden F, Just AC, Bobb JF, Koenen KC, Ascherio A, Weisskopf MG. Perinatal air pollutant exposures and autism spectrum disorder in the children of Nurses’s health study II participants. Environ Health Perspect. 2013;121:978–84.

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Jung CR, Lin YT, Hwang BF. Air pollution and newly diagnostic autism spectrum disorders: a population-based cohort study in Taiwan. PLoS One. 2013;8:e75510.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Talbott EO, Arena VC, Rager JR, Clougherty JE, Michanowicz DR, Sharma RK, Stacy SL. Fine particulate matter and the risk of autism spectrum disorders. Environ Res. 2015;140:414–20.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Guxens M, Ghassabian A, Gong T, Garcia-Esteban R, Porta D, Giorgis-Allemand L, Almqvist C, et al. Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies: the ESCAPE project. Environ Health Perspect. 2016;124:133–40.

    PubMed  Google Scholar 

  107. 107.

    • Kalkbrenner AE, Windham GC, Serre ML, Akita Y, Wang X, Hoffman K, Thayer BP, Daniels JL. Particulate matter exposure, prenatal and postnatal windows of susceptibility, and autism spectrum disorders. Epidemiology. 2015;26:30–42. This study reports how third-trimester exposure has the strongest association between air pollution and ASD.

    PubMed  Article  Google Scholar 

  108. 108.

    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. 2015;123:264–70.

    CAS  PubMed  Google Scholar 

  109. 109.

    Tachibana K, Takayanagi K, Akimoto A, Ueda K, Shinkai Y, Umezawa M, Takeda K. Prenatal diesel exhaust exposure disrupts the DNA methylation profile in the brain of mouse offspring. J Toxicol Sci. 2015;40:1–11.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Thirtamara Rajamani K, Doherty-Lyons S, Bolden C, Willis D, Hoffman C, Zelikoff J, Chen LC, Gu H. Prenatal and early life exposure to high level diesel exhaust particles leads to increased locomotor activity and repetitive behaviors in mice. Autism Res. 2013;6:248–57.

    PubMed  Article  Google Scholar 

  111. 111.

    • Allen JL, Liu X, Pelkowski S, Palmer B, Conrad K, Oberdörster G, Weston D, Mayer-Proschel M, Cory-Slechta D. Early postnatal exposure to ultrafine particulate matter air pollution: persistent ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice. Environ Health Perspect. 2014b;122:939–45. This study provides important evidence in an animal model of CNS alterations induced by air pollution which are similar to ASD.

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Allen JL, Oberdoerster G, Morris-Schaffer K, Wong C, Klocke C, Sobolewski M, Conrad K, Mayer-Proschel M, Cory-Slechta DA. Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders. Neurotoxicology. 2016.

  113. 113.

    Rich DQ, Liu K, Zhang J, Thurstin SW, Stevens TP, Pan Y, Kane C, Weinberger B, Ohman-Strickland P, Woodruff TJ, Duan X, Assibey-Mensah V, Zhang J. Differences in birth weight associated with the 2008 Bejing Olympics air pollution reduction: results from a natural experiment. Environ Health Perspect. 2015;123:880–7.

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Schembari A, de Hoogh K, Pedersen M, Dadvand P, Martinez D, Hoelk G, Petherick ES, Wright J, Nieuwenhujisen MJ. Ambient air pollution and newborn size and adiposity at birth: difference by maternal ethnicity (the born in Bradford study cohort). Environ Health Perspect. 2015;123:1208–15.

    PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev. 1979;3:79–83.

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Bayer SA, Altman J, Russo RJ, Zhang X. Timetables of neurogenesis in the human brain based on experimentally determined pattern in the rat. Neurotoxicology. 1993;14:83–144.

    CAS  PubMed  Google Scholar 

  117. 117.

    Block ML, Wu X, Pei Z, Li G, Wang T, Qin L, Wilson B, Yang J, Hong JS, Veronesi B. Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase. FASEB J. 2004;18:1618–20.

    CAS  PubMed  Google Scholar 

  118. 118.

    Roqué PJ, Dao K, Costa LG. Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms. Neurotoxicology. 2016;56:2014–214.

    Article  CAS  Google Scholar 

  119. 119.

    Martinez-Cerdeño V, Noctor SC. Cajal, Retzius, and Cajal-Retzius cells. Front Neuroanat. 2014;8:48.

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Jossin Y. Neuronal migration and the role of reelin during early development of the cerebral cortex. Mol Neurobiol. 2004;30:225–51.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Folsom TD, Fatemi SH. The involvement of reelin in neurodevelopmental disorders. Neuropharmacology. 2013;68:122–35.

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Sekine K, Kubo K, Nakajima K. How does reelin control neuronal migration and layer formation in the developing mammalian cortex? Neurosci Res. 2014;86:50–8.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Förster E. Reelin, neuronal polarity and process orientation of cortical neurons. Neuroscience. 2014;269:102–11.

    PubMed  Article  CAS  Google Scholar 

  124. 124.

    Yu NN, Tan MS, Yu JT, Xie AM, Tan L. The role of reelin signaling in Alzheimer’s disease. Mol Neurobiol. 2016;53:5692–700.

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Fatemi SH, Snow AV, Stary JM, Araghi-Niknam M, Brooks AI, Pearce DA, Reutiman TJ, Lee S. Reelin signaling is impaired in autism. Biol Psych. 2005;57:777–87.

    CAS  Article  Google Scholar 

  126. 126.

    Persico AM, D’Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C, et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry. 2001;6:150–9.

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Serajee FJ, Zhong H, Huq AHMM. Association of reelin polymorphysms with autism. Genomics. 2006;87:75–83.

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Wang Z, Hong Y, Zou L, Zhong R, Zhu B, Shen N, Chen W, Lou J, Ke J, Zhang T, Wang W, Miao X. Reelin gene variants and risk of autism spectrum disorders: an integrated meta-analysis. Am J Med Genet Pt B. 2014;165B:192–200.

    Article  CAS  Google Scholar 

  129. 129.

    Lammert DB, Howell BW. RELN mutations in autism spectrum disorder. Front Cell Neurosci. 2016;10:art 84. doi:10.3389/fncel.2016.0084.

    Article  Google Scholar 

  130. 130.

    Lintas C, Sacco R, Persico AM. Differential methylation at the RELN gene promoter in temporal cortex from autistic and typically developing post-puberal subjects. J Neurodev Dis. 2016;8:18.

    Article  Google Scholar 

  131. 131.

    Sakai K, Shoji H, Kohno T, Miyakawa T, Hattori M. Mice that lack the C-terminal region of reelin exhibit behavioral abnormalities related to neuropsychiatric disorders. Sc Rep. 2016;6:28636. doi:10.1038/srep28636.

    CAS  Article  Google Scholar 

  132. 132.

    Katsuyama Y, Terashima T. Developmental anatomy of reeler mutant mouse. Develop Growth Differ. 2009;51:271–86.

    CAS  Article  Google Scholar 

  133. 133.

    Reiner O, Karzburn E, Kshirsagar A, Kaibuchi K. Regulation of neuronal migration, an emerging topic in autism spectrum disorders (ASD). J Neurochem. 2016;136:440–56.

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Boyle MP, Bernard A, Thompson CL, Ng L, Boe A, Mortrud M, Hawrylcz MJ, Jones AR, Hevner RF, Lein ES. Cell-type-specific consequences of reelin deficiency in the mouse neocortex, hippocampus, and amygdala. J Comp Neurol. 2011b;519:2061–89.

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006;26:4752–62.

    CAS  PubMed  Article  Google Scholar 

  136. 136.

    Ghiani CA, Mattan NS, Nobuta H, Malvar JS, Boles J, Ross MG, Waschek JA, Carpenter EM, Fisher RS, de Vellis J. Early effects of lipopolysaccharide-induced inflammation of foetal brain development in rat. ASN Neuro. 2011;3(4):art:e00068.

    Article  CAS  Google Scholar 

  137. 137.

    Novais ARB, Guiramand J, Cohen-Sola C, Crouzin N, de Jesus Ferreira MC, Vignes M, Barbanel G, Cambonie G. N-acetyl-cysteine prevents pyramidal cell disarray and reelin-immunorecative neuron deficiency in CA3 after prenatal immune challenge in rats. Pediatr Res. 2013;73:750–5.

    CAS  Article  Google Scholar 

  138. 138.

    Depino AM. Early prenatal exposure to LPS results in anxiety- and depression-related behaviors in adulthood. Neuroscience. 2015;299:56–65.

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Uzunova G, Pallanti S, Hollander E. Excitatory/inhibitory imbalance in autism spectrum disorders: implications for interventions and therapeutics. World J Biol Psych. 2016;17:174–86.

    Article  Google Scholar 

  140. 140.

    Robertson CE, Ratai EM, Kanwisher N. Reduced GABAergic action in the autistic brain. Curr Biol. 2016;26:80–5.

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Shaun N, Thomas B. The STAT3-DMNT1 connection. JAK-STAT. 2012;1(4):257–60.

    Article  Google Scholar 

  142. 142.

    Noh JS, Sharma RP, Veldic M, Salvacion AA, Jia X, Chen Y, Costa E, Guidotti A, Grayson DR. DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc Natl Acad Sci. 2005;102:1749–54.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Kundakovic M, Chen Y, Costa E, Grayson DR. DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol Pharmacol. 2007;71:644–53.

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB, Rubenstein JL, Scheuer T, de la Iglesia HO, Catterall WA. Autistic-like behavior in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature. 2012;489:385–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Nouel D, Burt M, Zhang Y, Harvey L, Boksa P. Prenatal exposure to bacterial endotoxin reduces the number of GAD67- and reelin-immunoreactive neurons in the hippocampus of rat offspring. Eur Neuropsychopharmacol. 2012;22:300–3017.

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Schwartzer JJ, Koenig CM, Berman RF. Using mouse models of autism spectrum disorders to study the neurotoxicology of gene-environment interactions. Neurotoxicol Teratol. 2013;36:17–35.

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Brielmaier J, Matteson PG, Silverman JL, Senerth JM, Kelly S, Genestine M, Millonig JH, DiCicco-Bloom E, Crawley JN. Autism-relevant social abnormalities and cognitive deficits in engrailed-2 knockout mice. PLoS One. 2012;7(7):e40914. doi:10.1371/journal.pone.0040914.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN. Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav. 2008;7:152–63.

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Silverman JL, Yang M, Lord C, Crawley JN. Behavioral phenotyping assays for mouse models of autism. Nat Rev Neurosci. 2010;11:490–502.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    De Felice A, Scattoni ML, Ricceri L, Calamandrei G. Prenatal exposure to a common organophosphate insecticide delays motor development in a mouse model of idiopathic autism. PLoS One 10 (3): e0121663, 2015. doi:10.1371/journal.pone.0121663.

  151. 151.

    De Felice A, Greco A, Calamandrei G, Minghetti L. Prenatal exposure to the insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism. J Neuroinflammat. 2016;13:149.

    Article  CAS  Google Scholar 

  152. 152.

    Tueting P, Costa E, Dwivedi Y, Guidotti A, Impagnatiello F, Manev R, Pesold C. The phenotypic characteristics of heterozygous reeler mouse. Neuroreport. 1999;10:1329–34.

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Podhorna J, Didriksen M. The heterozygous reeler mouse: behavioral phenotype. Behav Brain Res. 2004;153:43–54.

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Biamonte F, Latini L, Giorgi FS, Zingariello M, Marino R, De Luca R, D’Ilio S, Majorani C, Petrucci F, Violante N, Senofonte O, Molinari M, Keller F. Associations among exposure to methylmercury, reduced reelin expression, and gender in the cerebellum of developing mice. Neurotoxicology. 2014;45:67–80.

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Giordano G, White CC, McConnachie LA, Fernandez C, Kavanagh TJ, Costa LG. Neurotoxicity of domoic acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Mol Pharmacol. 2006;70:2116–26.

    CAS  PubMed  Article  Google Scholar 

  156. 156.

    Nakamura S, Kugiyama K, Sugiyama S, Miyamoto S, Koide S, Fukushima H, Honda O, Yoshimura M, Ogawa H. Polymorphism in the 5′-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction. Circulation. 2002;105:2968–73.

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Weldy CS, White CC, Wilkerson HW, Larson TV, Stewart JA, Gill SE, Parks WC, Kavanagh TJ. Heterozygosity in the glutathione synthesis gene Gclm increases sensitivity to diesel exhaust particulate induced lung inflammation in mice. Inhal Toxicol. 2012;23:724–35.

    Article  CAS  Google Scholar 

  158. 158.

    Gu F, Chauhan V, Chauhan A. Impaired synthesis and antioxidant defense of glutathione in the cerebellum of autistic subjects: alterations in the activities and protein expression of glutathione-related enzymes. Free Rad Biol Med. 2013;65:488–96.

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Costa LG, Aschner M, Vitalone A, Syversen T, Porat-Soldin O. Developmental neuropathology of environmental agents. Annu Rev Pharmacol Toxicol. 2004;44:87–110.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

Research by the authors is supported by grants from NIEHS (R01ES22949, P30ES07033, P42ES04696, T32ES07032) and NICHD (U54HD083091) and by funds from the Department of Environmental and Occupational Health Sciences, University of Washington.

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Correspondence to Lucio G. Costa.

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This review article does not contain any studies with human or animal subjects performed by any of the authors. Studies with animals by the authors and reported elsewhere are referred to. These studies were approved by the Institutional Animal Review Board.

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This article is part of the Topical Collection on Mechanisms of Toxicity

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Costa, L.G., Chang, Y. & Cole, T.B. Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism. Curr Envir Health Rpt 4, 156–165 (2017). https://doi.org/10.1007/s40572-017-0135-2

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Keywords

  • Traffic-related air pollution
  • Diesel exhaust
  • Neuroinflammation
  • Autism spectrum disorders
  • Reelin
  • Gene-environment interactions