Environmental Factors in the Onset of Autism Spectrum Disorder

Current Developmental Disorders Reports

Volumn 1, Issue 1, 2014, Pages 8-19

  Persico, Antonio M ^a,b,c   Merelli, Sara ^c  

^a UNIVERSITY CAMPUS BIO MEDICO   (Italy)

^b IRCCS FONDAZIONE SANTA LUCIA   (Italy)

^c Mafalda Luce Center for Pervasive Developmental Disorders   (Italy)

Author keywords

Air pollution; Autism; Autism spectrum disorder; Benzo(a)pyrene; Environment; Environmental factors; Halogenated aromatic hydrocarbons; Heavy metals; Mercury; Misoprostol; MMR; Organophosphates; p cresol; PBDEs; PCBs; Pervasive Developmental Disorders; Pesticides; Polybrominated diphenyl ethers; Polychlorinated biphenyls; Thalidomide; Thimerosal; Vaccines; Valproate

Indexed keywords

EID: 84938073392     PISSN: None     EISSN: 21962987     Source Type: Journal    
DOI: 10.1007/s40474-013-0002-2     Document Type: Article

References (133)

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychiatric Publishing; 2013.
2. Robinson EB, Koenen KC, McCormick MC, Munir K, Hallett V, Happé F, et al. Evidence that autistic traits show the same etiology in the general population and at the quantitative extremes (5 %, 2.5 %, and 1 %). Arch Gen Psychiatry. 2011;68(11):1113–21.
3. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators; Centers for Disease Control and Prevention (CDC). Prevalence of Autism Spectrum Disorders - Autism and Developmental Disabilities Monitoring Network, 14 Sites, United States. MMWR Surveill Summ 2012; 61:1–19.
4. Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcín C, et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 2012;5(3):160–79. doi:10.1002/aur.239. Review.
5. Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9:341–55.
6. Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ, et al. Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism. 2012;3:9. By applying quantitative genetics techniques to simplex and multiplex families, the authors are able for the first time to estimate the relative weight of common genetic variants, each conferring a small, additive effect. This contribution is larger in multiplex families, where there is evidence of assortative mating in parents. The complex interplay of common and rare genetic variants in association with the environment is critical to the expression of ASD.
7. Landrigan PJ. What causes autism? Exploring the environmental contribution. Curr Opin Pediatr. 2010;22:219–25.
8. Persico AM, Napolioni V. Autism genetics. Behav Brain Res. 2013;251:95–112. doi:10.1016/j.bbr.2013.06.012.
9. Bromley RL, Mawer GE, Briggs M, Cheyne C, Clayton-Smith J, García-Fiñana M, et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry. 2013;84:637–43.
10. Kjaer D, Christensen J, Bech BH, Pedersen LH, Vestergaard M, Olsen J. Preschool behavioral problems in children prenatally exposed to antiepileptic drugs - A follow-up study. Epilepsy Behav. 2013 Sep 30. doi:pii: S1525-5050(13)00456-3. 10.1016/j.yebeh.2013.08.033 DOI: 10.1016/j.yebeh.2013.08.033
11. Cohen MJ, Meador KJ, Browning N, May R, Baker GA, Clayton-Smith J, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW; for the NEAD study group Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years.Epilepsy Behav. 2013 Sep 5. doi:pii: S1525-5050(13)00406-X. 10.1016/j.yebeh.20 DOI: 10.1016/j.yebeh.20
12. Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309:1696–703.
13. Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ, et al. Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol. 2005;47:551–5.
14. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001;276:36734–41.
15. Hill EJ, Nagel DA, O'Neil JD, Torr E, Woehrling EK, Devitt A, et al. Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8:e58822.
16. Rout UK, Clausen P. Common increase of GATA-3 level in PC-12 cells by three teratogens causing autism spectrum disorders. Neurosci Res. 2009;64:162–9.
17. Miyazaki K, Narita N, Narita M. Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Int J Dev Neurosci. 2005;23:287–97.
18. Ingram JL, Peckhan SM, Tisdale B, Rodier PM. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol. 2000;22:319–24.
19. Rinaldi T, Silberberg G, Markram H. Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid. Cereb Cortex. 2008;18:763–70.
20. Markram K, Rinaldi T, La Mendola D, Sandi C, Markram H. Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacol. 2008;33:901–12.
21. Rinaldi T, Kulangara K, Antoniello K, Markram H. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A. 2007;104:13501–6.
22. Schanen NC. Epigenetics of autism spectrum disorders. Hum Mol Genet. 2006;15(Spec No 2):R138–150.
23. Ben-David E, Shifman S. Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. Mol Psychiatry 2012 Nov 13. doi: 10.1038/mp.2012.148. [Epub ahead of print] DOI: 10.1038/mp.2012.148
24. Hallene KL, Oby E, Lee BJ, Santaguida S, Bassanini S, Cipolla M, et al. Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations. Neuroscience. 2006;142:267–83.
25. Ema M, Ise R, Kato H, ONeda S, Hirata-Koizumi M, Singh AV, et al. Fetal malformations and early embryonic gene expression in cynomologus monkeys maternally exposed to thalidomide. Reprod Toxicol. 2010;29:49–56.
26. Bandim JM, Ventura LO, Miller MT, Almeida HC, Costa AE. Autism and Möbius sequence: an exploratory study of children in northeastern Brazil. Arq Neuropsiquiatr. 2003;61:181–5.
27. Miller MT, Ventura L, Strömland K. Thalidomide and misoprostol: Ophthalmologic manifestations and associations both expected and unexpected. Birth Defects Res A Clin Mol Teratol. 2009;85:667–76.
28. Dufour-Rainfray D, Vourc'h P, Tourlet S, Guilloteau D, Chalon S, Andres CR. Fetal exposure to teratogens: evidence of genes involved in autism. Neurosci Biobehav Rev. 2011;35:1254–65.
29. Ploeger A, Raijmakers ME, van der Maas HL, Galis F. The association between autism and errors in early embryogenesis: what is the causal mechanism? Biol Psychiatry. 2010;67:602–7.
30. Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol. 2005;11:1–10.
31. Chess S, Fernandez P, Korn S. Behavioral consequences of congenital rubella. J Pediatr. 1978;93:699–703.
32. Ivarsson SA, Bjerre I, Vegfors P, Ahlfors K. Autism as one of several disabilities in two children with congenital cytomegalovirus infection. Neuropediatrics. 1990;21:102–3.
33. Sweeten TL, Posey DJ, McDougle CJ. Brief report: autistic disorder in three children with cytomegalovirus infection. J Autism Dev Disord. 2004;34:583–6.
34. Yamashita Y, Fujimoto C, Nakajima E, Isagai T, Matsuishi T. Possible association between congenital cytomegalovirus infection and autistic disorder. J Autism Dev Disord. 2003;33:455–9.
35. Engman ML, Lewensohn-Fuchs I, Mosskin M, Malm G. Congenital cytomegalovirus infection; the impact of cerebral cortical malformations. Acta Paediatr. 2010;99:1344–9.
36. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals: a silent pandemic. Lancet. 2006;368:2167–78.
37. Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511–33.
38. Akimoto H. Global air quality and pollution. Science. 2003;302:1716–9.
39. Sram RJ, Binkova B, Dejmek, Bobak M. Ambient air pollution and pregnancy outcomes: a review of the literature. Environ Health Perspect. 2005;113:375–82.
40. Hansen CA, Barnett AG, Pritchard. The Effect of Ambient Air Pollution during Early Pregnancy on Fetal Ultrasonic Measurements during Mid-Pregnancy. Environ Health Perspect. 2008;116:362–9.
41. Suglia SF, Gryparis A, Wright RO, Schwartz J, Wright RJ. Association of black carbon with cognition among children in a prospective birth cohort study. Am J Epidemiol. 2008;167:280–6.
42. Morales E, Julvez J, Torrent M, de Cid R, Guxens M, Bustamante M, et al. Association of early-life exposure to household gas appliances and indoor nitrogen dioxide with cognition and attention behavior in preschoolers. Am J Epidemiol. 2009;169:1327–36.
43. Kalkbrenner AE, Daniels JL, Chen JC, Poole C, Emch M, Morrissey J. Perinatal exposure to hazardous air pollutants and autism spectrum disorders at age 8. Epidemiology. 2010;21:631–41.
44. 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.
45. Volk HE, Lurmann F, Penfold B, Hertz-Picciotto I, McConnell R. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry. 2013;70:71–7.
46. 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.
47. Block ML, Calderón-Garcidueñas L. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci. 2009;32:506–16.
48. Genc S, Zadeoglulari Z, Fuss SH, Genc K. The adverse effects of air pollution on the nervous system. J Toxicol. 2012;2012:782462.
49. Block ML, Wu X, Pei Z, Li G, Wang T, Veronesi B, et al. 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.
50. Pereyra-Muñoz N, Rugerio-Vargas C, Angoa-Pérez M, Borgonio-Pérez G, Rivas-Arancibia S. Oxidative damage in substantia nigra and striatum of rats chronically exposed to ozone. J Chem Neuroanat. 2006;31:114–23.
51. Thirtamara Rajamani K, Doherty-Lyons S, Bolden C, Willis D, Hoffman C, Gu H, et al. 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(4):248–57. doi:10.1002/aur.1287.
52. Sheng L, Ding X, Ferguson M, McCallister M, Rhoades R, Hood DB, et al. Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. Toxicol Sci. 2010;118:625–34. Prenatal exposure to benzo(a)pyrene downregulates the postnatal expression of the autism gene MET during synaptogenesis, reduces MET promoter activity, and results in behavioral deficits in novel object discrimination. This study nicely demonstrates a specific gene x environment interaction involving a common airborne pollutant and an established autism gene using animal and cellular models.
53. Bouayed J, Desor F, Rammal H, Kiemer AK, Tybl E, Schroeder H, et al. Effects of lactational exposure to benzo[alpha]pyrene (B[alpha]P) on postnatal neurodevelopment, neuronal receptor gene expression and behaviour in mice. Toxicology. 2009;259:97–106.
54. Herbstman JB, Tang D, Zhu D, Qu L, Sjödin A, Li Z, et al. Prenatal exposure to polycyclic aromatic hydrocarbons, benzo[a]pyrene-DNA adducts, and genomic DNA methylation in cord blood. Environ Health Perspect. 2012;120:733–8.
55. Furlong CE, Holland N, Richter RJ, Bradman A, Ho A, Eskenazi B. PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity. Pharmacogenet Genomics. 2006;16:183–90.
56. Bouchard M, Chevrier J, Harley KG, Kogut K, Vedar M, Eskenazi B, et al. Prenatal exposure to organophosphate pesticides and IQ in 7-year-old children. Environ Health Perspect. 2011;119:1189–95.
57. Engel S, Wetmur J, Chen J, Zhu C, Barr D, Canfield R, et al. Prenatal exposure to organophosphates, paraoxonase 1, and cognitive development in childhood. Environ Health Perspect. 2011;119:1182–8.
58. Rauh V, Arunajadai S, Horton M, Perera F, Hoepner L, Barr D, et al. Seven-year neurodevelopmental scores and prenatal exposure to chlorpyrifos, a common agricultural pesticide. Environ Health Perspect. 2011;119:1196–201.
59. Rauh V, Perera F, Horton M, Whyatt R, Bansal R, Peterson BS, et al. Brain anomalies in children exposed prenatally to a common organophosphate pesticide. Proc Natl Acad Sci U S A. 2012;109:7871–6. Structural MRI study describing differences between 20 children prenatally exposed to chlorpyrifos and 20 controls (age 5.9-11.2 yrs). Prenatal chlorpyrifos (CPF) exposure was estimated on the basis of CPF concentrations measured in umbilical cord blood at birth. Main CPF effects include enlargement of several temporal, frontal, and postcentral regions, cuneus, and precuneus, along with various sex- and IQ-specific interactions.
60. Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect. 2007;115:1482–9.
61. Flaskos J. The developmental neurotoxicity of organophosphorus insecticides: a direct role for the oxon metabolites. Toxicol Lett. 2012;209:86–93.
62. Stamou M et al. Neuronal connectivity as a convergent target for gene x environment interactions that confer risk for Autism Spectrum Disorders. Neurotoxicol Teratol. 2013. doi:10.1016/j.ntt.2012.12.001.
63. Shelton F, Hertz-Picciotto I, Pessah IN. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environ Health Perspect. 2012;120:944–51.
64. Betancourt AM, Burgess SC, Carr RL. Effect of developmental exposure to chlorpyrifos on the expression of neurotrophin growth factors and cell-specific markers in neonatal rat brain. Toxicol Sci. 2006;92:500–6.
65. Quattrocchi CC, Wannenes F, Persico AM, Ciafrè SA, D’Arcangelo G, Farace MG, et al. Reelin is a serine protease of the extracellular matrix. J Biol Chem. 2002;277:303–9.
66. D'Amelio M, Ricci I, Sacco R, Liu X, D’Agruma L, Persico AM, et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005;10:1006–16.
67. Gaita L, Manzi B, Sacco R, Lintas C, Altieri L, Persico AM, et al. Decreased serum arylesterase activity in Autism Spectrum Disorders. Psychiatry Res. 2010;180:105–13.
68. Mullen BR, Khialeeva E, Hoffman DB, Ghiani CA, Carpenter EM. Decreased reelin expression and organophosphate pesticide exposure alters mouse behaviour and brain morphology. ASN Neuro. 2012;5(1):e00106. doi:10.1042/AN20120060.
69. Goines PE, Ashwood P. Cytokine dysregulation in Autism Spectrum Disorders (ASD): Possible role of the environment. Neurotoxicol Teratol. 2012. doi:10.1016/j.ntt.2012.07.006.
70. Costa LG, Giordano G. Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants. Neurotoxicology. 2007;28(6):1047–67.
71. Tsukimori K, Morokuma S, Hori T, Takahashi K, Hirata T, Otera Y, et al. Characterization of placental transfer of polychlorinated dibenzo-p-dioxins, dibenzofurans and polychlorinated biphenyls in normal pregnancy. J Obstet Gynaecol Res. 2013;39:83–90.
72. Roze E, Meijer L, Bakker A, Van Braeckel KN, Sauer PJ, Bos AF. Prenatal exposure to organohalogens, including brominated flame retardants, influences motor, cognitive, and behavioral performance at school age. Environ Health Perspect. 2009;117:1953–8.
73. Gascon M, Fort M, Martínez D, Carsin AE, Forns J, Vrijheid M, et al. Polybrominated diphenyl ethers (PBDEs) in breast milk and neuropsychological development in infants. Environ Health Perspect. 2012;120:1760–5.
74. Eskenazi B, Chevrier J, Rauch SA, Kogut K, Harley KG, Johnson C, et al. In utero and childhood polybrominated diphenyl ether (PBDE) exposures and neurodevelopment in the CHAMACOS study. Environ Health Perspect. 2013;121:257–62.
75. Boas M, Feldt-Rasmussen U, Main KM. Thyroid effects of endocrine disrupting chemicals. Mol Cell Endocrinol. 2012;355:240–8.
76. Craig ZR, Wang W, Flaws JA. Endocrine-disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling. Reproduction. 2011;142:633–46.
77. Fair PA, Stavros HC, Mollenhauer MA, DeWitt JC, Henry N, Kannan K, et al. Immune function in female B(6)C(3)F(1) mice is modulated by DE-71, a commercial polybrominated diphenyl ether mixture. J Immunotoxicol. 2012;9:96–107.
78. Watanabe W, Shimizu T, Sawamura R, Hino A, Konno K, Kurokawa M. Functional disorder of primary immunity responding to respiratory syncytial virus infection in offspring mice exposed to a flame retardant, decabrominated diphenyl ether, perinatally. J Med Virol. 2010;82:1075–82.
79. Bradner JM, Suragh TA, Wilson WW, Lazo CR, Stout KA, Kim HM, et al. Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: Role of dopamine handling in neurotoxicity. Exp Neurol. 2013;241:138–47.
80. Giordano G, Kavanagh TJ, Costa LG. Neurotoxicity of a polybrominated diphenyl ether mixture (DE-71) in mouse neurons and astrocytes is modulated by intracellular glutathione levels. Toxicol Appl Pharmacol. 2008;232:161–8.
81. Pessah IN, Cherednichenko G, Lein PJ. Minding the calcium store: Ryanodine receptor activation as a convergent mechanism of PCB toxicity. Pharmacol Ther. 2010;125:260–85.
82. Yang D, Kim KH, Phimister A, Bachstetter AD, Ward TR, Lein PJ, et al. Developmental exposure to polychlorinated biphenyls interferes with experience-dependent dendritic plasticity and ryanodine receptor expression in weanling rats. Environ Health Perspect. 2009;117:426–35.
83. Wayman GA, Yang D, Bose DD, Lesiak A, Ledoux V, Lein PJ, et al. PCB-95 promotes dendritic growth via ryanodine receptor-dependent mechanisms. Environ Health Perspect. 2012;120:997–1002. Golgi analysis of hippocampi from weanling rats prenatally exposed to PCB-95 via the maternal diet demonstrates that PCB-95 promotes dendritic overgrowth at concentrations as low as 2 pM. In culture, this effect is prevented by blocking ryanodine receptors (RyRs) either pharmacologically through FLA365 or using siRNA knockdown of RyRs.
84. Carayol J, Sacco R, Tores F, Rousseau F, Lewin P, Hager J, et al. Converging evidence for an association of ATP2B2 allelic variants with autism in males. Biol Psychiatry. 2011;70:880–7.
85. Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L, Sacco R, et al. Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Mol Psychiatry. 2010;15:38–52. This study describes excessive aspartate/glutamate transport in postmortem autistic brains. This abnormality is not due to genetic mutations, but to excess in calcium levels, which overstimulates transporter activity. Oxidative stress is one of the ultimate consequences of this process.
86. Bal-Price AK, Coecke S, Costa L, Crofton KM, Fritsche E, Goldberg A, et al. Conference report: advancing the science of developmental neurotoxicity (DNT) testing for better safety evaluation. Altex-Altern Anim Ex. 2012;29:202–15.
87. Woods R, Vallero RO, Golub MS, Suarez JK, Ta TA, Yasui DH, et al. Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation. Hum Mol Genet. 2012;21:2399–411.
88. Hertz-Picciotto I, Bergman A, Fängström B, Rose M, Krakowiak P, Pessah I, et al. Polybrominated diphenyl ethers in relation to autism and developmental delay: a case–control study. Environ Health. 2011;10:1.
89. Cheslack-Postava K, Rantakokko PV, Hinkka-Yli-Salomäki S, Surcel HM, McKeague IW, Kiviranta HA, et al. Maternal serum persistent organic pollutants in the Finnish Prenatal Study of Autism: A pilot study. Neurotoxicol Teratol. 2013;38:1–5. doi:10.1016/j.ntt.2013.04.001.
90. Mitchell MM, Woods R, Chi LH, Schmidt RJ, Pessah IN, Kostyniak PJ, et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environ Mol Mutagen. 2012;53:589–98.
91. Ashwood P, Schauer J, Pessah IN, Van de Water J. Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders. J Neuroimmunol. 2009;208:130–5.
92. Roegge CS, Schantz SL. Motor function following developmental exposure to PCBS and/or MEHG. Neurotoxicol Teratol. 2006;28:260–77.
93. Boucher O, Jacobson SW, Plusquellec P, Dewailly E, Ayotte P, Forget-Dubois N, et al. Prenatal methylmercury, postnatal lead exposure, and evidence of attention deficit/hyperactivity disorder among Inuit children in Arctic Québec. Environ Health Perspect. 2012;120(10):1456–61. doi:10.1289/ehp.1204976.%20Epub%202012%20Aug%2016.
94. Goodlad JK, Marcus DK, Fulton JJ. Lead and Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms: A meta-analysis. Clin Psychol Rev. 2013;33:417–25.
95. Desoto MC, Hitlan RT. Blood levels of mercury are related to diagnosis of autism: a reanalysis of an important data set. J Child Neurol. 2007;22:1308–11.
96. Hertz-Picciotto I, Green PG, Delwiche L, Hansen R, Walker C, Pessah IN. Blood mercury concentrations in CHARGE Study children with and without autism. Environ Health Perspect. 2010;118:161–6.
97. Wright B, Pearce H, Allgar V, Miles J, Whitton C, Alderson-Day B, et al. A comparison of urinary mercury between children with autism spectrum disorders and control children. PLoS One. 2012;7(2):e29547.
98. Albizzati A, Morè L, Di Candia D, Saccani M, Lenti C. Normal concentrations of heavy metals in autistic spectrum disorders. Minerva Pediatr. 2012;64:27–31.
99. Blanchard KS, Palmer RF, Stein Z. The value of ecologic studies: mercury concentration in ambient air and the risk of autism. Rev Environ Health. 2011;26:111–8.
100. Palmer RF, Blanchard S, Wood R. Proximity to point sources of environmental mercury release as a predictor of autism prevalence. Health Place. 2009;15:18–24.
101. Shandley K, Austin DW. Ancestry of pink disease (infantile acrodynia) identified as a risk factor for autism spectrum disorders. J Toxicol Environ Health A. 2011;74:1185–94.
102. Stamova B, Green PG, Tian Y, Hertz-Picciotto I, Pessah IN, Sharp FR, et al. Correlations between gene expression and mercury levels in blood of boys with and without autism. Neurotox Res. 2011;19:31–48.
103. Tian Y, Green PG, Stamova B, Hertz-Picciotto I, Pessah IN, Sharp FR, et al. Correlations of gene expression with blood lead levels in children with autism compared to typically developing controls. Neurotox Res. 2011;19:1–13.
104. Lahat N, Shapiro S, Froom P, Kristal-Boneh E, Inspector M, Miller A. Inorganic lead enhances cytokine-induced elevation of matrix metalloproteinase MMP-9 expression in glial cells. J Neuroimmunol. 2002;132:123–8.
105. Wanchu A, Sud A, Bambery P, Prasad R, Kumar V. Plasma and peripheral blood mononuclear cells levels of Zn and Cu among Indian patients with RA. Ann Rheum Dis. 2002;61:88.
106. Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998;351(9103):637–41.
107. Taylor B, Miller E, Farrington CP, Petropoulos MC, Favot-Mayaud I, Li J, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet. 1999;353(9169):2026–9.
108. Kaye JA, del Mar M-MM, Jick H. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ. 2001;322(7284):460–3.
109. Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002;347(19):1477–82.
110. Taylor B, Miller E, Lingam R, Andrews N, Simmons A, Stowe J. Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study. BMJ. 2002;324(7334):393–6.
111. Madsen KM, Lauritsen MB, Pedersen CB, Thorsen P, Plesner AM, Andersen PH, et al. Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data. Pediatrics. 2003;112(3 Pt 1):604–6.
112. Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between thimerosal-containing vaccine and autism. JAMA. 2003;290(13):1763–6.
113. Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B. Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics. 2004;114(3):584–91.
114. Verstraeten T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB, et al. Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics. 2003;112(5):1039–48.
115. Heron J, Golding J. Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United kingdom does not support a causal association. Pediatrics. 2004;114(3):577–83.
116. Institute of Medicine (US) Immunization Safety Review Committee. Immunization Safety Review: Vaccines and Autism. Washington (DC): National Academies Press (US); 2004.
117. Ida-Eto M, Oyabu A, Ohkawara T, Tashiro Y, Narita N, Narita M. Embryonic exposure to thimerosal, an organomercury compound, causes abnormal early development of serotonergic neurons. Neurosci Lett. 2011;505(2):61–4. doi:10.1016/j.neulet.2011.05.053.
118. Ida-Eto M, Oyabu A, Ohkawara T, Tashiro Y, Narita N, Narita M. Prenatal exposure to organomercury, thimerosal, persistently impairs the serotonergic and dopaminergic systems in the rat brain: implications for association with developmental disorders. Brain Dev. 2013;35(3):261–4. doi:10.1016/j.braindev.2012.05.004.
119. Ueha-Ishibashi T, Oyama Y, Nakao H, Umebayashi C, Nishizaki Y, Tatsuishi T, et al. Effect of thimerosal, a preservative in vaccines, on intracellular Ca2+ concentration of rat cerebellar neurons. Toxicology. 2004;195(1):77–84.
120. Migdal C, Foggia L, Tailhardat M, Courtellemont P, Haftek M, Serres M. Sensitization effect of thimerosal is mediated in vitro via reactive oxygen species and calcium signaling. Toxicology. 2010;274(1–3):1–9. doi:10.1016/j.tox.2010.04.016.
121. Guzzi G, Pigatto PD, Spadari F, La Porta CA. Effect of thimerosal, methylmercury, and mercuric chloride in Jurkat T Cell Line. Interdiscip Toxicol. 2012;5(3):159–61. doi:10.2478/v10102-012-0026-1.
122. Branch DR. Gender-selective toxicity of thimerosal. Exp Toxicol Pathol. 2009;61(2):133–6. doi:10.1016/j.etp.2008.07.002.
123. Hornig M, Chian D, Lipkin WI. Neurotoxic effects of postnatal thimerosal are mouse strain dependent. Mol Psychiatry. 2004;9(9):833–45.
124. Sulkowski ZL, Chen T, Midha S, Zavacki AM, Sajdel-Sulkowska EM. Maternal thimerosal exposure results in aberrant cerebellar oxidative stress, thyroid hormone metabolism, and motor behavior in rat pups; sex- and strain-dependent effects. Cerebellum. 2012;11(2):575–86. doi:10.1007/s12311-011-0319-5.
125. Sharpe MA, Gist TL, Baskin DS. B-lymphocytes from a population of children with autism spectrum disorder and their unaffected siblings exhibit hypersensitivity to thimerosal. J Toxicol. 2013;2013:801517. doi:10.1155/2013/801517.
126. Sharpe MA, Livingston AD, Baskin DS. Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA. J Toxicol. 2012;2012:373678. doi:10.1155/2012/373678.%20Epub%202012%20Jun%2028.
127. Berger BE, Navar-Boggan AM, Omer SB. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination–United States, 2001–2010. BMC Public Health. 2011;11:340. doi:10.1186/1471-2458-11-340.
128. Guinchat V, Thorsen P, Laurent C, Cans C, Bodeau N, Cohen D. Pre-, peri- and neonatal risk factors for autism. Acta Obstet Gynecol Scand. 2012;91:287–300.
129. Lyall K, Pauls DL, Spiegelman D, Ascherio A, Santangelo SL. Pregnancy complications and obstetric suboptimality in association with autism spectrum disorders in children of the Nurses' Health Study II. Autism Res. 2012;5:21–30.
130. 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. 2012;26:607–16. Activation of the maternal immune system by injecting the viral mimic poly(I:C) in mice during pregnancy, produces behavioral abnormalities in the offspring pertaining to autism core symptoms in humans, namely abnormal social, communication and stereotypic behaviors. Previous work by the same group supports a central role for IL-6 in this effect.
131. Altieri L, Neri C, Sacco R, Curatolo P, Benvenuto A, Muratori F, et al. Urinary p-cresol is elevated in small children with Autism Spectrum Disorder. Biomarkers. 2011;16:252–60.
132. Persico AM, Napolioni V. Urinary p-cresol in autism spectrum disorder. Neurotoxicol Teratol. 2013;36:82–90.
133. MacFabe DF, Cain NE, Boon F, Ossenkopp KP, Cain DP. Effects of the entericbacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behav Brain Res. 2011;217:47–54.