Causes of the Increasing Prevalence of Autism in the Children
Autism
Keywords:
Autism Spectrum Disorder, genetics, environmental factors, epigenetics, neurodevelopmentAbstract
Social communication impairments and limited, repetitive behavior. Its etiology is c3omplicated and consists of interaction of various genetic and environmental factors. The presented work provides an overview regarding the current evidence on genetic architecture of ASD including major signaling pathways and synaptic genes (SHANK3, FMR1, MECP2, and TSC1/2) that are important in the synaptic development and in neuronal functioning. Moreover, the crucial factors of environmental risk factors have been examined including maternal smoking, nutritional deficiencies, environmental toxins and vaccination. Although there are some weak, or even inconsistent associations between some environmental exposures and ASD, others, including air pollution, heavy metals, and prenatal complications, can also lead to a higher risk. Nevertheless, a lot of the observed associations are confounded by the fact that they involve a gene-environment association and confounding factors. Additionally, there is new evidence of biological processes of environmental exposures to ASD, such as epigenetic changes, oxidative stress, immune dysregulation, endocrine disruption, and neurotransmitter system changes. These processes indicate that environmental factors might affect neurodevelopment during key developmental periods and not necessarily be direct cause. Altogether, the ASD can be considered as a multifactorial disorder which is based on complicated interactions between environmental factors and genetic susceptibility. More longitudinal and mechanistic research is required for clarifying the causal mechanisms as well as enhance prevention measures.
References
Gillberg C, Coleman M. The biology of the autistic syndromes. 3rd ed. London: Mac Keith Press; 2000.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington (DC): American Psychiatric Association; 2013.
Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders. MMWR Surveill Summ. 2009;58(10):1-20.
Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M. How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology. 2008;29(1):190-201.
Herbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG, et al. Autism and environmental genomics. Neurotoxicology. 2006;27(5):671-684.
Kelleher RJ III, Bear MF. The autistic neuron: troubled translation? Cell. 2008;135(3):401-406.
Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474(7351):380-384.
Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, et al. Fragile X syndrome. Nat Rev Dis Primers. 2017;3:17065.
Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56(3):422-437.
Northrup H, Aronow ME, Bebin EM, Bissler JJ, Darling TN, de Vries PJ, et al. Tuberous sclerosis complex. GeneReviews®. 2023.
Südhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455(7215):903-911.
Missler M, Südhof TC, Biederer T. Synaptic cell adhesion. Cold Spring Harb Perspect Biol. 2012;4(4):a005694.
Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci. 2015;16(9):551-563.
De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209-215.
Monteiro P, Feng G. SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci. 2017;18(3):147-157.
Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, et al. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of SHANK3. Hum Mol Genet. 2011;20(15):3093-3108.
Bozdagi O, Tavassoli T, Buxbaum JD. Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism. Mol Autism. 2013;4:9.
Jiang YH, Ehlers MD. Modeling autism by SHANK gene mutations in mice. Neuron. 2013;78(1):8-27.
Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, et al. Meta-analysis of SHANK mutations in autism spectrum disorders. Hum Mutat. 2014;35(3):253-264.
Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, et al. Genetic and functional analyses of SHANK2 mutations suggest a multiple-hit model of autism spectrum disorders. PLoS Genet. 2012;8(2):e1002521.
Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. Mutations in the gene encoding SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39(1):25-27.
Wang X, Bey AL, Katz BM, Badea A, Kim N, David LK, et al. Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat Commun. 2016;7:11459.
Tang S, Zhang X, Li Y. Maternal smoking and autism spectrum disorder: a systematic review and meta-analysis. Front Psychiatry. 2023;14:1189701.
Garcia-Serna AM, Morales E. Neurodevelopmental effects of prenatal vitamin D. Nutrients. 2020;12(4):1227.
Stubbs G, Henley K, Green J. Vitamin D and autism spectrum disorder: a systematic review and meta-analysis. J Autism Dev Disord. 2022;52(4):1547-1560.
Lam J, Sutton P, Kalkbrenner A, Windham G, Halladay A, Koustas E, et al. A systematic review and meta-analysis of multiple airborne pollutants and autism spectrum disorder. PLoS One. 2016;11(9):e0161851.
Yoshimasu K, Kiyohara C, Takemura S, Nakai K. A systematic review of the epidemiological literature on environmental factors and autism spectrum disorders. Environ Health Prev Med. 2014;19(5):303-322.
De Palma G, Catalani S, Franco A, Brighenti M, Apostoli P. Lack of association between metallic elements analyzed in hair by ICP-MS and autism. J Autism Dev Disord. 2012;42(3):342-353.
Rossignol DA, Genuis SJ, Frye RE. Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry. 2014;4:e360.
James S, Montgomery P, Williams K. Chelation for autism spectrum disorder. Cochrane Database Syst Rev. 2015;(5):CD010766.
Hviid A, Hansen JV, Frisch M, Melbye M. Measles, mumps, rubella vaccination and autism: a nationwide cohort study. Ann Intern Med. 2019;170(8):513-520.
Uno Y, Kurosawa M, Aleksic B, Ozaki N. The relation between vaccination and autism spectrum disorder: a systematic review. J Autism Dev Disord. 2020;50(9):3166-3174.
Jain A, Marshall J, Buikema A, Bancroft T, Kelly JP, Newschaffer CJ. Autism occurrence by MMR vaccine status among US children with older siblings with and without autism. JAMA. 2015;313(15):1534-1540.
Bai J, Wong FW, Bauman A, Mohsin M. Parity and pregnancy outcomes. Am J Obstet Gynecol. 2002;186(2):274-278.
Bolton PF, Murphy M, Macdonald H, Whitlock B, Pickles A, Rutter M. Obstetric complications in autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry. 1997;36(2):272-281.
Ghaziuddin M, Ghaziuddin N, Greden J. Depression in persons with autism spectrum disorders. J Autism Dev Disord. 2002;32(4):299-306.
Gillberg C, Steffenburg S, Börjesson B, Andersson L. Immigration and autism: epidemiological study of children of immigrant families. J Intellect Disabil Res. 1995;39(Pt 2):141-144.
Kinney DK, Barch DH, Chayka B, Napoleon S, Munir KM. Environmental risk factors for autism: do they help explain the increased prevalence of autism? Med Hypotheses. 2010;74(1):102-106.
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 autism spectrum disorder. Environ Mol Mutagen. 2012;53(8):589-598.
Edlow AG, Guedj F, Sverdlov D, Pennings JL, Bianchi DW. Significant effects of maternal diet during pregnancy on the murine fetal brain transcriptome and offspring behavior. PLoS One. 2014;9(6):e88661.
Rangasamy S, D'Mello SR, Narayanan V. Epigenetics, autism spectrum disorders, and neurodevelopment. Neurotherapeutics. 2013;10(4):742-756.
Grafodatskaya D, Chung B, Szatmari P, Weksberg R. Autism spectrum disorders and epigenetics. J Am Acad Child Adolesc Psychiatry. 2010;49(8):794-809.
Balmer NV, Weng MK, Zimmer B, Ivanova VN, Chambers SM, Nikolaeva E, et al. Epigenetic changes and disturbed neural development in a human embryonic stem cell–based model relating to valproic acid teratogenicity. Hum Mol Genet. 2012;21(18):4104-4114.
Aarabi M, Christensen KE, Chan D, Leclerc D, Landry M, Ly L, et al. Testicular MTHFR deficiency, DNA hypomethylation, and abnormal spermatogenesis are associated with infertility and epigenetic inheritance. Hum Mol Genet. 2015;24(22):6301-6313.
van Montfoort AP, Hanssen LL, de Sutter P, Viville S, Geraedts JP, de Boer P. Assisted reproductive technologies and imprinting disorders: a systematic review. Hum Reprod Update. 2012;18(2):171-197.
Liu X, Lin J, Zhang H, Khan NU, Zhang J, Tang X, Cao X, Shen L. Oxidative stress in autism spectrum disorder: current progress of mechanisms and biomarkers. Front Psychiatry. 2022;13:813304.
Goines PE, Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol Teratol. 2013;36:67-81.
Volk T, Lukito S, Radua J, Luksch H, Roessner V, Beyer N. Atypical cytokine profiles in people on the autism spectrum: a comprehensive systematic review and meta-analysis including 54 cytokines. Mol Psychiatry. 2026.
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67-81.
Napoli E, Wong S, Hertz-Picciotto I, Giulivi C. Deficits in bioenergetics and impaired immune response in granulocytes from children with autism. Pediatrics. 2014 May 1;133(5):e1405-10.
Lai MC, Lombardo MV, Auyeung B, Chakrabarti B, Baron-Cohen S. Sex/gender differences and autism: setting the scene for future research. Brain. 2015;138(11):3073-3089.
Van Wijngaarden-Cremers PJ, van Eeten E, Groen WB, Van Deurzen PA, Oosterling IJ, Van der Gaag RJ. Gender and age differences in the core triad of impairments in autism spectrum disorders: a systematic review. J Autism Dev Disord. 2014;44(3):627-635.
Lai MC, Lombardo MV, Auyeung B, Chakrabarti B, Baron-Cohen S. Sex/gender differences and autism: setting the scene for future research. Brain. 2013;136(9):2799-2815.
Baron-Cohen S, Knickmeyer RC, Belmonte MK. Sex differences in the brain: implications for explaining autism. Science. 2005;310(5749):819-823.
McDougle CJ, Erickson CA, Stigler KA, Posey DJ. Neurochemistry in the pathophysiology of autism. J Clin Psychiatry. 2005;66(Suppl 10):9-18.
Neal AP, Guilarte TR. Molecular neurobiology of lead (Pb²⁺): effects on synaptic function. Mol Neurobiol. 2010;42(3):151-160. 60. Cao A,
Liu Y, Qi D, Li Z, Du Y, Xu Q, et al. Prenatal exposure to low-dose ciprofloxacin antibiotic increased male offspring's defensive aggressive behaviors via a gut-phosphatidylcholine-α7 nAChR axis. Brain Behav Immun. 2026.
Ni Y, Loftus CT, Szpiro AA, Young MT, Hazlehurst MF, Murphy LE, et al. Associations of pre- and postnatal air pollution exposures with child behavioral problems and cognitive performance: a US multi-cohort study. Environ Health Perspect. 2022;130(6):067008.
Dingemans MML, van den Berg M, Westerink RHS. Neurotoxicity of brominated flame retardants: (sub)cellular mechanisms and implications for neurodevelopment. Environ Health Perspect. 2011;119(7):900-907.
Wayman GA, Bose DD, Yang D, Lesiak A, Ledoux V, Bruun D, et al. PCB-95 promotes dendritic growth via ryanodine receptor–dependent mechanisms and disruption of calcium signaling. Environ Health Perspect. 2012;120(7):1003-1009.
Cao A, Liu Y, Qi D, Li Z, Du Y, Xu Q, Yue J, Zheng L, Wang Y, Cui J, Chen C. Prenatal exposure to low-dose ciprofloxacin antibiotic increased male offspring's defensive aggressive behaviors via a gut-phosphatidylcholine-α7 nAChR axis. Brain Behav Immun. 2026:S0889-1591(26)00174-2.
