Abstract
Worldwide, the rate of autism has been steadily rising. There are several environmental factors in concert with genetic susceptibilities that are contributing to this rise. Impaired methylation and mutations of mecp2 have been associated with autistic spectrum disorders, and related Rett syndrome. Genetic polymorphisms of cytochrome P450 enzymes have also been linked to autism, specifically CYP27B1 that is essential for proper vitamin D metabolism. Vitamin D is important for neuronal growth and neurodevelopment, and defects in metabolism or deficiency have been implicated in autistic individuals. Other factors that have been considered include: maternally derived antibodies, maternal infection, heavy metal exposure, folic acid supplementation, epigenetics, measles, mumps, rubella vaccination, and even electromagnetic radiation. In each case, the consequences, whether direct or indirect, negatively affect the nervous system, neurodevelopment, and environmental responsive genes. The etiology of autism is a topic of controversial debate, while researchers strive to achieve a common objective. The goal is to identify the cause(s) of autism to understand the complex interplay between environment and gene regulation. There is optimism that specific causes and risk factors will be identified. The results of future investigations will facilitate enhanced screening, prevention, and therapy for “at risk” and autistic patients.
Similar content being viewed by others
References
Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:1–15
Abraham IM et al (2001) Action of glucocorticoids on survival of nerve cells: promoting neurodegeneration or neuroprotection? Neuroendocrinology 13:749–760
Adams JB, Romdalvik J (2007) Mercury, lead, and zinc in baby teeth of children with autism versus controls. J Toxicol Environ Health 70:1046–1051
Adams JB et al. (2003) Exposure to heavy metals, physical symptoms, and developmental milestones in children with autism. Fall 2003 conference proceedings of defeat autism now! Portland, OR
Almeras L et al (2007) Developmental vitamin D deficiency alters brain protein expression in the adult rat: implications for neuropsychiatric disorders. Proteomics 7(5):769–780
American Medical Association (1989) Harmful effects of ultraviolet radiation. Council on scientific affairs. JAMA 262(3):380–384
Ashwood P et al (2006) The immune response in autism: a new frontier for autism research. J Leukoc Biol 80(1):1–15
Bailey A et al (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63–77
Ballatori N, Clarkson TW (1985) Biliary secretion of glutathione and of glutathione-metal complexes. Fundam Appl Toxicol 5:816–831
Bernard S et al (2001) Autism: a novel form of mercury poisoning. Med Hypothesis 56:462–471
Bhasin TK, Scendel D (2007) Sociodemographic risk factors for autism in a US metropolitan area. J Autism Dev Disord 37(4):667–677
Bird A (2008) The methyl-CpG-binding protein MeCP2 and neurological disease. Biochem Soc Trans 36:572–583
Bodnar LM et al (2007) High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern US and their neonates. J Nutr 137(2):447–452
Bohm HV, Stewart MG (2009) Brief report: on the concordance percentages for autistic spectrum disorder of twins. J Autism Dev Disord 39:806–808
Boris MD et al (2004) Association of MTHFR gene variants with autism. J Am Phys Surg 9(4):106–108
Braunschweig D et al (2008) Autism: maternally derived antibodies specific for fetal brain proteins. NeuroToxicology 22:6–231
Burne TH, Feron F et al (2004) Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle. Physiol Behav 81(4):651–665
Cannell JJ (2008) Autism and vitamin D. Med Hypotheses 70:750–759
Centers for Disease Control and Prevention (2009) Autism information center. http://www.cdc.gov/ncbddd/autism/faq_prevalence.htm. 27 May 2009
Chang Q et al (2006) The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49:341–348
Chen WG et al (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302(5646):885–889
Comi AM et al (1999) Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 14(6):388–394
Coy JF et al (1999) A complex pattern of evolutionary conservation and alternative polyadenylation within the long 3’-untranslated region of the methyl-CpG-binding protein 2 gene suggests a regulatory role in gene expression. Hum Mol Genet 8:1253–1262
Croen LA et al (2005) Maternal autoimmune diseases, asthma, and allergies, and childhood autism spectrum disorders. Arch Pediatr Adolesc Med 159:151–157
Cui X et al (2007) Maternal vitamin D deficiency alters neurogenesis in the developing rat brain. Int J Dev Neurosci 25:227–232
Deth R et al (2008) How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. NeuroToxicology 29:190–201
Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463
Epstein S, Schneider AE (2005) Drug and hormone effects on vitamin D metabolism. In: Feldman D, Pike JW, Glorieux FH (eds) Vitamin D. Elsevier, San Diego
Feron F et al (2005) Developmental vitamin D3 deficiency alters the adult rat brain. Brain Res Bull 65(2):141–148
Filipek PA, Accardo PJ, Ashwal S et al (2000) Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology 55:468–479
Fombonne E (1999) The epidemiology of autism: a review. Psychol Med 29:769–786
Fukushige S, Kondo E, Horii A (2008) Methyl-CpG targeted transcriptional activation allows re-expression of tumor suppressor genes in human cancer cells. Biochem Biophys Res Commun 377(2):600–605
Garcion E et al (2002) New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab 13(3):100–105
Gillberg C (1998) Chromosomal disorders and autism. J Autism Dev Disord 28:415–425
Gillberg C, Coleman M (2000) The biology of autistic syndromes, 3rd edn. Mac Keith, London (distributed by Cambridge University Press)
Goetzl L et al (2002) Elevated maternal and fetal serum interleukin-6 levels are associated with epidural fever. Am J Obstet Gynecol 187(4):834–838
Hardell L, Sage C (2008) Biological effects from electromagnetic field exposure and public exposure standards. Biomed Pharmacother 62:104–109
Herbert MR et al (2006) Autism and environmental genomics. NeuroToxicology 27:671–684
Hertz-Piciotto I et al (2006) The CHARGE study: an epidemiological investigation of genetic and environmental factors contributing to autism. Environ Health Perspect 114:1119–1125
Holick MF (1987) Photosynthesis of vitamin D in the skin: effect of environmental and lifestyle variables. Fed Proc 46:1876–1882
Holmes LB (1988) Does taking vitamins at the time of conception prevent neural tube defects? JAMA 260(21):3181
James SJ et al (2004) Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 80:1611–1617
Kalueff AV et al (2006) The vitamin D neuroendocrine system as a target for novel neurotropic drugs. CNS Neurol Disord Drug Targets 5(3):363–371
Kelleher RJ III, Bear MF (2008) The autistic neuron: troubled translation? Cell 135:401–406
Kern JK, Jones AM (2006) Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health Crit Rev 9(6):485–499
Li H, Yamagata T, Mori M et al (2005) Mutation analysis of Methyl-CpG binding protein family genes in autistic patients. Brain Dev 27:321–325
Liu J, Nyholt DR, Magnussen P et al (2001) A genome-wide screen for autism susceptibility loci. Am J Hum Genet 69:327–340
Liu L, Li Y, Tollefsbol TO (2008) Gene-environment interactions and epigenetic basis of human disease. Curr Issues Mol Biol 10(1–2):25–36
Loat CS et al. (2008) Methyl-CpG-binding protein 2 polymorphisms and vulnerability to autism. Genes Brain Behav 7(7):754–760
Mahaffey KR et al (2004) Blood organic mercury and dietary mercury intake: National Health and Nutrition Examination Survey. Environ Health Perspect 112:562–570
Mariea TJ, Carlo GL (2007) Wireless radiation in the etiology and treatment of autism: clinical observations and mechanisms. J Aust Coll Nutr Env Med 26(2):3–7
Martinowich K et al (2003) DNA methylation related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302:890–893
Marz P et al (1999) Role of interleukin 6 and soluble IL-6 receptor in region specific induction of astrocytic differentiation and neurotrophin expression. Glia 26:191–200
McGrath J et al (2001) Vitamin D: the neglected neurosteriod? Trends Neurosci 24(10):570–572
Miller E (2003) Measles-mumps-rubella vaccine and the development of autism. Semin Pediatr Infect Dis 14(3):199–206
Milunsky A, Jick H, Jick SS et al (1989) Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 262(20):2847–2852
Moore V, Goodson S (2003) How well does early diagnosis of Autism stand the test of time? Follow-up study of children assessed for autism at age 2 and development of an early diagnostic service. Autism 7:47–63
Moore ME et al (2005) Evidence that vitamin D3 reverses age-related inflammatory changes in the rat hippocampus. Biochem Soc Trans 33(4):573–577
Mulinare J, Cordero JF, Erickson JD, Berry RJ (1988) Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 260(21):3141–3145
Nagarajan R, Hogart A, Gwye Y, Martin M, LaSalle J (2006) Reduced MeCP2 expression in frequent in Autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics 1:172–182
Nan X et al. (1998) Gene silencing by methyl-CpG-binding proteins. Novartis Foundation symposium, vol 214, pp. 6–16 (discussion 16–21, 46–50)
National Center for Biotechnology Information (2008) MeCP2 (human). www.pubmed.gov
Nuber UA et al (2005) Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum Mol Genet 14:2247–2256
Otto M, Von Mühlendahl KE (2007) Electromagnetic fields (EMF): do they play a role in children’s environmental health (CEH)? Int J Hyg Environ Health 210:635–644
Rassoulzadegan M et al (2007) Epigenetic heredity in mice: involvement of RNA and miRNA. J Soc Biol 201(4):397–399
Rice C et al (2007) Prevalence of autism spectrum disorders-autism and developmental disabilities monitoring network. CDC Survey Rep 56:12–28
Rogers EJ (2008) Has enhanced folate status during pregnancy altered natural selection and possibly autism prevalence? A closer look at a possible link. Med Hypothesis 71:406–410
Rowland IR, Davies M, Evans J (1980) Tissue content of mercury in rats given methylmercury chloride orally: influence of intestinal flora. Arch Environ Health 35:155–160
Samaco RC et al (2004) Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum Mol Genet 13:629–639
Samaco RC et al (2008) A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. Hum Mol Genet 17(12):1718–1727
Scriver CR et al (2000) The metabolic and molecular basis of inherited disease. McGraw-Hill, New York
Shao Y, Wolpert CM, Raiford KL et al (2002) Genomic screen and follow-up analysis for autistic disorder. Am J Med Genet 114:99–105
Silva SC et al (2004) Autoantibody repertoires to brain tissue in autism nuclear families. J Neuroimmunol 152:176–182
Singer HS et al (2008) Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol 16:5–172
Smalley SL et al (1998) A decade of research. Arch Gen Psychiatry 45:953–961
Starmer J, Magnuson T (2009) A new model for random X-chromosome inactivation. Development 136(1):1–10
Steffenburg S et al (1989) A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 30:405–416
Stuck B et al (2002) Concomitant administration of varicella vaccine with combined measles, mumps, and rubella vaccine in healthy children aged 12 to 24 months of age. Asian Pac J Allergy Immunol 20(2):113–120
Szyf M (2009) Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol 49:243–263
Thornton I (2006) Out of time: a possible link between mirror neurons, autism and electromagnetic radiation. Med Hypotheses 67(2):378–382
Torres AR (2003) Is fever suppression involved in the etiology of autism and neurodevelopmental disorders? BMC Pediatr 3:9
Urakubo A et al (2001) Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain. Schizophr Res 47:27–36
Wakefield AJ, Murch SH, Anthony A et al (1998) Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 351:637–641
Zhang L, Wong MH (2006) Environmental mercury contamination in China: sources and impacts. Environ Int 33:108–121
Zhao X, Pak C, Smrt R, Jin P (2007) Epigenetics and neural developmental disorders. Epigenetics 2(2):126–134
Acknowledgments
The author would like to acknowledge Egidio Currenti, Research Scientist at the New York State Department of Health/Wadsworth Center and David O. Carpenter, MD, Director of the Institute of Health and Environment at the State University of New York at Albany for their encouragement and support.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Currenti, S.A. Understanding and Determining the Etiology of Autism. Cell Mol Neurobiol 30, 161–171 (2010). https://doi.org/10.1007/s10571-009-9453-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-009-9453-8