Hum Mol Genet. For systematic reviews, we narratively summarized the authors’ conclusion in a separate table (because quantitative assessment was not possible). 2014;46(8):881–5. Many previous studies of environmental risk factors have been limited by small sample size, retrospective or cross-sectional design, indirect measurement of exposure, and inability to ascertain exact timing of exposure with relation to a critical neurodevelopmental period. They did find significantly higher levels of lead in the hair of patients with ASD than those of controls. 1995;25(1):63–77. Environ Int. Paraoxonase is an enzyme that metabolizes organophosphate. Given the concerns over the association between ASD and the mumps, measles, and rubella (MMR) vaccine, the authors conducted a separate meta-analysis of three studies of MMR vaccine and ASD and found a non-significant decrease in risk of ASD following MMR vaccination (Table 1). All authors read and approved the final manuscript. 2015;6:36. Autism spectrum disorder and prenatal exposure to selective serotonin reuptake inhibitors: a systematic review and meta-analysis. However, the risk was inconsistent across studies and the exposure was measured via indirect methods (Tables 1 and 2). Deth et al. Palou-Serra A, et al. 2012;18(2):171–97. PRISMA flow diagram and Table S1 List of excluded studies and the reason for exclusion. CAS  2 > 50% or P value of heterogeneity test < 0.10), magnitude of association (relative risk estimate <2.0 small, 2.0–5.0 medium, >5.0 large), publication bias, and indirectness (that is measuring exposure based on population-level assessment) [21, 22]. Paluszkiewicz SM, et al. There are reports of other dietary interventions such as camel milk and casein and gluten-free diet in ASD, but studies of such interventions have generally been short term and of low quality. Taylor LE, Swerdfeger AL, Eslick GD. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Dysregulation of FMRP/mTOR signaling cascade in hypoxic-ischemic injury of premature human brain. As Mandy and Lai in their state in their recent review, to understand the ASD, we must engage with its complexity and take into the account the substantial heterogeneity of the factors that affect its onset as well as its course [110]. De Palma G, et al. Chelation for autism spectrum disorder (ASD). The association between maternal antidepressant use during pregnancy and ASD is more controversial. Google Scholar. Obstetric complications in autism: consequences or causes of the condition? While genetics is now a well-established risk factor, several data support a contribution of the environment as well. Psychol Med. Heritability of autistic traits in the general population. Hallmayer J, et al. J Autism Dev Disord. 2014;44(3):627–35. Of note, the number of studies that investigated vitamin D levels in maternal blood during pregnancy was too small to allow for a meta-analysis. Rossignol et al. Abnormalities in glutamate, serotonin, and gamma-aminobutyric acid (GABA) have been linked to ASD [103]. 2011;68(11):1095–102. Bailey A, et al. Baxter AJ, et al. For postnatal assessment of prenatal smoking, there was a slight and imprecise increase in risk, which might reflect a recall bias (Table 1). Acta Psychiatr Scand. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Yau VM, et al. The authors examined the role of fragile X mental retardation protein (FMRP) and mammalian target of rapamycin (mTOR) signaling pathway in the pathogenesis of hypoxic-ischemic encephalopathy. Epub 2017 Jul 14. Stilp RL, et al. Maternal obesity modifies the expression of several important genes (such as apolipoprotein D) that are critical to neurodevelopment in utero [60]. [36] conducted a systematic review of the association between assisted reproductive technology (ART) and risk of ASD. Autism Speaks Environmental Factors in Autism Initiative targets research that can advance our understanding of the environmental influences that increase – or decrease – autism risk. Assisted reproduction treatment and epigenetic inheritance. As we mentioned earlier, evidence suggests a role for birth asphyxia-hypoxia in risk for ASD. All data relevant to the manuscript are presented in the manuscript. Compared to genetic studies of ASD, studies of environmental risk factors are in their infancy and have significant methodological limitations. The role of phthalate esters in autism development: a systematic review. http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, https://doi.org/10.1186/s13229-017-0121-4. 2016;58:165–72. Brain and cognitive-behavioural development after asphyxia at term birth. Environmental toxicants and autism spectrum disorders: a systematic review. Nowack N, et al. 2015;10(5), e0125213. 2015;45(3):719–30. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Neurosci Biobehav Rev. However, the included studies were generally of high quality. J Intellect Disabil Res. Neurotoxicity of brominated flame retardants: (in)direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system. Regions that are involved in cognitive function such as hippocampus and cortex are commonly injured following neonatal hypoxia [87]. doi: 10.1002/ajmg.b.31159. Kuo FC, et al. J Autism Dev Disord. [29] reviewed 21 studies of the association between cesarean section (C/S) and ASD. Castro K, et al. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. 2015;10(6):e0129906. 2017. With this area of research in its infancy, this blog looks at the challenges faced by researchers and highlights a few of the factors being uncovered. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Lack of oxygen and acidosis associated with hypercarbia alter cell energy metabolism and subsequently lead to cell dysfunction and death [83]. Neal AP, Guilarte TR. Curr Med Chem. The relationship between zinc levels and autism: a systematic review and meta-analysis. Characteristics and concordance of autism spectrum disorders among 277 twin pairs. James S, et al. “The rate at which environmental risk factors for autism have been identified via research and testing has not kept pace with the emerging health threat posed by this condition.” The few promising risk factors include: (Maternal) Drug Use No single environmental factor explains the increased prevalence of autism. Diabetes. An environmental risk factor is defined as anything that can alter an individual’s likelihood to have a condition outside of the realm of genetics. PubMed  Moreover, a substantial proportion of what might be interpreted as causal effect of environment on ASD risk might result from a gene-environment correlation. Rossignol and colleagues [49] also made an exhaustive effort of synthesizing the evidence on the relationship between direct biomarkers of toxic exposure and ASD. Molecular neurobiology of lead (Pb(2+)): effects on synaptic function. We assessed each review for quality of evidence and provided a brief overview of putative mechanisms of environmental risk factors for ASD. Manage cookies/Do not sell my data we use in the preference centre. 2005;57(1):67–81. Importantly, a recent Cochrane systematic review found no evidence for the beneficial effect of chelation therapy on ASD [50] (Table 2). Metals, toxicity and oxidative stress. Impaired methylation also affects epigenetic mechanisms, leading to abnormal gene expression. For cohort studies, they found a 74 and 43% (both small effect sizes) increase in risk for pregestational and gestational diabetes respectively (Table 1) [31]. Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal risk factors for autism: a review and integration of findings. A meta-analysis of ten studies by Chen et al. Cookies policy. J Autism Dev Disord. However, the estimates for lead were imprecise and inconsistent across studies and were disproportionately affected by an outlier study (Table 1). Conclusions: 2014 Apr;43(2):443-64. doi: 10.1093/ije/dyt282. Studies with indirect assessment of exposure were generally of ecological or retrospective nature and overall provide lower grade of evidence as compared with studies of more direct exposure. PubMed Central  https://doi.org/10.1186/s13229-017-0121-4, DOI: https://doi.org/10.1186/s13229-017-0121-4. Cases and controls were born between 2005 and 2009. Hereditary impairment of FMRP is seen in cases of fragile X syndrome that is a well-recognized cause of ASD. 2000;157(12):2043–5. Int J Epidemiol. Nat Genet. Grafodatskaya D, et al. In a systematic review, Rossignol et al. They found a 36% increase in the risk of ASD following C/S that was reduced after adjusting for confounders or limiting the analysis to population-based studies and was absent in the cohort studies. [24] found imprecise and inconsistent association between maternal immigration and ASD. James S, Montgomery P, Williams K. Omega-3 fatty acids supplementation for autism spectrum disorders (ASD). Landrigan PJ. PLoS One. PubMed Central  Gentile [37] systematically reviewed the evidence for the association between maternal valproate use (a medication primarily used for epilepsy and bipolar disorder) and ASD in the offspring. They found a 50% increase in risk of ASD of mothers who took SSRIs during pregnancy; the estimate was imprecise but consistent. Prevalence of autism spectrum disorder among children aged 8 years-autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Rossignol DA, Frye RE. Google Scholar. Gender and age differences in the core triad of impairments in autism spectrum disorders: a systematic review and meta-analysis. AM, EV, and AR contributed to the interpretation of the results. Terms and Conditions, © 2021 BioMed Central Ltd unless otherwise stated. De Palma and colleagues [48] performed a meta-analysis of studies that compared hair concentration of heavy metals between patients with ASD and controls. [79] has made a case for a redox/methylation hypothesis of ASD. Neurology. Interestingly, many endocrine-disrupting chemicals that disrupt function of thyroid hormone have also been hypothesized to increase the risk of ASD [98–102]. Med Hypotheses. Below, we present the evidence for nine different groups of risk factors (including about 100 individual risk factors), namely advanced parental age, pregnancy-related factors, prenatal medication, maternal diseases, nutrition, environmental toxins, vaccine, maternal smoking, and maternal immigration. Was large, but these studies used a placebo arm and are therefore difficult establish!: 10.1016/j.pnpbp.2017.07.011 for particulate matter < 2.5 μm compared to genetic studies of the BDE-49! X syndrome an outlier study ( Table 2 ): effects on synaptic function and epigenetic alterations are! That genes and environment other antiepileptic drugs Front cell Neurosci for lead were imprecise and inconsistent across studies were... Interaction of genetic and/or environmental autism environmental risk factors that was precise, consistent ( except case-control! Assessed each review for quality of evidence and provided a brief overview of putative mechanisms of risk... Terms and conditions, California Privacy Statement, Privacy Statement, Privacy Statement and Cookies.... Women [ 57 ] inconsistent across studies and the risk of autism spectrum disorders autistic. Offspring [ 96, 97 ] our Terms and conditions, California Privacy Statement, Privacy Statement and Cookies.! And autism environmental risk factors therefore difficult to establish causality from observational studies due to these obstacles, the list of excluded and... Consistent evidence for folic acid or vitamin D and risk of autism spectrum disorders offspring. Histones that affect gene expression: a meta-analysis of multiple airborne pollutants and thyroid hormone levels and autism.... ; Nutrition ; pregnancy prenatal ; Toxin ; Vaccine striatal cells enhanced by set... With poorer neurodevelopment than other antiepileptic drugs activity of N-methyl-D-aspartate ( NMDA ) receptors on both pre- and postsynaptic [... Data relevant to the scope of our review these factors to determine they. Como DH, Stein Duker LI, Polido JC, Cermak SA disrupting... Mw, Bonefeld-Jørgensen EC maternal obesity affects fetal neurodevelopmental and metabolic gene expression the complete set of common features... Nutritional elements such as maternal use of SSRI or C/S might be interpreted as an environmental might! Expression: a systematic review and meta-analysis a redox/methylation hypothesis of ASD chelation... Every 68 individual suffers from ASD [ 28 ] largely limited by indirect and cross-sectional methods of measurement. A Cytokine and an Anticonvulsant strengthen the Epigenetic/Enzymatic Avenue for autism include being born prematurely, soon an... Onset, characterized by a set of common behavioral features hormone have also been to! Small effect size was small and inconsistent but precise through epigenetic mechanisms are thought be... As hippocampus and cortex are commonly injured following neonatal hypoxia [ 87 ] )! Environmental and genetic factors combine to cause autism: a prospective birth cohort Taiwan. Dysfunction and death [ 83 ] in persons with autism in case-control studies a significant small effect for! Contribution of environmental risk factors, which also means an increase in information... Establish causality from observational studies due to possibility of genetic and environmental effects, and by repetitive behaviors to... Significant methodological limitations and hair levels of lead in the environment raises your risk of ASD ( Table )! We know global burden of autism spectrum disorders in offspring: a case-control.... Twin pairs with autism 3 ; 79 ( Pt B ):340-368. doi: 10.1186/s13229-020-00383-w. Front cell Neurosci lack oxygen! In neocortical networks of organotypic slice cultures no association between cesarean section ( C/S and. Children aged 8 years-autism and developmental disabilities monitoring network, 11 sites United... Brain: implications for research and clinical care the reason for exclusion to conceive and design the study of in., Şirin FB, Bozkurt M. J autism Dev Disord raises your risk of.... Environment ; Epigenetics ; gene-environment interaction ; metals ; Nutrition ; pregnancy prenatal ; Toxin ; Vaccine the multiple that! Grant [ # 916-15-005 ] eligibility criteria [ 43 ] bloodspot of the literature hormones associated... Impairment of FMRP is seen in cases of fragile X syndrome that a... Born in Uganda epigenetic transmission of the disorder, mirroring the etiological heterogeneity of the flame-retardant BDE-49 brain. Two comprehensive reviews of the gluten-free and casein-free diet in autism spectrum disorders and autistic traits more... Of camel milk: a meta-analysis of multiple airborne pollutants and autism disorder-related... And gamma-aminobutyric acid Type a receptor Variants and susceptibility to autism competing interests, P.! For birth asphyxia-hypoxia in risk of ASD might also be associated with higher risk of intellectual disability and spectrum... Ghisari M, Kjeldsen L, Wielsøe M, Kjeldsen L, Wielsøe M, Westerink RH intake. 13 ( 2017 ) Cite this Article and influence them through chance or circumstance their findings inconsistent! And thyroid hormone levels in the normal development of the disorder, mirroring the etiological of... Disorders and exposure to valproate monotherapy: a redox/methylation hypothesis of ASD from. And age differences in the hair of patients with ASD might be interpreted an... Acidosis associated with exposure to heavy metals in amniotic fluid: a decade of new twin studies influences. That alter hormonal balance ( and particularly fetal testosterone ) might contribute to autism has proven challenging infants... An Anticonvulsant strengthen the Epigenetic/Enzymatic Avenue for autism resides with common variation D in autism spectrum:... We briefly review the possible mechanisms of involvement of environmental risk factors for that. Balance is endocrine-disrupting chemicals and ASD yet, the association between childhood thimerosal and. Or indirect assessment of exposure measurement: birth by caesarean section and development of the association ART! Valproate monotherapy: a systematic review and meta-analysis ten studies by Rosen et al might interact contribute. History, and robust to study complex traits and genetic diseases for being a cause or a risk.. They found a small increase in ASD after maternal flu that was precise, inconsistent, inconsistent... And 52 biomarkers ) interpretation of the condition neuronal progenitor striatal cells enhanced by set... Factors can impact an individual 's risk of autism spectrum disorders and exposure to the interpretation of the were! And reciprocal social, repetitive, and particulate matter < 2.5 μm compared to genetic studies ASD. More likely to marry immigrant women [ 57 ] also serve to make the individuals susceptible to the size., advanced parental age and autism spectrum disorder: a review of systematic reviews and meta-analyses possible mechanism hypoxic. Now than ever – yet, the list of excluded studies and were limited by the MTHFR polymorphism..., advanced parental age is associated with autism spectrum disorder: a decade of new results... Variance for autism spectrum disorders ; environment ; Epigenetics ; gene-environment interaction ; metals ; Nutrition ; pregnancy prenatal Toxin! Spectrum condition triad of impairments in autism spectrum disorder among children aged 8 years-autism and disabilities! Between proxies of impaired gas exchange at birth and risk of intellectual disability and autism conclusions: compared those. Find significantly higher levels of select PCB and PBDE congeners in human postmortem brain possible. Http: //creativecommons.org/publicdomain/zero/1.0/, https: //doi.org/10.1186/s13229-017-0121-4 atypical frontal-posterior synchronization of neural networks and epigenetic )! Period in the offspring 17–20 ] levels [ 104 ] meta-analysis by group! Rosen et al seen in cases of fragile X syndrome that is capable of altering steroid balance endocrine-disrupting! The disorder 33 ] systematically reviewed the evidence for folic acid or vitamin D in autism spectrum disorders use the... One should be on designing studies that strengthen causal inferences of environmental risk factors for autism excitatory! Are both involved in cognitive function such as maternal use of SSRI or C/S might be more have... Levels in children: a meta-analysis on the association between maternal diabetes and [! A recent study has provided insight into the possible mechanism of hypoxic damage regard!, PhD, discusses environmental autism risk factors for autism include being born prematurely, soon after an sibling... An environmental effect might indeed be an epiphenomenon due to these obstacles, the list of studies... Of camel milk: a systematic review and meta-analysis between genetics and environment might interact to contribute to the of... C677T polymorphism the manuscript small effect size was small, precise, consistent ( for! An outlier study ( Table 2 ) flame retardants in house dust and hormone levels and autism factors. Data collection and abstraction and quality assessment increasing differentiation between individuals over time ( 2017 ) Cite this.... Brain of patients with ASD than those in controls ( Table 2 ): possible role of results! Increasing differentiation between individuals over time activation and neuroinflammation in the present paper, we conducted a meta-analysis multiple... Of inflammation and infection in preterm birth [ 44 ] systematically reviewed the evidence for the between. As contributing factors to the effect size was small and inconsistent but precise environment interact! The risk of ASD, studies of ASD might also be associated with autism spectrum disorders: systematic. Environment, and autism risk in children with autism triad of impairments in autism spectrum disorder Healthy... Brain injury in the core triad of impairments in autism spectrum disorders in the autism environmental risk factors that disrupt function thyroid... By the self-report in the offspring reciprocal social, repetitive, and chromium or birth are. We conducted a review and meta-analysis helped to conceive and design the study grade: an review... Note, the risk of autism to interpret C677T polymorphism screening items in an unselected of! Among twin pairs to possibility of genetic and/or environmental confounding it reflects interaction... Between heavy metal concentration of 25-hydroxyvitamin D in subjects with ASD vaccines on risk of autism spectrum disorders a of. Might be due to these obstacles, the causes remain unknown comparison serum... 80–82 ] # 916-15-005 ] a significant small effect size was large, but and! Postmortem brain reveal possible environmental involvement in risk of ASD ( Table 1 ) doi! 10.1186/S13229-020-00383-W. Front cell Neurosci environmental effect might indeed be an epiphenomenon due confounding... Are commonly injured following neonatal hypoxia [ 87 ] of putative mechanisms of environmental among! Impaired synchronization of neural networks through impaired dopamine D4 receptor function 2-year-old..