Environmental Factors in the Onset of Autism Spectrum Disorder

Current Developmental Disorders Reports, Mar 2014

Autism spectrum disorder (ASD) is a heterogeneous clinical condition whose prevalence has grown considerably during the last decade. Genetic factors are thought to underpin the disorder, but common genetic variants and epigenetic mechanisms have been increasingly called into question for the majority of ASD cases. Growing prenatal exposure to new environmental toxicants has been shown to potentially affect brain development, leading to altered cognitive, social, attentive, behavioral, and motor performance. Both epidemiological evidence and mechanistic studies assessing oxidative stress, neuroinflammation, epigenetic alterations, and impaired signal transduction, all observed following neurotoxicant exposure, indeed lend biological plausibility to Gene x Environment interactions, whereby environmental toxicants interacting additively or synergistically with genetic liability, can push prenatal neurodevelopmental processes over the threshold for postnatal ASD expression. Research on environmental contributions to ASD and on specific Gene x Environment interaction models ultimately aims at defining targeted preventive strategies.

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Environmental Factors in the Onset of Autism Spectrum Disorder

Curr Dev Disord Rep Environmental Factors in the Onset of Autism Spectrum Disorder Antonio M. Persico 0 1 2 Sara Merelli 0 1 2 0 A. M. Persico 1 A. M. Persico Department of Experimental Neurosciences , I.R.C.C.S. “Fondazione Santa Lucia”, Via del Fosso di Fiorano 64, 00143 Rome , Italy 2 A. M. Persico ( 3 Unit of Child and Adolescent NeuroPsychiatry, Laboratory of Molecular Psychiatry and Neurogenetics, University “Campus Bio-Medico” , Via Alvaro del Portillo 21, 00128 Rome , Italy Autism spectrum disorder (ASD) is a heterogeneous clinical condition whose prevalence has grown considerably during the last decade. Genetic factors are thought to underpin the disorder, but common genetic variants and epigenetic mechanisms have been increasingly called into question for the majority of ASD cases. Growing prenatal exposure to new environmental toxicants has been shown to potentially affect brain development, leading to altered cognitive, social, attentive, behavioral, and motor performance. Both epidemiological evidence and mechanistic studies assessing oxidative stress, neuroinflammation, epigenetic alterations, and impaired signal transduction, all observed following neurotoxicant exposure, indeed lend biological plausibility to Gene x Environment interactions, whereby environmental toxicants interacting additively or synergistically with genetic liability, can push prenatal neurodevelopmental processes over the threshold for postnatal ASD expression. Research on environmental contributions to ASD and on specific Gene x Environment interaction models ultimately aims at defining targeted preventive strategies. Air pollution; Autism; Autism spectrum disorder; Benzo(a)pyrene; Environment; Environmental factors; Halogenated aromatic hydrocarbons; Heavy metals; Mercury; Misoprostol; MMR; Organophosphates; Pervasive Developmental Disorders; PBDEs; PCBs; p-cresol; Pesticides; Polybrominated diphenyl ethers; Polychlorinated biphenyls; Thalidomide; Thimerosal; Vaccines; Valproate Introduction Autism spectrum disorder (ASD) is an extended diagnostic category, which includes individuals with impaired social interaction and communication, as well as repetitive stereotyped behaviors, insistence on sameness and sensory abnormalities [ 1 ]. Severity ranges from “low-functioning” cases with absence of spoken language and severe intellectual disability, to “high-functioning” individuals with normal to high Intellective Quotient (IQ), subtle social deficits, and some restricted and obsessive interests. Individuals who display few signs of autism without meeting the full diagnostic criteria belong to the “broad autistic phenotype”, making ASD the categorical extreme of a quantitative continuum of traits present in the general population [ 2 ]. During the last decades, ASD prevalence estimates have risen to as much as 113/10,000 children in the USA [ 3 ], and 62/10,000 globally [ 4 ], corresponding to 1:88 and 1:161 children, respectively. This increase is so prominent that it appears hardly accountable solely to enhanced awareness, greater service availability, and broader diagnostic categories. While genetic components are considered extremely relevant to ASD etiology, candidate genes and copy-number variants currently explain about 20 % of syndromic and non-syndromic ASD cases [ 5 ]. This percentage will indeed rise once wholegenome sequencing becomes routinely implemented in the clinic, but it will almost certainly never explain all ASD cases. In fact, common genetic variants seemingly account for at least 50 % of ASD liability, leaving ample room for environmental contributions due to their low penetrance and additive effects [ 6 ]. Prenatal exposure to neurotoxic substances has been proven to alter brain maturation and to produce a wide array of neurodevelopmental deficits, in a way that has no counterpart in the adult brain [ 7 ]. The developing brain is particularly vulnerable during its “critical periods”, time windows of susceptibility when neuronal proliferation, migration, differentiation, maturation (i.e., neurite sprouting and pruning), synaptogenesis, and activitydependent synaptic remodelling occur. During these paramount processes, exposure to environmental disruptors can affect brain development, leading to functional deficits and behavioral disorders. In general, a positive epidemiological association, if not spuriously due to mere temporal coincidence, can stem from modulatory, additive, permissive, synergistic, and causal effects exerted by the environmental factor under scrutiny (Fig. 1). Patients not carrying rare, disruptive genetic variants may thus be accounted for by a “multiple-hit” pathogenic model based on complex Gene x Environment interactions, whereby multiple combinations of common genetic variants, each conferring a small risk, create a highly individualized spectrum of sensitivity to the detrimental effects of environmental factors [ 8 ]. This conceptual framework can pro (...truncated)


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Antonio M. Persico, Sara Merelli. Environmental Factors in the Onset of Autism Spectrum Disorder, Current Developmental Disorders Reports, 2014, pp. 8-19, Volume 1, Issue 1, DOI: 10.1007/s40474-013-0002-2