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)