I. 2. C. Impact of epigenetic and environmental factors in ASD PAGE 29-30
As genetics alone do not account for every case of ASD, epigenetic and environmental
factors might contribute to ASD (Hallmayer 2011) (Figure 2)
. ASD would be polygenic and
epistatic, and environmental factors would increase ASD risk (Carter et al. 2016;
Vijayakumar et al. 2016).
The epiphenomenon hypothesis argues for a primary role of genetic
factors, and suggests that these genetic factors would increase risks for prenatal and postnatal
complications (Glasson et al. 2004).
The heterogeneity hypothesis suggests that the relative
contribution of genetic and environmental factors varies among individuals with ASD
(Tordjman et al. 2014). The effects of environmental factors would depend on the
Gene variations and environmental factors would often lead to
increased brain oxidative stress in ASD (Tordjman et al. 2014).
Prenatal exposure to several toxins would increase the risks of ASD. ASD risk factors
include exposure to thalidomide, to valproic acid or to misoprostal during the first trimester of
pregnancy, viral and bacterial infections during the two first trimesters, and stress and vitamin
D deficiency in the third trimester (see Dietert et al. 2011 for a review).
Prenatal exposure to
organophosphate insecticides, pesticides or air pollution would also be linked to increased
ASD risk (Landrigan 2010; De Felice et al. 2016; Sealey et al. 2016).
Other physical stress
such fetal distress, birth injury, trauma or
neonatal anemia might contribute to
increased risk of ASD (Gardener et al.
However, meta-analyses were not
able to incriminate only one perinatal or
one neonatal factor that could explain
ASD etiology (Gardener et al. 2011).
Interactions between genetic and
environmental factors are mediated by
epigenetics (i.e. modulation of gene
expression through DNA cytosine
methylation and histone1
Usually, these modifications are
Histones are proteins packaging DNA into units called nucleosomes. The more condensed the DNA is (with
histones and other proteins), the less gene transcription is made. Post-translational modifications of histones can
modulate gene expression level (e.g. histone acetylation usually leads to increased gene expression).
A. An epigenetic landscape. As with a marble guided
toward the lowest local point, the clinical outcome of
an individual with ASD is influenced by genetic factors
(G), environmental factors (E), and gene-environment
B. Norms of reaction describing how individuals with
different genotypes respond to different environments.
Figure 2: Environmental and epigenetic factors
(Huguet et al. 2013)
Theoretical background – Autism Spectrum Disorder (I.2)
reversible, even though DNA methylation appears to be more stable than histone
modification. Importantly, epigenetic modifications can be transmitted across generations
(Franklin et al. 2010). Differential DNA methylation can affect synaptic plasticity and
neuronal excitability (Oh et al. 2013). A few post-mortem studies on ASD suggest epigenetic
modifications in ASD (James et al. 2013).
Interestingly, prenatal air pollution and valproate exposure would lead to epigenetic
modifications, which would affect brain structure and function (Tordjman et al. 2014). Many
rodent models of ASD use valproate administration during prenatal life, as it leads to the
emergence of autistic behaviors (Chapman and Cutler 1989; Markram et al. 2007; Markram
and Markram 2010).
In conclusion, ASD development would result from complex interactions between
multiple genetic variations or mutations, environmental factors and epigenetics, in specific
developmental critical windows. Gene expression has a major importance to control the
principle steps of brain development.
Results on epidemiology and etiology of ASD are summarized in Figure 3.
en page 29-30 approximativement