However, these results could also be interpreted within the framework of a GxE interaction model.95 If, for example, an association has been found in a sample with subjects frequently exposed to a particular environmental risk but not in those infrequently exposed, and exposure was not ascertained, the source of nonreplication will remain elusive. The existence of interactions between genetic background and environmental factors in autism

was first suggested for perinatal complications. Indeed, in an epidemiological study on autism that included a comparison group of siblings,96 unaffected siblings had fewer prenatal and perinatal complications Inhibitors,research,lifescience,medical than their affected siblings, but more than control subjects. This suggested that individuals with autism may react differently to the same environmental stimuli and may have less tolerance to

the prenatal experience compared with their siblings. Moreover, studies of animal models have suggested that Inhibitors,research,lifescience,medical genetic defects in synaptic function may alter sensitivity to the environment. Indeed a study has shown that neuroligin-deficient mutants of C. elegans Inhibitors,research,lifescience,medical nematodes are hypersensitive to oxidative stress.97 Another study reported that the hippocampal slices from MecP2- deficient mice are more susceptible to hypoxia.98 Conversely, it was shown in an animal models that the most significant pathology of the extremely premature brain is the disruption of synaptic development.99 It was thus hypothesized that synaptic gene defects could interact with environmental factor to increase autism risk. Another hypothesis is the interaction between genetic variations melatonin pathway genes and oxidative stress. Indeed, low plasma melatonin concentration Inhibitors,research,lifescience,medical is a frequent trait in ASD patients,100,101caused by a primary deficit in acetylserotonin-melhyl-transferase (ASMT) activity. It was suggested that genetic variations contribute

to the enzymatic deficit.100 Several studies have suggested an antioxidant effect of melatonin in vitro,102,103 and it was Inhibitors,research,lifescience,medical shown that the administration of melatonin reduces oxidative stress in newborn infants exposed to infection or fetal distress,104 and promotes oligodendroglial maturation in the newborn rat with abnormal white www.selleckchem.com/products/sotrastaurin-aeb071.html matter related to fetal hypoxia.105 Thus it could have a neuroprotective effect in the Dipeptidyl peptidase newborn exposed to fetal distress. Interestingly Gardener et al81 noted that several of the perinatal and neonatal risk factors they identified may be associated with an increased risk of hypoxia. We can thus hypothesize that a deficit of melatonin could be taken into account in the consequences of perinatal distress. Beyond these observations, available evidence for the contribution of GxE to autism risk comes from animal models. In a first study,106 mice haploinsufficient for the TSC2 gene demonstrated a lack of normal social approach behavior only when exposed to maternal immune activation.