**2. Environmental etiology**

Prenatal or perinatal infections by viral agents such as rubella and cytomegalovirus, as well as exposure to toxic agents, such as thalidomide, valproic acid and alcohol, are some of the best-known environmental causes of ASD (Chess et al., 1978; Christianson et al., 1994).

'Allergenic' environmental factors and autoimmune problems during pregnancy may also be involved in the etiology of autism. The presence of circulating maternal antibodies against fetal brain proteins suggests the possibility of their transposition in the blood-brainbarrier. Studies have demonstrated the presence of pro-inflammatory cytokines in the fetal brain, such as TNF (tumor necrosis factor) which is preformed in maternal mast cells (Vojda‐ ni, 2008; Angelidou et al., 2012).

Even premature birth has been implicated as a cause of ASD. Babies from gestations of less than 28 weeks have a high risk of neurological problems. A study in Atlanta, USA, showed that children born in the 33rd gestational week have a greater risk for autistic characteristics (Limperopoulos et al., 2008).

There is a link between oxidative stress and immune response (Viora et al., 2001). There are suggestions that environmental factors trigger oxidative stress in individuals genetically susceptible to autism, which would lead to losses in methylation and secondary neurologic deficits (Dardeno et al., 2010). Increased levels of oxidative stress markers have already been described in the cord blood of mothers who had premature births compared to those of mothers who had full term births (Joshi et al., 2008).

Premature birth is associated with the formation of reactive oxygen species (Davis & Auten, 2010). Stress typically results in the release of corticotropin-releasing hormone (CRH) with elevated levels of this hormone in plasma being associated with premature births (Warren et al., 1992; Chrousos, 1995). CRH may stimulate the release of a cytokine, interleukin-6 (IL-6), by mast cells, which are part of the immune system. IL-6, by injuring the blood-brain barrier due to stress related to CRH and mast cells, increases its permeability (Esposito et al., 2001). With the increased permeability, neurotoxic molecules can reach the brain and cause an in‐ flammatory process that contributes to the pathogenesis of ASD (Theoharides, 2008; Valent et al., 2012). This process has suggested a new possibility for the etiology of ASD.
