Tipping the Balance of Autism Risk

Potential Mechanisms Linking Pesticides and Autism

Janie F. Shelton; Irva Hertz-Picciotto; Isaac N. Pessah

Disclosures

Environ Health Perspect. 2012;120(7):944-951. 

In This Article

Immune Toxicity

Prenatal disruption of immune development can result in atopy, allergy, deficits in immune competence, and autoimmunity in early childhood (Hertz-Picciotto et al. 2008). Recent studies on intestinal flora have shown the immune system is highly involved and inextricably linked with neurodevelopment and subsequent behavior (Diamond et al. 2011; Heijtz et al. 2011). In turn, the immune response can also be strongly influenced by neurochemistry (Diamond et al. 2011). Children with autism experience a wide array of immune abnormalities. Recent reviews on this topic report altered cytokine profiles, altered cellular immunity, low levels of lymphocytes and T-cell mitogen responses, neuroinflammation, and autoantibodies directed at nuclear proteins (Ashwood et al. 2006; Goines and Van de Water 2010). Reduced levels of IgG and IgM have also been reported, which were correlated with a higher prevalence of aberrant behavioral symptoms in a study of 271 children with autism or developmental delay or who were typically functioning (Heuer et al. 2008). In a comparison of plasma cytokine levels from children with autism (n = 97) and typically developed controls (n = 87), cases had higher levels of proinflammatory cytokines compared with neurotypical children, and the concentrations of cytokines corresponded with impaired behavioral outcomes in a dose–response fashion (Ashwood et al. 2011).

Exposure to several types of pesticides may result in decreased immune competence, immune enhancement, and/or autoimmunity (Corsini et al. 2008). OPs are particularly immunotoxic (Galloway and Handy 2003) and have been shown to suppress natural killer cells, lymphokine-activated killer cells, and cytotoxic T lymphocytes by inhibiting granzymes, impairing the FasL/Fas pathways, and inducing apoptosis of immune cells (Li 2007). Pyrethroids have also been shown to be immunotoxic in animal models. Rats treated subchronically with permethrin showed large increases of superoxide anion production and hydrogen peroxide–myeloperoxidase activity in polymorphonuclear neutrophils (Gabbianelli et al. 2009). These effects were demonstrated not only for permethrin, but also for its major metabolites.

Insecticide exposures can induce inflammatory or suppressive immunological effects depending on the compound and the immunological outcome in question. Gestational exposure of rats to atrazine, an endocrine-disrupting triazine herbicide, demonstrated immunosuppressive effects [specifically, decreased delayed-type hypersensitivity (DTH) and antibody production] in male offspring only (Rooney et al. 2003). In a study of both male and female mice, gestational exposure to atrazine at nontoxic, environmentally relevant doses administered from GD14 to PND21, was associated with decreased socialization behaviors and changes in exploratory behavior, with males displaying feminized behavioral profiles (Belloni et al. 2011).

Neuroinflammation has been observed in the postmortem brain tissue of persons with autism across several age ranges (Li et al. 2009; Morgan et al. 2010; Vargas et al. 2005). Chlorpyrifos, an OP banned for residential use in 2002, and cyfluthrin, a type 2 pyrethroid used to replace chlorpyrifos, were compared for toxicological and toxicogenomic effects to primary human fetal astrocytes. Cyfluthrin had equivalent or more toxic effects in most assays, and up-regulated several insulin related genes and proinflammatory genes on the IFN-γ (interferon-γ) pathway, including IL6R (the gene for the interleukin 6 receptor) and GFAP (the gene for glial fibrillary acidic protein). Additionally, both compounds were found to promote inflammatory activation of astrocytes. The authors suggested that the combination of increased insulin production and inflammation could lead to a state of chronic brain inflammation that might significantly alter brain development (Mense et al. 2006).

Taken together, these studies indicate that gestational exposure to pesticides can induce immunological abnormalities as well as behavioral abnormalities. It is possible that the neurodevelopmental and the immune abnormalities observed in autism are downstream manifestations of the same underlying process given the tightly regulated interconnection between the developing systems in utero. The role of the immune phenomena as a cause, effect, or side effect of autism was recently reviewed and was postulated to be in part causal (Onore et al. 2012). In addition to autism, schizophrenia and major depressive disorders have also been noted to be accompanied by perturbations of the immune system, recently reviewed in an extensive monograph (Patterson 2011).

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