The interplay of early life exposure to environmental pollutants and folate system in the etiology of autistic behaviors

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Project summary Autism spectrum disorders (ASD) which are multifactorial complex disorders characterized by communication deficits and repetitive behaviors affect between 1 and 2% of children in the US and Canada. Air pollutants, phthalates, and pesticides are suspected of contributing to the etiology of ASD, whereas folic acid supplementation has been shown to play a protective role, particularly in genetically susceptible individuals with inefficient folate metabolism. Despite these critical findings from a few studies, several questions remain unanswered: 1) No previous study investigated these modifiable factors in a comprehensive way; 2) no previous study investigated the critical windows of susceptibility to these exposures; and 3) the interplay between environmental, nutritional, and genetic factors in the etiology of autism is still unclear. Our preliminary data show that folic acid supplementation is associated with lower autistic traits, but only in children of mothers with genetic susceptibility. In addition, we found that adequate folic acid supplementation in first trimester of pregnancy may prevent the detrimental effects of phthalates exposures regarding autistic traits. Building on these findings and a large comprehensively characterized pregnancy and birth cohort implemented in ten Canadian cities, we will examine the individual and joint contribution of identified modifiable risk factors of autism and its associated traits. We will measure phthalates and organophosphate pesticides across the three trimesters of pregnancy, and we will estimate monthly exposures to individual air pollutants such as nitrogen dioxide and particulate matter and its composition across pregnancy and during child’s first year. Additionally, we will measure folate autoantibodies that have been shown to be highly prevalent in mothers of autistic children, and folate levels in maternal blood sample during 1st and 3rd trimesters of pregnancy. Using sophisticated statistical models that can take into account complex mixtures of pollutants and time-varying exposures, we will 1) quantify the individual and cumulative effects of early exposure to multiple air pollutants, phthalates, and organophosphate pesticides on autistic traits; 2) identify whether these contaminants are associated with lower plasma folate levels in pregnant women; and 3) clarify the role of folate-related genetic polymorphisms, folate autoantibodies, and plasma folate in the associations between environmental contaminants and autistic traits. By answering these research questions, we will gain a better understanding of how strongly multiple pollutants and folic acid supplementation are associated with autistic traits, whether these chemicals are associated with circulating folate concentrations, and how these effects of multiple pollutants differ based on folic acid intake, genetic susceptibility, and the presence folate autoantibodies. These findings will have great clinical and public health implications and will be critical in informing better prevention strategies both at the individual and population level.