Diet and the exposome in autism: Discovering complex interactions with diet in autism etiology and variability - ABSTRACT Multiple factors contribute to the development of autism spectrum disorder (ASD), a developmental condition with early onset and heterogeneous phenotype. Prenatal diet is one of the few factors that has been associated with reductions in risk of ASD, and emerging evidence also suggests certain nutrients may mitigate the effects of other environmental exposures. At the same time, packaged and highly processed foods represent a major source of exposure to classes of chemicals linked with adverse neurodevelopment. The balance of risks and benefits in the diet, and effects on ASD, particularly within the context of other common risk factors, has not been well studied. The overarching goal of this project is to determine the role of diet and its complex interactions with other exposures in the development and presentation of autism spectrum disorder (ASD). This project will use existing data from up to 10,000 mother-child participants from the Environmental influences on Child Health Outcomes (ECHO) consortium, a large US program initiated with over 60 cohorts following a common protocol to study child health from gestation to adulthood. We address key gaps in the field under 3 related aims. 1) Examine complex interactions of prenatal diet and exposure to common chemicals on ASD. We focus on chemical exposures with diet as a major source and in common use, including pesticides, phthalates, and phenols, to better understand risks within the diet. We will first examine independent effects of under-studied but highly consumed “high burden foods” on ASD and related traits, and next use advanced mixture models to capture interactions between nutrients and measured levels of chemicals, and address potential mitigation of chemical exposure effects across sources by healthy components of the diet. We will utilize existing metabolomics data from prenatal measurements, which capture the biological effects of exposures, to determine pathways that may link these factors to ASD and bolster evidence for mechanisms that underlie associations. Next, we expand the consideration of the role of diet to: 2). Examine multi-exposure effects on ASD to determine key players in the prenatal exposome. Building from our prior work in ECHO, we will examine the ability of prenatal dietary factors to modify the effects of another common exposure rising in prevalence in the US in parallel with ASD: maternal metabolic conditions during pregnancy (which include obesity, gestational diabetes, and gestational hypertension). We will then use advanced data science approaches to determine how the wider set of prenatal risk factors across environmental, medical and lifestyle factors contributes to the gestational “exposome,” (the entirety of exposures), to influence ASD risk, and uncover key factors. As in aim 1, these analyses will be followed by mechanistic work using metabolomics data to determine key pathways underlying identified signals. As secondary outcomes across Aims 1 and 2, we will examine risk of not just ASD itself, but also its highly co-occurring conditions and ASD-related traits, to advance understanding of contributors to variability in ASD. Finally, we will make use of the large numbers in ECHO with information on childhood exposures to: 3). Determine dietary risks and deficiencies in children with ASD and examine how these contribute to phenotypic variability. These analyses will determine if autistic children experience worse nutrition than children without ASD, including higher intake of high burden foods, and assess whether these dietary differences contribute to symptom severity or risk of comorbidities, accounting for prenatal maternal exposures. Completion of these aims will aid discovery of novel interactions and exposures whose effects may be lessened or made worse by different aspects of diet. Ultimately, findings from this project will advance understanding of the role of diet in ASD and the broader ASD exposome, and present opport
