Potential Role of Acetaminophen and Pesticides in the Developmental Origins of Autism Spectrum Disorder via In Silico and Stem Cell Models

Acetaminophen (APAP) is the only non-prescription analgesic and anti-pyretic approved by the FDA for use among pregnant women. Epidemiological data shows that prenatal exposure to APAP is associated with an increased risk of Autism Spectrum Disorder (ASD), a disorder affecting 1 in 59 children nationwide. Still, the etiology of ASD remains under debate. The degree to which genetic and environmental factors, and their interactions, produce the range and heterogeneity of cognitive and developmental disorders is unknown. Pesticides—often implicated in neurodevelopmental disorders—frequently make their way into pregnant women’s food. Synergism between APAP and some pesticides could enhance the effect of one another to adversely affect fetal brain development and contribute to the increased prevalence of ASD. With these two potentially hazardous exposures frequenting pregnant women’s diet, examining their combined effects could reveal novel hypotheses as to why these two substances have been implicated in fetal neurodevelopmental abnormalities. Finding a relationship between APAP, pesticides, and ASD may help identify genes and targets implicated in the etiology of ASD. METHODS: We searched five public (PHeGenI, PubChem, CTD, Drugbank, Open Targets, and ClinVar) and two proprietary (Ingenuity Pathway Analysis and MetaCore) molecular databases for genes associated with APAP, pesticides and ASD. A network topology analysis including an MCODE cluster analysis of the STRING protein-protein interaction network of overlapping genes was performed using Cytoscape. Resulting clusters were functionally annotated for pathways and functions. Results from the molecular database analysis were complemented with a literature analysis from Coremine Medical. RESULTS: Six overlapping genes were identified that encode transporters (ABCB1, ABCB4), CYP450 enzymes (CYP1A2, CYP3A4), a cell surface death receptor (Fas), and Insulin-like Growth Factor 1 receptor. These genes were over-represented in two main clusters related to apoptosis and carbohydrate metabolism (FDR p <0.01). The complimentary literature analysis found clusters relating to similar biological functions such as regulation of cell growth and death, carbohydrate metabolism, and metabolism of reactive oxygen species. CONCLUSION: Our findings support the hypothesis that cell death processes and carbohydrate metabolism, which appear to be targeted by APAP and pesticide exposure, contribute to the etiology of ASD. Here we elucidate the relevance of these functions in the etiology of ASD and implications in future studies.