Plasma Metabolome, PON1 Status, Environmental Exposures and Childhood Autism

Background:  Few studies have examined Autism Spectrum Disorder (ASD) and the interplay between genetics and environmental factors. The paraoxonase 1 (PON1) gene regulates the breakdown of organophosphate (OP) pesticides in the body and serves as an important antioxidant. PON1 levels may be affected by single nucleotide polymorphisms (SNPs), therefore individuals with certain PON1 SNPs plus environmental exposure during pregnancy may be at an increased risk for having a child with autism.

Objectives:  The objective of this study was to examine a possible gene-environment interaction that focuses on prenatal environmental exposures and child metabolic vulnerability as a consequence of polymorphisms in the PON1 gene.

Methods:  All children (n=400) in the present study including children with Autism Spectrum Disorder (ASD; n=200), and typically developed control children (TD; n=200) are part of a large ongoing population-based case-control CHARGE (CHildhood Autism Risk from Genetics and Environment) Study. Blood plasma metabolome profiles were obtained by Nuclear Magnetic Resonance (NMR) spectroscopy. Untargeted metabolomics analysis using Chemomx NMR Suite 8.1 was used to identify and quantify 69 metabolites in each sample including amino acids, organic acids, sugars and other compounds. Concentration of PON1 were determined by ELISA kits (Cloud Clone Corp), and paraoxonase activity was measured using commercially available assay kits (Molecular Probes Inc.). SNP data, and environmental exposure data was previously collected in the CHARGE Study.

Results:  Children with ASD had higher levels of lactate, a metabolic waste product, and higher levels of the amino acids: alanine, serine, glycine, and tryptophan, consistent with mitochondrial dysfunction, and altered energy metabolism. In addition, ASD was associated with higher levels of uridine, a component of RNA previously reported to be inversely correlated with methylation capacity. Although we did not find a significant difference in the PON1 concentration and paraoxonase activity of children with ASD compared to controls, we did find that PON1 SNPs in coding and non-coding regions significantly affected its plasma concentrations. Moreover, there were a disproportionate number of children with ASD and specific PON1 SNPs that correlated with maternal organophosphate and pyrethroid exposures.

Conclusions:  Our results add to the growing body of literature indicating autism is associated with an altered metabolic state compared to typically developed controls. These results suggest that maternal environmental exposures during pregnancy in combination with genetics may impact a child’s metabolic outcome. Further studies are needed to understand how the metabolome affects neurodevelopmental outcome, or conversely if neurodevelopmental outcome affects the metabolome.