Newborn Metabolomics Linking Prenatal Air Pollution Exposure and Autism Spectrum Disorder Risk in Children

Abstract

Autism spectrum disorder (ASD) is the leading cause of disability in children younger than 5 years of age. Prenatal PM2.5 and nonfreeway NOx, have been associated with increased ASD risk in children. However, the key metabolic pathways and corresponding metabolite signatures in children that are altered by air pollution exposure and involved with ASD are unknown. To fill the gaps, an advanced metabolomics approach can be leveraged to investigate metabolic pathways and biological mechanisms linking air pollution exposure and ASD.Using electronic medical records, 50 ASD cases diagnosed before age 5 and 50 controls matched on birth year, medical center, sex, and race/ethnicity were randomly selected from all children born at Kaiser Permanente Southern California between 2007-2009. Weekly PM2.5 and monthly nonfreeway NOx exposures during pregnancy were estimated based on residential history using spatiotemporal prediction and California line-source dispersion models, respectively. Untargeted, high-resolution metabolomics was analyzed in archived newborn dry blood spots, resulting in 26,578 HILIC-positive and 27,614 C18-negative metabolomic features. Conditional logistic regression was used to identify metabolomic features associated with ASD diagnosis. Linear regression was used to investigate associations between prenatal air pollution exposure and metabolomic features. Beyond matching factors, maternal age, education level and household income categories were adjusted in the analyses. Mummichog pathway analysis was performed to identify metabolic pathways associated with air pollution exposures and ASD.Dysregulated aspartate and asparagine metabolism was associated with increased ASD risk (p=0.01) and higher PM2.5 exposure during the 1st trimester and the entire pregnancy (p<0.001). Nonfreeway NOx was associated with aspartate and asparagine metabolism(p=0.003), which also associated with increased ASD risk (p=0.01). Dysregulated metabolism reflected in aspartate and asparagine was associated with prenatal air pollution exposure, increasing our understanding of oxidative stress and inflammation related to ASD under adverse environmental conditions may inform about ASD risk in future studies.

Note:
Funding declaration: This study was supported by National Institutes of Environmental Health Sciences (R01 ES029963 (Xiang, McConnell); R56ES028121 (Xiang); P30ES007048 (McConnell); R00ES027870 (Chen), and by Kaiser Permanente Southern California Direct Community Benefit Funds. Joel Schwartz was supported by EPA grant RD-835872. This project is supported by the pilot project program of Southern California Environmental Health Center (P30ES007048). The funding agencies had no role in the design of the study, the analysis or interpretation of data, or the preparation or approval of the manuscript

Conflict of Interests: The authors declare they have no actual or potential competing interests. Joel Schwartz declares that he has testified on behalf of the U.S. Department of Justice in a case involving a Clean Air Act violation. Frederick Lurmann is employed by Sonoma Technology, Inc., Petaluma, CA.

Ethics statement: Both KPSC and University of Southern California Institutional Review Boards approved this study.

Keywords: dysregulated metabolic pathway, Autism spectrum disorder, Air pollution exposure, oxidative stress and inflammation, Metabolomics