PROJECT SUMMARY / ABSTRACT The emergent evidence indicates that exposures to regional air pollutants (AP) and near-roadway air pollutants (NRAP) are associated with the development of obesity and type 2 diabetes. Previous studies suggest that prenatal and early life exposures to AP may play critical roles in the etiology of childhood obesity. However, the mechanism linking AP exposures and obesity and diabetes is unknown. Studies investigating the pathogenesis of the AP-related obesity and diabetes etiology are urgently needed. Metabolomics technology provides epidemiologists and clinicians an unprecedented opportunity to examine the metabolic pathways linking exposures and disease traits. In this proposal, the candidate proposes to identify key metabolic pathways underlying the associations of childhood AP exposures with body fat, ectopic fat and diabetes traits such as glucose concentrations and insulin resistance via the metabolomics approach. Studies involved in the K99 and R00 phases encompass two important developmental periods (neonatal and adolescence). Therefore, this work may elucidate the critical periods of AP exposures that accelerate and/or alter the course of disease, and will potentially inform us with novel molecular targets for early intervention and prevention of obesity and diabetes. In the K99 mentored phase, the candidate will pair new measurement of targeted metabolomics of amino acids and fatty acids with existing AP exposure data and obesity and diabetes phenotypes in an ongoing substudy of the prospective Children’s Health Study (CHS), which is examining the metabolic health impacts of AP exposure in Southern California. Targeted metabolomics will be used to identify pathway(s) of amino acid and fatty acid metabolism that are associated with cumulative exposures to regional AP and NRAP from prenatal to adolescence, as well as metabolic disease traits in 200 CHS adolescents. Additionally, specific metabolites such as acylcarnitines and fatty acids will be analyzed to examine the hypothesized mechanism linking air pollution and obesity and metabolic disorders, such as inflammatory activation and leptin resistance. The proposed training objectives during the K99 phase, which includes personal mentorship, didactic courses and research seminars, meetings, and workshops, are designed to enhance the candidate’s knowledge and skills in four essential areas including 1) exposure assessment and environmental epidemiology, 2) metabolomics, 3) statistical modeling specific to metabolomics data and mediation analysis, and 4) career development. The accomplishment of the proposed training in the K99 phase will ensure the candidate to successfully conduct the K99/R00 research projects and to be well-equipped for future transition into an independent environmental health scientist. In the R00 phase, the candidate will apply the training and skills developed during the K99 phase on a prospective birth cohort study, the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) Study. The candidate will use the non-targeted metabolomics to discover novel metabolomic signatures related with prenatal AP exposures and neonatal and infant adiposity among 250 cord blood samples from the MADRES. Subsequently, targeted metabolomics will be analyzed in the cord blood samples from an independent group of 250 newborns from the MADRES to replicate previously identified metabolomic signatures. Both K99/R00 projects will fill critical gaps in our understanding of the metabolic pathways linking prenatal and chronic AP exposures and the development of childhood obesity and metabolic disorders. With the proposed projects and essential training obtained during the K99 phase, the candidate will be positioned to initiate her independent academic career and to carry out novel research to decipher the disease etiology related with environmental exposures, and to discover new cellular and molecular targets for early intervention and prevention of obesity and diabetes.

PROJECT NARRATIVE The proposed research is aimed to understand the metabolic pathways linking air pollution exposures and obesity and type 2 diabetes-related traits during two important developmental periods (neonatal and adolescence). This work may have international impact on improving air quality and early intervention and prevention of childhood obesity and other metabolic diseases.