Metabolic syndrome is increasingly prevalent, is usually associated with obesity and glucose dysregulation, and leads to increased risk of cardiovascular disease. Risks of obesity and diabetes type 2 begin in eariy childhood, including in utero programming, and environmental factors likely play a role in these risks. The effect of exposure to ambient air pollution (AAP) on risk of obesity and diabetes among children has been well studied. Our primary hypothesis is that oxidative stress induced by exposure to AAP leads to systemic inflammation which in turn leads to increased risk of obesity and diabetes. A secondary mechanistic hypothesis is that AAP-induced Treg dysfunction increases risks of obesity and diabetes. To test these hypotheses, analyses of children in the different stages of development represented in a piecewise, natural history design will be conducted (ages 0-2, 7-9, 16-19, and 19-22). Detailed historical information, anthropometric data, and blood samples will be collected for all subjects. Exposures to AAP will be estimated from in utero onward. The proposed study has the following aims: a) to determine whether chronic exposure to AAP, especially polycyclic aromatic hydrocarbons (PAHs), is associated with increased HbAlc, BMI, and 8-isoprostane (biomarker of oxidative stress), CRP (biomarker of systemic inflammation), leptin, adiponectin, and high-density lipoprotein (biomarkers of abnormal fat and glucose metabolism); b) to determine whether AAP-induced dysfunction of T regulatory (Treg) and T effector cells is associated with increased HbAlc and BMI; and c) to determine whether epigenetic modification of Foxp3 underiies the associations between Treg dysfunction and HbAlc or BMI. Using an experienced field center staff, 220 children in each ofthe two younger age groups and 100 subjects in each of the older groups will be recruited from Fresno and followed for variable durations depending on age. Working with the Exposure Core to generate lifetime pollutant exposure histories and the Biostatistics-Epidemiology Core to build marginal structural models, the multidisciplinary research team will conduct analyses of the associations between chronic exposures to air pollutants (or Treg functional parameters) and HbAlc, BMI, or the biomarkers of interest. ExpandCollapse Abstract