Though important findings regarding possible risk factors of acute lymphoblastic leukemia (ALL) have been made by CIRCLE and other childhood leukemia (CL) investigators, the timing and mechanisms by which the reported chemicals cause childhood ALL are only partially characterized, and additional risk factors of CL are likely to be discovered using evolving “omics” technology. Because children generally present with childhood leukemia during the first 5 years of life, in utero exposures should be a major focus of investigations regarding the etiology of childhood leukemia. We hypothesize that the ‘fetal exposome’ (representing all fetal exposures) affects causal pathways in childhood leukemia. Using archived neonatal blood spots (ANBS) from California, we propose to measure chemicals representing fetal exposures from 400 ALL cases and 800 matched controls combined from two epidemiologic studies, the California Childhood Leukemia Study (CCLS) and the California Mother-Child Birth Cohort (CA Birth Cohort). Analyses will employ liquid chromatography-high resolution mass spectrometry (LC-HRMS) to perform untargeted omics of small molecules and adducts of reactive electrophiles with human serum albumin (HSA) at cysteine amino acid at position 34 (‘Cys34 adductomics’). This data-driven design will allow us to characterize broad classes of maternal/fetal exposures received during gestation from diverse sources including pollution, diet, drugs and endogenous processes. By comparing omic profiles between childhood leukemia cases and controls, we will find discriminating chemical features in ANBS that will be annotated and used with data in Projects 1 and 3 to investigate causal pathways. In a separate analysis we will compare profiles of small molecules and Cys34 adducts in ANBS with those matched to maternal blood, collected during pregnancy from 200 ALL cases and 400 controls, and will test for associations between maternal exposures and childhood ALL. Finally, while conducting omics analyses of small molecules and adducts, we will target particular biomarkers of interest, including benzene (a known human leukemogen), coffee, smoking, alcohol consumption and reactive oxygen species (ROS). Given the dearth of existing data regarding fetal and maternal exposures during pregnancy, this project offers an exceptional opportunity to explore early-life causes of childhood leukemia and to validate our untargeted methods for pursuing these aims with ANBS. Since other States maintain ANBS for research purposes, a successful outcome from this project would provide important impetus to develop, maintain and exploit repositories of ANBS for investigations of all childhood diseases in the U.S. ExpandCollapse Abstract