Identifying In Utero Exposures that are Risk Factors for Childhood Leukemia

EPA Grant Number: R836159C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R836159
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Center for Integrative Research on Childhood Leukemia and the Environment - 2015
Center Director: Metayer, Catherine
Title: Identifying In Utero Exposures that are Risk Factors for Childhood Leukemia
Investigators: Rappaport, Stephen M. , Hubbard, Alan , Whitehead, Todd
Institution: University of California - Berkeley
EPA Project Officer: Louie, Nica
Project Period: September 1, 2015 through August 31, 2019
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text |  Recipients Lists
Research Category: Health , Children's Health

Objective:

The objective of this project is to characterize broad classes of maternal/fetal exposures received during gestation from diverse sources including pollution, diet, drugs and endogenous processes. Investigators will test for associations between maternal exposures and childhood acute lymphoblastic leukemia (ALL), and target particular biomarkers of interest, including benzene, coffee, smoking, alcohol consumption, and reactive oxygen species. 

Approach:

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. Investigators hypothesize that the ‘fetal exposome’ (representing all fetal exposures) affects causal pathways in childhood leukemia. Using archived neonatal blood spots (ANBS) from California, this project will 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 investigators 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, investigators 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 investigators 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, investigators 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 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. 

Rationale:

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.

Publications and Presentations:

Publications have been submitted on this subproject: View all 4 publications for this subprojectView all 12 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 2 journal articles for this subprojectView all 10 journal articles for this center

Relevant Websites:

CIRCLE - The Center for Integrative Research on Childhood Leukemia and the Environment Exit

Progress and Final Reports:

2016 Progress Report
2017 Progress Report


Main Center Abstract and Reports:

R836159    Center for Integrative Research on Childhood Leukemia and the Environment - 2015

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R836159C001 In Utero Chemical Exposures, Immune Status, and Childhood Leukemia
R836159C002 Identifying In Utero Exposures that are Risk Factors for Childhood Leukemia
R836159C003 Prenatal Exposures, Constitutive Genetics, DNA Methylation & Childhood Leukemia