In Utero Chemical Exposures, Immune Status, and Childhood Leukemia

EPA Grant Number: R836159C001
Subproject: this is subproject number 001 , 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: In Utero Chemical Exposures, Immune Status, and Childhood Leukemia
Investigators: Metayer, Catherine , Ma, Xiaomei , Selvin, Steve , Whitehead, Todd , Wiemels, Joseph
Current Investigators: Metayer, Catherine , Ma, Xiaomei
Institution: University of California - Berkeley , University of California - San Francisco , Yale University
Current Institution: University of California - Berkeley , Yale University
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 proposed project is to assess, for the first time, the interplay between in utero chemical exposures and the immune status of both the mother and the child in the development of childhood acute lymphoblastic leukemia (ALL). 

Specific Aim 1: Characterize immune status by measuring immunomodulatory cytokines in biospecimens.

Specific Aim 2: Examine whether in utero chemical exposures influence immune status.

Specific Aim 3: Assess the relation of in utero chemical exposures to the risk of childhood ALL, while accounting for immune status. 

Approach:

Investigators hypothesize that specific in utero chemical exposures will impact maternal and neonatal immune status and the altered immune status increases the risk of childhood ALL. To test this hypothesis, this project will leverage exceptional resources from two existing NIH-funded studies (through Core A): neonatal dried blood spots collected at birth from the California Childhood Leukemia Study (CCLS), a population-based case-control study, and paired samples of neonatal blood spots and second trimester maternal serum from the California Mother-Child Birth Cohort. In both populations, investigators will (1) characterize immune status by measuring immunomodulatory cytokines in biospecimens, (2) examine whether in utero chemical exposures (identified in Project 2) influence immune status, and (3) assess the relation of in utero chemical exposures to the risk of childhood ALL, while accounting for immune status. In the CCLS population, home dust measurements and self-reported chemical exposures will be used to further characterize in utero chemical exposures, and data on maternal infections during pregnancy will be used to help characterize maternal immune status. An engineered mouse model of childhood ALL will be used to elucidate mechanisms by which in utero chemical exposures and maternal/neonatal immune status interact to initiate ALL (through Core C). In addition, data on maternal/neonatal immune status will be incorporated in the analysis of DNA methylation (Project 3). This project will fill important knowledge gaps in the etiology of childhood ALL, and further the understanding of immunomodulatory effects of in utero chemical exposures. 

Rationale:

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. There is compelling evidence that childhood ALL is often initiated in utero and ALL risk is affected by neonatal immune status. Children who developed ALL tend to have had more fulminant infections during the first year of life, despite having had less frequent exposure to common infections than controls. One plausible explanation for this apparent immune dysregulation in children who develop ALL is aberrant in utero programming of the immune system. There are several lines of evidence that support this hypothesis. First, children who develop ALL later in life were observed to have lower levels of IL-10, an immunosuppressive cytokine, at birth. Second, both maternal infections during pregnancy and higher maternal immunoglobulin E (IgE) levels after birth are positively associated with ALL risk, suggesting a role for maternal modulation of fetal immune development in determining ALL risk. Finally, there are specific chemicals associated with increased risk of childhood ALL, some of which are potential modifiers of immune status, including polychlorinated biphenyls, polybrominated diphenyl ethers, polycyclic aromatic hydrocarbons, and tobacco smoke. 

Publications and Presentations:

Publications have been submitted on this subproject: View all 1 publications for this subprojectView all 12 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 1 journal articles for this subprojectView all 10 journal articles for this center

Relevant Websites:

The Center for Integrative Research on Childhood Leikemia and the Environment (CIRCLE) | University of California - Berkeley 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