2016 Progress Report: 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
Current Institution: University of California - Berkeley , Yale University
EPA Project Officer: Louie, Nica
Project Period: September 1, 2015 through August 31, 2019
Project Period Covered by this Report: September 1, 2015 through August 31,2016
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text |  Recipients Lists
Research Category: Health , Children's Health

Objective:

The potential 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) has not been studied. We hypothesize that specific in utero chemical exposures will impact maternal and neonatal immune status and increase the risk of childhood ALL. To test this hypothesis, we will leverage existing independent resources from two NIH-funded studies: the California Childhood Leukemia Study (CCLS, a population-based case-control study), and the California Mother-Child Birth Cohort (CA Birth Cohort, a cohort of children diagnosed with leukemia, healthy children without leukemia, and their mothers). Specifically, we propose the following aims:

Aim 1: Evaluate the impact of in utero chemical exposures and neonatal immune status at birth on childhood ALL risk, in the CCLS.

Aim 2: Evaluate the impact of in utero chemical exposures, maternal immune status during pregnancy, and neonatal immune status at birth on childhood ALL risk, in the CA Birth Cohort.

Aim 3: Elucidate the mechanism(s) by which in utero chemical exposures and maternal/neonatal immune status interact to initiate ALL in an engineered mouse model with a propensity to develop a mouse-analog of childhood ALL.

Progress Summary:

To accomplish Aim 1, we will rely on existing resources from the CCLS. Specifically, we propose to measure cytokines in neonatal dried blood spots collected from 1,000 childhood ALL cases and 1,000 controls from the CCLS. In preparation for our analysis, our initial steps were to update the CCLS biospecimen inventory, link the updated biospecimen inventory to a database of other CCLS resources (e.g., genetic data, interview data, methylation data), evaluate individual CCLS participants for inclusion in CIRCLE based on the database of resources, and select CCLS participants for whom we needed to request additional biospecimens from the California Department of Public Health (CDPH), California Biobank Program, Genetic Disease Screening Program, to complete the proposed CIRCLE work. We will request these additional biospecimens from the CDPH and, as per the CDPH letter of support.

To accomplish Aim 2, we will rely on existing resources from the CA Birth Cohort. Specifically, we propose to measure cytokines in biospecimens collected from 200 childhood ALL cases and their mothers plus 400 controls and their mothers. As stated for Aim 1, we have worked to evaluate and finalize the list of participants to be included in the research outlined in Aim 2. We have assessed the availability of biological specimens for all subjects and submitted a request to the CDPH to obtain neonatal dried blood spots for the children (cases and controls) and pregnancy blood specimens for the mothers. For Aim 2, as the number of case-mother pairs in the current birth cohort was slightly lower than initially projected, we have initiated a new data linkage effort to include more recent years of birth records and cancer registry data. In addition, we have considered the possibility of additional markers of immune status and further reviewed literature for chemicals that may impact the risk of childhood leukemia, immune status, or both, with a specific focus on the period of pregnancy.

In Aim 3, we will use a mouse model to elucidate mechanisms by which in utero chemical exposures interact with immune development to initiate childhood ALL. To accomplish Aim 3, we must select appropriate chemical exposures to be used in the mouse model experiments. To this end, we performed a literature search that characterized the known chemical risk factors for childhood ALL. In collaboration with Core C Leader, Scott Kogan, we ranked a series of putative ALL risk factors using the following criteria: the specificity of epidemiological evidence, the consistency of epidemiological findings, the magnitude of risk estimates in epidemiological studies, the prevalence of exposure, the feasibility of a public health intervention, and the urgency of the public health response. Based on these criteria we have selected four initial chemical exposures of interest to test in the mouse model of ALL. We are also actively in discussion with toxicologist, Martha Sandy, and her colleagues at the Office of Environmental Health Hazard Assessment (CalEPA), to plan a dosing regiment for the first mouse model experiment.

Future Activities:

In the next year, we plan to gather into the CIRCLE laboratory the necessary biological samples to complete Aims 1 and 2. We will commence measuring cytokines in these biological samples using the Luminex bead-based assay (Bio-Rad). It is anticipated that this laboratory work will require approximately 1 year to complete. We also will initiate preliminary data analyses using measurements of IL-10 levels in neonatal dried blood spots and information on immune development available from interviews of participating mothers. We also will continue to refine our animal model and commence chemical dosing on mouse experiments, for Aim 3. These experiments require extended periods of observation, which will extend into Years 3 and 4.

Journal Articles:

No journal articles submitted with this report: View all 1 publications for this subproject

Progress and Final Reports:

Original Abstract
  • 2017 Progress Report
  • 2018

  • 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