2017 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
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: July 1, 2016 through June 30,2017
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text |  Recipients Lists
Research Category: Health , Children's Health

Objective:

The overarching research theme of CIRCLE is to identify additional in utero chemical risk factors for childhood acute lymphoblastic leukemia (ALL) in an ethnically diverse population, and to understand how chemicals increase risk via immunological, genetic, and epigenetic mechanisms. The potential interplay between in utero chemical exposures and the immune status of both the mother and the child in the development of childhood ALL has not been studied. In this project, 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 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. We have refined the selection of subjects to be included in the cytokine analyses, some of which will overlap with subjects included in Projects 2 and 3. We have obtained about 95% of the biopsecimens, which are being processed at the UC Berkeley and UCSF laboratories for cytokine assays. Additional blood spots also have been requested to meet the target number. We have consolidated the database of other CCLS resources (e.g., interview data, dust data, genetic data, methylation data). While waiting for newly generated cytokine data, we have established the pipeline of statistical analyses and conducted preliminary analyses to assess the relationship between in utero chemical exposures and cytokine levels measured in blood spots from 114 childhood leukemia cases and 116 controls from a previous CCLS study (analyses in progress). In complement to the in utero immune-related hypothesis that is the focus of Project 1, we have completed analyses related to immune function—at birth and after birth—and childhood ALL: (1) we have analyzed data from the California Childhood Cancer Record Linkage Project (study population from which the California Mother-Child Birth Cohort is derived) and found that cesarean section (C-section), especially elective C-section, increases the risk of childhood ALL (manuscript published in the American Journal of Epidemiology; and (2) we have investigated the association between self-reported child’s allergies and the risk of childhood ALL, using CCLS subjects. No associations were observed for any allergy and specific allergy phenotypes (a manuscript has been submitted). This negative finding may be due to poor recall, stressing the need to conduct biomarker studies to better characterize the child’s immune function as proposed in this Project.

To accomplish Aim 2, we 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. We have obtained maternal pregnancy blood and platelet samples for cases and neonatal dried blood spots for their corresponding children. We also obtained the same maternal and child specimens for controls. The initial linkage between the maternal and child biobanks yielded less sample than expected mother/child cases. In order to maintain sufficient statistical power, we increase the case:control ratio from 1:2 to 1:3.

Available samples are being processed for cytokine analyses expanding the panel for additional markers of immune status. We recently have modified the sample processing to include a new technology that will help preserve the samples. Curiox droparray microplates involve the use of barrier-free microwells permitting the use of 80% less of the archived newborn blood spot extract to do the same immunoassays proposed in the grant. As the blood spots are a finite resource and property of the State, this sample streamlining is very helpful and will allow us and others to examine additional relevant markers. One such marker is arginase-1, a T-cell suppressive enzyme produced by nucleated erythrocytes and is easily detected in blood spot extracts in the pilot studies.

In Aim 3, we are using 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 have selected 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: polychlorinated biphenyls (PCBs), exemplified by the Arochlor 1260 mixture; polyaromatic hydrocarbons, exemplified by dibenz[a,h]anthracene, and insecticides, exemplified by cypermethrin and permethrin. Progress on the exposures of the leukemia-prone mouse model are detailed in the Progress Report for Core C. The Core has returned plasma samples for studies of cytokine changes in mothers and 5 week-old offspring following exposure to the PCB mixture and we anticipate analysis of the cytokine profiles in these samples to be completed in the current year. 

Future Activities:

In the next year, we will complete the acquisition of all biological samples needed for Aims 1 and 2. We will continue 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 continue the preliminary data analyses using measurements of IL-10 levels in neonatal dried blood sports and information on immune development available from interviews of participating mothers. We also will continue to refine the 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 on this Report : 1 Displayed | Download in RIS Format

Other subproject views: All 1 publications 1 publications in selected types All 1 journal articles
Other center views: All 25 publications 23 publications in selected types All 23 journal articles
Type Citation Sub Project Document Sources
Journal Article Wang R, Wiemels JL, Metayer C, Morimoto L, Francis SS, Kadan-Lottick N, DeWan AT, Zhang Y, Ma X. Cesarean section and risk of childhood acute lymphoblastic leukemia in a population-based, record-linkage study in California. American Journal of Epidemiology 2017;185(2):96-105. R836159 (2017)
R836159 (2018)
R836159C001 (2017)
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  • Relevant Websites:

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

    Progress and Final Reports:

    Original Abstract
  • 2016 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