2016 Progress Report: Prenatal Exposures, Constitutive Genetics, DNA Methylation & Childhood Leukemia

EPA Grant Number: R836159C003
Subproject: this is subproject number 003 , 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: Prenatal Exposures, Constitutive Genetics, DNA Methylation & Childhood Leukemia
Investigators: Wiemels, Joseph , Metayer, Catherine , Segal, Mark , Whitehead, Todd , de Smith, Adam
Institution: University of California - Berkeley , University of California - San Francisco
Current Institution: University of California - San Francisco , University of California - Berkeley
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


We will leverage existing 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). Additionally, we will test the effect of in utero chemical exposures on DNA methylation in pre-B cells (our target cell population), as well as on leukemogenesis, using an engineered mouse model for the first time.

Aim 1: Construct a constitutive genetic framework for DNA methylation profiles at birth.

Aim 2: Determine the perturbation of DNA methylation by in utero chemical, dietary, and immune factors, incorporating constitutive genetics, and the subsequent effect on childhood ALL risk.

Aim 3: Assess the impact of in utero chemical exposures on pre-B cell development, pre-B cell DNA methylation, and leukemogenesis in the offspring of exposed mice.

Progress Summary:

Aims 1 and 2: In our first year of Cycle 2 of CIRCLE, Project 3, we have made initial forays into investigations of the effects of genetics on epigenetics (Aim 1), while continuing our efforts in understanding chemical, dietary, and growth-related DNA methylation changes and their effects on leukemogenesis.

For the specific work in Aim 1, our primary activities included the fulfillment of our IRBs at several institutions, including the state of California, University of California-San Francisco (UCSF), and UC-Berkeley. Second, we have worked with the California Genetic Diseases Branch laboratory to complete a panel of cases and controls needed for this research (neonatal dried blood spots from 200 childhood ALL cases and 400 controls in the CA Birth Cohort, and another set of 200 childhood ALL cases and 400 controls from the CCLS). The samples currently are being inventoried or pulled for us and we expect to have them in hand during Year 2.

To ensure robust results and in preparation for our having data in hand for Aim 1, we have approached the problem of genetics and epigenetics with several analytical approaches. First, we are attempting to understand the genetic influence on CpG sites that already are confirmed to be associated with environmental exposures. The best characterized of these are CpGs for smoking, which now are well established for birth populations. As a first approach to understand genetic-epigenetic relationships, we used genome-wide SNP data to perform a GWAS association analysis of the top 10 CpG sites that are affected in children, by maternal smoking. An example of such a GWAS is the top CpG for smoking in the gene AHRR. Note that this CpG also is significantly associated with certain SNPs, even over the P-value threshold for genome-wide significance. The region was imputed showing a fairly large haplotype block association with DNA methylation at the AHRR CpG site cg05575921. We performed interaction analyses with maternal smoking and determined a lack of interaction with the SNP and smoking on the locus. In this case, defining the effects of maternal smoking on CpG variation will be much more accurate by taking into account genetic variation, proving the critical importance of understanding the effects of genetics, which is the main point of this aim. We have found that about one-half of the known smoking associated CpGs have strong genetic components.

Aim 3: For Aim 3, we have continued work on optimizing our mouse model for leukemia and preparing relevant chemical dosing strategies. This work has not progressed beyond this developmental state, and we plan to make additional progress in Year 2.

Future Activities:

In the next year, we plan to collect the necessary biological samples to complete this project in the laboratory and commence genotyping and DNA methylation analysis. The only modification to our original plan will be the use of a more comprehensive DNA methylation array, the EPICHM850K array, which contains about 400,000 additional markers from the HM450K array we mentioned in the original proposal. Once we have a set of genotype and DNA methylation data, we will start to perform more intensive environmental assessments on DNA methylation while incorporating genotype information. In the next year, 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 on this Report : 1 Displayed | Download in RIS Format

Other subproject views: All 3 publications 3 publications in selected types All 3 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 Gonseth S, Roy R, Houseman EA, de Smith AJ, Zhou M, Lee ST, Nussle S, Singer AW, Wrensch MR, Metayer C, Wiemels JL. Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes. Epigenetics 2015;10(12):1166-1176. R836159 (2017)
R836159 (2018)
R836159C003 (2016)
R834511 (2014)
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  • 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