Grantee Research Project Results

2016 Progress Report: Epigenetics Project

EPA Grant Number: R834513C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R834513
(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: Epigenetics Project
Investigators: Eskenazi, Brenda , Holland, Nina T.
Current Investigators: Eskenazi, Brenda
Institution: University of California - Berkeley
EPA Project Officer: Hahn, Intaek
Project Period: August 1, 2009 through July 31, 2014 (Extended to July 31, 2017)
Project Period Covered by this Report: June 1, 2015 through May 31,2016
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health

Objective:

In C, we are investigating molecular mechanisms with a main focus on epigenetic effects associated with prenatal and childhood exposure to persistent organic pollutants (DDT and PBDEs). We are also characterizing the differences in multiple epigenetic marks by host factors like age and sex in children from birth to 12 years of age and assessing relationships of epigenetic modifications in children with hormone levels and pubertal onset.

Progress Summary:

Progress Summary/Accomplishments

To analyze global DNA methylation in newborn children by three different assays.

In addition to repetitive element and 450K site-specific methylation, we also characterized DNA methylation of several imprinted genes. Imprinted genes exhibit expression in a parent-of- origin-dependent manner and are often involved in early growth and development. Collaborating with Dr. Susan Murphy (Duke University) and Cathrine Hoyo (NC State University), we used pyrosequencing methodologies to determine DNA methylation levels in 9 differentially methylated regions (DMRs) in 298 cord blood samples. A manuscript describing these analyses has been submitted (Tindula et al).

To determine ontogenetic changes in global DNA methylation in blood of children between birth and 12 years.

Aim completed in the last period.

To investigate the relationship of in utero and 9-year-old blood concentrations of DDT/E and PBDEs with global DNA methylation.

Aim completed in the last period.

To determine whether global methylation is associated with onset of puberty and hormonalchanges.

We published a manuscript examining the relationship of LINE-1 and Alu repetitive element methylation with onset of puberty (boys and girls) and hormonal levels (boys only) in CHAM1 children in Pediatric Research. Among girls, we observed a suggestive trend of increased odds of breast and pubic hair development with higher Alu and LINE-1 methylation in 9-y-old blood, respectively. The strongest association identified was an inverse association of LINE-1 methylation in 9-y-old girls with odds of experiencing menarche by age 12 (OR (95% CI): 0.63 (0.46, 0.87); P = 0.005). We observed a consistent inverse relationship for Alu and LINE-1 methylation at 9 y with luteinizing hormone (LH), testosterone and follicle-stimulating hormone levels in boys but it was only significant between LINE-1 and LH. (Huen et al. 2016).

To examine site-specific methylation in relation to age, sex, exposure to DDT/E and PBDEs and puberty onset.

Our findings related to differential methylation by sex using 450K were published in BMC Genomics in November 2015. We observed that ~3% of CpG sites were differentially methylated between girls and boys at birth (FDR P < 0.05). Of those CpGs, 3031 were located on autosomes, and 82.8% of those were hypermethylated in girls compared to boys. Beyond individual CpGs, we found 3604 sex-associated differentially methylated regions (DMRs) where the majority (75.8%) had higher methylation in girls. Using pathway analysis, we found that sex-associated autosomal CpGs were significantly enriched for gene ontology terms related to nervous system development and behavior. Among hits in our study, 35.9% had been previously reported as sex-associated CpG sites in other published human studies. Further, for replicated hits, the direction of the association with methylation was highly concordant (98.5-100%) with previous studies.To our knowledge, this is the first reported epigenome-wide analysis by sex at birth that examined DMRs and adjusted for confounding by cell composition. We confirmed previously reported trends that methylation profiles are sex-specific even in autosomal genes, and also identified novel sex-associated CpGs in our methylome-wide analysis immediately after birth, a critical yet relatively unstudied developmental window. (Yousefi et al.).
We also continued analysis of 450K methylation in relation to prenatal PBDE and DDT/E exposure. We did not identify any differentially methylated positions (DMPs) with these exposures.
We recently collaborated with Elior Rahmani and Dr. Eran Halperin (UCLA) to show that population structure (ancestry information) can be inferred from genome-wide methylation data such as that provided by the 450K BeadChip platform. A manuscript describing these data and the EPISTRUCTURE method used to infer ancestry from 450K data has been submitted to Epigenetics and Chromatin.
Building upon our work developed for this project, we have also been active participants in the Pregnancy and Childhood Consortium (PACE), an international consortium of birth cohorts with 450K BeadChip data. It provides a unique opportunity to join forces with multiple cohorts to investigate the relationships of cord blood DNA methylation with various exposures using much larger sample sizes. Thus far, we have been active in several projects. We have published papers on 450K cord blood methylation with smoking and maternal BMI (Joubert et al. 2016). Currently, we are spearheading efforts to determine sex differences in DNA methylation among PACE cohorts. We are also involved in several ongoing projects looking at cord blood DNA methylation in relation to birthweight (Kupers et al), gestational weight gain, and child BMI at various ages.

Future Activities:

The primary aims of this project are complete. We will continue with data analysis and publications examining epigenetic marks and health outcomes.

Journal Articles on this Report : 4 Displayed | Download in RIS Format

Publications Views
Other subproject views:	All 77 publications	38 publications in selected types	All 38 journal articles
Other center views:	All 697 publications	170 publications in selected types	All 169 journal articles

Publications
Type	Citation	Sub Project	Document Sources
Journal Article	Huen K, Harley K, Kogut K, Rauch S, Eskenazi B, Holland N. DNA methylation of LINE-1 and Alu repetitive elements in relation to sex hormones and pubertal timing in Mexican-American children. Pediatric Research 2016;79(6):855-862.	R834513 (2014) R834513 (2015) R834513 (Final) R834513C001 (2015) R834513C003 (2016)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Nature-Full Text-HTML Exit Abstract: Nature-Abstract Exit Other: Nature-Full Text-PDF Exit
Journal Article	Yousefi P, Huen K, Dave V, Barcellos L, Eskenazi B, Holland N. Sex differences in DNA methylation assessed by 450 K BeadChip in newborns. BMC Genomics 2015;16:911.	R834513C003 (2015) R834513C003 (2016)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: BioMed Central-Full Text-HTML Exit Abstract: BioMed Central-Abstract Exit Other: BioMed Central-Full Text-PDF Exit
Journal Article	Zhang, B., R. C. Owen, J. A. Perlinger, A. Kumar, S. Wu, M. Val Martin, L. Kramer, D. Helmig, and R. E. Honrath, A Lagrangian view of ozone production tendency in North American outflow in summers 2009 and 2010, Atmos. Chem. Phys., 14, 2267-2287, doi:10.5194/acp-14-2267-2014, 2014.	R834513C003 (2016)	not available
Journal Article	Furlong CE, Marsillach J, Jarvik GP, Costa LG. 2016. Paraoxonases-1,-2 and-3:What are their functions? Chem Biol Interact. doi:10.1016/j.cbi.2016.05.036. PMID:27238723.	R834513C003 (2016) R834514C004 (Final)	not available

Supplemental Keywords:

Epigenetics, methylation, DDT, DDE, PBDEs, flame retardants, puberty, RFA, Scientific Discipline, Health, INTERNATIONAL COOPERATION, Health Risk Assessment, Biochemistry, Children's Health, Environmental Policy, Biology, farmworkers, pesticide exposure, flame retardants, PBDE, children's vulnerablity, neurochemical effects, harmful environmental agents, biological markers, agricultural community

Progress and Final Reports:

Original Abstract

Main Center Abstract and Reports:

R834513 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).
R834513C001 CHAMACOS Cohort Project: Pesticides and PBDE on Neurobehavior and Puberty
R834513C002 Project B: Exposure Project: Mn, DDT/E and PBDE Exposure to Farmworker Children
R834513C003 Epigenetics Project
R834513C004 Community Outreach and Translation Core

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.