The overarching goal of the proposed research is to investigate the association of prenatal exposure to endocrine disrupting compounds (EDCs: phthalates and bisphenol A) with DNA methylation patterns and childhood obesity using novel epigenomic approaches. The program provides a research phase (ROO) for Allan Just PhD, an environmental epidemiologist, to become an independent academic investigator in epigenetic epidemiology. Prior research has demonstrated that human prenatal exposures can alter the fetal epigenome, and animal models have shown that phthalates and bisphenol A impact methylation and obesity risk in the offspring. The proposed research uses methylation microarrays and new sequencing-based technologies to investigate methylation patterns in the umbilical cord blood of two cohorts of human children. An epigenome-wide methylation microarray (Illumina Human Methylation 450K BeadChip), already being conducted on umbilical cord blood DNA from 540 children, will measure methylation in 480,000 individual sites spanning almost all known genes. Statistical models will relate these methylation measures to prenatal EDC exposures and to measures of obesity at age 4. These models use new statistical approaches that account for multiple comparisons and reflect the dependence between methylation sites within the genome. Replication in an independent cohort (n=180), using the same design, assures that findings are consistent and generalizable. All samples and obesity measures are already collected or ongoing in the two cohorts (called PROGRESS and PRISM) under existing grants led by collaborators. In the second phase, a novel technique, targeted enrichment, which has not yet been applied in large-scale epigenetic epidemiologic studies, will be used in conjunction with bisulfite treatment and next generation sequencing; this approach will generate new high resolution measures of all methylation sites in identified regions of interest. This research should provide greater power to detect associations between EDC exposures, methylation patterns, and obesity in children. This approach may also contribute to future epigenetic epidemiological studies by comparing the

Public Health Relevance

From conception onward, children are continually exposed to chemicals that may adversely impact their health. This proposal examines how one set of endocrine-disrupting chemicals (phthalates and bisphenol A) may change the methylation patterns in the umbilical cord blood of infants and how this predicts subsequent obesity. It develops new methods potentially widely useful in determining how chemicals in the environment affect child health and development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Transition Award (R00)
Project #
4R00ES023450-03
Application #
9177788
Study Section
Special Emphasis Panel (NSS)
Program Officer
Chadwick, Lisa
Project Start
2016-04-01
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Heiss, Jonathan A; Just, Allan C (2018) Identifying mislabeled and contaminated DNA methylation microarray data: an extended quality control toolset with examples from GEO. Clin Epigenetics 10:73
Wu, Shaowei; Gennings, Chris; Wright, Rosalind J et al. (2018) Prenatal Stress, Methylation in Inflammation-Related Genes, and Adiposity Measures in Early Childhood: the Programming Research in Obesity, Growth Environment and Social Stress Cohort Study. Psychosom Med 80:34-41
Joyce, Brian T; Zheng, Yinan; Zhang, Zhou et al. (2018) miRNA-Processing Gene Methylation and Cancer Risk. Cancer Epidemiol Biomarkers Prev 27:550-557
Felix, Janine F; Joubert, Bonnie R; Baccarelli, Andrea A et al. (2018) Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium. Int J Epidemiol 47:22-23u
Gutiérrez-Avila, Iván; Rojas-Bracho, Leonora; Riojas-Rodríguez, Horacio et al. (2018) Cardiovascular and Cerebrovascular Mortality Associated With Acute Exposure to PM2.5 in Mexico City. Stroke 49:1734-1736
Rosa, Maria José; Just, Allan C; Kloog, Itai et al. (2017) Prenatal particulate matter exposure and wheeze in Mexican children: Effect modification by prenatal psychosocial stress. Ann Allergy Asthma Immunol 119:232-237.e1
Rosa, Maria José; Pajak, Ashley; Just, Allan C et al. (2017) Prenatal exposure to PM2.5 and birth weight: A pooled analysis from three North American longitudinal pregnancy cohort studies. Environ Int 107:173-180
Adibi, Jennifer J; Buckley, Jessie P; Lee, Myoung Keun et al. (2017) Maternal urinary phthalates and sex-specific placental mRNA levels in an urban birth cohort. Environ Health 16:35
De Carli, Margherita M; Baccarelli, Andrea A; Trevisi, Letizia et al. (2017) Epigenome-wide cross-tissue predictive modeling and comparison of cord blood and placental methylation in a birth cohort. Epigenomics 9:231-240
Carmona, Juan J; Accomando Jr, William P; Binder, Alexandra M et al. (2017) Empirical comparison of reduced representation bisulfite sequencing and Infinium BeadChip reproducibility and coverage of DNA methylation in humans. NPJ Genom Med 2:13

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