Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome.

• Type of Material: Article
• Authors: Elmar W Tobi, Leiden University Medical Center; Roderick C Slieker, Leiden University Medical Center; Aryeh Stein, Emory University; H Eka D Suchiman, Leiden University Medical Center; P Eline Slagboom, Leiden University Medical Center; Erik W van Zwet, Leiden University Medical Center; Bastiaan T Heijmans, Leiden University Medical Center; LH Lumey, Leiden University Medical Center
• Language: English
• Date: 2015-05-05
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option D
• Publication Version: Final Published Version
• Copyright Statement: © The Author 2015.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/ije/dyv043
• Title of Journal or Parent Work: International Journal of Epidemiology
• ISSN: 0300-5771
• Grant/Funding Information: This study was supported by the U.S. National Institutes of Health [AG042190 to LHL and BTH, HL067914 to LHL], and the European Union's Seventh Framework Program IDEAL [259679 to P.E.S.].; Funding to pay the Open Access publication charges for this article was provided by NIH, grant AG042190.
• Keywords: DNA methylation; Dutch Famine; exposure; nutrition; Hunger Winter; prenatal
• Research Categories: Biology, Molecular; Health Sciences, Epidemiology; Health Sciences, Public Health

Abstract

BACKGROUND: The manipulation of pregnancy diets in animals can lead to changes in DNA methylation with phenotypic consequences in the offspring. Human studies have concentrated on the effects of nutrition during early gestation. Lacking in humans is an epigenome-wide association study of DNA methylation in relation to perturbations in nutrition across all gestation periods. METHODS: We used the quasi-experimental setting of the Dutch famine of 1944-45 to evaluate the impact of famine exposure during specific 10-week gestation periods, or during any time in gestation, on genome-wide DNA methylation levels at age ∼ 59 years. In addition, we evaluated the impact of exposure during a shorter pre- and post-conception period. DNA methylation was assessed using the Illumina 450k array in whole blood among 422 individuals with prenatal famine exposure and 463 time- or sibling-controls without prenatal famine exposure. RESULTS: Famine exposure during gestation weeks 1-10, but not weeks 11-20, 21-30 or 31-delivery, was associated with an increase in DNA methylation of CpG dinucleotides cg20823026 (FAM150B), cg10354880 (SLC38A2) and cg27370573 (PPAP2C) and a decrease of cg11496778 (OSBPL5/MRGPRG) (P < 5.9 × 10(-7), PFDR < 0.031). There was an increase in methylation of TACC1 and ZNF385A after exposure during any time in gestation (P < 2.0 × 10(-7), PFDR = 0.034) and a decrease of cg23989336 (TMEM105) after exposure around conception. These changes represent a shift of 0.3-0.6 standard deviations and are linked to genes involved in growth, development and metabolism. CONCLUSION: Early gestation, and not mid or late gestation, is identified as a critical time-period for adult DNA methylation changes in whole blood after prenatal exposure to famine.