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. 2012 Feb;120(2):296-302.
doi: 10.1289/ehp.1103927. Epub 2011 Oct 17.

In utero exposures, infant growth, and DNA methylation of repetitive elements and developmentally related genes in human placenta

Charlotte S Wilhelm-Benartzi  1 , E Andres Houseman, Matthew A Maccani, Graham M Poage, Devin C Koestler, Scott M Langevin, Luc A Gagne, Carolyn E Banister, James F Padbury, Carmen J Marsit
Affiliations

In utero exposures, infant growth, and DNA methylation of repetitive elements and developmentally related genes in human placenta

Charlotte S Wilhelm-Benartzi et al. Environ Health Perspect. 2012 Feb.

Abstract

Background: Fetal programming describes the theory linking environmental conditions during embryonic and fetal development with risk of diseases later in life. Environmental insults in utero may lead to changes in epigenetic mechanisms potentially affecting fetal development.

Objectives: We examined associations between in utero exposures, infant growth, and methylation of repetitive elements and gene-associated DNA in human term placenta tissue samples.

Methods: Placental tissues and associated demographic and clinical data were obtained from subjects delivering at Women and Infants Hospital in Providence, Rhode Island (USA). Methylation levels of long interspersed nuclear element-1 (LINE-1) and the Alu element AluYb8 were determined in 380 placental samples from term deliveries using bisulfite pyrosequencing. Genomewide DNA methylation profiles were obtained in a subset of 184 samples using the Illumina Infinium HumanMethylation27 BeadArray. Multiple linear regression, model-based clustering methods, and gene set enrichment analysis examined the association between birth weight percentile, demographic variables, and repetitive element methylation and gene-associated CpG locus methylation.

Results: LINE-1 and AluYb8 methylation levels were found to be significantly positively associated with birth weight percentile (p = 0.01 and p < 0.0001, respectively) and were found to differ significantly among infants exposed to tobacco smoke and alcohol. Increased placental AluYb8 methylation was positively associated with average methylation among CpG loci found in polycomb group target genes; developmentally related transcription factor binding sites were overrepresented for differentially methylated loci associated with both elements.

Conclusions: Our results suggest that repetitive element methylation markers, most notably AluYb8 methylation, may be susceptible to epigenetic alterations resulting from the intrauterine environment and play a critical role in mediating placenta function, and may ultimately inform on the developmental basis of health and disease.

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Conflict of interest statement

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
Association of LINE-1 (A) and AluYb8 (B) methylation with mean RPMM class methylation. The colored dots indicate the degree of average CpG class methylation, as indicated by the key. The red dashed lines represent the null limits for the permutation distribution of regression coefficient t-statistics (t-stat), adjusted for multiple comparisons.
Figure 2
Figure 2
Frequency of sequence features associated with RPMM class CpG loci: percentage of CpG loci found in LINE-1 (A), LINE-2 (B), Alu (C), and MIR (D), within a CGI (E), or having the associated gene considered a PcG protein target gene (F). The colored dots indicate the degree of average class methylation.
Figure 3
Figure 3
Association of LINE-1 (A) and AluYb8 (B) methylation with bioinformatically derived CpG class methylation. The colored dots indicate the degree of average class methylation. The red dashed lines represent the null limits for the permutation distribution of regression coefficient t-statistics (t-stat), adjusted for multiple comparisons.
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