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 AiuYb8 methylation levels were found to be significantly positively associated with birth weight percentile (p = 0.01 and p < 0.000 1, 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.
KEY WORDS: birth weight, epigenetics, fetal programming, in utero exposures, placenta, retrotransposon. Environ Health Perspect 120:296-302 (2012). http://dx.doi.org/10.1289/ehp.1103927 [Online 17 October 2011]
The importance of environmental exposures during intrauterine development on health throughout the life course is now well recognized in the epidemiologic literature (Barker 2004). The molecular mechanisms that underlie these observations remain unclear, although recent work suggests that alterations to placental function may lead to altered feta1 development and programming, likely playing a critical role in mediating these associations (Higgins et al. 2011; Lester and Padbury 2009). Throughout in utero development, the placenta, through the production of various enzymes and hormones, plays an important role in controlling growth and development through the transfer of nutrients and waste and in protecting the fetus from many xenobiotic insults (Robins et al. 2011). Recent work has demonstrated that placental genetic and epigenetic profiles may possibly serve as markers (Filiberto et al. 2011; Sood er al. 2006) of the intrauterine and extrauterine environment (Nelissen et al. 2011).
DNA methylation is a key mode of epigenetic regulation, which can lead to silencing of genomic regions. DNA methylation patterns are essential for the growth and maintenance of tissue-specific expression profiles in different cell types during development, and these patterns become set during in utero development (Hajkova et al. 2002; Jaenisch 1997; Rougier et al. 998). This is true...