DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific

Abstract

Prenatal famine in humans has been associated with various later-life consequences, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. Indeed, animal studies and our early human data on the imprinted IGF2 locus indicated a link between prenatal nutritional and DNA methylation. However, it remains unclear how common changes in DNA methylation are and whether they are sex- and timing-specific paralleling the later-life consequences of prenatal famine exposure. To this end, we investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to a war-time famine in 1944-45. Methylation of INSIGF was lower among individuals who were periconceptionally exposed to the famine (n = 60) compared with their unexposed same-sex siblings (P = 2 x 10(-5)), whereas methylation of IL10, LEP, ABCA1, GNASAS and MEG3 was higher (all P < 10(-3)). A significant interaction with sex was observed for INSIGF, LEP and GNASAS. Next, methylation of eight representative loci was compared between 62 individuals exposed late in gestation and their unexposed siblings. Methylation was different for GNASAS (P = 1.1 x 10(-7)) and, in men, LEP (P = 0.017). Our data indicate that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure and that these changes depend on the sex of the exposed individual and the gestational timing of the exposure.

Figure 1.

Difference in DNA methylation of CpG dinucleotides in siblings discordant for periconceptional exposure to famine. Bars in the figures represent the average absolute within-pair difference in DNA methylation and their standard errors for CpG dinucleotides. A positive difference indicates a higher methylation level among exposed individuals. The exact location of the CpG dinucleotides can be found using Supplementary Material, Table S1. (A) The absolute within-pair difference for CpG dinucleotides for which a significant overall difference of the locus in DNA methylation was observed. (B) As in (A), but for men. Only loci showing a significant interaction between sex and exposure are depicted. (C) As in (B), but for women only.