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

TLDR

Prenatal famine is linked to later‑life health outcomes, with epigenetic changes—particularly DNA methylation—believed to mediate these effects, as early studies on the IGF2 locus suggest. The study aims to determine whether DNA methylation changes after prenatal famine are common and whether they vary by sex and gestational timing. Researchers examined methylation at 15 growth‑ and metabolic‑related loci in famine‑exposed individuals and compared eight representative loci between those exposed late in gestation and unexposed siblings. They found persistent, locus‑specific methylation differences—such as lower INSIGF and higher IL10, LEP, ABCA1, GNASAS, and MEG3—whose magnitude varied by sex and gestational timing, indicating that prenatal famine induces common, sex‑ and timing‑specific epigenetic changes.

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 × 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 × 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.