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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 imprintedIGF2locus 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 ofINSIGFwas 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 ofIL10,LEP,ABCA1,GNASASandMEG3was higher (allP&lt; 10−3). A significant interaction with sex was observed forINSIGF,LEPandGNASAS. Next, methylation of eight representative loci was compared between 62 individuals exposed late in gestation and their unexposed siblings. Methylation was different forGNASAS(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.

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