Endocrine Abstracts

Epidemiologic studies suggest that adult disease risk may be associated with adverse environmental conditions early in development but the biological mechanisms behind these relations are unclear.

Our group used the circumstances of the Dutch famine of 1944–1945 to evaluate epigenetic changes in men and women with prenatal famine exposure during the Second World War. Study subjects were followed from birth to age ∼58 years. To minimize potential confounding by maternal genes, early family environment or gender, all study subjects were paired to one unexposed same-sex sibling control. We examined 60 probands with exposure early in gestation and 62 with exposure late in gestation together with their unexposed sibling for a total of 122 pairs. We first established that DNA methylation at the IGF2 locus is associated with exposure in early gestation and that there may be sex-specific associations with DNA methylation at other loci.

In a randomly selected subgroup with exposure early in gestation (n=24 pairs), we used next generation sequencing to systematically evaluate 28 classes of genomic regions within the genome for DNA methylation changes in relation to famine exposure. We found no associations with classes related to cancer prevalence such as CpG islands. We did however find associations with some classes defined by an open chromatin structure such as enhancers, especially those active during early blastocyst development. These associations were confirmed by mass spectrometry for four loci in this subgroup and also among the other 36 pairs with exposure early in gestation. The observed DNA methylation changes are in the order of 2–4%.

The identified loci map to genes involved in insulin signalling, regulation of developmental growth and lipid metabolism as will be presented in more detail. We are further exploring associations of the loci with measures of obesity and of glucose, insulin, and lipid metabolism.

Declaration of funding

This work was supported by NIH grants RO1 HL-67914 and R01 AG-042190 (PI:LHL).