Effects of stresses associated with extremely preterm birth may be biologically “recorded” in the genomes of individuals born preterm via changes in DNA methylation (DNAm) patterns. Genome-wide DNAm profiles were examined in buccal epithelial cells from 45 adults born at extremely low birth weight (ELBW; ≤1000 g) in the oldest known cohort of prospectively followed ELBW survivors (
Mage= 32.35 years, 17 male), and 47 normal birth weight (NBW; ≥2500 g) control adults ( Mage= 32.43 years, 20 male). Sex differences in DNAm profiles were found in both birth weight groups, but they were greatly enhanced in the ELBW group (77,895 loci) versus the NBW group (3,424 loci), suggesting synergistic effects of extreme prenatal adversity and sex on adult DNAm profiles. In men, DNAm profiles differed by birth weight group at 1,354 loci on 694 unique genes. Only two loci on two genes distinguished between ELBW and NBW women. Gene ontology (GO) and network analyses indicated that loci differentiating between ELBW and NBW men were abundant in genes within biological pathways related to neuronal development, synaptic transportation, metabolic regulation, and cellular regulation. Findings suggest increased sensitivity of males to long-term epigenetic effects of extremely preterm birth. Group differences are discussed in relation to particular gene functions.