This study investigates the long-term effects of prenatal exposure to famine during the Dutch Hunger Winter (1944–45) on DNA methylation in humans. Researchers found that individuals exposed to famine prenatally had significantly less DNA methylation of the imprinted IGF2 gene compared to their unexposed, same-sex siblings, 60 years later. The association was specific to periconceptional exposure, highlighting the critical role of very early development in establishing and maintaining epigenetic marks. These findings support the hypothesis that early-life environmental conditions can cause persistent epigenetic changes in humans. The study used the Hunger Winter Families Study, which included individuals exposed to famine and their unexposed siblings. DNA methylation of the IGF2 differentially methylated region (DMR) was measured using a quantitative mass spectrometry-based method. Periconceptional exposure was associated with a 5.2% lower methylation of the IGF2 DMR, independent of sex. In contrast, late gestational exposure did not show significant differences in methylation. The study also found that birth weight was not associated with IGF2 DMR methylation, indicating that famine exposure during early development can lead to epigenetic changes independent of birth weight. The results suggest that early-life environmental conditions, such as famine, can have lasting effects on epigenetic marks, which may contribute to adult disease risk. The study provides the first empirical evidence that transient environmental conditions early in human gestation can result in persistent epigenetic changes. These findings support the developmental origins hypothesis, which posits that adverse conditions during development can influence adult health. The study also highlights the importance of considering epigenetic factors in understanding the long-term effects of prenatal exposure to environmental stressors. Future research should explore the phenotypic consequences of these epigenetic changes and their potential implications for disease prevention.This study investigates the long-term effects of prenatal exposure to famine during the Dutch Hunger Winter (1944–45) on DNA methylation in humans. Researchers found that individuals exposed to famine prenatally had significantly less DNA methylation of the imprinted IGF2 gene compared to their unexposed, same-sex siblings, 60 years later. The association was specific to periconceptional exposure, highlighting the critical role of very early development in establishing and maintaining epigenetic marks. These findings support the hypothesis that early-life environmental conditions can cause persistent epigenetic changes in humans. The study used the Hunger Winter Families Study, which included individuals exposed to famine and their unexposed siblings. DNA methylation of the IGF2 differentially methylated region (DMR) was measured using a quantitative mass spectrometry-based method. Periconceptional exposure was associated with a 5.2% lower methylation of the IGF2 DMR, independent of sex. In contrast, late gestational exposure did not show significant differences in methylation. The study also found that birth weight was not associated with IGF2 DMR methylation, indicating that famine exposure during early development can lead to epigenetic changes independent of birth weight. The results suggest that early-life environmental conditions, such as famine, can have lasting effects on epigenetic marks, which may contribute to adult disease risk. The study provides the first empirical evidence that transient environmental conditions early in human gestation can result in persistent epigenetic changes. These findings support the developmental origins hypothesis, which posits that adverse conditions during development can influence adult health. The study also highlights the importance of considering epigenetic factors in understanding the long-term effects of prenatal exposure to environmental stressors. Future research should explore the phenotypic consequences of these epigenetic changes and their potential implications for disease prevention.