Researchers from Leiden University Medical Center in the Netherlands are back at it again: studying the long-term epigenetic effects of prenatal famine utilizing the Dutch Hunger Winter Cohort. The Dutch Hunger Winter was a famine that devastated the Netherlands in the winter of 1944-1945 amidst WWII, which produced a cohort that were in utero during this time frame, allowing for a population study of prenatal famine. Those individuals exposed to prenatal famine were found to be at a higher risk for malignant metabolic phenotypes as adults.
History lesson aside, previous work from the lab identified differentially methylated regions in adult individuals exposed to prenatal famine. Now, they have taken it one step further to more definitively identify DNA methylation as the link to adulthood metabolic conditions. Here, the talented team utilized Illumina’s 450K BeadChip array to screen over 450,000 methylation sites from whole-blood samples of 422 famine cohort members and 463 sibling controls to identify specific CpG sites associated with both prenatal famine and adult metabolic phenotypes. Mediation analysis was then used to determine the extent to which DNA methylation mediated the link between prenatal famine and adult outcome.
In their quest to find CpG sites linking prenatal famine to both BMI and serum triglyceride levels in adults, the talented team discovered that:
- A single CpG site mediates 13.4% of the relationship between prenatal famine and adulthood BMI
- Methylation at this CpG site is associated with PIM3 expression, which is involved in energy metabolism and glucose stimulated insulin secretion
- Six CpG sites mediate the relationship between prenatal famine and serum triglycerides
- Aggregately, these six sites mediate 80% of the relationship
- Methylation at the various identified CpG sites is associated with expression of the nearby genes including TXNIP, which is associated with β cell function and insulin production
- Focused analysis of those exposed to famine during early gestation (1-10 weeks) revealed two additional CpG sites linked to serum triglycerides, at PFKFB3 and METTL8 introns
- These two sites account for 36.3% of the relationship between early exposure to prenatal famine and serum triglyceride levels
- PFKFB3 and METTL8 are involved in glycolysis and adipogenesis, respectively
This work establishes DNA methylation as the link between prenatal famine and adulthood metabolic conditions. Co-senior author Bastiaan Heijmans concludes that “the nine genes we found are compelling candidates to explain the link between the prenatal environment and adult health. Now we need functional studies to unravel how an altered epigenetic regulation of these genes could impinge on metabolism in the long run.”
Although it may seem grim to consider that such adulthood phenotypes are being influenced from the earliest weeks of development, Heijmans added an optimistic note: “I hope that epigenetic studies like ours will at some point allow doctors to detect and treat health risks well before the development of disease.”
To learn more about the epigenetics involved in prenatal famine, click over to the full article in Science Advances, January 2018.