Famine is never a good thing, particularly if you’re a developing fetus. And while the role of maternal diet in fetal programming is nothing new to the world of DNA methylation, there’s still a lot to be learned about the subtle variations. When it comes to growth and metabolism, timing of the environmental exposure appears is important, whether it be the seasonal diet differences at conception affecting methyl donor avalibility or, as in today’s case, which trimester the mother experienced famine.
Researchers from Leiden University in the Netherlands used DNA methylation signatures to link prenatal famine exposure to later abnormalities in growth and metabolism. By using RRBS (Reduced representation bisulfite sequencing) on whole blood from 24 sibling pairs discordant for prenatal famine exposure (from the famous Dutch Hunger Winter Cohort), the team made some interesting observations in the children:
- There are a number prenatal famine exposure-related DMRs that occur in regulatory regions of intermediate levels of DNA methylation.
- There is differential DNA methylation in growth and metabolic pathways from first trimester famine exposure.
- But, quite surprisingly, these individuals were born with a normal birthweight, in stark contrast to those exposed to famine in the later trimesters, who are born with a signficantly lower birthweight.
- The team was able to “pin point” the sensitive developmental period to right after conception, and think it is occurring just after implantation, since that is when major methylation remodelling goes down.
- Adding function to finding, their confirmation experiments showed that DNA methylation in INSR was associated with birthweight, while CPT1A has a criminal association with cholesterol with both DMRs showing strong enhancer activity in vitro.
Ultimately, it appears that prenatal exposure to famine sets up a long-lasting metabolic and growth-related program, with variation coming from the timing of exposure. First author Elmar Tobi concludes that “Individuals conceived in the Dutch Hunger Winter may have survived this horrendous period of World War 2 thanks to many small epigenetic differences in growth and developmental pathways a few weeks after fertilization. These changes may be somewhat unfavourable for them as adults, as they seem slightly more at risk to obesity and diabetes. But overall they are a genomic testament of sort for human resilience. It is no mean feat for a tiny foetus to grow, when mum gets less than 25% of the minimum caloric. The Dutch Hunger Winter children, now in their seventies, offer a rare window on how the early environment may leave a lasting imprint on our epigenetic make-up.”
Learn more about the temporal differences of prenatal exposure in Nature Communications, November 2014