Researchers analysed how famine exposure - defined as 900 calories daily or less - during the Dutch Hunger Winter of 1944-1945 affected genome-wide DNA methylation levels in adulthood.
Writing in the International Journal of Epidemiology, the team used blood samples of 422 individuals exposed to the famine at any time during gestation and 463 controls without prenatal famine exposure to analyse the impact of maternal malnutrition. The team found that those born to mothers who were malnourished during the first 10 weeks of pregnancy had changes in DNA methylation known to suppress genes involved in growth, development, and metabolism that were present still at age 59.
"The first ten weeks of gestation is a uniquely sensitive period when the blood methylome - or whole-genome DNA methylation - is especially sensitive to the prenatal environment," commented senior author Dr L.H. Lumey, from the Mailman School of Public Health. "This is the period when a woman may not even be aware that she is pregnant."
“These findings provide additional evidence that the early gestation period is a critical time-window during which the prenatal environment may affect the human blood methylome,” added the researchers, who noted that although the findings suggest certain genes that impact growth and metabolism are impacted, the functional implications of the findings ‘need further exploration.’
Previous work in led by Lumey in the Netherlands revealed that famine exposure in the first pregnancy trimester was associated with a 10% increase in mortality at age 63 years.
Research details
The team analysed data from adults aged approximately 59, who were born in the Dutch famine of 1944–45 to evaluate the impact of famine exposure during specific 10-week gestation periods, or during any time in gestation, on genome-wide DNA methylation levels.
DNA methylation was assessed using the Illumina 450k array in whole blood among 422 individuals with prenatal famine exposure and 463 time- or sibling-controls without prenatal famine exposure, explained the team.
“In addition, we evaluated the impact of exposure during a shorter pre- and post-conception period,” they said.
Lumey and his colleagues found that DNA methylation in four CpG dinucleotides in whole blood (cg20823026, cg11496778, cg10354880 and cg27370573) were associated with prenatal famine exposure during the first 10 weeks of gestation.
However, no associations were found with famine exposure in other 10-week periods (weeks 11–20, 21–30 or 31 to delivery).
Furthermore, the authors revealed an association between any famine exposure and DNA methylation of two CpG dinucleotides (cg15659713 and cg26199857).
Gene functions
Regarding the four CpG dinucleotides linked to malnutrition in the first 10 weeks of exposure, the team noted that CpG cg20823026 is located between FAM150B which is involved in cell growth and differentiation andTMEM18, a known obesity gene.
CpG cg10354880 lies within a strong enhancer mapping to the SLC38A2 gene, whose function includes matching nutrient supply to foetal demand, they said.
“CpG dinucleotide cg11496778 is located distal from OSBPL5 which is implicated with intracellular cholesterol transport, and CpG dinucleotide cg27370573 lies in a CpG island in the proximal promoter of PPAP2Cinvolved in cell cycle regulation,” wrote Lumey and his colleagues.
Together these suggest that the impact of maternal malnutrition in this 10 week period has a lasting effect on genes that play a role in growth and metabolism – including specific genes relating to obesity and cholesterol.
“The CpG dinucleotides identified can be linked to genes in pathways involved in growth, development and lipid metabolism and are mostly located in exons and regulatory regions such as enhancers,” they noted.
"Further analysis of health outcomes among men and women with famine exposure is now needed,” said Lumey. “We are therefore looking if DNA-methylation can make a difference for obesity and diabetes risk in this population."
Source: International Journal of Epidemiology
Published online ahead of print, doi: 10.1093/ije/dyv043
“Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome”
Authors: Elmar W Tobi, et al