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Dutch mother and her children during the Dutch famine of 1944-45 Image Credit: South Schleswig Voter Federation

DNA reveals impact of malnutrition on fetus

This is the first study to look at prenatal nutrition and its affect on the genome of the adult that infant grows into.

Children whose mothers were malnourished at famine levels during the first 10 weeks of pregnancy, had DNA methylation changes that are known to suppress genes involved in growth, development, and metabolism. These changes were later documented at age 59 in those children who survived the famine in the winter of 1944-1945 in Holland.

The research was conducted at the Columbia University Mailman School of Public Health and Leiden University in the Netherlands, and was published in the International Journal of Epidemiology.

The study evaluated how famine — defined as 900 calories daily or less — during the Dutch Hunger Winter of 1944-1945, affected DNA methylation genome-wide. Also studied was the impact of short-term starvation in the weeks pre-conception and post-conception.

The study used blood samples from 422 individuals exposed to the famine at any time during gestation as compared to 463 controls, or people without prenatal famine exposure during the same period of time.

The study examined individuals born between February 1945 and March 1946 whose mothers were exposed to the famine during or immediately preceding pregnancy, and individuals conceived between March and May of 1945 — at the time of extreme famine. The control population was born at the same institutions, but their mothers did not experience famine while pregnant and neither did their siblings.

The findings show direct association between famine in weeks 1-10 of gestation with DNA changes — but not later in pregnancy. DNA methylation changes were especially seen in people conceived at the height of the famine — March to May 1945 — even if the fetus was not exposed all 10 weeks of early gestation.

"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," says L.H. Lumey, MD, PhD, an associate professor of Epidemiology at the Mailman School of Public Health. Earlier studies in other populations in the Netherlands led by Dr. Lumey, had examined the long-term impact of famine exposure and identifying early gestation as the most critical period.

The work conducted with over 45,000 military recruits revealed that famine exposure in the first trimester, was associated with a 10-percent increase in mortality by age 63 years.

"Further analysis of health outcomes among men and women with famine exposure is now needed. We are looking to see if DNA-methylation can make a difference for obesity and diabetes risk in this population," said Lumey. "We are also interested in sex-specific effects. But, for these questions much larger studies may be needed."

Abstract
Nutritional conditions in early life may affect adult health, but prior studies of mortality have been limited to small samples. We evaluated the relationship between pre-/perinatal famine exposure during the Dutch Hunger Winter of 1944–1945 and mortality through age 63 years among 41,096 men born in 1944–1947 and examined at age 18 years for universal military service in the Netherlands. Of these men, 22,952 had been born around the time of the Dutch famine in 6 affected cities; the remainder served as unexposed controls. Cox proportional hazards models were used to estimate hazard ratios for death from cancer, heart disease, other natural causes, and external causes. After 1,853,023 person-years of follow-up, we recorded 1,938 deaths from cancer, 1,040 from heart disease, 1,418 from other natural causes, and 523 from external causes. We found no increase in mortality from cancer or cardiovascular disease after prenatal famine exposure. However, there were increases in mortality from other natural causes (hazard ratio = 1.24, 95% confidence interval: 1.03, 1.49) and external causes (hazard ratio = 1.46, 95% confidence interval: 1.09, 1.97) after famine exposure in the first trimester of gestation. Further follow-up of the cohort is needed to provide more accurate risk estimates of mortality from specific causes of death after nutritional disturbances during gestation and very early life.

Co-authors are Elmar W. Tobi, Roderick C. Slieker, H. Eka D. Suchiman, P. Eline Slagboom, Erik W. van Zwet, and Bastiaan T. Heijmans of Leiden University Medical Center, and Aryeh D. Stein, Emory University Rollins School of Public Health. DNA analyses were performed by Tobi and Heijmans and their colleagues from the Molecular Epidemiology group at Leiden University Medical Center.
The study was supported by the National Institutes of Health grants AG042190 and HL067914. There were no reported conflicts of interest.

About Columbia University's Mailman School of Public Health
Founded in 1922, Columbia University's Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health. Its over 450 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change & health, and public health preparedness. It is a leader in public health education with over 1,300 graduate students from more than 40 nations pursuing a variety of master's and doctoral degree programs. The Mailman School is also home to numerous world-renowned research centers including ICAP (formerly the International Center for AIDS Care and Treatment Programs) and the Center for Infection and Immunity. For more information, please visit http://www.mailman.columbia.edu.

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