Over 10 years ago a landmark mouse study showed that a mother’s diet before and during pregnancy can change her offspring’s coat color by affecting the establishment of ‘epigenetic’ marks on the genome. It has remained unknown, however, whether such effects also occur in humans. Now, by studying naturally-occurring seasonal differences in the diet and nutritional status of women in rural Gambia, a team of researchers at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital and the London School of Hygiene & Tropical Medicine and Medical Research Council Unit, The Gambia found that mothers’ nutrition around the time of conception causes epigenetic changes that permanently and systemically impact their offspring. A report on their research appears today in the journal Nature Communications.
Previous research has shown that seasonal changes, during the rainy and dry seasons in rural Gambia, affect maternal nutritional status, causing infants born during the food-scarce rainy season to weigh less than those born during the dry season. In the current breakthrough, researchers showed that these seasonal variations also cause permanent changes to the child’s epigenome, which regulates the function of the genome.
The research focuses on special regions of the human genome called ‘metastable epialleles’. At these regions, DNA methylation (an epigenetic mark that controls gene expression) is established in the early embryo and then maintained in various tissues during fetal development, and for the rest of life. Researchers previously found that season of conception in rural Africans is associated with DNA methylation at metastable epialleles, but it was unclear exactly how this happened.
To further investigate, a team led by Dr. Branwen Hennig at the London School of Hygiene & Tropical Medicine and Dr. Robert Waterland at Baylor conducted this prospective study to determine specifically whether maternal nutrition around the time of conception affects establishment of DNA methylation at these genomic regions in her offspring, and whether these effects indeed occur systemically.
“If you can show the same season of conception effect in multiple tissues, that indicates it must have occurred in the early embryo before the different tissues diverged along their different developmental paths,” said Waterland.
Season leaves mark
The study required measuring maternal nutritional status very early in pregnancy – potentially before the women even knew they were pregnant. To do so, over 2,000 women of childbearing age were enrolled from 34 villages in rural West Africa. They were visited monthly for one year and asked to indicate their last menstrual cycle. At the first indication of a missed cycle, a blood sample was taken to confirm pregnancy and measure 13 blood biomarkers of maternal nutritional status.
At the same time, 30 women of childbearing age across three of the same villages were visited monthly and had their food intake measured and provided blood samples for biomarker assessment. Seasonal patterns of nutritional status in this ‘indicator group’ were used to extrapolate the values for the main group back to the actual time of conception.
Researchers followed the main group of women after child birth and took blood samples along with hair follicle DNA samples from the infants at around 6 months of age. They found that babies who were conceived in the rainy season had higher DNA methylation at six metastable epialleles. Remarkably, a nearly identical effect was found in both peripheral blood and hair follicle DNA.
“This suggests all the cells in these kids’ bodies have the same mark associated with their season of conception,” said Waterland.
Of all of the biomarkers they measured, researchers found that maternal homocysteine and cysteine concentrations in their blood around the time of conception were the strongest predictors of their infants’ DNA methylation at these metastable epialleles.
Defining optimal diet
“These were found to be the best biomarkers of predicting the nutritional influence on the baby’s methylation. In both cases, the effect was negative. Higher homocysteine and cysteine predicted lower methylation in the kids,” said Waterland. “So this very clearly answers the question, was it nutrition? Yes, maternal nutrition at the time of conception absolutely is affecting DNA methylation at these metastable epialleles in the children and that’s apparently affecting all the cells in their body. These early nutritional effects on the human epigenome are almost certainly happening all over the world.”
“Our on-going research is yielding strong indications that the methylation machinery can be disrupted by nutrient deficiencies and that this can lead to disease. Our ultimate goal is to define an optimal diet for mothers-to-be that would prevent defects in the methylation process. Pre-conceptional folic acid is already used to prevent defects in embryos. Now our research is pointing towards the need for a cocktail of nutrients, which could come from the diet or from supplements,” said Andrew Prentice, professor of international nutrition at the London School of Hygiene & Tropical Medicine and head of the MRC International Nutrition Group.
Others who took part in the study include Paula Dominguez-Salas, Sophie E. Moore, Sharon E. Cox, Anthony J. Fulford, and Matt Silver of the London School of Hygiene & Tropical Medicine; Eleonora Laritsky, Maria S. Baker, and Yongtao Guan of Baylor and the CNRC; Andrew W. Bergen and Gary E. Swan of SRI International; Roger A. Dyer and Sheila M. Innis of the University of British Columbia; and Steven H. Zeisel of the University of North Carolina at Chapel Hill.
This study was funded by the Wellcome Trust, UK; the Medical Research Council (MRC); the UK Department for International Development (DFID); the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK081557), USA; and the USDA ((CRIS 6250-51000-055).), USA. Additional institutions involved in the study included the University of North Carolina, USA; University of British Columbia, Canada; and SRI International, USA.