September 2018 Issue

Prenatal Nutrition: The Epigenetic Impact of Maternal Diets
By Jamie Santa Cruz
Today's Dietitian
Vol. 20, No. 9, P. 14

A mother's diet in pregnancy is now known to influence several aspects of her offspring's future health, including everything from the child's risk of diabetes to his or her cognitive development.1,2 The specific ways in which this occurs are unknown, but increasing research suggests that epigenetic alterations play a critical role.

What Is the Epigenome?
The word "epigenome" (literally, "on top of the genome") refers to a series of processes that regulate gene expression, turning genes on or off. According to Keith Godfrey, BM, PhD, FRCP, director of the Centre for Developmental Origins of Health & Disease at the University of Southampton in Southampton, United Kingdom, epigenetic processes function like a series of "dimmer switches" that control how strongly particular genes are expressed, but without altering the genetic code.

Several mechanisms of epigenetic gene regulation exist, but one of the best understood is DNA methylation, which involves the addition of a methyl group (one carbon atom plus three hydrogen atoms) to bases in the DNA sequence. Depending on where it occurs, methylation either can increase or decrease the expression of a given gene.

Obesity and Cardiometabolic Health
Although the field is still young, there's growing evidence that a mother's eating pattern during pregnancy (maternal diet) may epigenetically impact multiple aspects of a child's future health, including obesity and cardiometabolic health (ie, the development of cardiovascular diseases, insulin resistance, impaired glucose intolerance, hypertension, and dyslipidemia).

Some of the most important research in the field has been on maternal malnutrition, specifically the effects of the Dutch famine of 1944–1945. Multiple studies have found that when mothers were exposed to famine conditions during pregnancy, their children showed different patterns of methylation of multiple genes involved in growth and metabolic disease as compared with unexposed same-sex siblings.3-5 These epigenetic impacts were still visible decades later, providing crucial human evidence that diet during pregnancy could have a permanent epigenetic (not just transient) impact on the child. Moreover, the epigenetic changes corresponded to health outcomes; those exposed to famine in utero were known to have had higher rates of both obesity and coronary heart disease than those unexposed.6

Maternal low-carbohydrate diets also have been shown to epigenetically influence genes associated with weight and cardiometabolic health. One seminal human study found that mothers with carbohydrate intake in the lowest quartile for the population had newborns with higher methylation of the RXRA gene (associated with regulation of multiple genes related to energy metabolism and the formation of fatty tissue). In turn, those with higher methylation of RXRA at birth had a higher risk of obesity in childhood. The findings, which were replicated in a second independent cohort, strongly suggest that epigenetic markers at birth can predict later metabolic health, and also that DNA methylation is one mechanism through which a mother's diet can influence her child's risk of obesity.7

High-fat diets, Mediterranean diets, and low-glycemic diets also have been studied, with each showing various epigenetic impacts on genes related to obesity and cardiometabolic health.8-11 In mice, a high-fat diet induced epigenetic modifications of adipocytokine, adiponectin, and leptin genes, and also was associated with the development of a metabolic syndrome type phenomenon.8 Meanwhile, higher adherence to a Mediterranean diet has been associated with higher levels of methylation of MEG3-IG, which is theorized to be protective against type 2 diabetes.10 And among humans, a low-glycemic diet during pregnancy was associated with epigenetic changes in multiple genes related to cardiac functioning,11 suggesting a mechanism for why low-glycemic diets during pregnancy have been linked with improved cardiac health in offspring.12

Neurobehavioral Development
The epigenetic impact of maternal diet on neurobehavioral development (ie, the relationship between the action of the nervous system and behavior that could result in childhood learning disabilities) isn't as well studied as the epigenetic impact on cardiometabolic health, but there still are suggestions that the neurobehavioral impact may be significant.

For example, some research suggests that maternal diet may positively impact the long-term neuroplasticity (the brain's ability to form and reorganize synaptic connections) of the offspring's brain. A mouse study found that exposure to a Western diet (ie, a diet high in both fat and sugar) promotes methylation of the BDNF gene in the brain, with negative impacts on behavior. However, mice that had been exposed in utero to a maternal diet rich in omega-3 fatty acids were protected from the negative effects of the Western diet. Thus, study authors theorized that omega-3 exposure in utero might build up a "reservoir of neuroplasticity" to protect against future hardships.13

Multiple other studies have suggested an epigenetic connection between maternal diet and anxiety. When pregnant mice were fed a high-fat diet, their offspring showed reduced expression of multiple epigenetic regulators in multiple brain regions. These same offspring also were more prone to anxietylike behavior.14 A separate study found that when mice were fed a low-protein diet, male offspring (though not females) showed increased DNA methylation of the Npy1r gene in the amygdala (an almond-shaped set of neurons located deep inside the brain responsible for processing emotions) compared with controls; these offspring also were more prone to anxiety- and depressionlike behaviors.15

Cancer
Research on the epigenetic impact of maternal diet on cancer risk is still preliminary. However, in one rat study, a maternal high-fat diet promoted mammary tumor growth in both daughters and granddaughters; the same study found that a high-fat diet was associated with DNA methylation patterns in the mammary glands, suggesting that pregnancy diet may influence cancer risk through epigenetic means.16

Among humans, one study found that maternal folic acid supplementation was associated with a presumably beneficial reduction in DNA methylation of genes associated with cancer, metabolism, and infection in offspring; significantly, these methylation changes persisted for several decades after in-utero exposure and therefore may provide a mechanism explaining the beneficial effects of maternal folic acid supplementation that has been observed in offspring health in other research.17 Another study found that maternal folate exposure around the time of conception was associated with DNA methylation throughout the genome in their infants, but that two of the genes most sensitive to folate were STX11, a gene implicated in acute myeloid leukemia, and TFAP2A, implicated in neural crest development. Researchers concluded that these epigenetic impacts suggest a potential mechanism to explain the role of folate in protecting against both childhood cancers and neural tube defects.18

Implications for Dietitians
In general, research on the impact of maternal diet on a child's epigenome is still in its infancy, according to Godfrey. There's now significant research tying the epigenome of a child at birth to his or her later health, but as far as the links between the mother's diet and the epigenome of the child, "we're only at the moment scratching the surface," Godfrey says.

Still, the field of epigenetics is an exciting one because of its potential explanatory power, says Aisling Geraghty, PhD, a postdoctoral research fellow at the University College Dublin Perinatal Research Centre in Dublin, Ireland. "It could really help elucidate a lot of the mechanisms behind associations we can't currently explain," she says.

Indeed, there's speculation that epigenetics may eventually help explain connections between maternal diet and offspring risk of allergies, ADHD, autism, and more.19-21

A key implication of the ongoing research is that dietitians should encourage clients to take diet seriously both during pregnancy and before conception. "Relatively few women in most settings optimize their diet in anticipation of trying for a baby, and we think that's something that has to change going forward," Godfrey says. He encourages dietitians to continue reinforcing existing dietary recommendations from the USDA and international departments of health.

But while the field of epigenetics underscores the importance of a healthful diet during pregnancy, Geraghty urges dietitians not to draw too many conclusions from findings that have come out of the field to date. Much of the current research is observational, she says, and there's little proof—especially in human studies—of the causal impact of these epigenetic changes on the offspring's long-term health. More randomized controlled trials are needed to prove specific nutritional associations with precise health outcomes. Thus, for now, dietitians should pause before making strong dietary recommendations based on evidence from epigenetics. "If the research is there, that's fantastic," Geraghty says, but she adds, "just be cautious."

— Jamie Santa Cruz is a freelance writer of health and medical topics based in Parker, Colorado.

References
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2. Borge TC, Aase H, Brantsæter AL, Biele G. The importance of maternal diet quality during pregnancy on cognitive and behavioural outcomes in children: a systematic review and meta-analysis. BMJ Open. 2017;7(9):e016777.

3. Heijmans BT, Tobi EW, Stein AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A. 2008;105(44):17046-17049.

4. Tobi EW, Goeman JJ, Monajemi R, et al. DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun. 2014;5:5592.

5.Tobi EW, Lumey LH, Talens RP, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009;18(21):4046-4053.

6. Roseboom T, de Rooij S, Painter R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev. 2006;82(8):485-491.

7. Godfrey KM, Sheppard A, Gluckman PD, et al. Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes. 2011;60(5):1528-1534.

8. Masuyama H, Hiramatsu Y. Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouse offspring through epigenetic changes in adipocytokine gene expression. Endocrinology. 2012;153(6):2823-2830.

9. Dunn GA, Bale TL. Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice. Endocrinology. 2009;150(11):4999-5009.

10. Gonzalez-Nahm S, Mendez M, Robinson W, et al. Low maternal adherence to a Mediterranean diet is associated with increase in methylation at the MEG3-IG differentially methylated region in female infants. Environ Epigenet. 2017;3(2):dvx007.

11. Geraghty AA, Sexton-Oates A, O'Brien EC, et al. A low glycaemic index diet in pregnancy induces DNA methylation variation in blood of newborns: results from the ROLO Randomised Controlled Trial. Nutrients. 2018;10(4):455.

12. Danielsen I, Granström C, Haldorsson T, et al. Dietary glycemic index during pregnancy is associated with biomarkers of the metabolic syndrome in offspring at age 20 years. PLoS ONE. 2013;8(5):e64887.

13. Tyagi E, Zhuang Y, Agrawal R, Ying Z, Gomez-Pinilla F. Interactive actions of Bdnf methylation and cell metabolism for building neural resilience under the influence of diet. Neurobiol Dis. 2015;73:307-318.

14. Glendining KA, Fisher LC, Jasoni CL. Maternal high fat diet alters offspring epigenetic regulators, amygdala glutamatergic profile and anxiety. Psychoneuroendocrinology. 2018;96:132-141.

15. Nätt D, Barchiesi R, Murad J, et al. Perinatal malnutrition leads to sexually dimorphic behavioral responses with associated epigenetic changes in the mouse brain. Sci Rep. 2017;7(1):11082.

16. de Assis S, Warri A, Cruz MI, et al. High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring. Nat Commun. 2012;3:1053.

17. Richmond RC, Sharp GC, Herbert G, et al. The long-term impact of folic acid in pregnancy on offspring DNA methylation: follow-up of the Aberdeen Folic Acid Supplementation Trial (AFAST). Int J Epidemiol. 2018;47(3):928-937.

18. Gonseth S, Roy R, Houseman EA, et al. Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes. Epigenetics. 2015;10(12):1166-1176.

19. Potaczek DP, Harb H, Michel S, Alhamwe BA, Renz H, Tost J. Epigenetics and allergy: from basic mechanisms to clinical applications. Epigenomics. 2017;9(4):539-571.

20. Rijlaarsdam J, Cecil CA, Walton E, et al. Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early‐onset conduct problems. J Child Psychol Psychiatry. 2017;58(1):19-27.

21. Surén P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309(6):570-577.

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