DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: Results of a pilot randomized controlled trial

2 Department of Paediatrics, Box 116, Level 8, Addenbrooke's Hospital, University of Cambridge, Hills Rd., Cambridge CB2 0QQ, UK.
The FASEB Journal (Impact Factor: 5.04). 01/2012; 26(5):1782-90. DOI: 10.1096/fj.11-192708
Source: PubMed


Intrauterine exposures mediated by maternal diet may affect risk of cardiovascular disease, obesity, and type 2 diabetes. Recent evidence, primarily from animal studies and observational data in humans, suggests that the epigenome can be altered by maternal diet during the periconceptional period and that these programming events may underlie later disease risk. A randomized controlled trial of periconceptional micronutrient supplementation in The Gambia, where seasonal nutritional variations affect fetal growth and postnatal outcomes, provided a unique opportunity to test this hypothesis. Specifically, we targeted imprinted genes, which play important roles in allocation of maternal resources while being epigenetically regulated. DNA methylation at 12 differentially methylated regions (DMRs) was analyzed in cord blood samples from 58 offspring of women participating in a double-blind randomized-controlled trial of pre- and periconceptional micronutrient supplementation (including folate, zinc, and vitamins A, B, C, and D). We observed sex-specific effects of micronutrient supplementation, reducing methylation levels at two of the DMRs analyzed, IGF2R in girls and GTL2-2 in boys. This pilot study is the first to analyze DNA methylation in the context of a randomized controlled trial, and it provides suggestive evidence that periconceptional maternal nutrition alters offspring methylation at imprinted loci.

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    • "For example, in non-human primates, manipulation of the diet for relatively short periods prior to conception can alter the maternal and fetal epigenome with corresponding fetal changes in the metabolic phenotype [20-23]. In the human, periconceptional micronutrient supplementation favorably impacts methylation patterns in cord blood and in the young infant [24]. The closer to fertilization, the greater the potential for epigenetic changes and corresponding plasticity of the offspring in response to environmental change. "
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    ABSTRACT: Research directed to optimizing maternal nutrition commencing prior to conception remains very limited, despite suggestive evidence of its importance in addition to ensuring an optimal nutrition environment in the periconceptional period and throughout the first trimester of pregnancy.Methods/Study design: This is an individually randomized controlled trial of the impact on birth length (primary outcome) of the time at which a maternal nutrition intervention is commenced: Arm 1: >= 3 mo preconception vs. Arm 2: 12-14 wk gestation vs. Arm 3: none.192 (derived from 480) randomized mothers and living offspring in each arm in each of four research sites (Guatemala, India, Pakistan, Democratic Republic of the Congo). The intervention is a daily 20 g lipid-based (118 kcal) multi-micronutient (MMN) supplement. Women randomized to receive this intervention with body mass index (BMI) <20 or whose gestational weight gain is low will receive an additional 300 kcal/d as a balanced energy-protein supplement. Researchers will visit homes biweekly to deliver intervention and monitor compliance, pregnancy status and morbidity; ensure prenatal and delivery care; and promote breast feeding. The primary outcome is birth length. Secondary outcomes include: fetal length at 12 and 34 wk; incidence of low birth weight (LBW); neonatal/infant anthropometry 0-6 mo of age; infectious disease morbidity; maternal, fetal, newborn, and infant epigenetics; maternal and infant nutritional status; maternal and infant microbiome; gut inflammatory biomarkers and bioactive and nutritive compounds in breast milk. The primary analysis will compare birth Length-for-Age Z-score (LAZ) among trial arms (independently for each site, estimated effect size: 0.35). Additional statistical analyses will examine the secondary outcomes and a pooled analysis of data from all sites. Positive results of this trial will support a paradigm shift in attention to nutrition of all females of child-bearing age.Trial registration: NCT 01883193.
    BMC Pregnancy and Childbirth 03/2014; 14(1):111. DOI:10.1186/1471-2393-14-111 · 2.19 Impact Factor
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    • "Maternal micronutrient supplementation (with vitamins and minerals) around the time of conception had widespread and sexspecific effects on the epigenome of the offspring. Some of the observed DNA methylation changes were shown to persist into early infancy (Cooper et al., 2012; Khulan et al., 2012). Similar to fetal adaption to maternal malnutrition, neonates with intrauterine growth restriction exhibited specific changes in DNA methylation, in particular the hepatocyte factor 4 alpha (HNF4A) gene (Einstein et al., 2010). "
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    ABSTRACT: The epidemic increase of type 2 diabetes and obesity in developed countries cannot be explained by overnutrition, physical inactivity and/or genetic factors alone. Epidemiologic evidence suggests that an adverse intrauterine environment, in particular a shortage or excess of nutrients is associated with increased risks for many complex diseases later in life. An impressive example for the "fetal origins of adult disease" is gestational diabetes mellitus which usually presents in 1% to greater than 10% of third-trimester pregnancies. Intrauterine hyperglycemia is not only associated with increased perinatal morbidity and mortality, but also with increased lifelong risks of the exposed offspring for obesity, metabolic, cardiovascular, and malignant diseases. Accumulating evidence suggests that fetal overnutrition (and similarly undernutrition) lead to persistent epigenetic changes in developmentally important genes, influencing neuroendocrine functions, energy homeostasis and metabolism. The concept of fetal programming has important implications for reproductive medicine. Because during early development the epigenome is much more vulnerable to environmental cues than later in life, avoiding adverse environmental factors in the periconceptional and intrauterine period may be much more important for the prevention of adult disease than any (i.e. dietetic) measures in infants and adults. A successful pregnancy should not primarily be defined by the outcome at birth but also by the health status in later life.
    Molecular Human Reproduction 03/2013; 19(7). DOI:10.1093/molehr/gat020 · 3.75 Impact Factor
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    • "Such approaches, if validated with animal models and in clinical trials, offer the possibility of a " personalized medicine " approach to obesity therapeutics (Martínez, Cordero, Campión, & Milagro, 2012). Innovative clinical investigations to measure how an altered maternal uterine environment during gestation affects DNA methylation patterns have already been reported (Cooper et al., 2012). Although chromatin modifications are well studied in embryogenesis and cancer (Sharma, Kelly, & Jones, 2010), much less is known about their role in metabolic diseases. "
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    ABSTRACT: Disturbed body energy balance can lead to obesity and obesity-driven diseases such as Type 2 diabetes, which have reached an epidemic level. Evidence indicates that obesity-induced inflammation is a major cause of insulin resistance and Type 2 diabetes. Environmental factors, such as nutrients, affect body energy balance through epigenetic or chromatin-based mechanisms. As a bromodomain and external domain family transcription regulator, Brd2 regulates expression of many genes through interpretation of chromatin codes and participates in the regulation of body energy balance and immune function. In the severely obese state, Brd2 knockdown in mice prevented obesity-induced inflammatory responses, protected animals from insulin resistance, glucose intolerance and pancreatic beta cell dysfunction, and thus uncoupled obesity from diabetes. Brd2 provides an important model for investigation of the function of transcription regulators and the development of obesity and diabetes; it also provides a possible, innovative target to treat obesity and diabetes through modulation of the function of a chromatin code reader.
    Vitamins & Hormones 02/2013; 91:49-75. DOI:10.1016/B978-0-12-407766-9.00003-1 · 2.04 Impact Factor
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