Epigenetics, Maternal Diet and Metabolic Programming

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REVIEW ARTICLE

Epigenetics, Maternal Diet and Metabolic Programming

The Open Biology Journal 13 Dec 2019 REVIEW ARTICLE DOI: 10.2174/1874196701907010045

Abstract

Background:

The maternal environment influences embryonic and fetal life. Nutritional deficits or excesses alter the trajectory of fetus/offspring’s development. The concept of “developmental programming” and “developmental origins of health and disease” consists of the idea that maternal diet may remodel the genome and lead to epigenetic changes. These changes are induced during early life, permanently altering the phenotype in the posterior adult stage, favoring the development of metabolic diseases such as obesity, dyslipidemia, hypertension, hyperinsulinemia, and metabolic syndrome. In this review, it is aimed to overview epigenetics, maternal diet and metabolic programming factors and determine which of these might affect future generations.

Scope and Approach:

Nutrients interfere with the epigenome by influencing the supply and use of methyl groups through DNA transmethylation and demethylation mechanisms. They also influence the remodeling of chromatin and arginine or lysine residues at the N-terminal tails of histone, thus altering miRNA expression. Fats, proteins, B vitamins and folates act as important cofactors in methylation processes. The metabolism of carbon in the methyl groups of choline, folic acid and methionine to S-Adenosyl Methionine (SAM), acts as methyl donors to methyl DNA, RNA, and proteins. B-complex vitamins are important since they act as coenzymes during this process.

Key Findings and Conclusion:

Nutrients, during pregnancy, potentially influence susceptibility to diseases in adulthood. Additionally, the deficit or excess of nutrients alter the epigenetic machinery, affecting genes and influencing the genome of the offspring and therefore, predisposing the development of chronic diseases in adults.

Keywords: Epigenetic, Epigenome, Maternal programming, Fetus development, Maternal diet, DNA.

1. INTRODUCTION

Several environmental factors have significant effects on people's health and a great impact during embryonic and fetal development. Epidemiological studies on humans [1] and animal experiments [2] have proposed that various perinatal problems, such as placental deficiency [3], glucocorticoid exposure [4], nutritional insufficiencies or excesses [5], and stress [6], as well as maternal intestinal microbiome [7], may alter the development of the fetus/offspring, leading to a predisposition to the development of chronic non-communicable diseases. This relation between the conditions of the maternal environment and the health of the offspring leads to the concept of “developmental programming” or “Developmental Origins of Health and Disease (DOHaD)” which is defined as the response to a specific challenge to the organism in critical development that alters its course, causing health consequences that persist in adult life [8-10]. In humans, the term has been coined to refer to the first 1000 days of life, the period from conception to two years old [11]. An important finding in nutrition field was the discovery of the relation between dietary components and genome remodulation in utero and that the induction of epigenetic programming during the initial stages of life may permanently alter the organism’s phenotype in later stages [10, 12]. Substantial evidence of this theory have been found in the development of metabolic diseases, such as dyslipidemia, hypertension, hyperinsulinemia, obesity, as well as metabolic syndrome [13-15]. It has been postulated that the development of these diseases depends on an interaction between genes and risk factors in adulthood, interaction between genes and the fetal embryo, and the environment in early postnatal period [16]; therefore, the nutrition during pregnancy is crucial and may influence the health outcomes of the offspring later in life, as well as changes in nutrient composition (macro and/or micronutrients) of the maternal diet during the critical stages of fetal development [17].

Epigenetics study the heritable changes in gene expression not associated with any alteration in the Primary Deoxyribonucleic Acid (DNA) sequence, referring to the manner in which genetic information is organized, stored, and read. The modifications in epigenome include the methylation of DNA (most well-known and studied), histone modifications, the positioning of the nucleosome along the DNA and non-coding small and long Ribonucleic Acid (non-coding RNA: ncRNA), including micro RNA (miRNA) [18]. In the DNA of mammals, cytosines in Cytosine-Phosphorus-Guanine Dinucleotide (CpG islands) are frequently methylated. The chemical reaction of DNA methylation regulates the cell development, cell homeostasis and cell functions, particularly, gene expression control, repetitive DNA elements silencing, genomic imprinting, chromatin structure regulation, and the inactivation of the X chromosome in females [18]. In normal cells, the level of DNA methylation is well balanced; however, epigenetic modification patterns in individual genomic regions are affected by genetic and environmental factors [18].

Histone modifications are a complex epigenetic mechanism. This epigenetic modulation regulates chromatin structure, accessibility and transcription activities within the cell. These post-translational modifications play an important role in several cellular processes, such as gene transcription regulation, DNA repair, cell cycle, and metabolic control [19]. Recently, the importance of another epigenetic mechanism mediated by miRNAs and other small and long ncRNAs has been reported. Today, miRNAs are known to have an important role in the human genome, serving as a primary regulatory of genes encoding proteins [20]. With 16-29 nucleotides in length, this small non-coding RNA functions mainly by inhibiting the genes at the post-transcriptional level [18].

Fetal development has the characteristics of remarkable plasticity and a great capacity to react to environmental changes and lifestyle factors. Several studies have also shown that malnutrition or maternal nutrition may generate metabolic deregulation in the offspring through various epigenetic processes, such as DNA methylation, alteration in miRNA expression and histone modification, which may modulate placental gene expression and signaling during fetal development, generating dramatic changes in the programming of subsequent development [21]. In this review, it is aimed to overview epigenetics, maternal diet and metabolic programming factors and determine which of these might affect future generations.

2. EPIGENETICS

In general, nutrition conditions (e.g. high-calorie diets, calorie restriction), macronutrient derivatives (e.g., betaine, choline, and methionine), micronutrients such as vitamins (e.g., vitamins of B complex, folic acid, vitamin D, and retinoic acid), micro minerals or trace elements (e.g., Fe, Zn, and Se), and phytochemicals (e.g., polyphenols), may influence the epigenome in three ways (Fig. 1). Firstly, nutrients may remodel the structure of chromatin and lysine and/or arginine residues at the histone N-terminal tails [22]. Furthermore, nutrients directly impact the number of methyl groups for the formation of S-adenosylmethionine (AdoMet) (e.g., the supply or synthesis of methionine, homocysteine re-methylation, the supply of 5-methyltetrahydrofolate, regulation at low levels of methylenetetrahydrofolate reductase enzyme activity) [23]. In addition, nutrients modify the use of methyl groups through the mechanisms that include changes in methyltransferase activity and DNA demethylation activity [24]. Methyl-CpG binding proteins (i.e. MeCP2) have an important role in transcriptional repression due to their interaction with corepressor complexes, chromatin compaction and spatial organization of nuclear domains [25]. The aberrant functioning of methyl-CpG binding proteins is an important epigenetic pathway. Also, nutrients may alter the miRNAs expression that is implicated in the regulation of key proteins in the Folate-mediated Carbon Metabolism (FOCM) pathway [26, 27]. FOCM is involved in the regulation of homocysteine, methionine, vitamins of B complex, and methylation of proteins, histones, DNA and RNA [28].

Several dietary factors act as important cofactors of methylation reactions that interfere with the chemical availability and allosteric position of methyl groups [29]. The metabolism of carbon in the methyl groups of choline, folic acid and methionine to S-Adenosyl Methionine (SAM) acts as methyl donors to methyl DNA, RNA and proteins. Furthermore, B complex vitamins act as coenzymes in this epigenetic process [30]. The epigenetic interference of nutrition conditions, macronutrient derivatives, micronutrients, micro minerals or trace elements, and phytochemicals, is discussed in the following paragraphs.

3. NUTRITION CONDITIONS

The high-calorie diet may change DNA methylation profile. Studies performed on primates have observed that a high-calorie maternal diet may alter the chromatin structure of the fetus through epigenetic covalent histone modifications [31]. The dietary ingestion of calories was found to be significantly correlated with DNA methylation on leukocytes from 126 older individuals [32]. The study by Strakovsky, Zhang [33] showed that a high-fat maternal diet altered hepatic metabolism in the newborn in a sex-specific way. In addition, a high-fat maternal diet modulated fetal histone sirtuin 1 (SIRT1) and deacetylase protein activity in non-human primates showing that SIRT1 has an important regulatory role in fetal epigenome and metabolome [34]. Using an ovine model of maternal obesity, miRNA expression of the fetal muscle was altered showing an association with increased intramuscular adipogenesis during fetal development [35]. More recent work has observed that newborns of obese parents have altered DNA methylation patterns in printed genes [36]. In newborns, paternal obesity is associated with Insulin-like Growth Factor type 2 (IGF2) hypomethylation [37]. Environmental changes are associated with the susceptibility to sperm development. The acquired impression may be transferred to the next generation and enhance the chronic disease risk in older age [38]. On the other hand, maternal high fat diet modulates hypothalamic regulation of body weight and energy homeostasis, since it alters the gene expression of the leptin receptor, Proopiomelanocortin (POMC) and neuropeptide Y in the offspring [39]. Nutrient excess or deficit may alter the permanent deregulation of the hypothalamic circuits, including insulin and leptin resistance, which may be the basis for permanent increases in food intake and overweight [40]. These studies linked obesity with altered epigenetic regulation of several genes important for the metabolism. Maternal overnutrition is also associated with other metabolic diseases, such as hypertension, hyperlipidemia, insulin resistance and diabetes [41].

Calorie restriction without malnutrition slows aging and prevents cancer in animal models [42, 43]. Calorie restriction affects methylation and mRNAs expression patterns and chromatin structure and regulates metabolism, inflammation and lifespan [44-46]. In monkeys, moderated calorie restriction without malnutrition reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy [47]. In mice, calorie restriction without malnutrition prevented insulin resistance and impaired lipid metabolism in gestational diabetes offspring [48]. On the other hand, calorie restriction associated with maternal malnutrition has detrimental effects on the offspring. Research has established that low birth weight and maternal malnutrition are associated with insulin resistance in the key organs that control glucose homeostasis, establishing a direct association between maternal undernutrition and altered pancreatic β-cell function with the development of type 2 diabetes mellitus [49]. The possible involvement of deregulation in microRNA expression in the endocrine pancreas has been hypothesized as a mediator of early nutrition in the formation of β-cell mass and the subsequent risk of diabetes mellitus type 2 [50]. Recently, it has been discovered that rodents that were exposed to maternal undernutrition and subjected to a low dietary protein content during gestation, showed a decrease in pancreas and β-cell mass, as well as impaired function in fetal development. MicroRNA profiles have revealed an increased expression of different microRNAs, including miR-375, in the pancreas of the fetuses of mothers consuming a low-protein diet; this miR-375 is specifically expressed in the islet cells of the pancreas necessary for normal pancreatic genesis, influencing not only the β-cell mass but also insulin secretion [51].

4. MACRONUTRIENTS

As for lipids, recent studies have shown that the inadequate intake of long-chain polyunsaturated fatty acids (LCPUFA) during pregnancy may provoke aberrant DNA methylation patterns affecting clinically relevant gene expression, such as angiogenic factor genes [52, 53]. This may not only contribute to vascular deregulation associated with abnormal placentation but may also have harmful effects on fetal programming, resulting in an enhanced risk of cardiovascular disease in adulthood [54]. Specific components of the Mediterranean diet assessed by the PREDIMED study, specifically omega-3 fatty acids from extra-virgin olive oil and nuts, induce methylation changes in peripheral white blood cells associated with intermediate metabolism, diabetes, inflammation and signal transduction [55]. In another study performed on humans, prenatal olive oil intake altered placental histone acetylation of immune regulatory genes [56]. In mice, the diet enriched with LCPUFA omega-3 produced epigenetic changes in the promoter of leptin [57]. Additionally, in animal models, the diet supplementation with fish oil is associated with lower DNA methylation in the liver which persists for two generations, decreased lipid concentrations in blood, increased insulin-stimulated glucose uptake, and insulin sensitivity [58].

Other important nutrients during fetal development are amino acids. The metabolism of amino acids, such as glycine, histidine, methionine and serine, have a key role in the supply of methyl donors for the synthesis of DNA and proteins. For example, a diet low in proteins is associated with the deterioration of fetal growth and the development of obesity, hypertension and diabetes in the offspring [59]. Another example is the fact that protein restriction in the prenatal stage changes the extent of DNA methylation and the expression of the angiotensin 1 receptor gene (Agtr1), which has a role in the development of hypertension [60, 61]. It has also been reported that a maternal diet low in protein has an effect on the methylation status of the promoter gene and the expression of the glucocorticoid receptor gene (Nr3c1) and the Peroxisome Proliferator-activated Receptor (PPAR) in the liver through the acetylation of histones, H3 and H4, and the methylation of lysine H3K4. Both Nr3c1 and PPAR has an important role in normal embryogenesis and the regulation of lipids or blood pressure in adulthood [40, 62].

Carbohydrates also have an important epigenetic role [63]. For example, it has been observed that high glucose levels link diabetes and cancer via epigenetic alterations [64]. Hyperglycaemia also induced epigenetic changes in the promoter of nuclear factor kappa B (NF-κB) subunit p65 in aortic endothelial cells [65].

5. MICROMINERALS OR TRACE ELEMENTS

In the case of vitamins and minerals, studies conducted on mice showed that mice born from mothers administered with an excess of folic acid and other nutrients, such as vitamin B12, methionine, Zn, betaine and choline, have an altered epigenome [66, 67]. Choline has an active role in the epigenetic mechanisms, i.e., optimal intake of choline is involved in the transference of carbon or in methylation pathways, such as folic acid, since it helps in achieving fetal development successfully. Studies on animals showed that maternal choline supplementation during pregnancy modified histone and the methylation of DNA in the fetal liver and brain [67, 68].

A study on vitamins showed that the increase in the maternal levels of vitamin B12 during pregnancy was related to a decrease of DNA methylation in newborns, while the increase in serum levels of B12 was related to the decrease of IGFBPC3 gene methylation in intrauterine growth [69]. Another example of the studies on vitamins is the case of folic acid, a known donor of only one carbon for the methylation and synthesis of DNA [70]. In early postnatal development, when cell growth and proliferation processes are crucial, folic acid is a key factor [71].

Fig. (1). Possible effects of dietary components on epigenetic processes. AdoMet S-adenosylmethionine; FOCM folate-mediated carbon metabolism.

With the progression of pregnancy, folate is required in order to ensure the correct fetal development and placental functions. Folate prevents neural tube defects during fetal development [72] and its deficiency is associated with severe neurodevelopmental and neurological disorders [73]. Fryer, Nafee [74] observed that the intermediate levels associated with folate in the blood of the umbilical cord during the final stage of fetal development are inversely associated with the methylation of repetitive LINE-1 elements in lymphocytes from the umbilical cord of mothers who daily intake folic acid supplements. These results support the fact that folate and other intermediate carbon compounds have a regulatory role through the epigenetic mechanism of methylation of DNA. Restricted intake of methyl donors during the periconceptional period produces adverse phenotypes in the offspring of sheep, which has been correlated with the alterations in the DNA methylation of approximately 4% of the CpG islands. These results suggest that the epigenetic alteration of a small subgroup of genes is crucial for the programming events [74].

However, in the deficiency of folate,, methionine and vitamin B in pregnancy produces an alteration in the methylation of DNA, insulin resistance, an increase in high blood pressure, gene expression and changes in methylation related to the renin-angiotensin system, mitochondrial metabolism and phospholipid homeostasis [75]. Otherwise for vitamin B12 and its interaction with folate, a study showed that children whose mothers had low levels of vitamin B12 and high levels of folic acid were more insulin resistant and had a higher body fat percentage and abdominal fat at 6 years of age, which increases the risk of developing diabetes type 2 in the future [76]. Additionally, deficiencies of folic acid and vitamin B12 during pregnancy and breastfeeding cause signs of fetal programming, such as a decrease in weight at birth, an increase in central fat mass, liver steatosis and myocardial hypertrophy [77, 78]. The underlying molecular mechanisms are related to a decrease in the activity and expression of SIRT1 and PRMT1 and the posterior hypomethylation and hyperacetylation of PGC1-α [78].

Another nutrient mentioned is Zn, which is needed for the expression of numerous genes [79]. Due to its role in DNA methylation, Zn levels may have an essential role in the epigenome. It particularly plays a role during intrauterine life and childhood and its deficiency may contribute to an alteration in promoter methylation, which results in immune deregulation that may increase the future development of chronic diseases [80]. Thus, the results obtained in the studies carried out on animals showed that maternal Zn supplementation is associated with lower levels of DNA methylation in intestinal cells, which may alter the inflammatory status of intestinal mucus [81].

6. PHYTOCHEMICALS

Other nutrients related to epigenetic mechanisms are phytochemicals, such as lycopene, genistein, resveratrol, sulforaphane, epigallocatechin-3-gallate (EGCG), curcumin and allyl sulfur compounds [82-84]. However, the effects of some of these phytochemicals on epigenetic mechanisms are not elucidated well. They may act as demethylation agents that inhibit the methylation of DNA catalyzed by DNA (cytosine-5)-methyltransferase (DNMT1) in a dosage-dependant manner, predominantly through a non-competitive mechanism [18]. Besides, studies have shown that resveratrol reverted epigenetic and transcription changes induced by cigarette smoke in rats [85]. Maternal resveratrol supplementation prevented cognitive impairment in mice offspring through epigenetic changes and cell signaling pathways [86]. In another study performed on rats, maternal green tea polyphenol intake during lactation attenuated tubulointerstitial fibrosis and macrophage infiltration by down-regulating epigenetic modulators, such as DNMT1 [87]. Also, cannabis exposure during sensitive periods of development may alter gene regulation via epigenetic pathways [88].

6.1. Gut Microbiota and Metabolic Programming

Gut microbiota has a key role in obesity, which broadens the relationship between the composition of gut microbiota and nutritional status of the host, immune system and vulnerability to numerous diseases [89]. Also, it is established that the formation of gut microbiota starts before birth under intrauterine environment [90]. Thus, several studies have provided evidence to support that supplementing with prebiotics and probiotics, specifically during pregnancy, modifies the methylation status of DNA, particularly of obesity promoters and genes related to weight gain in mothers and their infants [91, 92]. Some examples of maternal prebiotic during pregnancy associated with programming offspring health, in animal models, are short-chain fructo-oligosaccharides that improve gut defense and immune response [93], galacto-oligosaccharides and inulin mixture that prevent food allergies [94] and oligofructose that decreases the risk of obesity [95]. Vahamiko, Laiho [96] carried out a pilot study that aimed to find out whether the administration of probiotic supplements during pregnancy might change DNA and the methylation status of obesity promoters and the genes related to weight gain in mothers and their children. The methylation status of DNA was analysed for obesity genes (623 genes) and the promoters of the gene related to weight gain (433) in children and women. The results suggested that supplementing with probiotics led to lower levels of methylation of DNA in 37 gene promoters and, in women, an increase in the levels of DNA methylation of a gene promoter. In their children, 68 gene promoters were altered, with the group supplemented with probiotics having a lower level of DNA methylation [96]. Wickens, Barthow [97] showed that early probiotic supplementation in pregnant women with a history of atopic disease reduced gestational diabetes mellitus. In another study, probiotic supplementation significantly reduced gestational weight gain and fasting blood glucose and improved insulin sensitivity [98]. In pregnant women, the consumption of probiotic yoghurt has shown beneficial effects for the mother and child [99, 100].

CONCLUSION

To conclude, nutrients and supplements may modulate epigenetic processes and metabolic programming during certain crucial moments of the fetal and early postnatal development. Identifying epigenetic processes altered by nutritional changes may help in finding new strategies to address the current problem in treating chronic diseases.

As seen in this review, the maternal diet might have a lifetime effect on the genome of a child and may potentially influence the risk of developing complex diseases in the posterior adult stage. Several components of the diet of the mother can alter epigenetic prints on the DNA. The specific effect of each type of dietary epigenetic modulator or their combination on the life of a fetus is still questioned due to insufficient data and methodological limitations.

One of the main characteristics of epigenetic mechanisms is their ability to respond to modulation, which makes early nutritional intervention possible in order to modify the risk of illness that may present in the long-term. Nonetheless, this modification may only be possible in specific epigenetic changes, which makes the identification of such changes a matter of great importance. This way, it would be easier to improve the environment that the fetus/offspring is exposed to during the critical moments of its development, which may be an important effort in public health to prevent long-term illnesses. There are three important topics to be highlighted, the effects on fetal programming when dietary factors are in excess or deficient amount, need to be better understood, the effect of the “dietary epigenetic modulators” on an organism genetically predisposed to specific illness, including transgenerational effects, and finally, the combined effect of different dietary epigenetic modulators or chronic exposure to a diet.

Future research is needed to better understand the impact of nutritional programming on the early life and its effect on biological functions. Also, research on epigenome modulators considering individual polymorphism is still scarce. Research on the impact of the cooking methods or industrial treatment on dietary epigenetic modulators present in food is also required. Investigating into this might open a new field of nutritional-epigenetic study that will contribute to guiding public policies that will determine the optimal dosage levels rather than minimal ones in order to satisfy the needs of both the mother and the fetus and benefit their health. Public policies should not only focus on the health of the population but also on the genetic printing of future generations that will be the next users of the health system.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

The authors would like to thank the translators Alejandra Carrillo and Catalina Gómez.

REFERENCES

1
Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 2011; 11(10): 726-34.
2
Rodenhiser D, Mann M. Epigenetics and human disease: Translating basic biology into clinical applications. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2006; 174(3): 341-8.
3
López-Pedrera C, Pérez-Sánchez C, Ramos-Casals M, Santos-Gonzalez M, Rodriguez-Ariza A, Cuadrado MJ. Cardiovascular risk in systemic autoimmune diseases: Epigenetic mechanisms of immune regulatory functions. Clin Dev Immunol 2012; 2012974648
4
Brookes E, Shi Y. Diverse epigenetic mechanisms of human disease. Annu Rev Genet 2014; 48: 237-68.
5
Smith ZD, Meissner A. DNA methylation: Roles in mammalian development. Nat Rev Genet 2013; 14(3): 204-20.
6
Jiang X, West AA, Caudill MA. Maternal choline supplementation: A nutritional approach for improving offspring health? Trends Endocrinol Metab 2014; 25(5): 263-73.
7
Hogg K, Price EM, Hanna CW, Robinson WP. Prenatal and perinatal environmental influences on the human fetal and placental epigenome. Clin Pharmacol Ther 2012; 92(6): 716-26.
8
Lin YJ. Metabolic syndrome in children and adolescents born premature and small-for-gestational age: A scenario of Developmental Origins of Health and Disease (DOHaD). Pediatr Neonatol 2018; 59(2): 109-10.
9
Barker DJ. The origins of the developmental origins theory. J Intern Med 2007; 261(5): 412-7.
10
Barker DJ, Lampl M, Roseboom T, Winder N. Resource allocation in utero and health in later life. Placenta 2012; 33(Suppl. 2): e30-4.
11
Szyf M. The early life environment and the epigenome. Biochim Biophys Acta 2009; 1790(9): 878-85.
12
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): 2823-30.
13
Wardhana W, Soeatmadji DW. The role of epigenetic changes in the development of diabetes mellitus. Acta Med Indones 2019; 51(1): 68-74.
14
Arpón A, Milagro FI, Santos JL, García-Granero M, Riezu-Boj JI, Martínez JA. Interaction among sex, aging, and epigenetic processes concerning visceral fat, insulin resistance, and dyslipidaemia. Front Endocrinol (Lausanne) 2019; 10: 496.
15
Park JH, Kim SH, Lee MS, Kim MS. Epigenetic modification by dietary factors: Implications in metabolic syndrome. Mol Aspects Med 2017; 54: 58-70.
16
Remely M, Stefanska B, Lovrecic L, Magnet U, Haslberger AG. Nutriepigenomics: The role of nutrition in epigenetic control of human diseases. Curr Opin Clin Nutr Metab Care 2015; 18(4): 328-33.
17
Danielewicz H, Myszczyszyn G, Dębińska A, Myszkal A, Boznański A, Hirnle L. Diet in pregnancy-more than food. Eur J Pediatr 2017; 176(12): 1573-9.
18
Chango A, Pogribny IP. Considering maternal dietary modulators for epigenetic regulation and programming of the fetal epigenome. Nutrients 2015; 7(4): 2748-70.
19
Kouzarides T. Chromatin modifications and their function. Cell 2007; 128(4): 693-705.
20
Malone CD, Hannon GJ. Small RNAs as guardians of the genome. Cell 2009; 136(4): 656-68.
21
Nugent BM, Bale TL. The omniscient placenta: Metabolic and epigenetic regulation of fetal programming. Front Neuroendocrinol 2015; 39: 28-37.
22
Zhang P, Torres K, Liu X, Liu C-G, Pollock RE. An overview of chromatin-regulating proteins in cells. Curr Protein Pept Sci 2016; 17(5): 401-10.
23
Abbasi IHR, Abbasi F, Wang L, et al. Folate promotes S-adenosyl methionine reactions and the microbial methylation cycle and boosts ruminants production and reproduction. AMB Express 2018; 8(1): 65.
24
Gao J, Cahill CM, Huang X, et al. S-Adenosyl methionine and transmethylation pathways in neuropsychiatric diseases throughout life. Neurotherapeutics 2018; 15(1): 156-75.
25
Clouaire T, Stancheva I. Methyl-CpG binding proteins: Specialized transcriptional repressors or structural components of chromatin? Cell Mol Life Sci 2008; 65(10): 1509-22.
26
Hardy TM, Tollefsbol TO. Epigenetic diet: Impact on the epigenome and cancer. Epigenomics 2011; 3(4): 503-18.
27
Curtin K, Samowitz WS, Ulrich CM, et al. Nutrients in folate-mediated, one-carbon metabolism and the risk of rectal tumors in men and women. Nutr Cancer 2011; 63(3): 357-66.
28
Williams SR, Yang Q, Chen F, Liu X, Keene KL, Jacques P, et al. Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke PLoS Genet 2014; 10(3): e1004214-e.
29
Shenderov BA, Midtvedt T. Epigenomic programing: A future way to health? Microb Ecol Health Dis 2014; 25: 25.
30
Oster M, Nuchchanart W, Trakooljul N, et al. Methylating micronutrient supplementation during pregnancy influences foetal hepatic gene expression and IGF signalling and increases foetal weight. Eur J Nutr 2016; 55(4): 1717-27.
31
Li Y. Epigenetic mechanisms link maternal diets and gut microbiome to obesity in the offspring. Front Genet 2018; 9: 342.
32
Passador J, Toffoli LV, Fernandes KB, Neves-Souza RD, Pelosi GG, Gomes MV. Dietary ingestion of calories and micronutrients modulates the DNA methylation profile of leukocytes from older individuals. J Nutr Health Aging 2018; 22(10): 1281-5.
33
Strakovsky RS, Zhang X, Zhou D, Pan YX. The regulation of hepatic Pon1 by a maternal high-fat diet is gender specific and may occur through promoter histone modifications in neonatal rats. J Nutr Biochem 2014; 25(2): 170-6.
34
Suter MA, Chen A, Burdine MS, et al. A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. FASEB J 2012; 26(12): 5106-14.
35
Yan X, Huang Y, Zhao JX, et al. Maternal obesity downregulates microRNA let-7g expression, a possible mechanism for enhanced adipogenesis during ovine fetal skeletal muscle development. Int J Obes 2013; 37(4): 568-75.
36
Soubry A, Murphy SK, Wang F, et al. Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int J Obes 2015; 39(4): 650-7.
37
Soubry A, Schildkraut JM, Murtha A, et al. Paternal obesity is associated with IGF2 hypomethylation in newborns: Results from a Newborn Epigenetics Study (NEST) cohort. BMC Med 2013; 11: 29.
38
Vickers MH. Early life nutrition, epigenetics and programming of later life disease. Nutrients 2014; 6(6): 2165-78.
39
Chen H, Simar D, Lambert K, Mercier J, Morris MJ. Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism. Endocrinology 2008; 149(11): 5348-56.
40
Lee HS. Impact of maternal diet on the epigenome during in utero life and the developmental programming of diseases in childhood and adulthood. Nutrients 2015; 7(11): 9492-507.
41
Pasternak Y, Aviram A, Poraz I, Hod M. Maternal nutrition and offspring's adulthood NCD's: a review. J matern fetal neonatal 2013; 26(5): 439-4.
42
Albanes D. Total calories, body weight, and tumor incidence in mice. Cancer Res 1987; 47(8): 1987-92.
43
Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 2010; 31(2): 89-98.
44
Hernandez-Saavedra D, Moody L, Xu GB, Chen H, Pan YX. Epigenetic regulation of metabolism and inflammation by calorie restriction. Advances in nutrition (Bethesda, Md) 2019; 10(3): 520-36.
45
Garcia-Segura L, Abreu-Goodger C, Hernandez-Mendoza A, et al. High-throughput profiling of caenorhabditis elegans starvation-responsive microRNAs. PLoS One 2015; 10(11)e0142262
46
Unnikrishnan A, Jackson J, Matyi SA, et al. Role of DNA methylation in the dietary restriction mediated cellular memory. Geroscience 2017; 39(3): 331-45.
47
Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009; 325(5937): 201-4.
48
Li T, Chen K, Liu G, et al. Calorie restriction prevents the development of insulin resistance and impaired lipid metabolism in gestational diabetes offspring. Pediatr Res 2017; 81(4): 663-71.
49
Ong TP, Ozanne SE. Developmental programming of type 2 diabetes: Early nutrition and epigenetic mechanisms. Curr Opin Clin Nutr Metab Care 2015; 18(4): 354-60.
50
Dumortier O, Hinault C, Gautier N, Patouraux S, Casamento V, Van Obberghen E. Maternal protein restriction leads to pancreatic failure in offspring: Role of misexpressed microRNA-375. Diabetes 2014; 63(10): 3416-27.
51
Alejandro EU, Gregg B, Wallen T, et al. Maternal diet-induced microRNAs and mTOR underlie β cell dysfunction in offspring. J Clin Invest 2014; 124(10): 4395-410.
52
Khot V, Chavan-Gautam P, Joshi S. Proposing interactions between maternal phospholipids and the one carbon cycle: A novel mechanism influencing the risk for cardiovascular diseases in the offspring in later life. Life Sci 2015; 129: 16-21.
53
Sundrani DP, Reddy US, Chavan-Gautam PM, Mehendale SS, Chandak GR, Joshi SR. Altered methylation and expression patterns of genes regulating placental angiogenesis in preterm pregnancy. Reprod Sci 2014; 21(12): 1508-17.
54
Khot VV, Chavan-Gautam P, Mehendale S, Joshi SR. Variable methylation potential in preterm placenta: implication for epigenetic programming of the offspring. Reprod Sci 2017; 24(6): 891-901.
55
Arpón A, Milagro FI, Razquin C, et al. Impact of consuming extra-virgin olive oil or nuts within a mediterranean diet on dna methylation in peripheral white blood cells within the predimed-navarra randomized controlled trial: a role for dietary lipids. Nutrients 2017; 10(1)E15
56
Acevedo N, Frumento P, Harb H, et al. Histone acetylation of immune regulatory genes in human placenta in association with maternal intake of olive oil and fish consumption. Int J Mol Sci 2019; 20(5)E1060
57
Shen W, Wang C, Xia L, et al. Epigenetic modification of the leptin promoter in diet-induced obese mice and the effects of N-3 polyunsaturated fatty acids. Sci Rep 2014; 4: 5282.
58
Hirabara SM, Folador A, Fiamoncini J, et al. Fish oil supplementation for two generations increases insulin sensitivity in rats. J Nutr Biochem 2013; 24(6): 1136-45.
59
Calkins K, Devaskar SU. Fetal origins of adult disease. Curr Probl Pediatr Adolesc Health Care 2011; 41(6): 158-76.
60
Goyal R, Goyal D, Leitzke A, Gheorghe CP, Longo LD. Brain renin-angiotensin system: Fetal epigenetic programming by maternal protein restriction during pregnancy. Reprod Sci 2010; 17(3): 227-38.
61
Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R. Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatr Res 2001; 49(4): 460-7.
62
Togher KL, Togher KL, O’Keeffe MM, et al. Epigenetic regulation of the placental HSD11B2 barrier and its role as a critical regulator of fetal development. Epigenetics 2014; 9(6): 816-22.
63
Harjes U. Epigenetic control by sugar. Nat Rev Cancer 2018; 18(10): 598-9.
64
Wu D, Hu D, Chen H, et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 2018; 559(7715): 637-41.
65
El-Osta A, Brasacchio D, Yao D, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 2008; 205(10): 2409-17.
66
Kolb AF, Petrie L. Folate deficiency enhances the inflammatory response of macrophages. Mol Immunol 2013; 54(2): 164-72.
67
Indrio F, Martini S, Francavilla R, et al. Epigenetic Matters: The Link between Early Nutrition, Microbiome, and Long-term Health Development. Front Pediatr 2017; 5: 178.
68
Davison JM, Mellott TJ, Kovacheva VP, Blusztajn JK. Gestational choline supply regulates methylation of histone H3, expression of histone methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a), and DNA methylation of their genes in rat fetal liver and brain. J Biol Chem 2009; 284(4): 1982-9.
69
McKay JA, Groom A, Potter C, et al. Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12. PLoS One 2012; 7(3): e33290.
70
Mahmoud AM, Ali MM. Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients 2019; 11(3): 608.
71
Fawal M-A, Jungas T, Kischel A, Audouard C, Iacovoni JS, Davy A. Cross Talk between one-carbon metabolism, Eph signaling, and histone methylation promotes neural stem cell differentiation. Cell Rep 2018; 23(10): 2864-2873.e7.
72
Schorah CJ, Smithells RW, Scott J. Vitamin B12 and anencephaly. Lancet 1980; 1(8173): 880.
73
Serrano M, Pérez-Dueñas B, Montoya J, Ormazabal A, Artuch R. Genetic causes of cerebral folate deficiency: Clinical, biochemical and therapeutic aspects. Drug Discov Today 2012; 17(23-24): 1299-306.
74
Fryer AA, Nafee TM, Ismail KM, Carroll WD, Emes RD, Farrell WE. LINE-1 DNA methylation is inversely correlated with cord plasma homocysteine in man: A preliminary study. Epigenetics 2009; 4(6): 394-8.
75
Chen G, Broséus J, Hergalant S, et al. Identification of master genes involved in liver key functions through transcriptomics and epigenomics of methyl donor deficiency in rat: Relevance to nonalcoholic liver disease. Mol Nutr Food Res 2015; 59(2): 293-302.
76
Roberfroid D, Huybregts L, Lanou H, et al. Prenatal micronutrient supplements cumulatively increase fetal growth. J Nutr 2012; 142(3): 548-54.
77
Henderson AM, Tai DC, Aleliunas RE, et al. Maternal folic acid supplementation with vitamin B12 deficiency during pregnancy and lactation affects the metabolic health of adult female offspring but is dependent on offspring diet. FASEB J 2018; 32(9): 5039-50.
78
Guéant JL, Elakoum R, Ziegler O, et al. Nutritional models of foetal programming and nutrigenomic and epigenomic dysregulations of fatty acid metabolism in the liver and heart. Pflugers Arch 2014; 466(5): 833-50.
79
Vanhees K, Vonhögen IG, van Schooten FJ, Godschalk RW. You are what you eat, and so are your children: the impact of micronutrients on the epigenetic programming of offspring. Cell Mol Life Sci 2014; 71(2): 271-85.
80
Li C, Guo S, Gao J, et al. Maternal high-zinc diet attenuates intestinal inflammation by reducing DNA methylation and elevating H3K9 acetylation in the A20 promoter of offspring chicks. J Nutr Biochem 2015; 26(2): 173-83.
81
Wong CP, Rinaldi NA, Ho E. Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation. Mol Nutr Food Res 2015; 59(5): 991-9.
82
Carlos-Reyes Á, López-González JS, Meneses-Flores M, et al. Dietary compounds as epigenetic modulating agents in cancer. Front Genet 2019; 10: 79.
83
Thakur VS, Deb G, Babcook MA, Gupta S. Plant phytochemicals as epigenetic modulators: role in cancer chemoprevention. AAPS J 2014; 16(1): 151-63.
84
Shankar E, Kanwal R, Candamo M, Gupta S. Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. Semin Cancer Biol 2016; 40-41: 82-99.
85
Lameira AG Jr, Françoso BG, Absy S, et al. Resveratrol reverts epigenetic and transcription changes caused by smoke inhalation on bone-related genes in rats. DNA Cell Biol 2018; 37(8): 670-9.
86
Izquierdo V, Palomera-Ávalos V, López-Ruiz S, Canudas A-M, Pallàs M, Griñán-Ferré C. Maternal resveratrol supplementation prevents cognitive decline in senescent mice offspring. Int J Mol Sci 2019; 20(5): 1134.
87
Kataoka S, Norikura T, Sato S. Maternal green tea polyphenol intake during lactation attenuates kidney injury in high-fat-diet-fed male offspring programmed by maternal protein restriction in rats. J Nutr Biochem 2018; 56: 99-108.
88
Szutorisz H, Hurd YL. High times for cannabis: Epigenetic imprint and its legacy on brain and behavior. Neurosci Biobehav Rev 2018; 85: 93-101.
89
Rastelli M, Knauf C, Cani PD. Gut microbes and health: A focus on the mechanisms linking microbes, obesity, and related disorders. Obesity (Silver Spring) 2018; 26(5): 792-800.
90
Koleva PT, Kim JS, Scott JA, Kozyrskyj AL. Microbial programming of health and disease starts during fetal life. Birth Defects Res C Embryo Today 2015; 105(4): 265-77.
91
Zambrano E, Nathanielsz PW. Mechanisms by which maternal obesity programs offspring for obesity: evidence from animal studies. Nutr Rev 2013; 71(Suppl. 1): S42-54.
92
Zhou L, Xiao X. The role of gut microbiota in the effects of maternal obesity during pregnancy on offspring metabolism. Biosci Rep 2018; 38(2)BSR20171234
93
Le Bourgot C, Le Normand L, Formal M, et al. Maternal short-chain fructo-oligosaccharide supplementation increases intestinal cytokine secretion, goblet cell number, butyrate concentration and Lawsonia intracellularis humoral vaccine response in weaned pigs. Br J Nutr 2017; 117(1): 83-92.
94
Bouchaud G, Castan L, Chesné J, et al. Maternal exposure to GOS/inulin mixture prevents food allergies and promotes tolerance in offspring in mice. Allergy 2016; 71(1): 68-76.
95
Paul HA, Bomhof MR, Vogel HJ, Reimer RA. Diet-induced changes in maternal gut microbiota and metabolomic profiles influence programming of offspring obesity risk in rats. Sci Rep 2016; 6: 20683.
96
Vähämiko S, Laiho A, Lund R, Isolauri E, Salminen S, Laitinen K. The impact of probiotic supplementation during pregnancy on DNA methylation of obesity-related genes in mothers and their children. Eur J Nutr 2019; 58(1): 367-77.
97
Wickens KL, Barthow CA, Murphy R, et al. Early pregnancy probiotic supplementation with Lactobacillus rhamnosus HN001 may reduce the prevalence of gestational diabetes mellitus: a randomised controlled trial. Br J Nutr 2017; 117(6): 804-13.
98
Dolatkhah N, Hajifaraji M, Abbasalizadeh F, Aghamohammadzadeh N, Mehrabi Y, Abbasi MM. Is there a value for probiotic supplements in gestational diabetes mellitus? A randomized clinical trial. J Health Popul Nutr 2015; 33: 25.
99
Sahhaf Ebrahimi F, Homayouni Rad A, Mosen M, Abbasalizadeh F, Tabrizi A, Khalili L. Effect of L. acidophilus and B. lactis on blood glucose in women with gestational diabetes mellitus: A randomized placebo-controlled trial. Diabetol Metab Syndr 2019; 11: 75.
100
Chen X, Jiang X, Huang X, He H, Zheng J. Association between probiotic yogurt intake and gestational diabetes mellitus: A case-control study. Iran J Public Health 2019; 48(7): 1248-56.