Nutrition in Epigenetics
The epigenotype could be used not only to predict susceptibility to certain cancers but also to assess the effectiveness of dietary modifications to reduce such risk. The influence of diet or dietary components on epigenetic modifications and the impact on cancer initiation or progression has been assessed herein. The occurrence of cancer is dependent on the interplay between the genome and the epigenome, which together interact with environmental factors, including nutrition.
The study of nutrition is complex as it is influenced by numerous variables that may have short e. Despite these challenges, the influence of nutrition on epigenetics has been extensively studied [ 1 , 2 , 3 , 4 ], although many outstanding questions remain. Epigenetics is the non-Mendelian inheritance of DNA modifications that may influence gene expression on one or more alleles, that is, epigenetic changes are heritable from cell to cell and may be heritable from parent to offspring [ 5 ]. Such epigenetic marks are acquired throughout life [ 6 ] and some are potentially reversible [ 7 ], but nonetheless, once established, are relatively stable [ 8 ].
It is widely accepted that there are critical windows during early development during which epigenetic marks are cleared and then re-established, and it is not surprising that an embryo would be particularly vulnerable to environmental influences during this time [ 9 ]. Although less pronounced, nutrition-induced epigenetic variation may occur throughout the life course [ 9 ]. Nutrition has trans-generational epigenetic effects, and more and more information is being gathered regarding when humans are most sensitive to nutritional epigenetic effects, and which nutritional components are likely to have the most profound impact.
In pregnant woman the disease risk of their offspring varied depending on which trimester the foetus was exposed to the famine of the Dutch Hunger Winter [ 9 ]. Offspring exposed during the first trimester suffered more frequently from cardiovascular disease and reduced cognitive function later in life; those exposed during the second trimester tended to suffer with impaired kidney and lung function; whilst those exposed during the third trimester suffered more commonly from impaired glucose tolerance [ 9 ]. However, although there is little to link this early life exposure to severe famine-induced IGF2 hypomethylation to health status in adulthood, energy restriction during critical periods does appear to be associated with a reduced rate of colorectal cancer CRC [ 10 ].
Over the past two decades a number of case-control and prospective cohort studies were carried out to test the potential protective effect of various food-patterns, -groups and -components on the risk of developing a number of different cancers by modifying the epigenome [ 2 , 16 , 17 , 18 ]. Some of these effects and potential mechanisms will be discussed. There is increasing attention on epigenetics, particularly as it is understood that genotype alone does not account for all cancer risk.
It is widely accepted that many cancers could be avoided through changes in lifestyle. In addition, it is useful to identify biomarkers for early signs of cancer development, since these can then be utilised to assess the potential benefit of a nutrient or food component for its effect on reducing cancer susceptibility [ 20 ]. Epigenetic modifications may qualify as such markers. An overview of epigenetics and the interplay between epigenetics, genetics and nutrition on the development of cancers, particularly breast, colon and colorectal cancers, are reviewed herein.
Uncontrolled cell proliferation is one of the hallmarks of cancer, and loss of cell cycle control could be a contributory factor. In order to determine the impact of a particular food on epigenetic modifications and risk of a disease, the intake of the food of interest needs to be assessed retrospectively or prospectively in a suitable human population.
To achieve this, a dietary intervention is often carried out. Before implementing a dietary intervention study it is first necessary to identify the dietary pattern, foods or food components to be included in the intervention [ 21 ]. Thereafter the intervention needs to be applied such that the study is sufficiently powered, and the data to be collected are identified. In prospective studies, communication with study participants occurs via printed material, face-to-face, telephonic, online or a combination of these methods.
Diet during early development can have long-lasting effects
Urinary or blood biomarkers may also be used, and such biomarkers have the advantage of being objective. Each of these techniques has strengths and weaknesses regarding data collection and may include under reporting, recall bias, inconsistencies, observation bias, ease of administration and ease of data collection and analysis [ 23 , 24 , 25 , 26 ].
In addition to nutrition, epigenetic host factors contribute to the development of cancer. Such factors include DNA methylation, histone modification and the action of epigenetically modified small non-coding RNAs. DNA methylation is, to date, the most commonly reported epigenetic modification which is not to say it is the most common ; it is the most readily studied and this is likely the reason why more is known about it.
DNA can be methylated sparsely throughout the genome at intergenic regions, or more densely at CpG islands that are often, but not exclusively located in promoter regions of tumour suppressor genes TSGs , DNA repair genes or oncogenes [ 7 ]. The aberrant methylation of promoter regions can influence gene expression, and abnormal levels of global methylation are associated with numerous cancers Figure 1. Histone tails can be post-transcriptionally modified, and these modifications together with other epigenetic marks determine whether the chromatin is active or inactive and this in turn affects the expression status of the genes within that chromatin region [ 7 ].
Small non-coding RNA can undergo DNA methylation or histone modification, thereby influencing the expression status of various genes. Before considering the interactions that may take place within the epigenome, genome and the environment with respect to the development of cancer, it is important to understand the types and roles of epigenetic marks we have detected to date. Although there is evidence to support the role of dietary components in the regulation of epigenetically modified gene expression, the mechanism of action of these dietary components may vary amongst different cancer types [ 27 ].
DNA methylation is a simple addition of a methyl group CH 3 to position 5 on the pyrimidine ring of the cytosine residue in a cytosine-guanine CG pair. Despite the potential mutagenic hazard of CpG dinucleotides, i. The genome of a young, healthy human is sparsely populated with CpG sites in intergenic regions and repetitive sequences, and many of these sites are methylated. In cancer, hypomethylation of these regions often takes place and hence the chromatin becomes less densely packaged and the DNA can be transcribed. Hypomethylation may occur in repetitive sequences or transposons, often leading to genome instability and DNA breakage.
In addition, hypomethylation may bring about loss of imprinting control or demethylation of promoters that ordinarily would be silenced e. Loss of imprinting of insulin like growth factor 2 , leading to microsatellite instability, was found to be associated with the development of CRC at a younger age [ 29 ], whilst Suter et al. In contrast to CpG sites in intergenic regions, promoter sites are frequently flanked by CpG dense regions, known as CpG islands and these islands are usually unmethylated.
This lack of methylation helps ensure that the chromatin remains open and therefore the genes within that chromatin domain can be transcribed. In contrast, DNA hypermethylation of a gene promoter usually leads to gene silencing and this is one of the most common somatic aberrations in cancer [ 33 ]. During cancer therapy it is desirable to reactivate TSGs, and this can sometimes be achieved by demethylating TSG promoters [ 34 ]. Clearly inhibition of tumour growth is more complex than reversal of aberrant TSG promoter methylation.
A characteristic of human cancers is abnormal gene expression, and this change in expression can be brought about by both genetic and epigenetic changes in oncogenes and TSG [ 41 ]. In order to identify potential biomarkers Kim et al. A decrease in OSMR expression was associated with progression of CRC such that more advanced disease, as indicated by tumour grade, was consistent with lower levels of gene expression [ 41 ].
Both Deng et al. Unlike Kim et al. Although dietary components have not been associated with a reduction in OSMR methylation, the authors speculate that this may be possible as both AZA and trichostatin A have been shown to increase OSMR gene expression [ 43 ].
If DNMT1 is absent, then passive demethylation takes place such that the amount of DNA methylation will halve each round of replication during the formation of daughter cells, leading to hypomethylation and aberrant gene expression. It is widely thought that dysregulation of the epigenome promotes the development of cancers and evidence continues to be published on the simultaneous progression in aberrant DNA methylation and advancement of cancers, particularly CRC [ 46 ]. Despite the importance of histone marks, much less is known about the influence of nutrition on histone modifications [ 20 ].
However, much is understood about the actual modifications. A nucleosome, which is the basic repeating unit in chromatin, allows DNA to be packaged within the nucleus. The nucleosomes are linked together by DNA of between 20—80 base pairs. Histone tails commonly extend from the N terminus of the histone proteins and the tails can be modified during embryonic development and throughout life [ 48 ].
Possible histone modifications include mono-, di-, and tri-methylation, acetylation, ubiquitylation, phosphorylation and ribosylation, and this most commonly occurs on the N terminus of histone tails [ 49 ]. Such modifications can influence the density of the chromatin, leading to a change in the accessibility of the DNA and hence its involvement in gene regulation [ 49 ].
Only rarely is it one specific histone modification that determines gene expression levels [ 20 ], and therefore results can appear contradictory between studies depending on the histone modifications assessed. Instead, it is the combination of specific histones and specific types of modification. This makes the interpretation of histone modifications challenging. Commonly, histone methylation leads to a condensed chromatin structure and suppressed gene expression [ 51 ]. Just as lysine and arginine residues on histones can be methylated, lysine can also be acetylated.
Histone acetylation usually leads to an open chromatin structure promoting gene expression [ 51 ]. Histone acetyl transferases are responsible for acetylation, and histone deactylases HDACs are responsible for the removal of acetyl groups. HDACs can target both histone and non-histone proteins such as transcription factors and DNA repair enzymes [ 52 ], so are important in the control of gene expression. Genes can be silenced by methylation of CpG islands and these genes can also be silenced by histone modifications without CpG methylation [ 53 ]. In breast cancers some histone lysine demethylases KDM are elevated e.
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Differential KDM expression is thought to be associated with aberrant histone methylation, particularly the demethylation of H3K4 [ 54 ]. Prognosis has also been associated with the expression levels of particular KDMs, for example low levels of KDM3B are correlated with shorter relapse-free survival [ 54 ]. In prostate cancer, several genes associated with DNA methylation and histone modifications have been found expressed at elevated levels [ 55 ].
In addition, increased H3K4diMe has been found in cancerous but not in normal prostate tissues and has been associated with risk of tumour recurrence [ 55 , 56 ]. H3K4diMe is correlated with activation of genes involved in cell proliferation and hence may influence tumourigenesis [ 55 , 56 ]. Some dietary components have a similar effect on HDACs as HDAC inhibitory drugs, and therefore might be useful in inducing cell cycle arrest or apoptosis in cancer cells [ 57 , 58 ].
These components will be discussed in Section 3. Small non-coding RNAs, which make up much of the RNA content of a cell, are approximately 20—30 base pairs in length, and, as the name suggests, are RNAs that are not translated into protein. They act in regulating gene expression by a number of mechanisms, including heterochromatin formation and inhibition of translation [ 50 , 61 ]. In turn, epigenetic effects are known to regulate miRNA expression. For example, miRNAa is epigenetically silenced by hypermethylation in HCT a colorectal cell line , and such hypermethylation has also been observed in cervical and gastric cancers [ 63 , 64 ].
This in turn leads to cyclin D kinase 6 overexpression, which is involved in cell-cycle progression [ 62 ]. Dysregulation of miRNAs is associated with the development of a number of cancers, and it is thought that miRNAs function as a genome surveillance mechanism [ 65 ]. There are a number of specific miRNAs that have been found to influence the expression of various genes. For example, partial methylation of the promoters of miRNAa and miRNA has been found in prostate cancer cells and tumours [ 66 ].
This partial methylation leads to decreased expression of these miRNAs [ 66 ]. This in turn results in the increased expression of TRIM68 and PGK-1 and these genes are associated with the progression of prostate cancer [ 66 ]. In breast cancer Qin et al. MiRNAb was expressed at high levels in aggressive breast cancer, and was found to target the homeobox D10 gene, which is a repressor gene involved in cell migration and invasion [ 67 ]. Aberrant promoter methylation or mutant p53 can result in the down regulation of miRNA expression due to the lack of pmiRNA binding in prostate cancer and numerous cancerous cell lines [ 68 ].
The atypical expression of numerous other miRNAs has been reported in a number of cancers, particularly metastatic cancers [ 62 , 69 ]. In the following sections the influence of nutrition on different types of epigenetic modifications and the risk of progression of cancers are outlined. There are a number of dietary components that are considered influential in the development or inhibition of cancer Table 1. These components include folate from green leafy vegetables, cinnamic acids from coffee, grain cereals, plums and kiwifruit, polyphenols such as epigallocatechingallate EGCG from green tea, resveratrol from red grapes and their products, sulforaphane and isothiocyanates from cruciferous vegetables, lignans from linseed, selenium and vitamin E.
It is thought that many of these dietary compounds provide a protective effect against cancer by influencing epigenetic modifications [ 7 ]. Such nutritional effects may be organ specific [ 70 ]. Estrogen receptor ; FADS2: Phosphatase and tensin homolog ; PUFA: The aforementioned three DNA modification mechanisms, namely methylation, histone modification and the action of small non-coding RNAs, interact to silence transposons and unpaired chromatin e. Aberrant epigenetic modifications and the risk of cancers both increase with age, with interactions of the genome and epigenome as well as with environmental factors such as diet type likely contributing to cancer risk [ 2 , 6 ].
The most sensitive time in the epigenome is during primordial germ cell development and early embryo development, i. However, there is also evidence that nutrition later in life can influence health with respect to the development of cancers. Cancer is caused by an imbalance in the mechanisms that control cell proliferation. The loss of control of cell proliferation can be due to genetic mutations and epigenetic aberrations, many of which accumulate over time. There are limitations associated with both epidemiological and intervention studies. Epidemiological studies, for example, cannot be used to differentiate between cause and effect; differences in genotype and lifestyle may cloud relatively small size effects due to diet; and cancer prevention trials take time depending on duration of cancer development [ 20 ].
Nonetheless, there are studies that convincingly show both early life and later life nutritional effects on the epigenome. Folate is an important one-carbon donor, and one-carbon metabolism is essential for the synthesis of DNA, proteins and phospholipids [ ]. Folate is obtained solely from the diet and is converted to 5,methylenetetrahydrofolate MTHF. Methyl groups from methionine and choline are used to form S-adenosyl-methionine SAM , which is an important DNA methylating agent [ ].
Deficiency in folate does not have the same impact in all tissues and at all stages of development. For example; Chang et al. Similarly, those with the MTHFD1 GA genotype were found to be at higher risk for giving birth to babies with a neural tube defect, thought to be due to a greater demand for choline for example, from eggs as a methyl donor [ ].
Folate deficiency is thought to exert its effect through a number of possible mechanisms namely: However, much of this work has been carried out in mouse models and therefore may not apply directly to humans [ , ].
The associations between folate and epigenetic modifications appear somewhat inconsistent, since they are dependent on the cell type, epigenotype and genotype [ , , ] and may vary depending on whether supplemental or dietary folate was consumed [ ]. It is apparent that adding extra folate to the diet may exert different effects depending on the amount consumed, the stage of development during which it is consumed [ , ] and the genetic and epigenetic background of the person taking it.
For example, people with the MTHF reductase TT genotype and a high intake of alcohol are at greater risk of aberrant methylation of cancer-related genes e. It is widely accepted that elevated ethanol consumption interferes with the production of SAM by inhibiting the availability of vitamin B6 and B12 [ 9 ], and therefore it is not surprising that risk of oral squamous cell carcinoma is acerbated by high alcohol and low folate intake. Similar to the findings in oral squamous cell carcinoma [ ], an association was found between an increased level of methylation in these gene promoters and people with low folate and high alcohol intake relative to a high folate and low alcohol intake [ ].
This finding is also consistent with data published by Supic et al. Whilst folate supplementation can be beneficial, it can also be harmful, as high serum folate levels may be detrimental in those who already harbour neoplastic lesions [ 84 ]. This is consistent with the role of folate derivatives as cofactors in nucleotide synthesis.
Epigenetics, Nutrition, and Our Health: How What We Eat Could Affect Tags on Our DNA
While epigenetics may be only one layer, it is a critical one. We may be able to manipulate the dietary bioactive compounds we consume in order to affect epigenetic alterations. More than 1 out of 3 U. By utilizing personalized services which are becoming increasingly popular, we may be able to better monitor our health and make the right choices to improve it.
Scientific research is demonstrating that nutrients in different foods and supplements we consume may be able to adjust or reverse epigenetic mechanisms. While more studies must be conducted, the collection of fascinating epigenetic evidence can be used to support better lifestyle choices which are oftentimes already recommended for their general health benefits.
Numerous foods and supplements used in many studies assessing mouse and human models lend support the notion that epigenetics is highly involved in adjusting epigenetic tags, affecting our health and susceptibility to disease. Polyphenols, for example, which are found in foods such as fruits, vegetables, olives, and chocolate, have been shown to be effective in promoting resilience again stress and reducing depression.
The combination of these compounds were found to epigenetically reduce stress and depression by modulating inflammatory responses and synaptic plasticity in the brains of those with depression. Phytochemicals like these are of particular interest to the scientific and health community due to their strong antioxidant, anti-inflammatory, antimicrobial, and anti-tumorigenic activities that contribute to health and wellness. Biochemically, there are inflammatory compounds that are self-perpetuating known as hydroxyl radicals and peroxynitrites, she explained.
Superoxide is developed in the creation of energy, ATP, but is also developed in abundance during a process called NOS uncoupling. This leads to peroxynitrite, a very inflammatory compound. Hall emphasizes the importance of using epigenetic information to create a focused protocol to support healthy biochemistry.
During the development of multicellular organisms, different cells and tissues acquire different programs of gene expression. It is well recognized that a series of precisely timed and regulated epigenetic changes are required to ensure the proper development of complex organisms like humans [ 15 , 27 ]. At the morula stage, an early step of embryonic development, DNA demethylation occurs to erase all of the parent-of-origin methylation marks, except those of the imprinted genes.
This allows for the inheritance of parental-specific monoallelic expression in somatic tissues throughout adulthood. This demethylation phase is followed by the de novo DNA methylation of the genome to establish the proper methylation patterns of the growing organism [ 28 ]. In such a way, as the embryo grows the offspring acquires their appropriate epigenetic features. In parallel to these changes occurring in somatic cells, another set of genomic reprogramming takes place in the cells of the germ line during gametogenesis [ 29 ]. In fact, during gonadal sex determination, primordial germ cells undergo genome-wide demethylation, which erases previous parental-specific methylation marks.
Afterward, for example in the male germ line, paternal methylation marks occur in specific genes in the gonocytes that subsequently will develop into spermatogonia.
The Interaction between Epigenetics, Nutrition and the Development of Cancer
Conversely, the female germ line establishes maternal methylation marks of imprinted genes at a later stage. In addition to DNA methylation, histone modifications are thought to play a role in the establishment of both sex-specific and non sex-specific marks because an extensive loss of histone methylation and acetylation occurs along with the loss of DNA methylation at the morula stage [ 30 ]. Epigenetic marks assure the proper expression of the imprinted genes throughout the embryonic development.
For example, genomic imprinting results in the monoallelic, parent-of-origin dependent expression of genes specifically required for key developmental steps. It is predictable from this scenario that the aberrant methylation of imprinted genes, mostly loss of imprinting LOI in the early stages of development, can alter the expression of critical genes, and then may bring out birth defects and adulthood diseases such as cancer [ 31 ]. In this regard, given the nature of the monoallelic expression, imprinted genes are particularly susceptible to the effect of epigenetic aberrations.
In addition, for the strict dependence of these early steps of development to nutritional support, inherited and acquired epigenetic marks are particularly vulnerable to the interference coming from environmental stimuli [ 32 ]. Due to the dynamic changes of the epigenetic regulation in development, particularly during gametogenesis and early embryogenesis, the epigenome displays labile nature, which allows it to respond and adapt to environmental stressors, including nutritional modification. For instance, periconceptional supplementation or restriction of the maternal diet with betaine, choline, folic acid, methionine, or vitamin B in experimental models have been shown to affect the establishment of DNA methylation patterns, altering the gene expression and phenotype of the offspring [ 33 ].
Three main experimental approaches are in use to better understand the underlying mechanism by which nutritional modifications affect the epigenetic profile during critical developmental windows: IGF2 is a key protein in human growth and development [ 34 ]. The IGF2 gene is maternally imprinted and is one of the best-characterized epigenetically regulated loci [ 32 ]. The imprinting of this locus is maintained through the methylation of a DNA sequence named the differentially methylated region DMR , the hypomethylation of which leads to bi-allelic expression of the IGF2 gene.
As illustrated by retrospective studies from the Dutch famine cohort [ 35 ] as well as in experimental animal studies [ 36 - 38 ], the IGF2 gene has been shown to be characterized by a labile methylation pattern depending on the nutritional or environmental stimuli received by the growing organism during the early life. Table 3 summarizes some data that support the observed developmental plasticity of the IGF2 locus. Notably, post-weaning mice fed a methyl-deficient diet exhibit permanent LOI and dysregulated expression of the IGF2 gene [ 37 ], suggesting that both childhood and maternal diet contribute to the LOI in the IGF2 locus in humans.
The agouti mouse has been extensively used to investigate the phenotypic impact of the nutritional modification during critical developmental periods, and the environmental influence on the fetal epigenome [ 39 ]. The agouti viable yellow A vy locus regulates mouse coat color; more importantly, the product of the agouti gene interferes with the regulation of body weight at the level of the hypothalamus.
DNA hypomethylation of the agouti gene promoter results in the accumulation of the agouti protein; as consequence, the mouse develops a yellow coat color as well as obesity. Conversely, hypermethylation of the promoter reduces the level of the agouti protein, and this, consequently, results in mice with lean phenotype and brown coat color.
Interestingly, feeding agouti female pregnant mice with a diet enriched with methyl donor supplementation such as folic acid, vitamin B12, choline and betaine has been shown to modify the phenotype of their heterozygote offspring [ 40 ]. This effect was confirmed to be mediated by the hypermethylation of the A vy promoter in the offspring of supplemented dams [ 41 ]. Table 4 provides additional evidences that specific maternal dietary treatments or environmental factors affect the phenotype of the agouti offspring through epigenetic mechanism.
The central brain region integrates various peripheral signals to regulate energy balance [ 42 ]. The hypothalamus plays a key role in the regulation of food intake and energy expenditure. For these reasons, the hypothalamus is an excellent organ candidate to study the epigenetic changes that mediate the developmental reprogramming of energy metabolism. Not surprisingly, maternal overnutrition [ 43 - 46 ] and undernutrition [ 47 , 48 ] have been shown to alter hypothalamic DNA methylation.
These changes in DNA methylation have been reported to persist from early life to adulthood [ 43 , 46 ], affecting the overall metabolism in the adult. Developing organisms seem to have a wide range of susceptibility to epigenetic changes [ 49 ]. Appropriate dynamics in epigenetic modifications are essential for embryogenesis, early fetal development and early postnatal growth.
Consequently, the inadequate establishment of epigenetic modifications during critical developmental periods due to changes in the maternal diet or other environmental factors may induce pediatric developmental diseases and even affect health in adulthood.
Since much of the reprogramming that occurs during early life may go unrecognized until adulthood, a better understanding of the interplay between genetic and epigenetic interaction in critical time windows of development would improve our ability to determine individual susceptibility to a wide range of diseases. We declare that we have no conflict of interest. National Center for Biotechnology Information , U. Journal List Clin Nutr Res v. Published online Jan Hyeran Jang 1, 2 and Carlo Serra 1, 2.
Find articles by Hyeran Jang. Find articles by Carlo Serra. This article has been cited by other articles in PMC. Abstract Increasing epidemiological evidence suggests that maternal nutrition and environmental exposure early in development play an important role in susceptibility to disease in later life. Nutrition, Reprogramming, Development, Epigenetic, Disease. Introduction Many human diseases that appear in adulthood are related to growth patterns during early life.
Dutch Famine Birth Cohort Insights in the importance of nutritional supply during a critical period on long-term disease outcome were gained from the Dutch Famine cohort. Why Your DNA Isn't Your Destiny Another interesting epidemiological study pointed out the importance of nutritional status during puberty and its impact on the offspring's health, by investigating if the availability of food to one generation affected longevity and health of the descendants.
Early nutrition and onset of metabolic phenotype in adult The three main insights of a number of studies from the Dutch and Norrbotten's cohorts are: Table 1 Experimental animal models with maternal dietary modifications during development or early life, and their impact on phenotype of offspring.
Open in a separate window. Table 2 Rodent small litter models of postnatal overnutrition, and their impact on metabolic phenotype. Epigenetics Since the Human Genome Project completed sequencing the 3 billion chemical base pairs that make up human DNA in April , it became clear not only that we are able to read nature's complete genetic blueprint, but also that the information stored in the sequence of the DNA is not enough per se to completely explain human development, physiology and disease. DNA methylation DNA methylation is a common modification in mammalian genomes and is considered a stable epigenetic mark transmitted through DNA replication and cell division [ 15 ].
Histone modification The DNA in the cells is packaged as chromatin. Developmental plasticity During the development of multicellular organisms, different cells and tissues acquire different programs of gene expression. Early life nutrition and altered epigenetic regulation Due to the dynamic changes of the epigenetic regulation in development, particularly during gametogenesis and early embryogenesis, the epigenome displays labile nature, which allows it to respond and adapt to environmental stressors, including nutritional modification.
Table 3 Effect of maternal dietary modifications on imprinted gene, IGF2. Agouti model The agouti mouse has been extensively used to investigate the phenotypic impact of the nutritional modification during critical developmental periods, and the environmental influence on the fetal epigenome [ 39 ].
Table 4 Effects of maternal diet or environmental factors on yellow agouti offspring.