Nutriepigenomics
Encyclopedia
Nutriepigenomics is the study of food nutrient
s and their effects on human health through epigenetic modifications. There is now considerable evidence that nutritional imbalances during gestation
and lactation
are linked to non-communicable diseases, such as obesity
, cardiovascular disease
, diabetes, hypertension
, and cancer
. If metabolic disturbances occur during critical time windows of development, the resulting epigenetic alterations can lead to permanent changes in tissue and organ structure or function and predispose individuals to disease.
Overview =
Epigenetics
relates to heritable changes in gene function that occur independently of alterations in primary DNA
sequence. Two major epigenetic mechanisms implicated in nutriepigenomics are DNA methylation
and histone
modification. DNA methylation in gene promoter regions usually results in gene silencing and influences gene expression. While this form of gene silencing is extremely important in development and cellular differentiation, aberrant DNA methylation can be detrimental and has been linked to various disease processes, such as cancer. The methyl groups used in DNA methylation are often derived from dietary sources, such as folate and choline
, and explains why diet can have a significant impact on methylation patterns and gene expression. Gene silencing can also be reinforced through the recruitment of histone deacetylases to decrease transcriptional activation. Conversely, histone acetylation induces transcriptional activation to increase gene expression. Dietary components can influence these epigenetic events, thereby altering gene expression and disturbing functions such as appetite control, metabolic balance and fuel utilization.
Various genetic sequences can be targeted for epigenetic modification. A transcriptome-wide analysis in mice found that a protein-restricted (PR) diet during gestation resulted in differential gene expression in approximately 1% of the fetal genes analyzed (235/22,690). Specifically, increased expression was seen in genes involved in the p53
pathway, apoptosis
, negative regulators of cell metabolism, and genes related to epigenetic control. Additional studies have investigated the effect of a PR-diet in rats and found changes in promoter methylation of both the glucocorticoid receptor and peroxisome proliferator-activated receptor (PPAR). Altered expression of these receptors can result in elevated blood glucose levels and affect lipid and carbohydrate metabolism. Feeding a PR-diet to pregnant and/or lactating mice also increased expression of glucokinase, acetyl-CoA carboxylase, PPARα, and acyl-CoA oxidase. Changes in expression were reportedly due to epigenetic regulation of either the gene promoter itself, or promoters of transcription factors that regulate gene expression. Additional genes that have been shown, either by in vitro
or in vivo
studies, to be regulated by epigenetic mechanisms include leptin, SOCS3, glucose transporter (GLUT)-4, POMC, 11-β-hydroxysteroid dehydrogenase type 2 and corticotrophin releasing hormone. Epigenetic modification of these genes may lead to “metabolic programming” of the fetus and result in long-term changes in metabolism
and energy homeostasis.
is a term used to describe the process in which fetuses adapt to their environment. Environmental cues, including dietary components, present in the in utero
environment can induce significant changes in the expression of the genome through epigenetic modifications. Fetal developmental plastic responses can cause changes in lean body mass, endocrinology, blood flow and vascular loading, and lead to increased risk of various diseases in adulthood.
secretion is associated with low birth weight and can lead to insulin resistance as babies accumulate body fat. Studies using intrauterine growth retarded (IUGR) rats have found that growth inhibition can lead to decreased expression of Pdx1 transcription factor, which is essential for differentiation and function of pancreatic beta cells. Decreased histone acetylation at the proximal promoter of Pdx1 is responsible for reduced Pdx1 expression and subsequently results in a cascade of histone deacetylation and methylation events that can result in type-2 diabetes.
(adiposity) and predisposes babies for obesity in childhood and adulthood. Animal studies have shown that maternal overnutrition may impact brain development and cause disruptions to programming of the hypothalamus
. Offspring that were exposed to a high-fat or high-caloric maternal diet had increased levels of insulin, glucose and leptin. It is hypothesized that these elevations are due to disturbances in the complex neuronal network that includes the neuropeptide Y (NPY) and proopiomelanocortin (POMC) pathways. This altered neuronal signaling can consequently impact food-intake behavior and lead to diet-induced obesity in adulthood. While epigenetic modifications are most likely involved in the development of obesity, the specific target genes have yet to be identified. Genes involved in adipogenesis, such as fibroblast growth-factor-2, phosphatase and tensin homologue, cyclin-dependent kinase inhibitor 1A and oestrogen receptor-alpha, possess multiple CpG islands in their promoter sites and may act as epigenetic targets. Furthermore, it has been shown that prenatal exposure to a hypomethylating agent, such as bisphenol A
(BPA), is associated with increased body weight and suggests modified DNA methylation as a mechanism for increasing susceptibility to obesity.
(SAM), which is used to supply DNA methyltransferases with methyl groups. Therefore, changes in folate supply have a substantial effect on DNA methylation patterns. Low levels of folate are associated with an increased risk of preterm delivery, poor growth of the placenta and uterus, and intrauterine growth retardation. Several complex diseases, including cancer, cardiovascular diseases and autism
have also been linked to maternal folate status. Based on animal studies it has been hypothesized that reduced folate intake could increase the risk of neural tube defects
by reducing the amount of methylayed DNA during cranial neural tube closure. Recently it was discovered that folate protection from congenital heart defects is linked to epigenetics and Wnt signaling. Multiple environmental factors target the Wnt signaling pathway
during embryogenesis and can cause misregulation of the pathway. Folic acid
metabolism generates SAM, thereby altering the methylation states of histones H3K9, H3K4, and H3K27 and genetically altering Wnt signaling.
have been studied in relation to perinatal nutrition. An important factor to consider when investigating perinatal nutrition is whether the baby was breast-fed
or formula-fed. Studies have shown that breast-fed babies have increased bone mass compared to those were not breast-fed, and that this small increase in bone mass during a period of critical development could potentially program the skeleton to continue along a “healthy” growth trajectory. It has also been shown that maternal vitamin D
insufficiency during late pregnancy is associated with reduced bone size and mineral mass in late childhood. Peak bone mass has shown to be a good predictor of risk of fracture and osteoporosis, with even a small increase in peak bone mass resulting in a much lower risk of bone fracture. Research shows that genetic markers explain only a small proportion of variation in bone mass and risk of fracture. Therefore, healthy bone programming is most likely influenced by various epigenetic mechanisms, such as imprinting of the growth promoting genes IGF-2, or changes to the hypothalamic-pituitary-adrenal axis
(HPA).
. Specifically, n-3 fatty acids, iodine, iron and choline have been shown to influence brain development and impact cognitive ability and behavior. The greatest evidence for a link between nutrition and neurodevelopment comes from studies that show low birth weight associated with low IQ and increased risk of schizophrenia
. Several studies suggest that breast-feeding promotes long-term neurodevelopment by providing the nutrients necessary for proper brain development. A study in mice showed that choline-deficient diets during the late gestation period impaired fetal brain development, including decreased cell proliferation and reduced visual-spatial and auditory memory. These cognitive changes appeared to be due to altered histone and DNA methylation patterns in the fetal hippocampus
, thus providing a link between maternal nutrition, epigenetics, and early brain development.
against pancreatic islets. The introduction of certain foods in the first few months of life, such as berries and cereal, is significantly associated with increased risk of islet autoantibody development compared to babies who are exposed to solid foods later in life. While the pathogenesis behind development of autoantibodies remains largely unknown, it is very probable that an epigenetic link exists between perinatal diet and risk of type-1 diabetes.
and tumor
formation. Compounds found in foods, such as genistein
and tea polyphenols, are able to regulate DNA methyltransferases and histone acetylation in cultured cancer cells and may provide protection against certain types of cancer. Other dietary compounds, such as diallyl disulfide
present in garlic and sulforaphane
present in cruciferous vegetables, have been associated with cancer prevention in clinical trials. This is due to their ability to inhibit histone deacetylase (HDAC) enzymes and prevent silencing of important regulatory genes.
Many believe epigenetic regulation is cleared during the fertilization process, yet more evidence for transgenerational effects (TGEs) are being revealed. These TGEs take place when the epigenetic regulatory patterns are not sufficiently erased during fertilization, possibly due to nutrition levels in previous generations. Later generations may be affected from caloric and protein restriction, high-fat interventions and endocrine disruption in earlier generations. Differences within the nutritional behavior of the maternal rat are believed to cause malprogramming in the F1 generation and may then be passed to subsequent generations.
Maternal rats fed a PR-diet during the entire length of pregnancy led to metabolic-related problems in the F1 and F2 generations, even with normal nutrition during the F1 pregnancy. These effects have also been seen in the F3 generation depending on the length of protein restriction. If protein restriction occurred solely during pregnancy, the F1 and F2 offspring had higher systolic blood pressure and lower nephron numbers, possibly predisposing them to hypertension. Altered glucose utilization was detected in the grand-offspring of maternal rats fed a PR-diet during pregnancy and lactation, potentially resulting in diabetes later on in life
Protein-restriction in the F0 generation led to hypomethylation of promoters involved in metabolism in the F1 and F2 generations, even though the F1 pregnant rat was given a normal diet. The exact mechanism of this situation has yet to be elucidated; however, direct transmission is a distinct possibility, meaning the epigenetic marks were preserved during spermatogenesis
and oogenesis
, when they are normally erased.
. Popular areas to investigate include IUGR studies, whereby rodents, and sometimes sheep, are subjected to a variety of nutritional conditions. A model for studying IUGR in rodent was developed by Simmons et al (2010) and is used to investigate type II diabetes. The maternal rats have their uterine arteries ligated, causing altered use of glucose and insulin in the fetus and can therefore serve as a model for diabetes. These growth-retarded rats were found to be highly similar to human fetuses, as they both display symptoms such as lowered glucose and insulin levels. Gestational diabetes
may also be studied through chemical induction using streptozotocin
treatment of the pregnant rats. Streptozotocin can cause destruction of the beta cells within the pancreas depending on the concentration given.
The predominant means of investigating nutriepigenetics involves varying the nutritional conditions to which a subject is exposed to and monitoring the effects thereafter. Restricting caloric and protein intake are the two most common methods. A pregnant rodent may have their caloric intake reduced up to 30-50% of normal intake. Protein restricted rodents are given 8-9% casein
, as opposed to control rats that are fed 20% casein. Micronutrients, such as zinc and iron, may also be restricted to investigate the effects on offspring. Additionally, rats fed diets lacking or including methyl donors are often used to study the effects of diet on epigenomics, as variations within the methylation of DNA are common means of silencing or expressing genes. Supplementing maternal rats with folic acid, vitamin B12
, choline and betaine leads to increased levels of DNA methylation at CpG sites and causes a coat color change. This is an example of epigenetically modifiable loci called a “metastable epiallele”, of which only a few have been identified. The above is an example of the “agouti” gene locus, whereby the insertion of a transposable element upstream to the Agouti gene is hypermethylated from the supplementation and causes a change in the rat’s coat color. Diets containing higher carbohydrate and fat content attempt to mimic typical Western-style diets may also be used in nutriepigenetic studies. Another method used is “catch-up”, where offspring of rats born to mothers subjected to various diets are subsequently cross-fostered to mothers fed normal diets.
A highly specific diet, termed an “EpiG diet”, may be employed for an individual believed to be at higher risk of developing a metabolic disorder. These diets may include supplementation with methyl donors, such as folate. There are also many other natural compounds, such as resveratrol
, curcumin
and green tea that have been termed “epigenetic modifiers”, as they have anti-cancer capabilities in addition to being used as treatments for metabolic diseases. However, the functions of these compounds still require long-term studies to evaluate their effect over time.
There also exists potential for therapeutic treatments that may correct metabolic disorders, such as type II diabetes. Components of garlic and cruciferous vegetables
are known to possess HDAC inhibitors that modify the acetylation of histone proteins and may contain a protection against cancer. These same compounds have also been implicated in irritable bowel syndrome
(IBS) and colon cancer, as they may modify the histones normally implicated in these diseases.
Elucidation of disease pathways is another future direction for nutriepigenomic studies. For example, choline-deficient diets and alcohol metabolism during pregnancy may have very similar metabolic pathways. Therefore, animal studies using choline-restricted diets may assist in investigations of fetal alcohol spectrum disorders.
When compared to studies of maternal transmission, investigations into the role of paternal diets are lacking. A review demonstrated the nutrition of both parents do in fact play a role in determining the health of their offspring. A germ-line study reported paternal rats fed a high-fat diet led to insulin dysfunction in the F1 offspring. While this likely occurs via epigenetic modifications similar to those postulated in the maternal diets, the exact mechanism remains to be defined. Assessing the role of epigenetic mechanisms may be easier using paternal inheritance, as sperm transmits epigenetic and genetic information, whereas the female cells also transmit mitochondrial DNA
.
Nutrient
A nutrient is a chemical that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment. They are used to build and repair tissues, regulate body processes and are converted to and used as energy...
s and their effects on human health through epigenetic modifications. There is now considerable evidence that nutritional imbalances during gestation
Gestation
Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
and lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
are linked to non-communicable diseases, such as obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, diabetes, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, and cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. If metabolic disturbances occur during critical time windows of development, the resulting epigenetic alterations can lead to permanent changes in tissue and organ structure or function and predispose individuals to disease.
Overview =
Epigenetics
Epigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
relates to heritable changes in gene function that occur independently of alterations in primary DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
sequence. Two major epigenetic mechanisms implicated in nutriepigenomics are DNA methylation
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
and histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
modification. DNA methylation in gene promoter regions usually results in gene silencing and influences gene expression. While this form of gene silencing is extremely important in development and cellular differentiation, aberrant DNA methylation can be detrimental and has been linked to various disease processes, such as cancer. The methyl groups used in DNA methylation are often derived from dietary sources, such as folate and choline
Choline
Choline is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
, and explains why diet can have a significant impact on methylation patterns and gene expression. Gene silencing can also be reinforced through the recruitment of histone deacetylases to decrease transcriptional activation. Conversely, histone acetylation induces transcriptional activation to increase gene expression. Dietary components can influence these epigenetic events, thereby altering gene expression and disturbing functions such as appetite control, metabolic balance and fuel utilization.
Various genetic sequences can be targeted for epigenetic modification. A transcriptome-wide analysis in mice found that a protein-restricted (PR) diet during gestation resulted in differential gene expression in approximately 1% of the fetal genes analyzed (235/22,690). Specifically, increased expression was seen in genes involved in the p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
pathway, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, negative regulators of cell metabolism, and genes related to epigenetic control. Additional studies have investigated the effect of a PR-diet in rats and found changes in promoter methylation of both the glucocorticoid receptor and peroxisome proliferator-activated receptor (PPAR). Altered expression of these receptors can result in elevated blood glucose levels and affect lipid and carbohydrate metabolism. Feeding a PR-diet to pregnant and/or lactating mice also increased expression of glucokinase, acetyl-CoA carboxylase, PPARα, and acyl-CoA oxidase. Changes in expression were reportedly due to epigenetic regulation of either the gene promoter itself, or promoters of transcription factors that regulate gene expression. Additional genes that have been shown, either by in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
or in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
studies, to be regulated by epigenetic mechanisms include leptin, SOCS3, glucose transporter (GLUT)-4, POMC, 11-β-hydroxysteroid dehydrogenase type 2 and corticotrophin releasing hormone. Epigenetic modification of these genes may lead to “metabolic programming” of the fetus and result in long-term changes in metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
and energy homeostasis.
Nutriepigenomics and Development
The period of development in which the nutritional imbalance occurs is very important in determining which disease-related genes will be affected. Different organs have critical developmental stages, and the time point at which they are compromised will predispose individuals to specific diseases. Epigenetic modifications that occur during development may not be expressed until later in life depending on the function of the gene. While the majority of studies implicate prenatal and perinatal periods as critical time windows, some research has shown that nutritional intake during adulthood can also affect the epigenome.Prenatal
Developmental plasticityDevelopmental plasticity
Developmental plasticity is a general term referring to changes in neural connections during development as a result of environmental interactions as well as neural changes induced by learning...
is a term used to describe the process in which fetuses adapt to their environment. Environmental cues, including dietary components, present in the in utero
In utero
In utero is a Latin term literally meaning "in the womb". In biology, the phrase describes the state of an embryo or fetus. In legal contexts, the phrase is used to refer to unborn children. Under common law, unborn children are still considered to exist for property transfer purposes.-See also:*...
environment can induce significant changes in the expression of the genome through epigenetic modifications. Fetal developmental plastic responses can cause changes in lean body mass, endocrinology, blood flow and vascular loading, and lead to increased risk of various diseases in adulthood.
Low Birth Weight
Fetal exposure to calcium, folate, magnesium, high or low protein, and zinc have all been associated with birth weight. Numerous studies have investigated the link between birth weight and risk of disease and have found that low birth weight is significantly associated with coronary heart disease, stroke and type-2 diabetes. Most importantly, these associations occurred after adjusting for lifestyle factors, implying a genetic basis for onset of disease. Impaired insulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretion is associated with low birth weight and can lead to insulin resistance as babies accumulate body fat. Studies using intrauterine growth retarded (IUGR) rats have found that growth inhibition can lead to decreased expression of Pdx1 transcription factor, which is essential for differentiation and function of pancreatic beta cells. Decreased histone acetylation at the proximal promoter of Pdx1 is responsible for reduced Pdx1 expression and subsequently results in a cascade of histone deacetylation and methylation events that can result in type-2 diabetes.
Obesity
Obesity during pregnancy and high-fat maternal diets both show strong associations with obesity in offspring. As the number of overweight reproductive-age women increases, the number of overweight children and infants also increases. It has been postulated that maternal obesity causes an accumulation of fat in fetal adipose tissueAdipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
(adiposity) and predisposes babies for obesity in childhood and adulthood. Animal studies have shown that maternal overnutrition may impact brain development and cause disruptions to programming of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
. Offspring that were exposed to a high-fat or high-caloric maternal diet had increased levels of insulin, glucose and leptin. It is hypothesized that these elevations are due to disturbances in the complex neuronal network that includes the neuropeptide Y (NPY) and proopiomelanocortin (POMC) pathways. This altered neuronal signaling can consequently impact food-intake behavior and lead to diet-induced obesity in adulthood. While epigenetic modifications are most likely involved in the development of obesity, the specific target genes have yet to be identified. Genes involved in adipogenesis, such as fibroblast growth-factor-2, phosphatase and tensin homologue, cyclin-dependent kinase inhibitor 1A and oestrogen receptor-alpha, possess multiple CpG islands in their promoter sites and may act as epigenetic targets. Furthermore, it has been shown that prenatal exposure to a hypomethylating agent, such as bisphenol A
Bisphenol A
Bisphenol A is an organic compound with two phenol functional groups. It is used to make polycarbonate plastic and epoxy resins, along with other applications....
(BPA), is associated with increased body weight and suggests modified DNA methylation as a mechanism for increasing susceptibility to obesity.
Folate
It has long been realized that maternal folate intake during pregnancy is linked to fetal development and growth, and can reduce the risk of serious birth defects. Folate is a source of S-adenosyl methionineS-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...
(SAM), which is used to supply DNA methyltransferases with methyl groups. Therefore, changes in folate supply have a substantial effect on DNA methylation patterns. Low levels of folate are associated with an increased risk of preterm delivery, poor growth of the placenta and uterus, and intrauterine growth retardation. Several complex diseases, including cancer, cardiovascular diseases and autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
have also been linked to maternal folate status. Based on animal studies it has been hypothesized that reduced folate intake could increase the risk of neural tube defects
Neural tube defects
Neural tube defects are one of the most common birth defects, occurring in approximately one in 1,000 live births in the United States. An NTD is an opening in the spinal cord or brain that occurs very early in human development. In the 2nd week of pregnancy called gastrulation, specialized cells...
by reducing the amount of methylayed DNA during cranial neural tube closure. Recently it was discovered that folate protection from congenital heart defects is linked to epigenetics and Wnt signaling. Multiple environmental factors target the Wnt signaling pathway
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
during embryogenesis and can cause misregulation of the pathway. Folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
metabolism generates SAM, thereby altering the methylation states of histones H3K9, H3K4, and H3K27 and genetically altering Wnt signaling.
Perinatal
Another critical developmental time window is the perinatal period, which refers to the time period immediately before and after birth. It has been shown that maternal diet in late pregnancy and an infant’s diet in the beginning weeks can all have significant impacts on gene expression. Therefore, perinatal nutrition refers to both late-stage in utero nutrition and lactation.Bone Health
Bone mass and the development of osteoporosisOsteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
have been studied in relation to perinatal nutrition. An important factor to consider when investigating perinatal nutrition is whether the baby was breast-fed
Breastfeeding
Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts rather than from a baby bottle or other container. Babies have a sucking reflex that enables them to suck and swallow milk. It is recommended that mothers breastfeed for six months or...
or formula-fed. Studies have shown that breast-fed babies have increased bone mass compared to those were not breast-fed, and that this small increase in bone mass during a period of critical development could potentially program the skeleton to continue along a “healthy” growth trajectory. It has also been shown that maternal vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
insufficiency during late pregnancy is associated with reduced bone size and mineral mass in late childhood. Peak bone mass has shown to be a good predictor of risk of fracture and osteoporosis, with even a small increase in peak bone mass resulting in a much lower risk of bone fracture. Research shows that genetic markers explain only a small proportion of variation in bone mass and risk of fracture. Therefore, healthy bone programming is most likely influenced by various epigenetic mechanisms, such as imprinting of the growth promoting genes IGF-2, or changes to the hypothalamic-pituitary-adrenal axis
Hypothalamic-pituitary-adrenal axis
The hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...
(HPA).
Neurodevelopment
Imbalances in maternal nutrition can also have a significant effect on fetal neurodevelopment. Brain development occurs most rapidly during fetal development and infancy, and research has shown that exposure to certain environmental conditions can have long lasting effects on cognitionCognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
. Specifically, n-3 fatty acids, iodine, iron and choline have been shown to influence brain development and impact cognitive ability and behavior. The greatest evidence for a link between nutrition and neurodevelopment comes from studies that show low birth weight associated with low IQ and increased risk of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. Several studies suggest that breast-feeding promotes long-term neurodevelopment by providing the nutrients necessary for proper brain development. A study in mice showed that choline-deficient diets during the late gestation period impaired fetal brain development, including decreased cell proliferation and reduced visual-spatial and auditory memory. These cognitive changes appeared to be due to altered histone and DNA methylation patterns in the fetal hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, thus providing a link between maternal nutrition, epigenetics, and early brain development.
Type-1 Diabetes
It has been postulated that breast-feeding may also protect against type-1 diabetes, with research showing that formula-fed infants are at an increased risk of developing islet autoantibodies. Individuals with type-1 diabetes experience a pre-clinical diabetes phase characterized by autoimmunityAutoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
against pancreatic islets. The introduction of certain foods in the first few months of life, such as berries and cereal, is significantly associated with increased risk of islet autoantibody development compared to babies who are exposed to solid foods later in life. While the pathogenesis behind development of autoantibodies remains largely unknown, it is very probable that an epigenetic link exists between perinatal diet and risk of type-1 diabetes.
Adulthood
The majority of research in nutriepigenomics has focused on nutritional imbalances during gestation and lactation periods. However, foods that are consumed during adulthood can also impact gene expression and disease pathogenesis. Cancer is the disease most commonly associated with adult nutrition and epigenetic modifications. DNA hypomethelation promotes cancer progression by allowing increased gene transcription, while hypermethylation can silence tumor suppressor genes and further promote uncontrolled cell divisionCell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
and tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
formation. Compounds found in foods, such as genistein
Genistein
Genistein is one of several known isoflavones. Isoflavones, such as genistein and daidzein, are found in a number of plants including lupin, fava beans, soybeans, kudzu, and psoralea being the primary food source, also in the medicinal plant, Flemingia vestita and coffee Besides functioning as...
and tea polyphenols, are able to regulate DNA methyltransferases and histone acetylation in cultured cancer cells and may provide protection against certain types of cancer. Other dietary compounds, such as diallyl disulfide
Diallyl disulfide
Diallyl disulfide is an organosulfur compound found in plants of the genus Allium. Along with diallyl trisulfide and diallyl tetrasulfide, it is one of the principal components of the distilled oil of garlic. It is a yellowish liquid which is insoluble in water and has a strong garlic odor...
present in garlic and sulforaphane
Sulforaphane
Sulforaphane is an organosulfur compound that exhibits anticancer, antidiabetic, and antimicrobial properties in experimental models. It is obtained from cruciferous vegetables such as broccoli, Brussels sprouts or cabbages. The enzyme myrosinase transforms glucoraphanin, a glucosinolate, into...
present in cruciferous vegetables, have been associated with cancer prevention in clinical trials. This is due to their ability to inhibit histone deacetylase (HDAC) enzymes and prevent silencing of important regulatory genes.
Transgenerational effects
See main article Transgenerational epigeneticsTransgenerational epigenetics
Epigenetic inheritance is the transmittance of information from one generation to the next that affects the traits of offspring without alteration of the primary structure of DNA or from environmental cues...
Many believe epigenetic regulation is cleared during the fertilization process, yet more evidence for transgenerational effects (TGEs) are being revealed. These TGEs take place when the epigenetic regulatory patterns are not sufficiently erased during fertilization, possibly due to nutrition levels in previous generations. Later generations may be affected from caloric and protein restriction, high-fat interventions and endocrine disruption in earlier generations. Differences within the nutritional behavior of the maternal rat are believed to cause malprogramming in the F1 generation and may then be passed to subsequent generations.
Maternal rats fed a PR-diet during the entire length of pregnancy led to metabolic-related problems in the F1 and F2 generations, even with normal nutrition during the F1 pregnancy. These effects have also been seen in the F3 generation depending on the length of protein restriction. If protein restriction occurred solely during pregnancy, the F1 and F2 offspring had higher systolic blood pressure and lower nephron numbers, possibly predisposing them to hypertension. Altered glucose utilization was detected in the grand-offspring of maternal rats fed a PR-diet during pregnancy and lactation, potentially resulting in diabetes later on in life
Protein-restriction in the F0 generation led to hypomethylation of promoters involved in metabolism in the F1 and F2 generations, even though the F1 pregnant rat was given a normal diet. The exact mechanism of this situation has yet to be elucidated; however, direct transmission is a distinct possibility, meaning the epigenetic marks were preserved during spermatogenesis
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
and oogenesis
Oogenesis
Oogenesis, ovogenesis or oögenesis is the creation of an ovum . It is the female form of gametogenesis. The male equivalent is spermatogenesis...
, when they are normally erased.
Models used in nutriepigenomic studies
Most research to date use common rodent models to investigate the role of nutrition on phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. Popular areas to investigate include IUGR studies, whereby rodents, and sometimes sheep, are subjected to a variety of nutritional conditions. A model for studying IUGR in rodent was developed by Simmons et al (2010) and is used to investigate type II diabetes. The maternal rats have their uterine arteries ligated, causing altered use of glucose and insulin in the fetus and can therefore serve as a model for diabetes. These growth-retarded rats were found to be highly similar to human fetuses, as they both display symptoms such as lowered glucose and insulin levels. Gestational diabetes
Gestational diabetes
Gestational diabetes is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy . It is widely accepted as a disease only in the United States, there is some question whether the condition is natural during pregnancy...
may also be studied through chemical induction using streptozotocin
Streptozotocin
Streptozotocin is a naturally occurring chemical that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals...
treatment of the pregnant rats. Streptozotocin can cause destruction of the beta cells within the pancreas depending on the concentration given.
The predominant means of investigating nutriepigenetics involves varying the nutritional conditions to which a subject is exposed to and monitoring the effects thereafter. Restricting caloric and protein intake are the two most common methods. A pregnant rodent may have their caloric intake reduced up to 30-50% of normal intake. Protein restricted rodents are given 8-9% casein
Casein
Casein is the name for a family of related phosphoprotein proteins . These proteins are commonly found in mammalian milk, making up 80% of the proteins in cow milk and between 60% and 65% of the proteins in human milk....
, as opposed to control rats that are fed 20% casein. Micronutrients, such as zinc and iron, may also be restricted to investigate the effects on offspring. Additionally, rats fed diets lacking or including methyl donors are often used to study the effects of diet on epigenomics, as variations within the methylation of DNA are common means of silencing or expressing genes. Supplementing maternal rats with folic acid, vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
, choline and betaine leads to increased levels of DNA methylation at CpG sites and causes a coat color change. This is an example of epigenetically modifiable loci called a “metastable epiallele”, of which only a few have been identified. The above is an example of the “agouti” gene locus, whereby the insertion of a transposable element upstream to the Agouti gene is hypermethylated from the supplementation and causes a change in the rat’s coat color. Diets containing higher carbohydrate and fat content attempt to mimic typical Western-style diets may also be used in nutriepigenetic studies. Another method used is “catch-up”, where offspring of rats born to mothers subjected to various diets are subsequently cross-fostered to mothers fed normal diets.
Future directions
The possibilities of utilizing nutriepigenomics for intervention are quite expansive. This can include preventative therapies, such as providing an optimal regime for nutrition during pregnancy and lactation. It is already common place for pregnant mothers to supplement their diets with choline and folate to prevent the development of neurological disabilities in the fetus.A highly specific diet, termed an “EpiG diet”, may be employed for an individual believed to be at higher risk of developing a metabolic disorder. These diets may include supplementation with methyl donors, such as folate. There are also many other natural compounds, such as resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
, curcumin
Curcumin
Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family . The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric...
and green tea that have been termed “epigenetic modifiers”, as they have anti-cancer capabilities in addition to being used as treatments for metabolic diseases. However, the functions of these compounds still require long-term studies to evaluate their effect over time.
There also exists potential for therapeutic treatments that may correct metabolic disorders, such as type II diabetes. Components of garlic and cruciferous vegetables
Cruciferous vegetables
Vegetables of the family Brassicaceae are called cruciferous vegetables. The vegetables are widely cultivated, with many genera, species, and cultivars being raised for food production such as cauliflower, cabbage, cress, bok choy, broccoli and similar green leaf vegetables...
are known to possess HDAC inhibitors that modify the acetylation of histone proteins and may contain a protection against cancer. These same compounds have also been implicated in irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
(IBS) and colon cancer, as they may modify the histones normally implicated in these diseases.
Elucidation of disease pathways is another future direction for nutriepigenomic studies. For example, choline-deficient diets and alcohol metabolism during pregnancy may have very similar metabolic pathways. Therefore, animal studies using choline-restricted diets may assist in investigations of fetal alcohol spectrum disorders.
When compared to studies of maternal transmission, investigations into the role of paternal diets are lacking. A review demonstrated the nutrition of both parents do in fact play a role in determining the health of their offspring. A germ-line study reported paternal rats fed a high-fat diet led to insulin dysfunction in the F1 offspring. While this likely occurs via epigenetic modifications similar to those postulated in the maternal diets, the exact mechanism remains to be defined. Assessing the role of epigenetic mechanisms may be easier using paternal inheritance, as sperm transmits epigenetic and genetic information, whereas the female cells also transmit mitochondrial DNA
Mitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
.