Overview
editMetabolic imprinting and metabolic programming, although slightly different in meaning, are used interchangeably in the field of epigenetics. Metabolic programming focuses on the epigenetic changes that occur in early development, in response to the nutritional environment. Epigenetic changes are heritable modifications to the chromatin that affect the expression of genes and their products, but leave the DNA sequence unaltered. Metabolic imprinting refers more specifically, to the biological phenomena responsible for these changes, occurring at the genomic level. [1]
The term ‘imprinting’ is an adaptive response to a nutritional change, characterized by:
• The susceptibility of the individual during a critical window in early development
• Producing a measurable health outcome
• Having a persistent effect into adulthood
• Exceeding a certain threshold for the effect or condition to persist [2]
Metabolic imprinting is not to be confused with immunologic memory, or hormonal imprinting. [1] Studies in both humans and animals have shown that the nutritional environment during gestation and early post-natal stages may have long-term consequences for health. Evidence of causality between early dietary exposures and health outcomes remains inconclusive, although links between fetal nutrition and disease outcomes have been established. These diseases include, but are not limited to, an increased risk of cardiovascular disease, obesity, type II diabetes and hypertension. [2]
Risk factors
editRisk factors for future disease outcomes can be measured by biomarkers, indicators of the status of an individuals health at a given point in time. Cholesterol level, for example, is a biomarker that predicts risk for cardiovascular disease. [1]
Low birth weight
editLow birth weight is a risk factor for elevated adult Body mass index, cardiovascular disease, high blood pressure, and glucose intolerance. [2] Animal studies have shown that fetal under-nutrition in gestation results in low birth weight. [3] The effects of under-nutrition vary depending on the time of gestation. Under-nutrition in early gestation can result in normally proportioned offspring with low birth weight; whereas under- nutrition in late gestation results in dis-proportionate offspring with normal birth weight. Other factors such as maternal uterus size and cigarette smoking affect the size of offspring. A small uterus results in decreased birth size, and cigarette smoking can lead to restricted fetal growth. [4]
Despite evidence proving these associations, many confounding variables, including socioeconomic status, weaken the relations between disease and birth weight.[1] Other environmental factors throughout an individual’s lifetime play a role in determining adult health status.[2]
Maternal dietary exposures
editFurther information: Avon Longitudinal Study of Parents and Children
The following risk factors were identified from the Avon Longitudinal Study of Parents and Children cohort to correlate with the corresponding health endpoint. [1]
• Infant feeding method and obesity
• Seafood consumption in pregnancy and neurodevelopmental outcomes
• Soya-protein and peanut oil exposure and peanut allergies
• Maternal mineral and folate intake and bone health in offspring
• Insulin-like growth factor-1 levels and intelligence of offspring at 9 years
• Pre-natal paracetamol exposure and asthma and atopy
• Early rate of weight gain and development of diabetes, and insulin resistance
Potential mechanisms
editProposed mechanisms explain how the effects of metabolic imprinting are maintained in proliferating cells.[2] Such mechanisms focus on the epigenetic modifications that occur during critical developmental periods of increased growth.[3] Various mechanisms include epigenetic modifications, changes to organ structure during organogenesis, changes to cell structure during hyperplasia, clonal selection, and hepatocyte polyploidization.[2]
Epigenetic modifications
editDNA methylation is an epigenetic mechanism that regulates gene expression. [5] Methylation patterns of the genome are altered by protein deficiency and depletion of vitamins, such as folate.[3] Under-nutrition in gestation, and deficiency of these nutrients may cause changes to the methylation patterns in genes during development. DNA methylation represses gene expression, leading to altered gene expression in different tissues. These changes are passed on to the daughter cells through replication, and can become permanent in the genome. [3]
DNA methylation is a mechanism of metabolic differentiation, the process by which cells develop a stable pattern of gene expression early in development. There are other epigenetic mechanisms that regulate metabolic differentiation. Modifications to DNA binding proteins and modifications to chromatin structure affect the rate of gene expression on the level of transcription. [2],[5]
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Organ structure during organogenesis
editOrganogenesis is a narrow window in gestation where cells of the embryo differentiate into different tissues that subsequently become organs.[6] This process occurs in response to environmental signals.[2] Proper nutrition is critical during organ development. Nutritional imbalances can result in inherent abnormalities. Animals studies have shown that deficiencies in vitamins, such as niacin and folate, result in defects to the central nervous system; although research lacks to prove these effects in humans. [6]
Changes to cell number
editThe size and number of cells in an organism is directly related to the availability of nutrients required for cell growth and proliferation. Nutritional deficiency or excess during critical periods of cell proliferation (hyperplasia) and cellular growth (hypertrophy) can permanently influence the number of cells in specific tissues despite later nutritional status. [2]
Clonal selection
editCellular proliferation is the initial multiplication of a population of founder cells. These cells, although having undergone cellular differentiation to become a specialized cell type, remain susceptible to genetic and epigenetic changes. Even subtle changes to the founder cells will result in clones that may have an advantage in the nutritional environment. For example, in an environment deficient in fatty acids, clones with increased efficiency for fat uptake, will develop more quickly than the rest of the cellular population. This metabolic difference will become dominant in the tissue, and will persist in adulthood, even if fatty acids are readily available. [2]
Hepatocyte Polyploidization
editA large portion of hepatocytes are polylpoid in order to increase the metabolic function of the liver. Polyploidy refers to cells containing more than two copies of each chromosome, in the case of diploid human cells. Polyploidization is the process of chromosomal multiplication that occurs during a critical period in postnatal development. The hepatocyte ploidy is maintained stably after development. Disruptions to the nutritional environment during the critical period may affect the polyploidization of hepatocytes, and alter the liver metabolism in adulthood. [2]
References
edit- ^ a b c d e Hanley, B; Dijane, J; Fewtrell, M; Grynberg, A; Hummel, S; Junien, C; Koletzko, B; Lewis, S; Renz, H; Symonds, M; Gros, M; Harthorn, L; Mace, K; Samuels, F; van Der Beek, EM (2010). "Metabolic imprinting, programming and epigenetics - a review of present priorities and future opportunities". British Journal of Nutrition. 104 (S1): S1-S25. doi:10.1017/S0007114510003338. PMID 20929595. Retrieved 15 October 2015.
- ^ a b c d e f g h i j k Waterland, RA; Garza, C (1999). "Potential mechanisms of metabolic imprinting that lead to chronic disease". Am J Clin Nutr. 69 (2): 179–197. doi:10.1093/ajcn/69.2.179. PMID 9989679.
- ^ a b c d Patel, Mulchand; Srinivasan, Malathi (2002). "Metabolic Programming: Causes and Consequences". J. Biol. Chem. 277 (3): 1629–1632. doi:10.1074/jbc.R100017200. PMID 11698417. S2CID 5565049.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Godfrey, Keith; Barker, David (2000). "Fetal nutrition and adult disease". Am J Clin Nutr. 71 (5 Suppl): 1344S–52S. doi:10.1093/ajcn/71.5.1344s. PMID 10799412.
- ^ a b Nussbaum, Robert; McInnes, Roderick; Huntington, Willard (2016). Thompson &Thompson Genetics in Medicine (Eighth ed.). Philadelphia: Elsevier. pp. 21–42.
- ^ a b Lanham-New, Susan; Macdonald, Ian; Roche, Helen (2011). Nutrition and Metabolism Volume 5 of The Nutrition Society Textbook (2 ed.). John Wiley & Sons.