Early Human Development 90S2 (2014) S23–S24
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Review
Epigenetics and neonatal nutrition Umberto Simeoni a, *, Catherine Yzydorczyk a , Benazir Siddeek a , Mohamed Benahmed a,b a Division b INSERM
of Pediatrics & DOHaD Laboratory, CHUV & University of Lausanne, Switzerland U1065 Nice, France
article info
summary
Keywords: Epigenetics Programming Developmental Immune system Nutrition Neonate
Epigenetic changes have long-lasting effects on gene expression and are related to, and often induced by, the environment in which early development takes place. In particular, the period of development that extends from pre-conception to early infancy is the period of life during which epigenetic DNA imprinting activity is the most active. Epigenetic changes have been associated with modification of the risk for developing a wide range of adulthood, non-communicable diseases (including cardiovascular diseases, metabolic diseases, diseases of the reproductive system, etc.). This paper reviews the molecular basis of epigenetics, and addresses the issues related to the process of developmental programming of the various areas of human health. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The period of development that extends from pre-conception to early infancy is the period of life during which epigenetic DNA imprinting activity is the most active. Epigenetic changes have long-lasting effects on gene expression and are related to, and often induced by, the environment in which early development takes place. Furthermore they may induce a particular risk for developing specific chronic disease at adulthood, known as non-communicable diseases (including cardiovascular diseases such as stroke or coronary heart disease, metabolic diseases such as overweight, obesity and diabetes, diseases of the reproductive system such as male infertility, prostate, testicle or breast cancer). Epigenetics are now recognized as the molecular basis for the Developmental Origins of Health and Disease (DOHaD) concept, also known as foetal or developmental programming, or the theory of Barker [1]. The period of vulnerability covering early development has also been referred to as the 1000 days period (i.e. from conception to the second anniversary). Today, epidemiological and experimental studies in animals have shown that all biological and physiological systems undergo naturally the process of developmental programming, including the immune system, fertility, cellular senescence and longevity, and even behavioural functions.
* Corresponding author. E-mail address: [email protected] (U. Simeoni). 0378-3782/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved.
2. Epigenetics during early development phases and the risk for altered health over the life course Epigenetic marks induce durable changes in the levels of gene expression, where genes become up- or down-regulated according to concomitant early environmental clues. Three principal mechanisms are responsible for such alterations: gene DNA methylation/demethylation, histones modifications, and non-coding RNAs, whose production is itself controlled by the two first mentioned mechanisms. For example, usually the activity of a gene that is methylated is down-regulated, while on the contrary that of a gene that is de-methylated is up-regulated. The methyl groups involved in the methylation process, as well as several co-factors (such as folate) of the corresponding enzymes (DNA-methyltransferases) originate typically in the nutritional environment. Endocrine disruptors, which are usually environmental pollutants, markedly affect the small, non-coding RNAs, such as micro-RNAs, which are able to interfere with mRNA and affect protein synthesis. Epigenetic marks do not affect the gene DNA sequence; they are nevertheless preserved across the process of mitosis, and can even be transmitted trans-generationally over several generations. The period of early development is characterized by important epigenetic changes; for example, the inactivation of the unneeded part of the genome while stem cells are differentiating into a specific lineage is obtained by epigenetic mechanisms. Maternal and paternal gametes may carry preconceptionally acquired epigenetic marks that will be preserved in the epigenome of their developing infants. It is thus easy to understand that this period is particularly sensitive to changes in, and signals from, the environment, as it is a period of
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U. Simeoni et al. / Early Human Development 90S2 (2014) S23–S24
programming according to the signals received from the early, parental, maternal and postnatal environment [2]. 3. The long-term effects of the neonatal environment and nutrition Pathological pre- and perinatal conditions, such as preterm birth, intrauterine growth restriction, intrauterine exposure to maternal overweight or diabetes, and early exposure to contaminants such as dioxins, PCBs or bisphenol A, have been shown to induce epidemic-like long-term effects that affect various systems, with relatively similar mechanisms [3–6]. Neonatal and infantile nutrition plays an important role in long-term consequences of adverse perinatal conditions, either as the principal or as a second hit. This is true for adverse conditions due to economical and sanitary factors encountered in developing countries, but also for pre- and perinatal diseases and complications of pregnancy that are key issues in rich countries. A slightly higher blood pressure is observed at the age of twenty in patients born preterm, a marker that has been otherwise associated with increased cardiovascular risk in later life. A reduced nephron endowment is likely to play a role in the long-term development of hypertension, due to single nephron glomerular hyperfiltration, microproteinuria, and early glomerular sclerosis, according to the Brenner hypothesis. This mechanism is characteristic of intrauterine growth restriction, as it has been shown that the number of nephrons, which is definitely acquired in utero during nephrogenesis, is correlated with birth weight. The renin–angiotensin system seems to be a key factor in the progression toward end-stage renal insufficiency, as shown by animal studies [7]. Work in rat models in our laboratory and in others shows that early postnatal nutrition influences renal function and blood pressure at adulthood. Contrary to what is observed in humans, nephrogenesis is still on-going in the neonatal rat, up to 7–9 days of life. This confers to such animal model a moderate similarity with situations of postnatal on-going nephrogenesis in human preterm infants. We observed that postnatal, transient overfeeding during lactation in normal rat pups induced elevated blood pressure and increased glomerular sclerosis at adulthood [8]. Moreover, this was accentuated, together with proteinuria and a decreased glomerular filtration rate, when overfeeding was superimposed on foetal growth restriction [9]. Such physiological changes are accompanied by marked changes in the kidney transcriptome, in which the transcription of around 20% of the whole genome has been altered, possibly via epigenetic mechanisms [10]. This means that excess nutrient intakes during the neonatal period, even when they originate in breast milk, may induce long-term hypertension, and decreased renal function, in particular when associated with previous growth restriction. Recent data suggest that postnatal, extrauterine growth restriction observed in many preterm infants during their initial hospital stay is due to suboptimal postnatal parenteral and enteral nutrition [11]. It may be followed by postnatal catch-up growth after discharge and end in inappropriate body
composition at adulthood: Thomas et al. have shown recently that central abdominal and visceral fat is increased in young adults born preterm [12]. Optimized early postnatal nutrition, mimicking constant intrauterine intakes especially in terms of protein quantity, seems feasible and avoids postnatal growth restriction in very preterm infants [13]. In the absence of available randomized controlled trials, it is unclear whether such nutritional approach will allow a reduced neonatal mortality and morbidity and an optimal neurodevelopment, without long-term cardiovascular and metabolic consequences due to altered early programming in these patients. It may however be anticipated that, in the current state of the art and of knowledge, providing optimal early nutrition to preterm infants is the best option to favour growth and development, and that avoiding extrauterine growth restriction in these infants may avoid the need for catch-up growth and its potentially deleterious longterm effects on the future health of preterm-born patients as adults. Conflict of interest statement The authors have no conflicts of interest to declare. References 1. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989;2(8663):577–80. 2. Hanson M, Godfrey KM, Lillycrop KA, Burdge GC, Gluckman PD. Developmental plasticity and developmental origins of non-communicable disease: theoretical considerations and epigenetic mechanisms. Prog Biophys Mol Biol 2011;106(1): 272–80. 3. Simeoni U, Barker DJ. Offspring of diabetic pregnancy: long-term outcomes. Semin Fetal Neonatal Med 2009;14(2):119–24. 4. Hovi P, Andersson S, Eriksson JG, Jarvenpaa AL, Strang-Karlsson S, Makitie O, et al. Glucose regulation in young adults with very low birth weight. N Engl J Med 2007;356(20):2053–63. 5. Bouskine A, Nebout M, Brucker-Davis F, Benahmed M, Fenichel P. Low doses of bisphenol A promote human seminoma cell proliferation by activating PKA and PKG via a membrane G-protein-coupled estrogen receptor. Environ Health Perspect 2009;117(7):1053–8. 6. Siddeek B, Inoubli L, Lakhdari N, Rachel PB, Fussell KC, Schneider S, et al. MicroRNAs as potential biomarkers in diseases and toxicology. Mutat Res Genet Toxicol Environ Mutagen 2014;764–765:46–57. 7. Simeoni U, Ligi I, Buffat C, Boubred F. Adverse consequences of accelerated neonatal growth: cardiovascular and renal issues. Pediatr Nephrol 2011;26(4): 493–508. 8. Boubred F, Buffat C, Feuerstein JM, Daniel L, Tsimaratos M, Oliver C, et al. Effects of early postnatal hypernutrition on nephron number and long-term renal function and structure in rats. Am J Physiol Renal Physiol 2007;293(6):F1944–9. 9. Boubred F, Daniel L, Buffat C, Feuerstein JM, Tsimaratos M, Oliver C, et al. Early postnatal overfeeding induces early chronic renal dysfunction in adult male rats. Am J Physiol Renal Physiol 2009;297(4):F943–51. 10. Vaiman D, Gascoin-Lachambre G, Boubred F, Mondon F, Feuerstein JM, Ligi I, et al. The intensity of IUGR-induced transcriptome deregulations is inversely correlated with the onset of organ function in a rat model. PloS One 2011;6(6): e21222. 11. Ziegler EE. Meeting the nutritional needs of the low-birth-weight infant. Ann Nutr Metab 2011;58(Suppl 1):8–18. 12. Thomas EL, Parkinson JR, Hyde MJ, Yap IK, Holmes E, Dore CJ, et al. Aberrant adiposity and ectopic lipid deposition characterize the adult phenotype of the preterm infant. Pediatr Res 2011;70(5):507–12. 13. Rigo J, Senterre T. Intrauterine-like growth rates can be achieved with premixed parenteral nutrition solution in preterm infants. J Nutr 2013;143(12 Suppl): 2066S-2070S.
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Review
Epigenetics and neonatal nutrition Umberto Simeoni a, *, Catherine Yzydorczyk a , Benazir Siddeek a , Mohamed Benahmed a,b a Division b INSERM
of Pediatrics & DOHaD Laboratory, CHUV & University of Lausanne, Switzerland U1065 Nice, France
article info
summary
Keywords: Epigenetics Programming Developmental Immune system Nutrition Neonate
Epigenetic changes have long-lasting effects on gene expression and are related to, and often induced by, the environment in which early development takes place. In particular, the period of development that extends from pre-conception to early infancy is the period of life during which epigenetic DNA imprinting activity is the most active. Epigenetic changes have been associated with modification of the risk for developing a wide range of adulthood, non-communicable diseases (including cardiovascular diseases, metabolic diseases, diseases of the reproductive system, etc.). This paper reviews the molecular basis of epigenetics, and addresses the issues related to the process of developmental programming of the various areas of human health. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The period of development that extends from pre-conception to early infancy is the period of life during which epigenetic DNA imprinting activity is the most active. Epigenetic changes have long-lasting effects on gene expression and are related to, and often induced by, the environment in which early development takes place. Furthermore they may induce a particular risk for developing specific chronic disease at adulthood, known as non-communicable diseases (including cardiovascular diseases such as stroke or coronary heart disease, metabolic diseases such as overweight, obesity and diabetes, diseases of the reproductive system such as male infertility, prostate, testicle or breast cancer). Epigenetics are now recognized as the molecular basis for the Developmental Origins of Health and Disease (DOHaD) concept, also known as foetal or developmental programming, or the theory of Barker [1]. The period of vulnerability covering early development has also been referred to as the 1000 days period (i.e. from conception to the second anniversary). Today, epidemiological and experimental studies in animals have shown that all biological and physiological systems undergo naturally the process of developmental programming, including the immune system, fertility, cellular senescence and longevity, and even behavioural functions.
* Corresponding author. E-mail address: [email protected] (U. Simeoni). 0378-3782/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved.
2. Epigenetics during early development phases and the risk for altered health over the life course Epigenetic marks induce durable changes in the levels of gene expression, where genes become up- or down-regulated according to concomitant early environmental clues. Three principal mechanisms are responsible for such alterations: gene DNA methylation/demethylation, histones modifications, and non-coding RNAs, whose production is itself controlled by the two first mentioned mechanisms. For example, usually the activity of a gene that is methylated is down-regulated, while on the contrary that of a gene that is de-methylated is up-regulated. The methyl groups involved in the methylation process, as well as several co-factors (such as folate) of the corresponding enzymes (DNA-methyltransferases) originate typically in the nutritional environment. Endocrine disruptors, which are usually environmental pollutants, markedly affect the small, non-coding RNAs, such as micro-RNAs, which are able to interfere with mRNA and affect protein synthesis. Epigenetic marks do not affect the gene DNA sequence; they are nevertheless preserved across the process of mitosis, and can even be transmitted trans-generationally over several generations. The period of early development is characterized by important epigenetic changes; for example, the inactivation of the unneeded part of the genome while stem cells are differentiating into a specific lineage is obtained by epigenetic mechanisms. Maternal and paternal gametes may carry preconceptionally acquired epigenetic marks that will be preserved in the epigenome of their developing infants. It is thus easy to understand that this period is particularly sensitive to changes in, and signals from, the environment, as it is a period of
S24
U. Simeoni et al. / Early Human Development 90S2 (2014) S23–S24
programming according to the signals received from the early, parental, maternal and postnatal environment [2]. 3. The long-term effects of the neonatal environment and nutrition Pathological pre- and perinatal conditions, such as preterm birth, intrauterine growth restriction, intrauterine exposure to maternal overweight or diabetes, and early exposure to contaminants such as dioxins, PCBs or bisphenol A, have been shown to induce epidemic-like long-term effects that affect various systems, with relatively similar mechanisms [3–6]. Neonatal and infantile nutrition plays an important role in long-term consequences of adverse perinatal conditions, either as the principal or as a second hit. This is true for adverse conditions due to economical and sanitary factors encountered in developing countries, but also for pre- and perinatal diseases and complications of pregnancy that are key issues in rich countries. A slightly higher blood pressure is observed at the age of twenty in patients born preterm, a marker that has been otherwise associated with increased cardiovascular risk in later life. A reduced nephron endowment is likely to play a role in the long-term development of hypertension, due to single nephron glomerular hyperfiltration, microproteinuria, and early glomerular sclerosis, according to the Brenner hypothesis. This mechanism is characteristic of intrauterine growth restriction, as it has been shown that the number of nephrons, which is definitely acquired in utero during nephrogenesis, is correlated with birth weight. The renin–angiotensin system seems to be a key factor in the progression toward end-stage renal insufficiency, as shown by animal studies [7]. Work in rat models in our laboratory and in others shows that early postnatal nutrition influences renal function and blood pressure at adulthood. Contrary to what is observed in humans, nephrogenesis is still on-going in the neonatal rat, up to 7–9 days of life. This confers to such animal model a moderate similarity with situations of postnatal on-going nephrogenesis in human preterm infants. We observed that postnatal, transient overfeeding during lactation in normal rat pups induced elevated blood pressure and increased glomerular sclerosis at adulthood [8]. Moreover, this was accentuated, together with proteinuria and a decreased glomerular filtration rate, when overfeeding was superimposed on foetal growth restriction [9]. Such physiological changes are accompanied by marked changes in the kidney transcriptome, in which the transcription of around 20% of the whole genome has been altered, possibly via epigenetic mechanisms [10]. This means that excess nutrient intakes during the neonatal period, even when they originate in breast milk, may induce long-term hypertension, and decreased renal function, in particular when associated with previous growth restriction. Recent data suggest that postnatal, extrauterine growth restriction observed in many preterm infants during their initial hospital stay is due to suboptimal postnatal parenteral and enteral nutrition [11]. It may be followed by postnatal catch-up growth after discharge and end in inappropriate body
composition at adulthood: Thomas et al. have shown recently that central abdominal and visceral fat is increased in young adults born preterm [12]. Optimized early postnatal nutrition, mimicking constant intrauterine intakes especially in terms of protein quantity, seems feasible and avoids postnatal growth restriction in very preterm infants [13]. In the absence of available randomized controlled trials, it is unclear whether such nutritional approach will allow a reduced neonatal mortality and morbidity and an optimal neurodevelopment, without long-term cardiovascular and metabolic consequences due to altered early programming in these patients. It may however be anticipated that, in the current state of the art and of knowledge, providing optimal early nutrition to preterm infants is the best option to favour growth and development, and that avoiding extrauterine growth restriction in these infants may avoid the need for catch-up growth and its potentially deleterious longterm effects on the future health of preterm-born patients as adults. Conflict of interest statement The authors have no conflicts of interest to declare. References 1. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989;2(8663):577–80. 2. Hanson M, Godfrey KM, Lillycrop KA, Burdge GC, Gluckman PD. Developmental plasticity and developmental origins of non-communicable disease: theoretical considerations and epigenetic mechanisms. Prog Biophys Mol Biol 2011;106(1): 272–80. 3. Simeoni U, Barker DJ. Offspring of diabetic pregnancy: long-term outcomes. Semin Fetal Neonatal Med 2009;14(2):119–24. 4. Hovi P, Andersson S, Eriksson JG, Jarvenpaa AL, Strang-Karlsson S, Makitie O, et al. Glucose regulation in young adults with very low birth weight. N Engl J Med 2007;356(20):2053–63. 5. Bouskine A, Nebout M, Brucker-Davis F, Benahmed M, Fenichel P. Low doses of bisphenol A promote human seminoma cell proliferation by activating PKA and PKG via a membrane G-protein-coupled estrogen receptor. Environ Health Perspect 2009;117(7):1053–8. 6. Siddeek B, Inoubli L, Lakhdari N, Rachel PB, Fussell KC, Schneider S, et al. MicroRNAs as potential biomarkers in diseases and toxicology. Mutat Res Genet Toxicol Environ Mutagen 2014;764–765:46–57. 7. Simeoni U, Ligi I, Buffat C, Boubred F. Adverse consequences of accelerated neonatal growth: cardiovascular and renal issues. Pediatr Nephrol 2011;26(4): 493–508. 8. Boubred F, Buffat C, Feuerstein JM, Daniel L, Tsimaratos M, Oliver C, et al. Effects of early postnatal hypernutrition on nephron number and long-term renal function and structure in rats. Am J Physiol Renal Physiol 2007;293(6):F1944–9. 9. Boubred F, Daniel L, Buffat C, Feuerstein JM, Tsimaratos M, Oliver C, et al. Early postnatal overfeeding induces early chronic renal dysfunction in adult male rats. Am J Physiol Renal Physiol 2009;297(4):F943–51. 10. Vaiman D, Gascoin-Lachambre G, Boubred F, Mondon F, Feuerstein JM, Ligi I, et al. The intensity of IUGR-induced transcriptome deregulations is inversely correlated with the onset of organ function in a rat model. PloS One 2011;6(6): e21222. 11. Ziegler EE. Meeting the nutritional needs of the low-birth-weight infant. Ann Nutr Metab 2011;58(Suppl 1):8–18. 12. Thomas EL, Parkinson JR, Hyde MJ, Yap IK, Holmes E, Dore CJ, et al. Aberrant adiposity and ectopic lipid deposition characterize the adult phenotype of the preterm infant. Pediatr Res 2011;70(5):507–12. 13. Rigo J, Senterre T. Intrauterine-like growth rates can be achieved with premixed parenteral nutrition solution in preterm infants. J Nutr 2013;143(12 Suppl): 2066S-2070S.
