A write- up of Dr Raman Subramaniam (Consultant Obstetrician and Gynaecologist Fetal Medicine and Gynaecological Centre)
Genetics (nature) and environment (nurture) both influence the development of an individual. In the Asian population, which makes up 60% of the world’s population, non-communicable diseases are prevalent. Obesity, for example, has become a major global health problem; for instance, the proportion of adults with a body mass index of 25 or greater has exceeded 40% among men in Singapore, and among both men and women in Malaysia (1).
The thrifty phenotype
Early genetic and environmental influences may be contributing to the occurrence of these disease in the infant’s later life (2). The “developmental origins hypothesis” posits that the foetus make cellular, metabolic, and physiological adaptations in response to its changing environment to prepare it for postnatal life (3). The phenotype of the developing individual has been described as “thrifty”; for example, during periods of starvation, the foetus reduces insulin secretion and increases peripheral insulin resistance, thus directing more glucose to the brain and heart, and less to skeletal muscles (4). Developmental plasticity exists, with a single genotype potentially giving rise to a range of different phenotypes.
Dutch Famine studies
The influence of nature over nurture can be seen in the outcomes from the Dutch famine studies. In the winter of 1944, there were massive food shortages in the Netherlands due to the war. Consequently, calorie consumption dropped from 2,000 to 500 per day. Children born or raised during this time, and who were exposed to famine, were small and short in stature, and had many diseases including, oedema, anaemia, diabetes and depression later in life (5). The risk of having smaller babies persisted for two generations (6). The infants exposed to famine while in utero had increased risk of insulin resistance and metabolic syndrome as adults. Increases in psychiatric disorders (e.g. schizophrenia, major affective disorder) also occurred when these infants later reached adult life (7-8). Even six decades later, these individuals had less DNA methylation of the imprinted insulin-like growth factor II gene compared with their well-fed, same-sex siblings (9). The periconceptional period was identified as being important in the association between famine and DNA methylation. This study provided the first evidence that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.
Epigenetics in early life and health outcomes in adults
The expression of our genes is not fixed. Epigenetic regulation of the genes can produce stable changes to the DNA and chromatin structure that alter gene expression. Methylation of DNA and modifications of the histones by acetylation/deacetylation are primarily involved (10-12). The epigenetic programming that occurs early in life can influence outcomes later in life (13-14),such as the development of non-communicable disease such as obesity and type 2 diabetes in later life (15). Moreover, it appears that this epigenetic programming may occur across generations (16). For example, malnourishment of a pregnant women may result in suboptimal foetal development, and the birth of an infant at risk of obesity and insulin resistance. Later in life, these individuals may experience gestational diabetes and give birth to large babies, who are themselves at risk of repeating the cycle. (16)
To illustrate, the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study is following a large parent-offspring cohort from Singapore, primarily to evaluate the influences operating during early development, and determine if these influences may affect the infant’s metabolic trajectory during later life (Figure 1). (17)Available data from the trial have illustrated the important influence of maternal nutrition on the risk of preterm birth and birth size of their neonates (18).
These observations highlight that optimal nutrition of infants, and their parents, is essential if children are to reach their full potential in lifelong health (19). Early intervention is associated with good outcomes; late intervention is associated with less favourable outcomes (Figure 1).
Figure 1.Factors related to the development of obesity and associated disorders10
Early intervention may reduce the risk of non-communicable disease. The preconception period is critical; promoting a healthy start to life means that the beneficial effects of intervention can have greater impact.
- Ng M. et al (2014). Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384(9945):766-781.
- Barker, DJ. Developmental origins of chronic disease. Public Health 2012;126(3):185-189.
- Lebenthal, E. et al (2007). Novel concepts in the developmental origins of adult health and disease. J Nutr 2007;137(4):1073-1075
- Hales, C.N. et al (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992;35(7):595-601.
- Susser M. and Stein Z. (1994). Timing in prenatal nutrition: a reprise of the Dutch Famine Study. Nutr Rev 1994;52(3):84-94.
- Emanuel I. et al (1992). Intergenerational studies of human birthweight from the 1958 birth cohort. 1. Evidence for a multigenerational effect. Br J Obstet Gynaecol 1992;99(1):67-74
- Hulshoff Pol H.E. et al. (2000). Prenatal exposure to famine and brain morphology in schizophrenia. Am J Psychiatry 2000;157(7):1170-1172.
- Brown A.S. et al (2000). Further evidence of relation between prenatal famine and major affective disorder. Am J Psychiatry 2000;157(2):190-195.
- Heijmans B.T. et al (2008). Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 2008;105(44):17046-17049.
- Gluckman P.D. et al (2005). The developmental origins of adult disease. Matern Child Nutr 2005;1(3):130-141
- Heerwagen M.J. et al (2010). Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am J Physiol Regul Integr Comp Physiol 2010;299(3):R711-722
- Zaidi S.K. et al (2010). Architectural epigenetics: mitotic retention of mammalian transcriptional regulatory information. Mol Cell Biol 2010;30(20):4758-4766
- Godfrey K.M. et al (2010). Developmental origins of metabolic disease: life course and intergenerational perspectives. Trends Endocrinol Metab 2010;21(4):199-205
- Koletzko B. et al (2011). Programming research: where are we and where do we go from here? Am J Clin Nutr 2011;94(6 Suppl):2036s-2043s
- Hanson M.A. et al (2014). Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev 2014;94(4):1027-1076
- Gluckman P.D. et al (2005). Metabolic disease: evolutionary, developmental and transgenerational influences. Nestle Nutr Workshop Ser Pediatr Program 2005;55:17-27
- Soh S.E. et al (2014). Insights from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort study. Ann Nutr Metab 2014;64(3-4):218-225
- Chia A.R. et al (2016). A vegetable, fruit, and white rice dietary pattern during pregnancy is associated with a lower risk of preterm birth and larger birth size in a multiethnic Asian cohort: the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study. Am J Clin Nutr 2016;104(5):1416-1423
- Black R.E. et al (2013). Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 2013;382(9890):427-451