The nutritional basis of the fetal origins of adult disease

Abstract

It is now widely accepted that the risks of a number of chronic diseases in adulthood may have their origins before birth. Such diseases include non insulin-dependent diabetes mellitus, hypertension and coronary heart disease. Professor David Barker and colleagues in Southampton have produced a large proportion of the data in this field over the last decade,1 although the relationship between early life events and adult disease had been raised many years earlier.2 Most of this work has been based on epidemiological studies wherein cohorts of subjects whose birth records were available have been traced into adulthood. They have shown that measurements made on babies at birth, including birthweight, length, body proportions and placental weight, are strongly related to either later disease incidence (coronary heart disease mortality, non-insulin-dependent diabetes)3,4 or risk factors for those diseases (hypertension, glucose intolerance, hyperlipidaemia).1,5,6 Such relationships have been shown to hold in many different populations and are apparent from early childhood.7,8 The basis of these epidemiological observations is proposed to be that of programming. That is, an event operating at a critical or sensitive period results in a long-term change in the structure or function of the organism. Programming is a well-established biological phenomenon, and there are many common and well-known examples. Female rats given testosterone during the first 4 days of life develop a male pattern of gonatotropin secretion after puberty, and despite normal ovarian and pituitary function, fail to develop normal patterns of female sexual behaviour.9 Administration of androgen at 10 days of age has no such effect. Similarly, transient immunization of neonatal rats against growth hormone releasing factor results in permanent impairment of pituitary growth hormone secretion and permanent impairment of growth rate.10 Exposure of neonatal rats to short periods of stimulation, handling or various stressors results in permanent changes in hypothalamic structure and systemic responses to stress.11,12 Since most examples of programming involve a critical period early in life, this phenomenon as the proposed basis of the epidemiological observations is both epidemiologically and biologically plausible. Thus a programming stimulus in fetal life is proposed to lead both to changes in size at birth and also to altered homeostatic mechanisms such as regulation of blood pressure or insulin sensitivity, which in turn result in susceptibility to disease in later life.13 The question which then arises concerns the nature of the programming stimulus. Undernutrition was proposed early as a likely programming stimulus, although others such as excessive fetal exposure to glucocorticoids have also been proposed.14–16 This review will focus on nutrition as the hypothesized primary programming stimulus. It will examine the experimental basis for this hypothesis, a number of assumptions and misconceptions surrounding the hypothesis, and the need for caution in applying the results of animal experiments to the human situation. The proposal that nutrition in fetal life is a central stimulus for programming of susceptibility to adult disease is now supported by three main sets of evidence. The first is that manipulation of nutrition during pregnancy in animals can be shown to produce many of the phenomena observed in the epidemiological studies. Publication of the early epidemiological studies led us and many others to attempt to verify experimentally the link between reduced birth size and later disease risk. Size at birth is readily manipulated in experimental animals by altering maternal nutrition in pregnancy. Experimental scientists thus began by using these approaches to investigate the consequences of size at birth for postnatal physiology, producing a rapidly burgeoning literature in the area over recent years. For example, reducing the proportion of protein in the diet of pregnant rats results in offspring which have reduced size at birth and also elevated blood pressure17 and glucose intolerance18–20 in adult life. A variety of experimental approaches to reduce maternal nutrition in pregnancy have lead to similar observations in rats,21 guinea pigs22 and sheep.23 Thus there can no longer be any doubt that changes in maternal nutrition in animals can both change size at birth and also permanently alter (programme) aspects of the physiology of the offspring in a way that is consistent with the disease susceptibility observed in human studies. The second line of evidence is based on ‘pseudo experiments’ of maternal nutritional manipulation in human pregnancy, most notably that of the Dutch Hunger Winter. These studies have shown that women exposed during pregnancy to the nutritional limitation imposed by severe famine have offspring with reduced birth size24 and an increased risk of glucose intolerance25 and obesity in adult life.26,27 Thus there