Developmental Plasticity and Human Disease: Research Directions
Total Page：16
File Type：pdf, Size：1020Kb
Symposium | doi: 10.1111/j.1365-2796.2007.01802.x Developmental plasticity and human disease: research directions P. D. Gluckman1,2 & M. A. Hanson3 From the 1Centre for Human Evolution, Adaptation and Disease, Liggins Institute, University of Auckland, Auckland, New Zealand, 2National Research Centre for Growth and Development, Auckland, New Zealand, and 3Centre for Developmental Origins of Health and Disease, University of Southampton, Southampton, UK Abstract. Gluckman PD, Hanson MA (Liggins Insti- ment. Nevertheless, numerous questions remain, inclu- tute, University of Auckland, Auckland; National ding the current burden of disease that can be Research Centre for Growth and Development, Auck- attributed to early environmental factors; the path- land, New Zealand; and University of Southampton, ways, mechanisms and windows of plasticity; the Southampton, UK). Developmental plasticity and identification of early markers of environmentally human disease: research directions (Symposium). induced change; and the feasibility, costs and benefits J Intern Med 2007; 261: 461–471. of intervention. A focused agenda of research is nee- ded to convince policy makers of the importance of The conceptual basis of the ‘developmental origins’ developmental factors in human disease. paradigm has converged on the role of developmental plasticity responding to signals from the early envi- Keywords: fetal growth retardation, insulin resistance, ronment, with heightened risk of disease if the leptin, obesity, pregnancy, type 2 diabetes mellitus. induced phenotype does not match the later environ- gators. We now consider the DOHaD phenomenon to Introduction be a subset of a broader and normal biological phe- Although it is nearly two decades since the first nomenon – that of developmental plasticity – but one observations relating early environment to later dis- that can under some circumstances be maladaptive ease were made, there remains debate and uncertainty and lead to greater risk of disease. Developmental as to how understanding the so-called ‘developmental plasticity encompasses those processes that generate origins (DOHaD) paradigm’ can be applied to alternative phenotypes from a single genotype through improving human health. The questions that have the actions of environmental cues acting during devel- emerged are multiple and there is now a broad and opment. They allow environmental influences to ‘tune interdisciplinary research agenda. Despite some confu- the match’ of the organism to its expected environ- sion and debate, there is now overwhelming epidemi- ment beyond that achieved through natural selection ological and prospective data relating early life events (i.e. inherited genotype). to the risk of heart and cardiovascular disease, type 2 diabetes, obesity, osteoporosis and other disorders in During the 1990s a considerable experimental litera- later life. ture emerged showing that the equivalent of the DOHaD phenomenon could be replicated experiment- This relationship has been termed ‘programming’, but ally in animals by manipulating maternal nutrition or we generally resist the term – it implies a determinis- fetal growth or by mimicking stress by administering tic process and set of mechanisms akin to the genetic glucocorticoids to the pregnant mother (reviewed in ‘programme’ of development and, as this review will [1, 2]). The long-term effects do not necessarily highlight, its use may influence the mindset of investi- require alterations in birth size. Indeed an important ª 2007 Blackwell Publishing Ltd 461 P. D. Gluckman & M. A. Hanson | Symposium: Developmental plasticity and disease concept is that alterations in birthweight are not cohort studies will always have the issue of relevance necessary for early life events to induce other pheno- to current populations. What are needed are better sur- typic changes with later consequences. Indeed, com- rogates of both change in development induced early parative studies point out that quite major phenotypic in the life-course and consequential change in disease changes can occur as a result of subtle, but evolutio- risk, preferably from current prospective cohorts. As narily important, signals, as in the case of environ- will be discussed, epigenetic measures may be useful mentally induced polyphenism in insects [3]. Recent markers of the former and measures of lipid depos- mechanistic studies have focused on the possible role ition (particularly visceral fat) and metabolism in chil- of epigenetic changes in mediating these events, either dren might be very relevant early outcome measures. directly or indirectly. A related issue comes from the tendency to examine However, whilst there is increasing evidence that the the attributable risk in relation to a single outcome normal processes of developmental plasticity operate such as heart disease, whereas the experimental and in humans and can be affected by the early environ- clinical data demand a more holistic approach. Thus, ment and that this may influence later disease risk, an adverse early life environment can induce a cluster the outstanding questions are multiple and important of outcomes, including visceral adiposity, central and and require systematic and integrated consideration. peripheral changes in the regulation of satiety, food This paper highlights the most important of these preference, fat metabolism, insulin sensitivity, endot- questions in the hope that it will assist the biomedical helial dysfunction, altered tempo of development, research community to focus their effort. altered nutrient compartmentalization and growth, neuroendocrine changes, mood disorders and reduced nephron and neurone number [7]. It seems likely that How important are early environmental factors in the concurrent environment, developmental factors the ecology of human disease? and genotypic variation all influence the particular An ongoing debate [4, 5] arising from the epidemio- balance of organ and system changes reflected in the logical studies is how important this framework is to variation in the expression of this ‘metabolic pheno- the prevalence of diseases appearing in middle and type’. Thus, it is more appropriate to estimate the glo- old age. The debate is confounded by several factors: bal attributable risk arising from early life factors in some studies use only surrogates for disease risk relation to their contribution to the origin of the meta- (e.g. measures of blood pressure or insulin sensitiv- bolic phenotype rather than to individual components. ity) and birthweight itself is a very crude measure of the prenatal environment. Further, current models A key issue is to what extent do genetic confounders consider that there is an interaction of the prenatal, play a role in understanding these relationships. Stud- infant and later environments in generating disease ies of glucokinase mutations led to the proposition of risk, and this generally is not considered appropri- the ‘fetal insulin hypothesis’ in which mutations ately in most of these analyses. The problem is that affecting glucokinase influenced both fetal growth the only population-based estimate that examines and the later risk of metabolic disease [8]. Undoubt- life-time disease risk comes from a Finnish cohort edly there are mutations in several genes related to born in the 1930s [6]. The relevance of that popula- insulin action that could have this effect, and further tion to current populations is uncertain. Yet that studies are needed of this genetic confounding. But as study suggests that a very large component of the is discussed below, recent evidence would suggest attributable risk of heart disease and diabetes lies in that insulin resistance appears after and not before perinatal growth. birth. This issue of how important are early life events The effect of environmental influences must of course needs to be addressed in new ways as retrospective be influenced by the genotype. This is best illustrated 462 ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 261; 461–471 P. D. Gluckman & M. A. Hanson | Symposium: Developmental plasticity and disease by studies such as those on PPARc2 polymorphisms [17]. This may be a distinct pathway, but as all fetal [9, 10] and by the demonstration that the effects of growth is somewhat constrained [18] it may simply maternal constraint on birth size are dominant in first- be a more acute form of developmental mismatch born children whereas the effects of insulin gene rather than a distinct pathway. polymorphisms are more evident in subsequent preg- nancies [11]. The experimental data clearly exclude a Thirdly, we need to note that infants of diabetic and prevailing genetic explanation for the DOHaD phe- obese mothers become obese and insulin resistant nomenon. Further, a number of the polymorphisms themselves by a distinct pathway [19]. The outcome reported may well be very population-specific. Thus for the infants of diabetic mothers is discussed below we are left with the question: to what extent do poly- and is likely to represent a pathological pathway morphisms interact with developmental cues in reflecting increased fat mass, probably arising in utero increasing or reducing disease risk and to what extent secondary to fetal hyperinsulinaemia [20]. The mecha- are these variations population-specific? The matter is nisms operating in maternal obesity are less clear. In further confounded by the recent recognition of epi- this regard it is important to note the often-overlooked genetic inheritance [12], making