Early developmental conditioning of later health and disease: physiology or pathophysiology?

Abstract

Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention.

FIGURE 1.

Lifecourse view of noncommunicable disease (NCD) risk. Risk increases in a nonlinear way as a result of declining plasticity and accumulative damage from lifestyle-imposed or other challenges. The effect of mismatch between developmentally and evolutionarily influenced phenotype and adult environment also increases through the lifecourse. Interventions in adults, especially those at high risk, can be beneficial, but only to a degree. Screening in middle-aged adults may also be too late to reduce risk substantially. Interventions in adolescents and young adults are likely to be more effective and, importantly, can reduce the risk of NCDs in the next generation. The prenatal period establishes risk through interaction between genetic, epigenetic, and environmental factors. [Based on the author's graph prepared for the World Health Organization (660).]

FIGURE 2.

The mismatch concept of NCD risk in relation to the nutritional/energy balance in the environment. Humans have evolved to remain healthy over a wide range of adult environments, at least in terms of survival to reproductive age (Darwinian fitness). The level of the environment for health is lower and its range is less following development in an impaired environment, for example, with low or unbalanced nutrient provision. If the adult environment is richer, the risk of NCDs is correspondingly increased. Epigenetic processes are involved in these developmental effects. Note that predictive adaptive responses that confer fitness advantage need operate only for a match between developmental environment and environment up to the time of reproduction. Any further mismatch, for example, as adult lifestyle becomes less healthy, adds to the risk of NCDs in ways against which the developed phenotype may confer little protection. [From Gluckman and Hanson (214), with permission from AAAS.]

FIGURE 3.

Left: predicted systolic blood pressure (SBP) as a function of birth weight in 20 Nordic studies, obtained using pooled estimates from spline regressions with a knot point at a birth weight of 4 kg. [From Gamborg et al. (188), by permission of Oxford University Press.] Right: prevalence of type 2 diabetes in 1179 Pima Indians aged 20–39 yr in relation to birthweight. [From McCance DR, Pettitt DJ, Hanson RL, Jacobsson LTH, Knowler WC, Bennett PH. BMJ 308: 2000. Reprinted with permission from BMJ Publishing Group, Ltd.]

FIGURE 4.

Characteristics of linear reaction norms. In A, the vertical displacement represents the degree of a particular phenotypic attribute, or the level of the genotype-specific relation between environment and phenotype. The broken line represents the average phenotypic value of the genotype across environments. The slope represents the degree of plasticity in relation to the environment. In B, there is genetic variation in the reaction norm of the phenotype (arrows), but no plasticity (slope = 0) and no variation for plasticity (slope does not change with environment). In C, there is both genetic variation and plasticity but no variation of plasticity (slope > 0 but is constant across environment). In D, there is genetic variation, plasticity, and variation for plasticity. In addition, in D, the heritability (extent of variation of phenotype in a particular environment accounted for by genetic variation) of the trait is lower at the left than at the right end of the environmental axis. [Modified from Pigliucci (468). Reprinted with permission of Johns Hopkins University Press.]

FIGURE 5.

Waddington's “epigenetic landscape.” In contemporary terms, the ball may be viewed as a group of pluripotent stem cells, for which the final destination in terms of final committed cell line depends on the path selected at a series of bifurcations. In Waddington's model, phenotypic development is “canalized” by processes which restrict its variability in the face of variation in genotype. Such processes are essential for replication of the lineage. Processes that reduce the steepness of the walls of the valley therefore increase plasticity. [From Waddington (619). Reprinted by permission from Macmillan Publishers Ltd.]

FIGURE 6.

The time scales of adaptive processes. [From Kuzawa and Bragg (332), with permission from University of Chicago Press.]

FIGURE 7.

Physiological adaptive processes in developmental conditioning.

FIGURE 8.

Components of lifecourse strategies induced during development, derived from a range of animal species in relation to integrated adaptive responses that increase Darwinian fitness, but argued to be applicable to humans. [Modified from Gluckman et al. (217). Copyright 2007 John Wiley and Sons.]

FIGURE 9.

Placental adaptive responses. [From Myatt (418). Copyright 2006 John Wiley and Sons.]

FIGURE 10.

Pathophysiological nonadaptive processes involved in developmental disruption.

FIGURE 11.

Summary of findings from prospective studies in Southampton, illustrating aspects of risk established in mother and affecting her offspring, leading in turn to an intergenerational risk cycle. (Courtesy of Professor Hazel Inskip.)