Peter D. Gluckman

Effect of in utero and early-life conditions on adult health and disease.

Many lines of evidence, including epidemiologic data and extensive clinical and experimental studies, indicate that early life events play a powerful role in influencing later susceptibility to certain chronic diseases. This review synthesizes evidence from several disciplines to support the contention that environmental factors acting during development should be accorded greater weight in models of disease causation.

Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial

BACKGROUND Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy. METHODS 234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34-35 degrees C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation--ie, severe loss of background amplitude, and seizures--and those with less severe changes. FINDINGS In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, p=0.05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1.8; 0.49-6.4, p=0.51), but was beneficial in infants with less severe aEEG changes (n=172, 0.42; 0.22-0.80, p=0.009). INTERPRETATION These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.

Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity

OBJECTIVE Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans. RESEARCH DESIGN AND METHODS Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5′ from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5–95% range ≥10%, we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort. RESULTS In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4–31], P = 0.009, n = 64, and β = 20% [9–32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1–19], P = 0.023, n = 64 and β =12% [4–20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2–10] and β = 4% [1–7], respectively, both P = 0.002, n = 239). CONCLUSIONS Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.

Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.

Hypothermia has been proposed as a neuroprotective strategy. However, short-term cooling after hypoxia-ischemia is effective only if started immediately during resuscitation. The aim of this study was to determine whether prolonged head cooling, delayed into the late postinsult period, improves outcome from severe ischemia. Unanesthetized near term fetal sheep were subject to 30 min of cerebral ischemia. 90 min later they were randomized to either cooling (n = 9) or sham cooling (n = 7) for 72 h. Intrauterine cooling was induced by a coil around the fetal head, leading initially to a fall in extradural temperature of 5-10 degrees C, and a fall in esophageal temperature of 1.5-3 degrees C. Cooling was associated with mild transient systemic metabolic effects, but not with hypotension or altered fetal heart rate. Cerebral cooling reduced secondary cortical cytotoxic edema (P < 0.001). After 5 d of recovery there was greater residual electroencephalogram activity (-5.2+/-1.6 vs. -15.5+/-1.5 dB, P < 0.001) and a dramatic reduction in the extent of cortical infarction and neuronal loss in all regions assessed (e.g., 40 vs. 99% in the parasagittal cortex, P < 0.001). Selective head cooling, maintained throughout the secondary phase of injury, is noninvasive and safe and shows potential for improving neonatal outcome after perinatal asphyxia.

Ten Putative Contributors to the Obesity Epidemic

The obesity epidemic is a global issue and shows no signs of abating, while the cause of this epidemic remains unclear. Marketing practices of energy-dense foods and institutionally-driven declines in physical activity are the alleged perpetrators for the epidemic, despite a lack of solid evidence to demonstrate their causal role. While both may contribute to obesity, we call attention to their unquestioned dominance in program funding and public efforts to reduce obesity, and propose several alternative putative contributors that would benefit from equal consideration and attention. Evidence for microorganisms, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects as contributing factors to the obesity epidemic are reviewed herein. While the evidence is strong for some contributors such as pharmaceutical-induced weight gain, it is still emerging for other reviewed factors. Considering the role of such putative etiological factors of obesity may lead to comprehensive, cause specific, and effective strategies for prevention and treatment of this global epidemic.

Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life

Objective  Maternal undernutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. We investigated whether these effects may persist in subsequent generations.

Epigenetic Mechanisms and the Mismatch Concept of the Developmental Origins of Health and Disease

There is now considerable evidence that elements of the heritable or familial component of disease susceptibility are transmitted by nongenomic means, and that environmental influences acting during early development shape disease risk in later life. The underlying mechanisms are thought to involve epigenetic modifications in nonimprinted genes induced by aspects of the developmental environment, which modify gene expression without altering DNA sequences. These changes result in life-long alterations in gene expression. Such nongenomic tuning of phenotype through developmental plasticity has adaptive value because it attempts to match an individuals responses to the environment predicted to be experienced. When the responses are mismatched, disease risk increases. An example of such mismatch is that arising either from inaccurate nutritional cues from the mother or placenta before birth, or from rapid environmental change through improved socioeconomic conditions, which contribute substantially to the increasing prevalence of type-2 diabetes, obesity, and cardiovascular disease. Recent evidence suggests that the effects can be transmitted to more than the immediately succeeding generation, through female and perhaps male lines. Future research into epigenetic processes may permit us to develop intervention strategies.

Changing times: the evolution of puberty

An evolutionary and life history perspective is used to consider the evolution of puberty. The age of menarche would have evolved by the Neolithic to be matched to social maturity. It is suggested that in developed countries menarche is now returning to a similar age as in the Neolithic as infection and undernutrition, features of post-Neolithic society, have reduced impact. But recently the psychosocial expectations on adolescents in western societies have changed and social maturity now significantly follows menarche. The implications of the developing mismatch between the ages of biological puberty and social maturation are discussed. Evolutionary arguments are presented to explain the unique pubertal growth spurt of humans. Moreover, a life history perspective can reconcile the apparently conflicting observations that both poor fetal growth and better childhood nutrition are associated with earlier menarche.

Developmental Origins of Disease Paradigm: A Mechanistic and Evolutionary Perspective

Fetal growth is determined by the interaction between the environment and the fetal genome. The fetal environment, in turn, is determined by the maternal environment and by maternal and placental physiology. There is evidence that the interaction between the fetal environment and genome can determine the risk of postnatal disease, as well as the individuals capacity to cope with the postnatal environment. Furthermore, the role of various forms of maternal constraint of fetal growth in determining the persistence of these responses is reviewed. A limited number of biologic processes can contribute to the mechanistic basis of these phenomena. In addition to immediate homeostatic responses, the developing organism may make predictive adaptive responses of no immediate advantage but with long-term consequences. An evolutionary perspective is provided, as well as a review of possible biologic processes. The “developmental origins of disease” paradigm is a reflection of the persistence of such mechanisms in humans who now live in very different environments from those within which they evolved. The developmental origins paradigm and its underlying mechanistic and evolutionary basis have major implications for addressing the increasing burden of metabolic and cardiovascular disease.

A role for IGF-1 in the rescue of CNS neurons following hypoxic-ischemic injury

Three days after unilateral hypoxic-ischemic injury in infant rats insulin-like growth factor 1 (IGF-1) production by astrocytes was enhanced in the injured region. This was associated with increased expression of mRNA for IGF binding protein-3 but not for binding protein-1. In adult rats a single lateral cerebroventricular injection of IGF-1 two hours following a similar injury markedly reduced neuronal loss. It is suggested that endogenous IGF-1 is neurotrophic and that centrally administered IGF-1 may have therapeutic potential for brain injury.