Predictive Adaptive Response Research Articles

Intergenerational response of steroidogenesis-related genes to maternal malnutrition.

We sought to examine whether rat maternal food restriction (MFR) affects the expression of steroidogenesis-related genes Cyp19, Cyp17a1, Insl3 and Gdf-9 in the ovaries of offspring from the first (FRG1) and second (FRG2) generations at pre-pubertal age (week 4) and during adulthood (week 8). At week 4, MFR significantly increased the expression of RNAs for all analyzed genes in both FRG1 and FRG2 females, which may indicate that MFR affects the onset of the reproductive lifespan, by inducing early pubertal onset. At week 8, the Cyp19 gene was still upregulated in MRF-subjected animals (Cyp19: P=0.0049 and P=0.0508 in FRG1 and FRG2, respectively), but MFR induced a significant decrease in Cyp17 and Gdf-9 gene expression in the offspring of both FRG1 and FRG2 females when compared with the controls (Cyp17: P=0.0018 and P=0.0016, respectively; Gdf-9: P=0.0047 and P=0.0023, respectively). This suggests that females at week 8, which should normally be in their optimal reproductive capacity, experience premature ovarian aging. At week 4, the activation of Cyp19 and Cyp17 was higher in the FRG1 ovaries than in the FRG2 ovaries, whereas the extent of Insl3 and Gdf-9 activation was lower in the FRG1 ovaries. This may indicate that FRG2 females were more vulnerable to MFR than their mothers (FRG1) and grandmothers, which is consistent with the 'predictive adaptive response' hypothesis. Our findings reveal that MFR may induce intergenerational ovarian changes as an adaptive response to ensure reproductive success before death.

Predictions of children\u2019s emotionality from evolutionary and epigenetic hypotheses

Sex-dependent effects of mismatched prenatal-postnatal maternal conditions are predicted by combining two evolutionary hypotheses: that foetal conditions provide a forecast of likely postnatal environments (Predictive Adaptive Response), and that the female foetus is better adapted than the male to maternal adversity (Trivers-Willard hypothesis). Animal studies have implicated glucocorticoid mechanisms modifiable by effects of postnatal tactile stimulation on glucocorticoid receptor gene expression. In this study we examined behavioural predictions in humans based on these evolutionary and epigenetic models. Mothers in a general population cohort provided self-reported anxiety scores at 20 weeks pregnancy, and at 9 weeks, 14 months and 3.5 years postpartum, and frequency of infant stroking at 9 weeks. Mothers and teachers reported child symptoms at 7 years. SEM models with maximum-likelihood estimates made use of data from 887 participants. There was a three-way interaction between prenatal and postnatal anxiety and maternal stroking in the prediction of irritability, seen only in girls. This arose because lower maternal stroking was associated with higher irritability, only in the mismatched, low-high and high-low maternal anxiety groups. We provide evidence that mechanisms likely to have evolved well before the emergence of humans, contribute to the development of children’s emotionality and risk for depression.

Discrimination, segregation, and chronic inflammation: Testing the weathering explanation for the poor health of Black Americans.

Several studies have reported a relation between race-related stressors and the poor health of Black Americans. Such findings raise questions regarding the mediating biological mechanisms that might account for this link. The present study investigated elevated systemic inflammation, a factor shown to be a strong predictor of chronic illness and mortality in all ethnic populations, as a possible factor. Using 7 waves of data from the Family and Community Health Study, collected over a 20-year period from over 400 Black Americans, we investigated the extent to which exposure to discrimination and segregation at various points in the life course predicted adult inflammation at age 28. Our analyses examined whether cumulative stress, stress generation, or predictive adaptive response (PAR) models best accounted for any associations that existed between these race-related stressors and adult inflammation. At every wave of data collection, assessments of discrimination and segregation were related to adult inflammation. However, multivariate analyses using structure equation modeling indicated that the PAR model best explained the effect of these race-related stressors on inflammation. Exposure to discrimination and segregation during the juvenile years predicted adult inflammation and amplified the inflammatory effect of adult exposure to these race-related stressors. These effects were considerably more robust than that of traditional health risk factors such as diet, exercise, smoking, and low SES. Implications of these findings are discussed, including the limitations of the widely accepted risk factor approach to increasing the health of Black Americans. (PsycINFO Database Record

Prenatal undernutrition attenuates fasting-induced reproductive dysfunction in pre-pubertal male rats

Prenatal undernutrition affects various physiological functions, such as metabolic and reproductive functions, after birth, and such changes are associated with the pathogeneses of certain diseases. It has been hypothesized that these changes are predictive adaptive responses that help individuals to endure similar conditions in the postnatal period. Thus, we evaluated the effects of prenatal undernutrition on the responses of the body weight (BW) regulation system and reproductive functions to fasting in the pre-pubertal period in male rats. Prenatally normally nourished and undernourished rats exhibited similar reductions in BW and visceral fat after 48 h fasting in the pre-pubertal period. Furthermore, these two groups displayed similar fasting-induced patterns of change in their hypothalamic levels of appetite regulatory factors; i.e., neuropeptide Y and pro-opiomelanocortin. These results indicate that prenatal undernutrition had no marked effects on BW regulation in male rats. On the other hand, serum luteinizing hormone and testosterone levels were decreased by 48 h fasting in the prenatally normally nourished rats, whereas the levels of these hormones did not change in the prenatally undernourished rats. However, the hypothalamic mRNA level of kisspeptin 1 (Kiss1), which is a positive regulator of gonadotropin-releasing hormone/gonadotropins, was reduced by fasting in both groups. These results indicate that prenatal undernutrition might attenuate fasting-induced reproductive dysfunction in the postnatal period; however, these changes might not be induced by alterations in the hypothalamic Kiss1 system. Further studies are needed to clarify the mechanisms involved in these changes in reproductive function.

Can early-life growth disruptions predict longevity? Testing the association between vertebral neural canal (VNC) size and age-at-death

This study tests the association of vertebral neural canal (VNC) size and age-at-death in a Portuguese skeletal collection from the 19th–20th century. If the plasticity and constraint model best explains this association, VNC size would be negatively related to mortality risk. If the predictive adaptive response (PAR) model is a better fit, no association can be inferred between VNC size and age-at-death. Ninety individuals were used in this study. The anteroposterior and transverse diameters of all vertebrae were measured. A Cox regression analysis was performed by sex to assess the effect of VNC size on age-at-death, after adjusting for the effects of year of birth and cause of death. Several measurements of VNC diameters have a statistically significant effect on age-at-death, but when the covariates were considered, this association became non-significant. The PAR model seems the best fit to explain the relation between VNC and age-at-death. Individuals who went through stressful events early in life were prepared to face a stressful environment later in life, allowing them to cope with adversity without affecting longevity. However, developmental plasticity may be buffered by maternal capital accumulated over several generations, and health hazards encountered throughout life can contribute to health outcomes and longevity.

Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques

Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to determine whether a gain-of-function nonsynonymous OXTR SNP interacted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavioral differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.

A 'phenotypic hangover': the predictive adaptive response and multigenerational effects of altered nutrition on the transcriptome of Drosophila melanogaster.

The Developmental Origins of Health and Disease hypothesis predicts that early-life environmental exposures can be detrimental to later-life health and that mismatch between the pre- and post-natal environment may contribute to the growing non-communicable disease epidemic. Within this is an increasingly recognized role for epigenetic mechanisms; for example, epigenetic modifications can be influenced by nutrition and can alter gene expression in mothers and offspring. Currently, there are few whole-genome transcriptional studies of response to nutritional alteration. Thus, we sought to explore how nutrition affects the expression of genes involved in epigenetic processes in Drosophila melanogaster. We manipulated Drosophila food macronutrient composition at the F0 generation, mismatched F1 offspring back to a standard diet and analysed the transcriptome of the F0–F3 generations by RNA sequencing. At F0, the altered (high-protein, low-carbohydrate) diet increased expression of genes classified as having roles in epigenetic processes, with co-ordinated down-regulation of genes involved in immunity, neurotransmission and neurodevelopment, oxidative stress and metabolism. Upon reversion to standard nutrition, mismatched F1 and F2 generations displayed multigenerational inheritance of altered gene expression. By the F3 generation, gene expression had reverted to F0 (matched) levels. These nutritionally induced gene expression changes demonstrate that dietary alterations can up-regulate epigenetic genes, which may influence the expression of genes with broad biological functions. Furthermore, the multigenerational inheritance of the gene expression changes in F1 and F2 mismatched generations suggests a predictive adaptive response to maternal nutrition, aiding the understanding of the interaction between maternal diet and offspring health, with direct implications for the current non-communicable disease epidemic.

Long-term effects of early nutrition and environmental matching on developmental and personality traits in zebra finches

Developmental plasticity is a key feature of many organisms and individuals can benefit from early programming to optimize their phenotypes for the expected environmental conditions. However, environmental conditions may sometimes change unexpectedly. Mismatches between early and adult life, for example, can have important repercussions for adult phenotypes, potentially leading to better performance under matched than mismatched conditions as predicted by the predictive adaptive response hypothesis. We conducted a long-term experimental manipulation of dietary conditions in a population of zebra finches, Taeniopygia guttata. Broods were exposed to two early nutritional treatments until independence and we used a split-brood design to independently manipulate nutritional conditions after independence to create matched and mismatched nutritional environments in later life. Developmental trajectories of all individuals were followed for more than 5 years and we scored behavioural responses in trials in a special environment and while interacting with a special object three times during adult life. Overall, we found no evidence for early programming affecting morphology. Tarsus and wing length were exclusively influenced by the early nutrition. Body weight showed lasting effects of the early treatment and independent effects of nutritional condition during adulthood, but no effects of environmental matching or mismatching. Special-object trials showed effects of the adult nutritional treatment while environmental matching affected hopping activity in special environments. These behavioural responses showed substantial long-term individual stability over a 3-month period and were only marginally smaller when measured over a period of more than 4 years. Interestingly, survival of individuals from low-quality early nutritional condition was higher compared with high-quality early condition individuals, which became evident only after years of survival monitoring. Beyond the nutritional treatment itself, we found sizable brood identity effects that slowly but steadily declined with age, indicating a significant but decaying effect of natural variation in parental provisioning on adult phenotypes.

Long-term fitness consequences of early environment in a long-lived ungulate.

Cohort effects can be a major source of heterogeneity and play an important role in population dynamics. Silver-spoon effects, when environmental quality at birth improves future performance regardless of the adult environment, can induce strong lagged responses on population growth. Alternatively, the external predictive adaptive response (PAR) hypothesis predicts that organisms will adjust their developmental trajectory and physiology during early life in anticipation of expected adult conditions but has rarely been assessed in wild species. We used over 40 years of detailed individual monitoring of bighorn ewes (Ovis canadensis) to quantify long-term cohort effects on survival and reproduction. We then tested both the silver-spoon and the PAR hypotheses. Cohort effects involved a strong interaction between birth and current environments: reproduction and survival were lowest for ewes that were born and lived at high population densities. This interaction, however, does not support the PAR hypothesis because individuals with matching high-density birth and adult environments had reduced fitness. Instead, individuals born at high density had overall lower lifetime fitness suggesting a silver-spoon effect. Early-life conditions can induce long-term changes in fitness components, and their effects on cohort fitness vary according to adult environment.

Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition

BackgroundSevere acute malnutrition (SAM) in infants may present as one of two distinct syndromic forms: non-edematous (marasmus), with severe wasting and no nutritional edema; or edematous (kwashiorkor) with moderately severe wasting. These differences may be related to developmental changes prior to the exposure to SAM and phenotypic changes appear to persist into adulthood with differences between the two groups. We examined whether the different response to SAM and subsequent trajectories may be explained by developmentally-induced epigenetic differences. MethodsWe extracted genomic DNA from muscle biopsies obtained from adult survivors of kwashiorkor (n=21) or marasmus (n=23) and compared epigenetic profiles (CpG methylation) between the two groups using the Infinium® 450K BeadChip array. FindingsWe found significant differences in methylation of CpG sites from 63 genes in skeletal muscle DNA. Gene ontology studies showed significant differential methylation of genes in immune, body composition, metabolic, musculoskeletal growth, neuronal function and cardiovascular pathways, pathways compatible with the differences in the pathophysiology of adult survivors of SAM. InterpretationThese findings suggest persistent developmental influences on adult physiology in survivors of SAM. Since children who develop marasmus have lower birth weights and after rehabilitation have different intermediary metabolism, these studies provide further support for persistent developmentally-induced phenomena mediated by epigenetic processes affecting both the infant response to acute malnutrition and later life consequences. FundingSupported by a Grant from the Bill and Melinda Gates Foundation (Global Health OPP1066846), Grand Challenge “Discover New Ways to Achieve Healthy Growth.” Evidence Before This StudyPrevious research has shown that infants who develop either kwashiorkor or marasmus in response to SAM differ in birth weight and subsequently have different metabolic patterns in both infancy and adulthood. Added Value of This StudyThis study demonstrates epigenetic differences in the skeletal muscle of adult survivors of marasmus versus kwashiorkor and these differences are in genes that may underlie the longer-term consequences. Implications of All the Available EvidenceThese data are compatible with the different clinical responses to SAM arising from developmentally-induced epigenetic changes laid down largely before birth and provide evidence for the predictive adaptive response model operating in human development.

Maternal folate depletion during early development and high fat feeding from weaning elicit similar changes in gene expression, but not in DNA methylation, in adult offspring.

The 'Predictive Adaptive Response' hypothesis suggests that the in utero environment when mismatched with the post-natal environment can influence later life health. Underlying mechanisms are poorly understood, but may involve gene transcription changes regulated via epigenetic mechanisms. In a 2 × 2 factorial design, female C57Bl/6 mice were randomised to low or normal folate diets (0.4 mg/2 mg folic acid/kg diet) prior to and during pregnancy and lactation with offspring randomised to high- or low-fat diets at weaning. Genome-wide gene expression and promoter DNA methylation were measured using microarrays in adult male livers. Maternal folate depletion and high fat intake post-weaning influenced gene expression (1859 and 1532 genes, respectively) and promoter DNA methylation (201 and 324 loci, respectively) but changes in expression and methylation were poorly matched for both dietary interventions. Expression of 642 genes was altered in response to both maternal folate depletion and post-weaning high fat feeding, treatments imposed separately. In addition, there was evidence that the combined dietary insult (i.e. maternal folate depletion followed by high fat post-weaning) caused the largest expression change for most genes. Our observations align with, and provide evidence in support of, a potential underlying mechanism for the 'Predictive Adaptive Response' hypothesis.

Isoflurane Exposure Induces Cell Death, Microglial Activation and Modifies the Expression of Genes Supporting Neurodevelopment and Cognitive Function in the Male Newborn Piglet Brain.

Exposure of the brain to general anesthesia during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex, incompletely understood and may be sexually dimorphic, but include developmentally inappropriate apoptosis, inflammation and a disruption to cognitively salient gene expression. We investigated the effects of a 6h isoflurane exposure on cell death, microglial activation and gene expression in the male neonatal piglet brain. Piglets (n = 6) were randomised to: (i) naive controls or (ii) 6h isoflurane. Cell death (TUNEL and caspase-3) and microglial activation were recorded in 7 brain regions. Changes in gene expression (microarray and qPCR) were assessed in the cingulate cortex. Electroencephalography (EEG) was recorded throughout. Isoflurane anesthesia induced significant increases in cell death in the cingulate and insular cortices, caudate nucleus, thalamus, putamen, internal capsule, periventricular white matter and hippocampus. Dying cells included both neurons and oligodendrocytes. Significantly, microglial activation was observed in the insula, pyriform, hippocampus, internal capsule, caudate and thalamus. Isoflurane induced significant disruption to the expression of 79 gene transcripts, of these 26 are important for the control of transcription and 23 are important for the mediation of neural plasticity, memory formation and recall. Our observations confirm that isoflurane increases apoptosis and inflammatory responses in the neonatal piglet brain but also suggests novel additional mechanisms by which isoflurane may induce adverse neural and cognitive development by disrupting the expression of genes mediating activity dependent development of neural circuits, the predictive adaptive responses of the brain, memory formation and recall.

Children's growth in an adaptive framework: explaining the growth patterns of American slaves and other historical populations

This article presents a new adaptive framework for understanding children's growth in the past. Drawing upon the recent work on adaptive responses in relation to growth, it presents prenatal and postnatal adaptive mechanisms that affect the growth patterns of children. The most novel adaptive response to the historical literature is the prenatal predictive adaptive response where the metabolism and growth trajectory of a child is programmed to match predicted conditions later in life. Having discussed the framework in detail, a reinterpretation of the growth pattern of American slaves is then suggested. It seems likely that a mismatch between relatively good conditions in utero and absolutely appalling conditions in infancy and early childhood led slave children to become extremely stunted by the age of three or four. However, after this age, slave children experienced catch‐up growth because their immune systems had become more developed and because their diet improved tremendously and hookworm exposure was reduced. Thus, it seems that American slave children may have experienced substantial catch‐up growth because they were prenatally programmed for a higher metabolism and growth trajectory. The article concludes by setting out some stylized facts about children's growth in the past and pointing toward areas of future research.

The influence of weather conditions during gestation on life histories in a wild Arctic ungulate.

The internal predictive adaptive response (internal PAR) hypothesis predicts that individuals born in poor conditions should start to reproduce earlier if they are likely to have reduced performance in later life. However, whether this is the case remains unexplored in wild populations. Here, we use longitudinal data from a long-term study of Svalbard reindeer to examine age-related changes in adult female life-history responses to environmental conditions experienced in utero as indexed by rain-on-snow (ROSutero). We show that females experiencing high ROSutero had reduced reproductive success only from 7 years of age, independent of early reproduction. These individuals were able to maintain the same annual reproductive success between 2 and 6 years as phenotypically superior conspecifics that experienced low ROSutero Young females born after high ROSutero engage in reproductive events at lower body mass (about 2.5 kg less) than those born after low ROSutero The mean fitness of females that experienced poor environmental conditions in early life was comparable with that of females exposed to good environmental conditions in early life. These results are consistent with the idea of internal PAR and suggest that the life-history responses to early-life conditions can buffer the delayed effects of weather on population dynamics.

Prenatal stress effects in a wild, long-lived primate: predictive adaptive responses in an unpredictable environment.

Prenatal maternal stress affects offspring phenotype in numerous species including humans, but it is debated whether these effects are evolutionarily adaptive. Relating stress to adverse conditions, current explanations invoke either short-term developmental constraints on offspring phenotype resulting in decelerated growth to avoid starvation, or long-term predictive adaptive responses (PARs) resulting in accelerated growth and reproduction in response to reduced life expectancies. Two PAR subtypes were proposed, acting either on predicted internal somatic states or predicted external environmental conditions, but because both affect phenotypes similarly, they are largely indistinguishable. Only external (not internal) PARs rely on high environmental stability particularly in long-lived species. We report on a crucial test case in a wild long-lived mammal, the Assamese macaque (Macaca assamensis), which evolved and lives in an unpredictable environment where external PARs are probably not advantageous. We quantified food availability, growth, motor skills, maternal caretaking style and maternal physiological stress from faecal glucocorticoid measures. Prenatal maternal stress was negatively correlated to prenatal food availability and led to accelerated offspring growth accompanied by decelerated motor skill acquisition and reduced immune function. These results support the ‘internal PAR’ theory, which stresses the role of stable adverse internal somatic states rather than stable external environments.

Female reproductive competition explains variation in prenatal investment in wild banded mongooses.

Female intrasexual competition is intense in cooperatively breeding species where offspring compete locally for resources and helpers. In mammals, females have been proposed to adjust prenatal investment according to the intensity of competition in the postnatal environment (a form of ‘predictive adaptive response’; PAR). We carried out a test of this hypothesis using ultrasound scanning of wild female banded mongooses in Uganda. In this species multiple females give birth together to a communal litter, and all females breed regularly from one year old. Total prenatal investment (size times the number of fetuses) increased with the number of potential female breeders in the group. This relationship was driven by fetus size rather than number. The response to competition was particularly strong in low weight females and when ecological conditions were poor. Increased prenatal investment did not trade off against maternal survival. In fact we found the opposite relationship: females with greater levels of prenatal investment had elevated postnatal maternal survival. Our results support the hypothesis that mammalian prenatal development is responsive to the intensity of postnatal competition. Understanding whether these responses are adaptive requires information on the long-term consequences of prenatal investment for offspring fitness.

Social Influences on Executive Functions Development in Children and Adolescents: Steps Toward a Social Neuroscience of Predictive Adaptive Responses.

This commentary discusses the findings and implications of four empirical papers that establish a reciprocal, longitudinal link between the social environment and executive functions from childhood to adolescence. Two future directions are suggested by this work. The first is a call for measurement research to clarify the nomological network of various measurements of self-regulation and executive functions across a variety of methods and procedures. The second new direction is to broaden the analysis of executive function to include a wider array of predictive adaptive responses to various environmental conditions, including those where youth are chronically marginalized or otherwise stressed. Findings from these studies suggest that the executive functions within the brain guide adaptation in both deviant as well as competent responses to the social environment. Understanding various forms of adaptation will enhance the potential for prevention as well as avoid iatrogenic intervention strategies with misinformed targets.

Birth weight predicted baseline muscular efficiency, but not response of energy expenditure to calorie restriction: An empirical test of the predictive adaptive response hypothesis.

Aiming to test the evolutionary significance of relationships linking prenatal growth conditions to adult phenotypes, this study examined whether birth size predicts energetic savings during fasting. We specifically tested a Predictive Adaptive Response (PAR) model that predicts greater energetic saving among adults who were born small. Data were collected from a convenience sample of young adults living in Albuquerque, NM (n = 34). Indirect calorimetry quantified changes in resting energy expenditure (REE) and active muscular efficiency that occurred in response to a 29-h fast. Multiple regression analyses linked birth weight to baseline and postfast metabolic values while controlling for appropriate confounders (e.g., sex, body mass). Birth weight did not moderate the relationship between body size and energy expenditure, nor did it predict the magnitude change in REE or muscular efficiency observed from baseline to after fasting. Alternative indicators of birth size were also examined (e.g., low v. normal birth weight, comparison of tertiles), with no effects found. However, baseline muscular efficiency improved by 1.1% per 725 g (S.D.) increase in birth weight (P = 0.037). Birth size did not influence the sensitivity of metabolic demands to fasting-neither at rest nor during activity. Moreover, small birth size predicted a reduction in the efficiency with which muscles convert energy expended into work accomplished. These results do not support the ascription of adaptive function to phenotypes associated with small birth size. © 2015 Wiley Periodicals, Inc. Am. J. Hum. Biol. 28:484-492, 2016. © 2015 Wiley Periodicals, Inc.

Father's death does not affect growth and maturation but hinders reproduction: evidence from adolescent girls in post-war Estonia

The popular concept of predictive-adaptive responses poses that girls growing up without a father present in the family mature and start reproduction earlier because the father's absence is a cue for environmental harshness and uncertainty that favours switching to a precocious life-history strategy. Most studies supporting this concept have been performed in situations where the father's absence is caused by divorce or abandonment. Using a dataset of Estonian adolescent girls who had lost their fathers over the period of World War II, we show that father's death did not affect the rate of pubertal maturation (assessed on the basis of development of breasts and axillary hair) or growth. Father's death did not affect the age of first birth but, contrary to predictions, reduced lifetime reproductive success. Our findings thus do not support the concept of predictive-adaptive responses and suggest that alternative explanations for covariation between fatherlessness and early maturation are required.

Reversing Fetal Undernutrition by Kick-Starting Early Growth.

The relationship between poor maternal nutritional status and enhanced chronic disease risk in the offspring is now abundantly established in both experimental models and in epidemiological data from human populations worldwide. The classic studies of Barker et al (1), demonstrating a relationship between low birth weight (LBW) and increased risk of cardiovascular disease, hypertension, and dyslipidemia, paved the way for extensive research into the influence of the intrauterine environment on development of chronic diseases. In these original studies, men in their sixties who were smallest at birth had a 3-fold higher death rate from ischemic heart failure compared with those with high birth weights (1). Likewise, incidence of type 2 diabetes and glucose intolerance was also significantly higher in men with LBWs (2). To add to an expanding list of ailments, it is now well accepted that the propensity to develop obesity, type 2 diabetes, immunologic dysfunction, insulin resistance and related metabolic diseases is, in part, influenced by the maternal in utero environment (3). The focus of many investigations on LBW and conditions that lead to small babies arises from the fact that environmental factors and nutrient supply play an important role in determining birth weight and alterations in birth weight represent a gross deviation in the fetal experience. Nonetheless, changes in birth weight should not be confused to be a sine quo non in developmental programming, because it is quite evident that longterm alterations in risk occur well below the threshold of alterations in body weight at birth. Over the last decade and half, an explosion of studies using a variety of approaches has shown that developmental programming occurs in the contexts of both maternal undernutrition and overnutrition (3). Although one’s genetic makeup, postnatal diet, and lifestyle factors such as physical activity indisputably are important proximate causes of obesity, the influence of gestational experiences is evident in the Uor J-shaped relationship between birth weight and later obesity risk, suggesting that both extremes of nutritional environments lead to detrimental changes in the offspring. Certainly, this is relevant to the current global epidemic of obesity and ubiquitous consumption of calorically dense diets, high in fat and simple sugars both before and during pregnancy (4, 5). The conceptual framework provided by the developmental origins of health and disease hypothesis posits that unfavorable prenatal and postnatal environments, specifically during sensitive periods in development, lead to permanent alterations in organ structure and function that may confer increased risk towards a variety of chronic diseases (6). As elaborated in the predictive adaptive response hypothesis (7, 8), these adaptive changes, facilitated by the process of developmental plasticity are designed to be beneficial in ensuring short-term survival and preparing for a “predicted” postnatal environment. However, when presented with a highly discrepant postnatal environment, mismatch ensues and these changes may prove disadvantageous or maladaptive, thereby increasing predisposition to disease. Evidence from follow up of individuals affected during the Dutch Hunger Winter famine during the latter part of the Second World War and the Chinese famine (1959–1961) lend strong support to this hypothesis (9, 10). Furthermore, high rates of obesity and diabetes in populations where poor maternal nutrition is historically prevalent in combination with current trends of urbanization, as evidenced in many developing nations, also presents an ongoing natural experiment. Despite