New findings on the maternal and placental programming of chronic disease lead to four conclusions: (1) Growth of the placental surface is polarized from the time of implantation, so that growth along the major axis, the length, is qualitatively different from growth along the minor axis, the breadth. (2) The human fetus may attempt to compensate for undernutrition by expansion of the placental surface along its minor axis. This only occurs if the mother was well nourished before conception, and may have long-term costs that include hypertension. (3) The effects of placental size on long-term health are conditioned by the mother’s nutritional state, as indicated by her socio-economic status, height and body mass index. (4) The maternal–placental programming of chronic disease differs in boys and girls. Boys invest less than girls in placental growth but more readily expand the placental surface if they become undernourished in mid-late gestation. Boys are more responsive to their mothers’ current diets while girls respond more to their mothers’ lifetime nutrition and metabolism.

Uteroplacental insufficiency and poor postnatal nutrition impair adult glucose tolerance and insulin secretion in male rat offspring, which can be partially ameliorated by improving postnatal nutrition. Uteroplacental insufficiency was induced in the WKY rat on day 18 of pregnancy (Restricted) compared to sham-operated Controls. Pups were then cross-fostered onto Control or Restricted mothers one day after birth resulting in: (Pup-on-Mother) Control-on-Control, Control-on-Restricted, Restricted-on-Control and Restricted-on-Restricted. Endocrine pancreatic morphology and markers of intrinsic β-cell function and glucose homeostasis were assessed in male offspring at 6 months. Pancreatic and hepatic gene expression was quantified at postnatal day 7 and 6 months. Restricted pups were born 10–15% lighter than Controls and remained lighter at 6 months. Relative islet and β-cell mass were 51–65% lower in Restricted-on-Restricted compared to Controls at 6 months. Non-fasting plasma C-reactive protein levels were also increased, suggestive of an inflammatory response. Overall, the average number of islets, small islets and proportion of β-cells per islet correlated positively with birth weight. Intrinsic β-cell function, estimated by insulin secretion relative to β-cell mass, was unaffected by Restriction, suggesting that the in vivo functional deficit was attributable to reduced mass, not function. Importantly, these deficits were ameliorated when lactational nutrition was normalized in Restricted-on-Control offspring, who also showed increased pancreatic Igf1r, Pdx1 and Vegf mRNA expression at 7 days compared to Control-on-Control and Restricted-on-Restricted. This highlights lactation as a critical period for intervention following prenatal restraint, whereby deficits in endocrine pancreatic mass and associated impaired in vivo insulin secretion can be ameliorated.

The fetal insulin hypothesis proposes that low birth weight and susceptibility to type 2 diabetes (T2D) could both be two phenotypes of the same genotype. Insulin is a key growth factor in utero, and T2D is characterized by insulin resistance and/or beta-cell dysfunction. Therefore, genetic variants impacting on insulin secretion and action are likely to alter both fetal growth and susceptibility to T2D. There are three lines of evidence in support of this hypothesis. (1) Studies of rare monogenic diabetes have shown mutations in a single gene, such as GCK or KCNJ11, can cause diabetes by reducing insulin secretion, and these mutations are also associated with reduced birth weight. (2) Epidemiological studies have indicated that children born to fathers with diabetes are born smaller. As the father cannot influence the intrauterine environment, this association is likely to reflect genes inherited by the fetus from the father. (3) The most compelling evidence comes from recent genome-wide association studies. Variants in the CDKAL1 and HHEX-IDE genes that predispose to diabetes, if present in the fetus, are associated with reduced birth weight. These data provide evidence for a genetic contribution to the association between low birth weight and susceptibility to T2D. This genetic background is important to take into consideration when investigating the impact of environmental determinants and developing strategies for intervention and prevention.

The associations between fetal environment and diabetes risk are likely mediated by the offspring’s diminished pancreatic β-cell function or reduced insulin sensitivity. Our ability to distinguish between these mechanisms is impeded by the lack of markers describing an individual’s gestational environment. Fingerprints, however, are permanently fixed in the first half of gestation, and increased values of a dermatoglyphic marker that contrasts fingerprint ridge counts between the thumbs and fifth fingers (Md15) have been linked to type 2 diabetes. Among 763 adults without known diabetes from the Dutch Hunger Winter Families Study, we tested the associations of Md15 with homeostatic assessment indices of β-cell function (HOMA-b) and insulin sensitivity (QUICKI). For either outcome index, linear regression models included terms for Md15 tertiles and for maternal history of diabetes as reported by each participant. All models were corrected for sibling pairs and adjusted for age, sex and famine exposures. Increased Md15 was associated with decreased HOMA-b (P = 0.03 for Md15 tertile 3 v. 1) but not with QUICKI. In contrast, maternal history of diabetes was associated with decreased QUICKI (P < 0.001) but not with HOMA-b. Birth weight (available for 520 participants) was positively associated with increased QUICKI (P = 0.04 for birth weight tertile 3 v. 1) but not with HOMA-b. Fingerprint Md15, maternal history of diabetes and birth weight may help to identify specific defects in the control of adult glucose metabolism. Research into the environment associated with Md15 variation may suggest prenatal strategies for optimizing β-cell function in adult life.

While early-life estrogens are thought to play a physiologic role in prostate gland development, inappropriate estrogenic exposures either in dose, type or temporally can reprogram the prostate gland and increase susceptibility to abnormal prostate growth with aging including carcinogenesis. This review discusses the evidence for developmental estrogenic reprogramming that leads to adult prostate disease in a rat model. We propose that estrogen imprinting of the prostate is mediated through both structural reorganization of the gland early in life and epigenomic reprogramming that permits life-long memory of the inappropriate developmental exposures including heightened sensitivity to rising estradiol levels with aging. Complex interactions between early epigenetic programming and later-life experiences results in an emergence of multiple epigenomic outcomes, with some contributing to carcinogenesis with aging.

Autism spectrum disorders (ASD) are life-long neurodevelopmental conditions. The pathophysiology is poorly understood, and the clinical diagnosis can only be made through behavioural assessments. The prevalence of ASD has increased eight-fold over the last three decades. Paralleling this rise, research interest in the disorder has been accumulating, centering on two aspects: risk factors that would explain the increase in prevalence, and precursors that could predict an emergence of ASD prior to 2 years of age. As regard factors responsible for the increased prevalence, an increasing trend of low birthweight (4.2% in 1980 v. 9.6% in 2006 at Japan) and advanced paternal age at birth are potentially implicated. To explore these issues, and to yield an early diagnostic algorithm for ASD, the authors initiated the ongoing Hamamatsu Birth Cohort for Mothers and Children (HBC) in 2007. The strengths of the HBC include frequent, direct face-to-face assessments of all the participating mothers and children during the first 4 years of life (12 assessments); this depth of assessments will disclose subtle changes in the developmental domains of individuals with ASD, which might otherwise be overlooked.

A total of 1200 pregnant women are to be recruited by the end of 2010. Assembled information comprises a range of variables related to the mother’s characteristics and child development. The comprehensiveness of the HBC will provide an informative data source that will elucidate early trajectories of children with ASD in addition to revealing detailed, developmental properties of typically developing children.

Gene markers for cardiomyocyte growth, proliferation and remodeling were examined in mouse fetuses and adult male offspring exposed to maternal low-protein (LP) diet during pregnancy. Whole heart volume, measured by magnetic resonance imaging, was smaller in day 15 LP fetuses v. those from chow-fed dams (C), whereas heart volume was greater in adult LP v. C offspring. These LP offspring were hypertensive and had larger cardiomyocytes v. C animals. The mRNA levels of cyclin G1, a marker for cell growth, were lower in LP fetal hearts v. C hearts, but similar in the left ventricle of adult LP and C offspring. Opposite trends were found in brain natriuretic peptide levels (a marker of cardiac hypertrophy). Thus, maternal LP during pregnancy results in smaller fetal hearts and is accompanied by changes in expression of genes involved in cardiomyocyte growth, which are associated with cardiac hypertrophy and hypertension in adulthood.

In the last decades, the developmental origins of health and disease (DOHaD) have emerged as a vigorous field combining experimental, clinical, epidemiological and public health research. Its goal is to understand how events in early life shape later morbidity risk, especially of non-communicable chronic diseases. As these diseases become the major cause of morbidity and mortality worldwide, research arising from DOHaD is likely to gain significance to public health and economic development. But action may be hindered by the lack of a firm mechanistic explanation and of a conceptual basis, especially regarding the evolutionary significance of the DOHaD phenomenon. In this article, we provide a succinct historical review of the research into the relationship between development and later disease, consider the evolutionary and developmental significance and discuss the underlying mechanisms of the DOHaD phenomenon. DOHaD should be viewed as a part of a broader biological mechanism of plasticity by which organisms, in response to cues such as nutrition or hormones, adapt their phenotype to environment. These responses may be divided into those for immediate benefit and those aimed at prediction of a future environment: disease occurs in the mismatch between predicted and realized future. The likely mechanisms that enable plasticity involve epigenetic processes, affecting the expression of genes associated with regulatory pathways. There is now evidence that epigenetic marks may be inherited and so contribute to non-genomic heritable disease risk. We end by discussing the global significance of the DOHaD phenomenon and its potential applications for public health purposes.

We previously reported that a maternal high fat (HF) diet resulted in adult offspring with increased adiposity and hyperleptinemia. As leptin has an inhibitory effect on adrenal steroidogenesis and a stimulatory effect on epinephrine synthesis, we hypothesized that key adrenal steroidogenic and catecholaminergic enzymes would be altered in these offspring. Wistar rats were randomized into three groups at weaning: (1) control dams fed a standard control chow diet from weaning and throughout pregnancy and lactation (CON), (2) dams fed a HF diet from weaning and throughout pregnancy and lactation (MHF) and (3) dams fed standard control chow diet throughout life until conception, then fed a HF diet in pregnancy and lactation (PLHF). Dams were mated at day 100 (P100). After birth at P22 (weaning), male offspring were fed a standard control chow (con) or high fat (hf) diet. At P160, plasma samples and adrenal tissues were collected. Postweaning hf diet significantly elevated plasma corticosterone concentrations in PLHF-hf offspring compared to PLHF-con. MHF nutrition increased adrenal adrenocorticotrophic hormone receptor (ACTH-R) mRNA levels compared to CON-con. 3β-hydroxysteroid dehydrogenase (3βHSD) mRNA levels were decreased in MHF compared to PLHF offspring. Phenylethanolamine N-methyltransferase (PNMT) mRNA levels were increased in MHF-hf offspring compared to MHF-con. Plasma homocysteine (HCY) concentrations were significantly elevated in CON-hf and MHF-hf offspring compared to chow-fed offspring, associated with elevated intakes of methionine and reduced intakes of pyridoxine. Immunoreactive leptin receptor (ObRb) and PNMT were colocalized in medullary chromaffin cells. This study suggests that a postweaning HF diet in offspring induced changes in adrenal gene expression levels that are dependent upon the level of maternal nutrition.

Birth weight is emerging as a potentially important risk factor for several chronic diseases with adult onset, including breast cancer. Because participant recall is frequently used to gather data on early life exposures, it is essential that the accuracy of recall be assessed and validated. Self-reported birth weights and birth certificate weights were compared in women aged 35–51 years from the Western New York Exposures and Breast Cancer (WEB) Study, a population-based case–control study. A total of 180 participants had both birth certificate and interview data on birth weight. Participants reported birth weight to one of six categories (<5, 5–5.5, 5.6–7, 7.1–8.5, 8.6–10 and >10 lbs). The Spearman correlation for self-reported and birth certificate weights was 0.67. Sixty percent of participants reported weights with exact agreement with birth certificate; unweighted and weighted kappas (κ) were 0.39 and 0.68, respectively. Spearman correlations were similar for cases (0.67) and controls (0.68). Controls exhibited a significantly higher unweighted κ (0.51) than cases (0.27; P = 0.03), but weighted κ were not statistically different [controls, 0.73; cases, 0.64 (P = 0.32)]. Demographic and anthropometric characteristics were not different between participants who underreported, overreported, or correctly reported their birth weight for either cases or controls. Overall, the level of agreement for report of birth weight and actual birth weight was fair to moderate.

The biological mechanisms in the association between maternal body mass index (BMI) and birth weight are not well understood, but are likely to involve maternal plasma glucose levels and nutrient transport across the placenta, both important modulators of fetal growth. Adipose tissue contributes to circulating levels of interleukins that may affect glucose metabolism and possibly also placental transport of nutrients. We investigated possible mediating roles of Interleukin 6 (IL-6) and Interleukin 1 Receptor antagonist (IL-1Ra) in 208 pregnant women. Known and hypothesized dependencies between BMI in early pregnancy and fasting glucose, IL-1Ra and IL-6 at gestational weeks 30–32, and birth weight were specified in a path diagram. Standardized regression coefficients, expressing direct, indirect and total effects, were estimated by Bayesian path analysis. Mean (s.d.) BMI was 24.9 kg/m2 (4.2) and mean (s.d.) birth weight 3748 g (454). The total effect of BMI on birth weight was 0.24 (95% credibility interval (CrI) [0.12, 0.36]). The direct effect of IL-1Ra on birth weight was not statistically significant, but significant effects of BMI on IL-1Ra (0.61, 95% CrI [0.51, 0.72]), of IL-1Ra on fasting glucose (0.17, 95% CrI [0.01, 0.34]) and of fasting glucose on birth weight (0.14, 95% CrI [0.01, 0.27]) implied an indirect pathway from BMI via IL-1Ra on birth weight. Approximately 20% of the effect of BMI on birth weight was mediated through IL-1Ra. For IL-6, no such effects were found. Our results indicate that IL-1Ra may be a mediator in the association between BMI and birth weight.

Dramatic improvements in life expectancy during the 20th century are commonly attributed to improvements in either health care services or the social and economic environment. We evaluated the hypothesis that improving infant survival produces improvements in adult (⩾40 years) mortality rates. We used generalizations of age-period-cohort models of mortality that explicitly account for the exponential increase of adult mortality rates with age (Gompertz model) to determine whether year of birth or year of death better correlate with observed patterns of adult mortality. We used data from Canada and nine other countries obtained from the Human Mortality Database. Five-year birth cohorts between 1900 and 1944 showed consistent improvements in age-specific mortality rates. According to the akaike information criteria, Gompertz-Cohort models significantly better predicted the observed patterns of adult mortality than Gompertz-Period models, demonstrating that year of birth correlates better with adult mortality than year of death. Infant mortality strongly correlated with the initial set point of adult mortality in a Gompertz-period-cohort. Selected countries exhibited elevated adult mortality rates for the 1920 and 1944 birth cohorts, suggesting that the period before the first year of life may be uniquely vulnerable to environmental influences. These findings suggest that public health investments in the health of mothers and children can be a broad primary prevention strategy to prevent the chronic diseases of the adult years.

To investigate the mechanisms for the previously reported development of adult cardiac hypertrophy in male rats following growth restriction, the levels of oxidative stress and activation of signaling kinases were measured in the left ventricle (LV) of adult rat offspring. In experiment one, bilateral uterine vessel ligation to induce uteroplacental insufficiency and growth restriction in the offspring (Restricted) or sham surgery was performed during pregnancy. Litters from sham mothers had litter size either reduced (Reduced Litter), which also restricted postnatal growth, or were left unaltered (Control). In males, Reduced Litter offspring had increased LV phosphorylation of AMPKα, p38 MAPK and Akt compared with Restricted and Controls (P < 0.05). In females, both Restricted and Reduced Litter adult offspring had increased LV phosphorylation of p38 MAPK and Akt, however, only Restricted offspring had increased phosphorylation of AMPKα (P < 0.05). In addition, only Restricted male offspring displayed LV oxidative stress (P < 0.05). Experiment two investigated in mothers exposed to uteroplacental insufficiency or sham surgery the effects of cross-fostering offspring at birth, and therefore the effects of the postnatal lactational environment. Surprisingly, the cross-fostering itself resulted in increased LV phosphorylation of AMPKα and Akt in females and increased phosphorylation of Akt in males compared with Control non-cross-fostered offspring (P < 0.05). In conclusion, kinase signaling in the adult LV can be programmed by uteroplacental insufficiency induced growth restriction in a gender-specific manner. In addition, the heart of adult rats is also sensitive to programming following the postnatal intervention of cross-fostering alone as well as by postnatal growth restriction.

Earlier, we reported that antenatal micronutrient supplementation reduced the risk of metabolic syndrome and microalbuminuria among offspring at 6–8 years of age in rural Nepal. In the same birth cohort, we examined associations of size at birth (weight, length and ponderal index), and gestational age, with cardiometabolic risk factors in childhood across all antenatal micronutrient interventions. There was an inverse association between birth weight and systolic blood pressure (SBP, β = −1.20 mm Hg/kg; 95% confidence interval (CI): −1.93, −0.46) and diastolic blood pressure (DBP, β = −1.24 mm Hg/kg; 95% CI: −2.00, −0.49). Current child body mass index was positively associated with SBP but not with DBP. Birth weight was unassociated with insulin resistance, but each kilogram of increase was associated with a reduced risk of high triglycerides (odds ratio (OR) = 0.64/kg; 95% CI: 0.41, 0.97) and an increased risk of high waist circumference (OR = 3.16/kg; 95% CI: 2.47, 4.41). In this rural Nepalese population of children 6–8 years of age with a high prevalence of undernutrition, size at birth was inversely associated with blood pressure and triglycerides and positively associated with waist circumference.

Individuals exposed in utero to maternal obesity have increased risk of developing type 2 diabetes mellitus and obesity in adulthood. The molecular mechanisms underlying this association are unknown. We have therefore used a murine model of maternal obesity, in which the offspring of obese dams develop hyperinsulinaemia by 3 months of age indicative of insulin resistance. Here, we investigate the effects of maternal diet-induced obesity on the expression/phosphorylation of key hepatic insulin signalling proteins and the expression of anti-oxidant enzymes in male offspring. At 3 months of age, offspring of obese dams had decreased levels of insulin receptor substrate (IRS) 1 (P < 0.01), whereas the ratio of phosphorylated IRS1 Ser307 to total IRS1 was significantly increased (P < 0.001), suggesting that it was less active. Protein expression of the PI3K p85α subunit was decreased (P < 0.01) and there was a tendency for phosphorylation of Akt at Ser473 to be reduced (P = 0.08) in the offspring of obese dams. protein kinase Cζ (P < 0.001) and glycogen synthase kinase 3β (P < 0.05) levels were increased in these animals in comparison with controls. Maternal obesity also resulted in increased phosphorylation of p38 mitogen-activated protein kinase at Thr180/Tyr182 (P < 0.01) and raised c-Jun N-terminal kinase 1 expression (P < 0.5) in the offspring. The expression of antioxidant enzymes was also affected by maternal obesity with CuZnSOD (P < 0.001) and glutathione reductase (P < 0.05) being increased, whereas glutathione peroxidase 1 was reduced (P < 0.05) in the offspring. We conclude that maternal obesity leads to alterations in hepatic insulin signalling protein expression and phosphorylation. These molecular changes may contribute to the development of insulin resistance.

Physical activity is a known protective factor, with benefits for both metabolic and psychological aspects of health. Our objective was to verify early and late determinants of physical activity in young adults. A total of 2063 individuals from a birth cohort in Ribeirão Preto, Brazil, were studied at the age of 23–25 years. Poisson regression was performed using three models: (1) early model considering birth weight, gestational age, maternal income, schooling and smoking; (2) late model considering individual’s gender, schooling, smoking and body mass index; and (3) combined (early + late) model. Physical activity was evaluated using the International Physical Activity Questionnaire, stratifying the individuals into active or sedentary. The general rate of sedentary behavior in the sample was 49.6%. In the early model, low birth weight (relative risk (RR) = 1.186, confidence interval (95%CI) 1.005–1.399) was a risk factor for sedentary activity. Female gender (RR = 1.379, 95%CI = 1.259–1.511) and poor schooling (RR = 1.126, 95%CI = 1.007–1.259) were associated with sedentary behavior in the late model. In the combined model, only female gender and participant’s schooling remained significant. An interaction between birth weight and individual’s schooling was found, in which sedentary behavior was more prevalent in individuals born with low birth weight only if they had higher educational levels. Variables of early development and social insertion in later life interact to determine an individual’s disposition to practice physical activities. This study may support the theoretical model ‘Similarities in the inequalities’, in which opposed perinatal backgrounds have the same impact over a health outcome in adulthood when facing unequal social achievement during the life-course.

A primary challenge for nutrition policy in low-income settings is to position nutrition as an investment rather than simply as a form of social spending that governments grant poor people to the degree that governments prioritize equity. Various economic models have produced estimates of the economic costs of malnutrition as a combination of the impact of malnutrition on mortality, on health care costs for the survivors, including those that manifest in adult years, and on the lost productivity attributable to malnutrition. However, these estimates often center on the costs of early mortality and are sensitive to assumptions on how to place a dollar cost on mortality. This study argues that even when focusing only on the productivity impact of malnutrition – clearly a lower bound of the full costs – the economic consequences of malnutrition are substantial. Stating this somewhat differently, the economic returns to preventing malnutrition are on a par with those investments generally considered at the heart of economic development strategies. Moreover, the body of evidence that has been accumulated to indicate these productivity gains is both substantial and robust.