Developmental programming can be defined as a response to a specific challenge to the mammalian organism during a critical developmental time window that alters the trajectory of development with persistent effects on offspring phenotype and predisposition to future illness. We focus on the need for studies in relevant, well-characterized animal models in the context of recent research discoveries on the challenges, mechanisms and outcomes of developmental programming. We discuss commonalities and differences in general principles of developmental programming as they apply to several species, including humans. The consequences of these differences are discussed. Obesity, metabolic disorders and cardiovascular diseases are associated with the highest percentage of morbidity and mortality worldwide. Although many of the causes are associated with lifestyle, high-energy diets and lack of physical activity, recent evidence has linked developmental programming to the epidemic of metabolic diseases. A better understanding of comparative systems physiology of mother, fetus and neonate using information provided by rapid advances in molecular biology has the potential to improve the lifetime health of future generations by providing better women's health, diagnostic tools and preventative and therapeutic interventions in individuals exposed during their development to programming influences.

Population aging and subsequent projected large increases in chronic conditions will be important health concerns in low- and middle-income countries. Although evidence is accumulating, little is known regarding the impact of poor early-life conditions on older adult (50 years and older) health in these settings. A systematic review of 1141 empirical studies was conducted to identify population-based and community studies in low- and middle-income countries, which examined associations between early-life conditions and older adult health. The resulting review of 20 studies revealed strong associations between (1) in utero/early infancy exposures (independent of other early life and adult conditions) and adult heart disease and diabetes; (2) poor nutrition during childhood and difficulties in adult cognition and diabetes; (3) specific childhood illnesses such as rheumatic fever and malaria and adult heart disease and mortality; (4) poor childhood health and adult functionality/disability and chronic diseases; (5) poor childhood socioeconomic status (SES) and adult mortality, functionality/disability and cognition; and (6) parental survival during childhood and adult functionality/disability and cognition. In several instances, associations remained strong even after controlling for adult SES and lifestyle. Although exact mechanisms cannot be identified, these studies reinforce to some extent the importance of early-life environment on health at older ages. Given the paucity of cohort data from the developing world to examine hypotheses of early-life conditions and older adult health, population-based studies are relevant in providing a broad perspective on the origins of adult health.

The developmental origins hypothesis suggests that morbidity and premature mortality arise, in part, from adverse exposures in utero and early in development. Evidence suggests a connection between early nutritional deficits and adult morbidity; however, the effects on mortality have been less well studied and previous studies provide conflicting results. We extracted Finnish birth cohort death rates from the Human Mortality Database. Our test asks whether men or women born during the 1867–1868 Great Finnish Famine exhibited death rates in old age different from expected, based on death rates among Finnish cohorts born 1818–1866. We found no support for the argument that exposure to the Finnish famine in utero induced excess mortality from age 60 to 89 in either men or women. Our results suggest that the Finnish famine did not induce, via epigenetic changes or any other mechanism, premature mortality in older age among exposed individuals.

The in utero origins of breast cancer are an increasing focus of research. However, the long time period between exposure and disease diagnosis, and the lack of standardized perinatal data collection makes this research challenging. We assessed perinatal factors, as proxies for in utero exposures, and breast cancer risk using pooled, population-based birth and cancer registry data. Birth registries provided information on perinatal exposures. Cases were females born in Norway, Sweden or Denmark who were subsequently diagnosed with primary, invasive breast cancer (n = 1419). Ten controls for each case were selected from the birth registries matched on country and birth year (n = 14,190). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using unconditional regression models. Breast cancer risk rose 7% (95% CI 2–13%) with every 500 g (roughly 1 s.d.) increase in birth weight and 7% for every 1 s.d. increase in birth length (95% CI 1–14%). The association with birth length was attenuated after adjustment for birth weight, while the increase in risk with birth weight remained with adjustment for birth length. Ponderal index and small- and large-for-gestational-age status were not better predictors of risk than either weight or length alone. Risk was not associated with maternal education or age, gestational duration, delivery type or birth order, or with several pregnancy complications, including preeclampsia. These data confirm the positive association between birth weight and breast cancer risk. Other pregnancy characteristics, including complications such as preeclampsia, do not appear to be involved in later breast carcinogenesis in young women.

Maternal pre-pregnancy obesity has been linked with an increased risk for negative emotionality and inattentiveness in offspring in early childhood. The aim of this study was to examine the association between maternal pre-pregnancy body mass index (BMI) and the development of affective problems (dysthymic disorder, major depressive disorder) throughout childhood and adolescence. In the Western Australian Pregnancy Cohort (Raine) Study, 2900 women provided data on their pre-pregnancy weight, and height measurements were taken at 18 weeks of gestation. BMI was calculated and categorized using standardized methods. Live-born children (n = 2868) were followed up at ages 5, 8, 10, 14 and 17 years using the Diagnostic and Statistical Manual of Mental Disorders-oriented scales of the Child Behavior Checklist (CBCL/4–18). Longitudinal models were applied to assess the relationships between maternal pre-pregnancy BMI and affective problems from age 5 through 17. There was a higher risk of affective problems between the ages of 5 and 17 years among children of women who were overweight and obese compared with the offspring of women in the healthy pre-pregnancy weight range (BMI 18.5–24.99) after adjustment for confounders, including paternal BMI. Maternal pre-pregnancy overweight and obesity may be implicated in the development of affective problems, including depression, in their offspring later in life.

During foetal development, calcium requirements are met as a consequence of maternal adaptations independent of vitamin D status. In contrast, after birth, dependency on vitamin D appears necessary for calcium metabolism and skeletal health. We used a rodent model (Sprague-Dawley rats), to determine if maternal vitamin D deficiency during pregnancy had a deleterious effect on bone structure at birth. Vitamin D deplete females were maintained under deplete conditions until birth of the pups, whereupon all dams were fed a vitamin D replete diet. Offspring were harvested at birth, and 140 days of age. Bones were analyzed using micro-computed tomography and strength tested to study differences in bone structure, density and strength and subjected to elemental analysis using plasma mass spectrometry to determine strontium, barium and calcium contents. Offspring from deplete mothers displayed altered trabecular parameters in the femur at birth and 140 days of age. In addition, at 140 days of age there was evidence of premature mineralization of the secondary ossification centre of the femoral head. Elemental analysis showed increased strontium uptake in the femur of the developmentally vitamin D-deficient offspring. Vitamin D depletion during development in the offspring may have a long-lasting effect, despite repletion of vitamin D from birth. This may have consequences for human health given the low vitamin D levels seen during pregnancy and current lifestyle of sun avoidance due to the risk of skin cancer.

The dynamic aspect of early life growth is not fully captured by typical analyses, which focus on one specific time period. To better understand how infant and young child growth relate to the development of adult body composition, the authors characterized body mass index (BMI) trajectories using latent class growth analysis (LCGA) and evaluated their association with adult body composition. Data are from the Cebu Longitudinal Health and Nutrition Survey, which followed a birth cohort to age 22 years (n = 1749). In both males and females, LCGA identified seven subgroups of respondents with similar BMI trajectories from 0 to 24 months (assessed with bimonthly anthropometrics). Trajectory groups were compared with conventional approaches: (1) accelerated growth between two time points (0–4 months), (2) continuous BMI gain between two points (0–4 months and 0–24 months) and (3) BMI measured at one time point (24 months) as predictors of young adult body composition measures. The seven trajectory groups were distinguished by age-specific differences in tempo and timing of BMI gain in infancy. Infant BMI trajectories were better than accelerated BMI gain between 0 and 4 months at predicting young adult body composition. After controlling for BMI at age 2 years, infant BMI trajectories still explained variation in adult body composition. Using unique longitudinal data and methods, we find that distinct infant BMI trajectories have long-term implications for the development of body composition.

Although it is accepted that impaired placental perfusion in complicated pregnancy can slow fetal growth and programme an increased risk of cardiovascular dysfunction at adulthood, the relative contribution of reductions in fetal nutrition and in fetal oxygenation as the triggering stimulus remains unclear. By combining high altitude (HA) with the chick embryo model, we have previously isolated the direct effects of HA hypoxia on embryonic growth and cardiovascular development before hatching. This study isolated the effects of developmental hypoxia on cardiovascular function measured in vivo in conscious adult male and female chickens. Chick embryos were incubated, hatched and raised at sea level (SL, nine males and nine females) or incubated, hatched and raised at HA (seven males and seven females). At 6 months of age, vascular catheters were inserted under general anaesthesia. Five days later, basal blood gas status, basal cardiovascular function and cardiac baroreflex responses were investigated. HA chickens had significantly lower basal arterial PO2 and haemoglobin saturation, and significantly higher haematocrit than SL chickens, independent of the sex of the animal. HA chickens had significantly lower arterial blood pressure than SL chickens, independent of the sex of the animal. Although the gain of the arterial baroreflex was decreased in HA relative to SL male chickens, it was increased in HA relative to SL female chickens. We show that development at HA lowers basal arterial blood pressure and alters baroreflex sensitivity in a sex-dependent manner at adulthood.

In this study, we determined the gene and/or protein expression of hypothalamic–pituitary–adrenal (HPA) axis regulatory molecules following synthetic glucocorticoid exposures. Pregnant sheep received intramuscular saline or betamethasone (BET) injections at 104 (BET-1), 104 and 111(BET-2) or 104, 111 and 118 (BET-3) days of gestation (dG). Samples were collected at numerous time-points between 75 dG and 12 weeks postnatal age. In the BET-3 treatment group, fetal plasma cortisol levels were lower at 145 dG than controls and gestational length was lengthened significantly. The cortisol:adrenocorticotropic hormone (ACTH) ratio in fetal plasma of control and BET-3 fetuses rose significantly between132 and 145 dG, and remained elevated in lambs at 6 and 12 weeks of age; this rise was truncated at day 145 in fetuses of BET-3 treated mothers. After BET treatment, fetal and postnatal pituitary proopiomelanocortin mRNA levels were reduced from 109 dG to 12 weeks postnatal age; pituitary prohormone convertase 1 and 2 mRNA levels were reduced at 145 dG and postnatally; hypothalamic arginine vasopressin mRNA levels were lowered at all time-points, but corticotrophin-releasing hormone mRNA levels were reduced only in postnatal lambs. Maternal BET increased late fetal and/or postnatal adrenal mRNA levels of ACTH receptor and 3β hydroxysteroid dehydrogenase but decreased steroidogenic acute regulatory protein and P450 17-α hydroxylase. The altered mRNA levels of key HPA axis regulatory proteins after maternal BET injections suggests processes that may subserve long-term changes in HPA activity in later life after prenatal exposure to synthetic glucocorticoids.

Atherosclerosis is the underlying cause of cardiovascular disease and stroke. Endothelial cell dysfunctions are early events in atherosclerosis, resulting in the recruitment of circulating monocytes. The immune system can elicit an inflammatory response toward the atherosclerotic lesion, thereby accelerating lesion growth. Risk factors for atherosclerosis include hypertension, smoking, stress perception or low birth weight. As prenatal stress challenge decreases the birth weight and affects the offspring's postnatal immune response, we aimed to investigate whether prenatal stress contributes to the development of atherosclerosis in mice. Syngenic pregnant apolipoprotein E-deficient (apoE−/−) dams were exposed to sound stress on gestation days 12.5 and 14.5. The presence and size of atherosclerotic plaques in the offspring at the age of 15 weeks was evaluated by histomorphology, accompanied by flow cytometric analysis of the frequency and phenotype of monocytes/macrophages and regulatory T (Treg) cells in the blood. Further, cytokine secretion of peripheral blood lymphocytes was analyzed. In response to prenatal stress challenge, an increased frequency of large atherosclerotic plaques was detectable in apoE−/− offspring, which was particularly profound in females. Prenatal stress also resulted in alterations of the offspring's immune response, such as a decreased frequency of Treg cells in blood, alterations of macrophage populations in blood and an increased secretion of inflammatory cytokines. We provide novel evidence that prenatally stressed adult offspring show an increased severity of atherosclerosis. As Treg cells are key players in dampening inflammation, the observed increase in atherosclerosis may be due to the lack of Treg cell frequency. Future interdisciplinary research is urgently required to understand the developmental origin of prenatal stress-induced atherosclerosis. The availability of our model may facilitate and foster such research endeavors.