Embryonic and fetal programming of physiological disorders in adulthood

In the past decade, data from numerous epidemiological studies have indicated strong inverse associations between birth weight and risk of coronary heart disease, hypertension, type 2-diabetes, and other diseases in adulthood. The "Barker hypothesis" thus postulates that a number of organ structures and functions undergo programming during embryonic and fetal life. This developmental programming determines the set points of physiological and metabolic responses in adult life. Alterations of nutrient availability during gestation may lead to developmental adaptations, via hormonal maneuvers by the embryo and fetus that readjust these set points. These adaptive measures have short-term benefits to the embryo and fetus, so that the newborn will be better prepared for the adverse environment (e.g., undernutrition). However, adequate nutritional support during postnatal life that enables catch-up growth may create metabolic conflicts that predispose the adult to aberrant physiological functions and, ultimately, increased risk of disease. It is plausible that other adverse in utero conditions, including exposure to developmental toxicants, may similarly alter adult disease susceptibility. This article provides an overview of the Barker hypothesis, its supporting evidence, the current advances in understanding the biological mechanisms underlying this phenomenon, and its implications for developmental toxicology.     

Acute undernutrition is not associated with excess of females at birth in humans: the Dutch hunger winter

It has been suggested that maternal undernutrition results in adjustment of the sex ratio at birth, favouring females. We tested this hypothesis using births during the Dutch Hunger Winter of 1944-1945, an acute severe famine of seven months' duration. There was no evidence of an excess of female births among deliveries of human infants exposed to famine in any period in gestation. Indeed, among deliveries to women maximally exposed to famine prior to conception, there was an excess (odds ratio = 1.31, 95% CI 1.09-1.58; p = 0.004) of male offspring. Our data do not provide any support for acute and severe maternal undernutrition as a trigger for an increase in female conceptions or in male foetal deaths in human populations.     

In utero programming of cardiovascular disease

Low birth weight, thinness and short body length at birth are now known to be associated with increased rates of cardiovascular disease and non-insulin dependent diabetes in adult life. The fetal origins hypothesis proposes that these diseases originate through adaptations which the fetus makes when it is undernourished. These adaptations may be cardiovascular, metabolic or endocrine. They permanently change the structure and function of the body. Prevention of the diseases may depend on prevention of imbalances in fetal growth or imbalances between pre- and post-natal growth, or imbalances in nutrient supply to the fetus.     

Famine in the Young and Risk of Later Hospitalization for COPD and Asthma

Background

Undernutrition during critical periods of growth and development may permanently affect lung physiology and function.

Objectives

To investigate whether acute undernutrition in childhood or young adulthood increases the risk of later hospitalization for obstructive airways disease, chronic obstructive pulmonary disease (COPD), or asthma.

Methods

We studied 7,841 women from Prospect-EPIC who experienced the 1944–45 Dutch famine between ages 0 and 21. Pulmonary outcomes were measured by registered hospital admissions and exposure-blinded computed tomography (CT) in a subgroup of 295 women. With Cox proportional hazard regression we explored effects of famine exposure on risk of hospitalization for obstructive airways disease, COPD, and asthma. With logistic regression we explored effects of famine on risk of CT evidence of pulmonary disease.

Results

Risks of hospitalization for obstructive airways disease, COPD, and asthma were increased after moderate famine exposure, and significantly increased after severe famine exposure: hazard ratios for obstructive airways disease were 1.31 (95% CI: 0.97 to 1.77) and 1.57 (95% CI: 1.10 to 2.23) respectively. Associations between famine exposure and hospitalization for COPD were stronger in ever-smokers than in never-smokers.

Conclusions

Acute undernutrition in childhood or young adulthood is associated with an increased risk of later COPD and asthma hospitalization, possibly through increased sensitivity for tobacco smoke.     

Hypertension, diabetes and overweight: looming legacies of the Biafran famine

Background

Sub-Saharan Africa is facing rapidly increasing prevalences of cardiovascular disease, obesity, diabetes and hypertension. Previous and ongoing undernutrition among pregnant women may contribute to this development as suggested by epidemiological studies from high income countries linking undernutrition in fetal life with increased burden of non-communicable diseases in later life. We undertook to study the risks for hypertension, glucose intolerance and overweight forty years after fetal exposure to famine afflicted Biafra during the Nigerian civil war (1967–1970).

Methods and Findings

Cohort study performed in June 27–July 31, 2009 in Enugu, Nigeria. Adults (n = 1,339) born before (1965–67), during (1968–January 1970), or after (1971–73) the years of famine were included. Blood pressure (BP), random plasma glucose (p-glucose) and anthropometrics, as well as prevalence of hypertension (BP>140/90 mmHg), impaired glucose tolerance (IGT; p-glucose 7.8–11.0 mmol/l), diabetes (DM; p-glucose ≥11.1 mmol/l), or overweight (BMI>25 kg/m²) were compared between the three groups. Fetal-infant exposure to famine was associated with elevated systolic (+7 mmHg; p<0.001) and diastolic (+5 mmHg; p<0.001) BP, increased p-glucose (+0.3 mmol/L; p<0.05) and waist circumference (+3cm, p<0.001), increased risk of systolic hypertension (adjusted OR 2.87; 95% CI 1.90–4.34), IGT (OR 1.65; 95% CI 1.02–2.69) and overweight (OR 1.41; 95% CI 1.03–1.93) as compared to people born after the famine. Limitations of this study include the lack of birth weight data and the inability to separate effects of fetal and infant famine.

Conclusions

Fetal and infant undernutrition is associated with significantly increased risk of hypertension and impaired glucose tolerance in 40-year-old Nigerians. Prevention of undernutrition during pregnancy and in infancy should therefore be given high priority in health, education, and economic agendas.     

Maternal protein restriction during lactation induces early and lasting plasma metabolomic and hepatic lipidomic signatures of the offspring in a rodent programming model

Perinatal undernutrition affects not only fetal and neonatal growth but also adult health outcome, as suggested by the metabolic imprinting concept. However, the exact mechanisms underlying offspring metabolic adaptations are not yet fully understood. Specifically, it remains unclear whether the gestation or the lactation is the more vulnerable period to modify offspring metabolic flexibility. We investigated in a rodent model of intrauterine growth restriction (IUGR) induced by maternal protein restriction (R) during gestation which time window of maternal undernutrition (gestation, lactation or gestation–lactation) has more impact on the male offspring metabolomics phenotype. Plasma metabolome and hepatic lipidome of offspring were characterized through suckling period and at adulthood using liquid chromatography–high-resolution mass spectrometry. Multivariate analysis of these fingerprints highlighted a persistent metabolomics signature in rats suckled by R dams, with a clear-cut discrimination from offspring fed by control (C) dams. Pups submitted to a nutritional switch at birth presented a metabolomics signature clearly distinct from that of pups nursed by dams maintained on a consistent perinatal diet. Control rats suckled by R dams presented transiently higher branched-chain amino acid (BCAA) oxidation during lactation besides increased fatty acid (FA) β-oxidation, associated with preserved insulin sensitivity and lesser fat accretion that persisted throughout their life. In contrast, IUGR rats displayed permanently impaired β-oxidation, associated to increased glucose or BCAA oxidation at adulthood, depending on the fact that pups experienced slow postnatal or catch-up growth, as suckled by R or C dams, respectively. Taken together, these findings provide evidence for a significant contribution of the lactation period in metabolic programming.     

Growth in utero and serum cholesterol concentrations in adult life.

OBJECTIVE--To see whether reduced rates of fetal growth are related to raised serum cholesterol concentrations in adult life. DESIGN--Follow up study of men and women whose size at birth had been recorded. SETTING--Jessop and Northern General Hospitals, Sheffield. SUBJECTS--219 men and women born in the Jessop Hospital during 1939-40. MAIN OUTCOME MEASURES--Serum concentrations of total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B. RESULTS--Men and women who had had a small abdominal circumference at birth had raised serum concentrations of total and low density lipoprotein cholesterol and apolipoprotein B. This was independent of the duration of gestation. Serum concentrations of total cholesterol fell by 0.25 mmol/l (95% confidence interval 0.09 to 0.42) with each 1 in (2.54 cm) increase in abdominal circumference. The corresponding figure for serum low density lipoprotein cholesterol was 0.26 mmol/l (0.11 to 0.42) and for serum apolipoprotein B 0.04 g/l (0.02 to 0.07). Small head and chest circumferences at birth and short length were each associated with raised serum low density lipoprotein cholesterol concentrations but the trends disappeared in a simultaneous regression with abdominal circumference at birth. The association between abdominal circumference at birth and low density lipoprotein cholesterol concentration was independent of social class, current body weight, cigarette smoking, and alcohol consumption. CONCLUSION--Raised serum cholesterol concentrations in adult life are associated with impaired growth during late gestation, when fetal undernutrition has a disproportionate effect on liver growth. Impaired liver growth may permanently alter low density lipoprotein cholesterol metabolism.     

Pathways linking the early environment to long-term health and lifespan

The intrauterine environment is a major contributor to normal physiological growth and development of an individual. Disturbances at this critical time can affect the long-term health of the offspring. Low birth weight individuals have strong correlations with increased susceptibility to type 2 diabetes and cardiovascular disease in later-life. These observations led to the Thrifty Phenotype Hypothesis which suggested that these associations arose because of the response of a growing fetus to a suboptimal environment such as poor nutrition. Animal models have shown that environmentally induced intrauterine growth restriction increases the risk of a variety of diseases later in life. These detrimental features are also observed in high birth weight offspring from mothers who were obese or consumed a high fat diet during gestation. Recent advances in our understanding of the mechanisms underlying this phenomenon have elucidated several potential candidates for the long-term effects of the early environment on the function and metabolism of a cell. These include: (1) Epigenetic alterations (e.g. DNA methylation and histone modifications), which regulate specific gene expression and can be influenced by the environment, both during gestation and early postnatal life and (2) Oxidative stress that changes the balance between reactive oxygen species generation (e.g. through mitochondrial dysfunction) and antioxidant defense capacity. This has permanent effects on cellular ageing such as regulation of telomere length. Further understanding of these processes will help in the development of therapeutic strategies to increase healthspan and reduced the burden of age-associated diseases.     

Perinatal nutrition and hormone-dependent programming of food intake

It is increasingly accepted that alterations of the intrauterine and early postnatal nutritional, metabolic and hormonal environment may predispose individuals to development of diseases in later life. Results from studies of the offspring of diabetic mothers strongly support this hypothesis. It has also been suggested that being light at birth leads to an increased risk of the metabolic syndrome (Syndrome X) in later life (the Barker hypothesis). The pathophysiological mechanisms that underlie this programming are unclear. However, hormones are important environment-dependent organizers of the developing neuroendocrine-immune network, which regulates all the fundamental processes of life. Hormones can act as 'endogenous functional teratogens' when present in non-physiological concentrations, induced by alterations in the intrauterine or neonatal environment during critical periods of perinatal life. Perinatal hyperinsulinism is pathognomic in offspring of diabetic mothers. Early hyperinsulinism also occurs as a result of early postnatal overfeeding. In rats, endogenous hyperinsulinism, as well as peripheral or intrahypothalamic insulin treatment during perinatal development, may lead to 'malprogramming' of the neuroendocrine systems regulating body weight, food intake and metabolism. This results in an increased disposition to become obese and to develop diabetes throughout life. Similar malprogramming may occur due to perinatal hypercortisolism and hyperleptinism. With regard to 'small baby syndrome' and the thrifty phenotype hypothesis, we propose that early postnatal overfeeding of underweight newborns may substantially contribute to their long-term risk of obesity and diabetes. In summary, a complex malprogramming of the central regulation of body weight and metabolism may provide a general aetiopathogenetic concept, explaining perinatally acquired disposition to later disease and, thereby, opening a wide field for primary prevention.     

Perinatal Protein Malnutrition Affects Mitochondrial Function in Adult and Results in a Resistance to High Fat Diet-Induced Obesity

Epidemiological findings indicate that transient environmental influences during perinatal life, especially nutrition, may have deleterious heritable health effects lasting for the entire life. Indeed, the fetal organism develops specific adaptations that permanently change its physiology/metabolism and that persist even in the absence of the stimulus that initiated them. This process is termed “nutritional programming”. We previously demonstrated that mothers fed a Low-Protein-Diet (LPD) during gestation and lactation give birth to F1-LPD animals presenting metabolic consequences that are different from those observed when the nutritional stress is applied during gestation only. Compared to control mice, adult F1-LPD animals have a lower body weight and exhibit a higher food intake suggesting that maternal protein under-nutrition during gestation and lactation affects the energy metabolism of F1-LPD offspring. In this study, we investigated the origin of this apparent energy wasting process in F1-LPD and demonstrated that minimal energy expenditure is increased, due to both an increased mitochondrial function in skeletal muscle and an increased mitochondrial density in White Adipose Tissue. Importantly, F1-LPD mice are protected against high-fat-diet-induced obesity. Clearly, different paradigms of exposure to malnutrition may be associated with differences in energy expenditure, food intake, weight and different susceptibilities to various symptoms associated with metabolic syndrome. Taken together these results demonstrate that intra-uterine environment is a major contributor to the future of individuals and disturbance at a critical period of development may compromise their health. Consequently, understanding the molecular mechanisms may give access to useful knowledge regarding the onset of metabolic diseases.     

In utero substrate restriction by placental insufficiency or maternal undernutrition decreases optical redox ratio in foetal perirenal fat

Intrauterine growth restriction (IUGR) can result from reduced delivery of substrates, including oxygen and glucose, during pregnancy and may be caused by either placental insufficiency or maternal undernutrition. As a consequence of IUGR, there is altered programming of adipose tissue and this can be associated with metabolic diseases later in life. We have utilised two sheep models of IUGR, placental restriction and late gestation undernutrition, to determine the metabolic effects of growth restriction on foetal perirenal adipose tissue (PAT). Two-photon microscopy was employed to obtain an optical redox ratio, which gives an indication of cell metabolism. PAT of IUGR foetuses exhibited higher metabolic activity, altered lipid droplet morphology, upregulation of cytochrome c oxidase subunit genes and decreased expression of genes involved in growth and differentiation. Our results indicate that there are adaptations in PAT of IUGR foetuses that might be protective and ensure survival in response to an IUGR insult.     

Early life undernutrition and adult height: The Dutch famine of 1944–45

Current research shows strong associations between adult height and several positive outcomes such as higher cognitive skills, better earning capacity, increased chance of marriage and better health. It is therefore relevant to investigate the determinants of adult height. There is mixed evidence on the effects of undernutrition during early life on adult height. Therefore, our study aims at assessing the impact of undernutrition during gestation and at ages younger than 15 on adult height.We used data from the Longitudinal Aging Study Amsterdam. Exposure to undernutrition was determined by place of residence during the Dutch famine during World War II. Included respondents were born between 15 May 1930 and 1 November 1945 and lived in the northern part of the Netherlands during the famine period (n = 1008). Exposure data was collected using interviews and questionnaires and adult height was measured. Exposed and non-exposed respondents were classified in the age categories pregnancy- age 1 (n = 85), age 1–5 (n = 323), age 6–10 (n = 326) or puberty (age 11–15, n = 274). Linear regression analyses were used to test the associations of adult height with exposure. The robustness of the regression results was tested with sensitivity analyses.In the models adjusted for covariates (i.e., number of siblings, education level of parents, and year of birth) and stratified by gender, adult height was significantly shorter for females exposed at ages younger than 1 (−4.45 cm [−7.44–−1.47]) or at ages younger than 2 (−4.08 cm [−7.20–−0.94]). The results for males were only borderline significant for exposure under age 1 (−3.16 [−6.82–0.49]) and significant for exposure under age 2 (−4.09 cm [−7.20–−0.96]). Exposure to the Dutch famine at other ages was not consistently significantly associated with adult height.In terms of public health relevance, the study’s results further underpin the importance of supporting pregnant women and young parents exposed to undernutrition.     

Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep

It has been proposed that fetal adaptations to intrauterine nutrient deprivation permanently reprogram the cardiovascular system. We investigated the impact of restricted periconceptional nutrition and/or restricted gestational nutrition on fetal arterial blood pressure (BP), heart rate, rate pressure product, and the fetal BP responses to ANG II and the angiotensin-converting enzyme inhibitor captopril during late gestation. Restricted periconceptional nutrition resulted in an increase in fetal mean arterial BP between 115 and 125 days gestation (restricted 41.5 +/- 2.8 mmHg, n = 12; control 38.5 +/- 1.5 mmHg, n = 13) and between 135 and 147 days gestation (restricted 50.5 +/- 2.2 mmHg, n = 8; control 42.5 +/- 1.9 mmHg, n = 10) as well as an increase in the rate pressure product in twin, but not singleton, fetuses between 115 and 147 days gestation. Mean BP and fetal plasma ACTH were also positively correlated in twin, but not singleton, fetuses. This is the first demonstration that maternal undernutrition during the periconceptional period results in an increase in fetal arterial BP. This increase occurs concomitantly with an increase in fetal ACTH but is not dependent on activation of the fetal renin-angiotensin system.     

Nutritional programming of blood pressure and renal morphology

A range of epidemiological evidence from several diverse populations, supports the hypothesis that risk of essential hypertension, coronary heart disease and non-insulin dependent diabetes is, in part, programmed by intrauterine nutritional status. Animal models developed to investigate the mechanisms that are responsible for such programming are becoming more important as challenges to the epidemiological data become more robust. With strong evidence from animal studies it is now widely accepted that maternal nutritional status in pregnancy is a major programming influence upon the fetus. This paper considers the hypothesis that renal structure and function are determined by prenatal nutrition and that this is a key mechanism in the programming of hypertension. The feeding of low protein diets or other insults in pregnancy that have an impact upon the development of cardiovascular functions, also appears to impact upon nephron number. In the sheep nephron number is related to weight at birth following nutrient restriction, and in the rat low protein diets reduce nephron number by approximately 30%. However, it is possible that hypertension and reduced renal reserve merely coincide and are not causally associated. A study of rats fed low protein diets supplemented with additional nitrogen sources found that whilst only glycine could reverse the hypertensive effects of low protein diets, all supplements could normalise nephron number. The evidence thus suggests that prenatal undernutrition may programme renal structure in later life, but that renal programming is not one of the primary mechanisms leading to hypertension.     

Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat

Epidemiological evidence suggests that hypertension and coronary heart disease are programmed by exposure to a poor diet during intrauterine life. It has been proposed that the prenatal environment may exert an adverse effect on the development of the kidney and hence later control of blood pressure. These assertions are supported by animal experiments. In the rat, fetal exposure to a maternal low protein diet is associated with disproportionate patterns of fetal growth and later elevation of blood pressure. Pregnant female rats were fed control (18% casein) or low protein diets throughout pregnancy, or during specific periods. Nephron number was determined at day 20 gestation, full term and 4 weeks of age. Exposure to low protein throughout gestation, or in mid-late gestation increased total nephron number at day 20. By term nephron number was reduced, relative to controls, in rats that were undernourished between days 8-14 or 15-22 gestation. At 4 weeks postnatally rats exposed to low protein throughout fetal life had a reduced (13%) nephron complement and blood pressures 13 mmHg above control animals. Lower renal size and elevated blood pressure persisted to 19 weeks of age, at which time glomerular filtration rate was normal. The data are consistent with the hypothesis that maternal undernutrition may programme the renal nephron number and hence impact upon adult blood pressure and the development of renal disease.     

Programming of glucose-insulin metabolism in adult sheep after maternal undernutrition

The present study examines the effects of late vs. early gestation undernutrition on adult glucose-insulin homeostasis in sheep and investigates whether the lower birth weight of twins alters glucose-insulin handling in adult life. Pregnant sheep were fed to requirement (100% intake) from day 0 of gestation to term [ approximately 147 days of gestation (dGA), control singles (CS) n = 5; control twins (CT) n = 5] or to 50% requirement from days 0-30 dGA [nutrient restricted during early gestation (NRE); n = 5] or day 110-term [NR during late nutrition (NRL); n = 4]. At all other times, NR sheep received 100% intake. All sheep lambed naturally; offspring were weaned at 10 wk and were reared on pasture until 1 yr of age. At this time, indwelling catheters were inserted, and 2-4 days later, basal metabolic and endocrine status and responses to an intravenous glucose tolerance test (IVGTT) and feeding were assessed. Adipose and skeletal muscle were then sampled after humane euthanasia and were analyzed for expression of insulin-signaling proteins and GLUT4. Between groups, birth weight of singletons was similar and increased relative to twins. At 1 yr of age, weights were similar between groups. The areas under the curve for glucose and insulin during the IVGTT were greater in NRL vs. other groups, indicating glucose intolerance. This was associated with reduced adipose, but not muscle, GLUT4, and increased adipose tissue mass. Adult glucose-insulin homeostasis in sheep was unaffected by fetal number. In conclusion, prenatal undernutrition, specifically during late gestation, affects adult offspring intermediary metabolism, and, in particular, glucose-insulin homeostasis.     

Nutritional regulation of fetal growth and implications for productive life in ruminants

The maternal nutritional and metabolic environment is critical in determining not only the reproductive success but also the long-term health and viability of the offspring. Changes in maternal diet at defined stages of gestation coincident with different stages of development can have pronounced effects on organ and tissue function in later life. This includes adipose tissue for which differential effects are observed between brown and white adipose tissues. One early, critical window of organ development in the ruminant relates to the period covering uterine attachment, or implantation, and rapid placental growth. During this period, there is pronounced cell division within developing organelles in many fetal tissues, leading to their structural development. In sheep, a 50% global reduction in caloric intake over this specific period profoundly affects placental growth and morphology, resulting in reduced placentome weight. This occurs in conjunction with a lower capacity to inactivate maternal cortisol through the enzyme 11β-hydroxysteroid dehydrogenase type 2 in response to a decrease in maternal plasma cortisol in early gestation. The birth weight of the offspring is, however, unaffected by this dietary manipulation and, although they possess more fat, this adaptation does not persist into adulthood when they become equally obese as those born to control fed mothers. Subsequently, after birth, further changes in fat development occur which impact on both glucocorticoid action and inflammatory responses. These adaptations can include changes in the relative populations of both brown and white adipocytes for which prolactin acting through its receptor appears to have a prominent role. Earlier when in utero nutrient restricted (i.e. between early-to-mid gestation) offspring are exposed to an obesogenic postnatal environment; they exhibit an exaggerated insulin response, which is accompanied by a range of amplified and thus, adverse, physiological or metabolic responses to obesity. These types of adaptations are in marked contrast to the effect of late gestational nutrient restriction, which results in reduced fat mass at birth. As young adults, however, fat mass is increased and, although basal insulin is unaffected, these offspring are insulin resistant. In conclusion, changes in nutrient supply to either the mother and/or her fetus can have profound effects on a range of metabolically important tissues. These have the potential to either exacerbate, or protect from, the adverse effects of later obesity and accompanying complications in the resulting offspring.     

Intrauterine undernutrition and programming as a new risk of cardiovascular disease in later life

It is believed that atherogenesis is a multifactorial process, which could already start in utero. Development of atherosclerosis progresses over decades and leads to the cardiovascular morbidity and mortality in adulthood. At present, we have no exact explanation for all the risk factors acting in the pathogenesis of atherosclerosis. This review should provide an overview about the possible role of intrauterine undernutrition in the development of risk factors for cardiovascular disease. Intrauterine undernutrition leads to changes in fetal growth and metabolism and programs later development of some of these risk factors. A number of experimental and human studies indicates that hypertension as well as impaired cholesterol and glucose metabolism are affected by intrauterine growth. Intrauterine undernutrition plays an important role and acts synergistically with numerous genetic and environmental factors in the development of atherosclerosis. There is evidence that undernutrition of the fetus has permanent effects on the health status of human individuals.     

Reduced levels of placental long chain polyunsaturated fatty acids in preterm deliveries

Reports suggest that the placenta in preterm birth may provide clues to predicting the risk of individuals developing chronic diseases in later life. Placental delivery of long chain polyunsaturated fatty acids (LCPUFA) (constituents of the cell membrane and precursors of prostaglandins) is essential for the optimal development of the central nervous system of the fetus. The present study examines the levels of LCPUFA and their association with placental weight and birth outcome in 58 women delivering preterm and 44 women delivering at term. Docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels were lower (p<0.01) in women delivering preterm. There was a positive association of placental DHA with placental weight (p=0.036) and nervonic acid with head circumference (p=0.040) in the preterm group. Altered placental LCPUFA status exists in Indian mothers delivering preterm, which may influence the birth outcome.