Both reductions in birth weight and preeclampsia (PE) have been associated with decrements in scores on tests of intelligence in children and adolescents. We examined whether these decrements persist into middle adulthood and expand into other domains of cognitive functioning. Using data from the Early Determinants of Adult Health project and from the ancillary project, Fetal Antecedents of Major Depression and Cardiovascular Disease, we selected term same-sex sibling sets or singletons from these sets, from the New England Family Study (NEFS) and the Child Health and Development Studies (CHDS), discordant on either fetal growth or PE, to test the hypotheses that prenatal exposure to inflammation was associated with decrements in attention, learning and executive function 40 years later. Exposure was defined as a continuous measure of percentile birth weight for gestational age, reduced fetal growth (<20th percentile of birth weight for gestational age) or maternal PE. Given that the sample was comprised, in part, of sibling sets, the analyses were performed using mixed models to account for the inter-sibling correlations. Analyses were performed separately by study site (i.e. NEFS and CHDS). We found few statistically significant associations (suggesting a possible type II error) consistent with previous literature, suggesting that the associations with low birth weight do not persist into midlife. We discuss the possible reasons for the lack of associations, which include the possible mediating effects of the postnatal environment.

Maternal food restriction is known to cause developmental hypertension in offspring. We have previously shown that maternal high-protein diet can reverse fetal programming of hypertension and that branched-chain amino acid (BCAA) concentrations in maternal and fetal plasma were increased by maternal high-protein intake. Then, we hypothesized that isocaloric supplementation with BCAA to a maternal food restriction can reverse the adverse outcome. Pregnant rats were divided into four groups at 7.5 days postcoitum: normally nourished (NN) and 70% undernourished (UN) groups with and without BCAA supplementation (NN–standard diet (SD), NN–BCAA, UN–SD and UN–BCAA groups). Compared with pups in the NN groups, those in the UN–SD group had significantly increased systolic blood pressure (SBP) at 8 and 16 weeks of age (P < 0.05). However, the elevation of SBP was not observed in offspring in the UN–BCAA group. Offspring glomeruli number of the UN groups was significantly lower (P < 0.05) than that of the NN groups, independent of BCAA supplementation. Angiotensin II receptor type 2 (ATR2) mRNA and protein expression in the kidney was significantly augmented in the UN–BCAA group at 30 weeks of age. In conclusion, BCAA supplementation during maternal food restriction prevents developmental hypertension together with increased ATR2 expression in adult offspring kidney.

Fetal exposure to caffeine is associated with adverse pregnancy outcomes. Animal and human studies suggest that caffeine may have effects on the developing reproductive system. Here we report on mothers’ smoking, coffee and alcohol use, recorded during pregnancy, and semen quality in sons in the age group of 38–47 years. Subjects were a subset of the Child Health and Development Studies, a pregnancy cohort enrolled between 1959 and 1967 in the Kaiser Foundation Health Plan near Oakland, California. In 2005, adult sons participated in a follow-up study (n = 338) and semen samples were donated by 196 participants. Samples were analyzed for sperm concentration, motility and morphology according to the National Cooperative Reproductive Medicine Network (Fertile Male Study) Protocol. Mean sperm concentration was reduced by approximately 16 million sperms for sons with high prenatal exposure (5 cups of maternal coffee use per day) compared with unexposed sons (P-value for decreasing trend = 0.09), which translates to a proportionate reduction of 25%. Mean percent motile sperm decreased by approximately 7 points (P-value = 0.04), a proportionate decline of 13%, and mean percent sperm with normal morphology decreased by approximately 2 points (P-value = 0.01), a proportionate decline of 25%. Maternal cigarette and alcohol use were not associated with son's semen quality. Adjusting for son's contemporary coffee, alcohol and cigarette use did not explain the maternal associations. Findings for son's coffee intake and father's prenatal coffee, cigarette and alcohol use were non-significant and inconclusive. These results contribute to the evidence that maternal coffee use during pregnancy may impair the reproductive development of the male fetus.

Young people who are born very preterm exhibit a narrower arterial tree as compared with people born at term. We hypothesized that such arterial narrowing occurs as a direct result of premature birth. The aim of this study was to compare aortic and carotid artery growth in infants born preterm and at term. Observational and longitudinal cohort study of 50 infants (21 born very preterm, all appropriate for gestational age, 29 controls born at term) was conducted. Diameters of the upper abdominal aorta and common carotid artery were measured with ultrasonography at three months before term, at term and three months after term-equivalent age. At the first assessment, the aortic end-diastolic diameter (aEDD) was slightly larger in very preterm infants as compared with fetal dimensions. Fetal aortic EDD increased by 2.6 mm during the third trimester, whereas very preterm infants exhibited 0.9 mm increase in aEDD during the same developmental period (P < 0.001 for group difference). During the following 3-month period, aortic growth continued unchanged (+0.9 mm) in very preterm infants, whereas postnatal growth in term controls slowed down to +1.3 mm (P < 0.001 v. fetal aortic growth). At the final examination, aEDD was 22% and carotid artery EDD was 14% narrower in infants born preterm compared with controls, also after adjusting for current weight (P < 0.01). Aortic and carotid artery growth is impaired after very preterm birth, resulting in arterial narrowing. Arterial growth failure may be a generalized vascular phenomenon after preterm birth, with implications for cardiovascular morbidity in later life.

Rat offspring born to dams fed a high multivitamin diet (HV) are shown to have increased risks of obesity and metabolic syndrome. We hypothesized that a low-vitamin postweaning diet would enhance these characteristics in offspring born to HV dams. During pregnancy, Wistar rats were fed the AIN-93G diet with or without a 10-fold increase in vitamin content. In Experiment 1, at weaning, males were fed the recommended diet (RV) or a diet with 1/3 the vitamin content (1/3 RV) for 12 weeks. In Experiment 2, males and females were fed the RV diet or 1/6 RV diet for 35 weeks. Body weight was measured on a weekly basis, food intake on a daily basis, and for 1 h after an overnight fast following glucose gavage at 6, 12 and 24 weeks. Blood glucose and insulin responses to an oral glucose load were measured at 30 weeks. Males from HV dams, compared with those from RV dams, gained more weight in Experiment 1 (+7%, P < 0.05) and Experiment 2 (+11%, P < 0.0001), along with higher glucose response (+33%, P < 0.05). The 1/6 RV pup diet led to lower weight gain in males (−16%, P < 0.0001) and females (−13%, P < 0.0005), and lower food intake in males (−9%, P < 0.01) independent of the gestational diet. Females on the 1/6 RV diet and from HV dams had higher 1 h food intake (+36%, P < 0.05) and lower insulin response (−25%, P < 0.05) compared with those from RV dams. Exposure of the offspring to low-vitamin diets did not amplify the expression of the metabolic syndrome observed in those born to dams fed an HV diet.

Exposure of fetuses to endocrine disrupting chemicals (EDCs), such as the estrogenic drug diethylstilbestrol (DES), disrupts development of the reproductive system and affects other aspects of adult phenotype including diseases, consistent with the developmental origins of health and disease hypothesis. To determine whether diet could influence the effects of DES, we compared mice fed a commonly used combination of soy-based Purina 5008 (breeding and lactation) and 5001 (post-weaning) with mice fed soy-based Purina 5002 throughout life. We exposed fetal CD-1 mice (F1) in utero on different feeds to a 0 (controls), low (0.1 μg/kg/day) or high (50 μg/kg/day) dose of DES via feeding the dam (F0) on gestation days 11–17. Compared to 5008, 5002 feed significantly increased serum estradiol in control fetuses. On 5008 (but not 5002) feed, DES significantly increased fetal serum estradiol at a low dose and reduced it at a high dose. Diet influenced the effects of in utero DES on F1 female onset of puberty and the uterine response to estradiol (an inverted-U dose–response relationship seen for DES on uterine weight with 5008/5001 feed was not observed with 5002). Both low- and high-dose DES reduced daily sperm production (DSP) in adult F1 males on 5008/5001 feed, whereas males fed 5002 showed no DES-induced reduction in DSP. Thus, we observed a number of low-dose effects of in utero DES exposure on Purina 5008/5001 feed that were not observed using Purina 5002, a feed commonly used in industry-funded toxicological studies conducted for regulatory purposes.

Malnutrition during pregnancy causes intrauterine growth restriction and long-term changes in the offspring's physiology and metabolism. To explore molecular mechanisms by which the intrauterine environment conveys programming in fetal kidneys, an organ known to undergo substantial changes in many animal models of late gestational undernutrition, we used a microswine model of maternal protein restriction (MPR) in which sows were exposed to isocaloric low protein (LP) diet during late gestation/early lactation to encompass the bulk of nephrogenesis. To define general v. model-specific effects, we also used a sheep model of placental insufficiency. In kidneys from near-term fetal and neonatal microswine LP offspring, per cell levels of total RNA, poly(A)+ mRNA and transcripts of several randomly chosen housekeeping genes were significantly reduced compared to controls. Microarray analysis revealed only a few MPR-resistant genes that escape such downregulation. The ratio of histone modifications H3K4m3/H3K9m3 (active/silenced) was reduced at promoters of downregulated but not MPR-resistant genes suggesting that transcriptional suppression is the point of control. In juvenile offspring, on a normal diet from weaning, cellular RNA levels and histone mark patterns were recovered to near control levels, indicating that global repression of transcription is dependent on ongoing MPR. Importantly, cellular RNA content was also reduced in ovine fetal kidneys during placental insufficiency. These studies show that global repression of transcription may be a universal consequence of a poor intrauterine environment that contributes to fetal restriction.

We have previously shown that neonatal high oxygen (O2) exposure in rats leads to hypertension and vascular dysfunction in adulthood. Pulse-wave velocity (PWV), an indirect measure of vascular biophysical properties (arterial stiffness or distensibility), is a sensitive marker of cardiovascular health. Its measurement in rats is mostly based on invasive hemodynamics measurements, prohibiting longitudinal studies particularly relevant in models of developmental programming of cardiovascular dysfunctions. With this study, we sought (1) to verify the feasibility and validity of measuring of aortic PWV in Sprague–Dawley rats by ultrasound; (2) to use the technique to compare aortic PWV in adult rats exposed to O2 as newborns (80% day 3–10 of life) v. controls; and (3) to develop an algorithm to calculate PWV in a non-invasive manner. We calculated aortic PWV using standard echocardiography and electrocardiogram, and validated the measures with PWV obtained by intraaortic catheters. Aortic full length was measured at sacrifice. PWV was significantly increased in O2 exposed (505 ± 18 cm/s) v. control animals (421 ± 17 cm/s, P < 0.01). With regard to weight, femur length and distance from the manubrium to the anal margin (MA length), the latter showed the best correlation (R = 0.84, P < 0.0001) with full aorta length derived from (L) = 0.339 × (MA length) + 4.281. The current data using echo-Doppler method demonstrated increased aortic stiffness in adult rats exposed to hyperoxia as newborns and suggests that non-invasive longitudinal studies of aortic PWV can be performed using the proposed algorithm for estimation of the full aorta length.

Maternal undernutrition (MUN) results in growth-restricted newborns with reduced nephron numbers that is associated with increased risk of hypertension and renal disease. The total adult complement of nephrons is set during nephrogenesis suggesting that MUN affects the staged development of nephrons in as yet unknown manner. A possible cause may be the increased renal apoptosis; therefore, we investigated whether apoptotic signaling and cell death were increased in MUN rat kidneys. Pregnant rat dams were fed an ad libitum diet [control] or were 50% food restricted (MUN) starting at embryonic day (E) 10. Male offspring kidneys (n = 5 each, MUN and control) were analyzed for mRNA using quantitative PCR (E20) and for protein expression using Western blotting and immunohistochemistry (E20 and postnatal day 1, P1). Apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Upregulation of pro-apoptotic protein expression was detected at E20 (Fas receptor, caspase 9) and at P1 (caspase 3, Bax). The anti-apoptotic factor Bcl2 was significantly decreased in P1 kidneys. Kidney TUNEL showed apoptotic nuclei significantly increased in the P1 nephrogenic zone (MUN 3.3 + 0.3 v. C 1.6 + 0.5, P = 0.002). The majority of apoptotic nuclei co-localized to mesenchyme and pretubular aggregates in the nephrogenic zone. Differential regulation of apoptosis in mesenchyme and pretubular aggregates following parturition suggests a mechanism for nephropenia in gestational programming of the kidney.

Exposure to environmental chemicals and other environmental stressors have health impacts on the fetus that may not be apparent until later in life. The concept of developmental origins of disease should be expanded to include these early life exposures in addition to the effects of nutrition and maternal factors. This paper will describe the toxicological, biological and epidemiological issues that are pertinent to conducting research on environmental exposures early in life and their health consequences over the life span.

Epidemiological studies suggest that glucocorticoid excess in the fetus may contribute to the pathophysiology of cardiovascular diseases in adulthood. However, the impact of maternal glucocorticoid on the cardiovascular system of the offspring has not been much explored in studies involving humans, especially in childhood. The objective of this study was to assess the influence of maternal cortisol concentrations on child arterial elasticity. One hundred and thirty pregnant women followed from 1997 to 2000, and respective children 5–7 years of age followed from 2004 to 2006 were included in the study. Maternal cortisol was determined in saliva by an enzyme immunoassay utilizing the mean concentration of nine samples of saliva. Arterial elasticity was assessed by the large artery elasticity index (LAEI; the capacitive elasticity of large arteries) by recording radial artery pulse wave, utilizing the equipment HDI/PulseWave CR-2000 Cardiovascular Profiling System®. The nutritional status of the children was determined by the body mass index (BMI). Insulin concentration was assessed by chemiluminescence, and insulin resistance by the homeostasis model assessment. Blood glucose, total cholesterol and fractions (LDL-c and HDL-c) and triglyceride concentrations were determined by automated enzymatic methods. The association between maternal cortisol and child arterial elasticity was assessed by multivariate linear regression analysis. There was a statistically significant association between maternal cortisol and LAEI (P = 0.02), controlling for birth weight, age, BMI and HDL-c of the children. This study suggests that exposure to higher glucocorticoid concentrations in the prenatal period is associated to lower arterial elasticity in childhood, an earlier cardiovascular risk marker.

Feeding a low protein (LP) diet in rat pregnancy is associated with impaired cardiovascular health and function, possibly as a result of tissue remodelling. To assess whether cardiomyocytes retain differences induced by protein restriction, cells from neonatal rats exposed to control or LP diets in utero were cultured for a period of 10 days. At the end of this period, no differences in cell size, proliferation differentiation or metabolic function were noted. When treated with dexamethasone (0.1–10 μM) for 2 days, it was noted that insulin-stimulated glucose uptake was enhanced, but only in cells from LP rats. Increased glucocorticoid sensitivity of cardiomyocytes from LP rats could not be explained by differential expression of the glucocorticoid receptor or the glucose transporters, GLUT1 and GLUT4. The findings of the study suggest that sensitivity to endocrine signals may be permanently programmed by undernutrition through mechanisms that are preserved in vitro.

Unbalanced nutrition during critical windows of development is implicated in determining the susceptibility to hypertension and cardiovascular disease in adult life, but the underlying mechanisms during fetal life have not been fully elucidated. We investigated the effects of moderate nutritional restriction during critical windows in gestation on late gestation fetal sheep growth, cardiovascular and renal renin-angiotensin system function. Ewes were fed 100% nutrient requirements (control), or 40–50% nutrient requirements during the peri-implantation period (1–31 days gestation (dGA), PI40 and PI50), or 50% nutrient requirements in late gestation (104–127 dGA). At 125 ± 2 dGA, fetal cardiovascular and renal function were measured at baseline, and during frusemide, angiotensin II (Ang II), phenylephrine and hypoxia challenges. Maternal undernutrition had no effect on fetal biometry, kidney weight, nephron number, basal cardiovascular function or cardiovascular and renal responses to frusemide. Fetal blood pressure response to Ang II was blunted in PI50 (P < 0.05), but not in PI40 groups. There was no difference between groups in the cardiovascular or endocrine response to hypoxia. The lack of effect of moderate undernutrition within key developmental windows of fetal kidney development on fetal renal structure and function suggests that renal mechanisms do not underlie our previous observations of cardiovascular dysfunction in adulthood following early-life undernutrition.