Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, type 2 diabetes and cardiovascular disease and can be considered the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of disease, from the relatively benign simple steatosis to the more serious non-alcoholic steatohepatitis, which can progress to liver cirrhosis, hepatocellular carcinoma and end-stage liver failure, necessitating liver transplantation. Although the increasing prevalence of NAFLD in developed countries has substantial implications for public health, many of the precise mechanisms accounting for the development and progression of NAFLD are unclear. The environment in early life is an important determinant of cardiovascular disease risk in later life and studies suggest this also extends to NAFLD. Here we review data from animal models and human studies which suggest that fetal and early life exposure to maternal under- and overnutrition, excess glucocorticoids and environmental pollutants may confer an increased susceptibility to NAFLD development and progression in offspring and that such effects may be sex-specific. We also consider studies aimed at identifying potential dietary and pharmacological interventions aimed at reducing this risk. We suggest that further human epidemiological studies are needed to ensure that data from animal models are relevant to human health.

The prenatal environment is now recognized as a key driver of non-communicable disease risk later in life. Within the developmental origins of health and disease (DOHaD) paradigm, studies are increasingly identifying links between maternal morbidity during pregnancy and disease later in life for offspring. Nutrient restriction, metabolic disorders during gestation, such as diabetes or obesity, and maternal immune activation provoked by infection have been linked to adverse health outcomes for offspring later in life. These factors frequently co-occur, but the potential for compounding effects of multiple morbidities on DOHaD-related outcomes has not received adequate attention. This is of particular importance in low- or middle-income countries (LMICs), which have ongoing high rates of infectious diseases and are now experiencing transitions from undernutrition to excess adiposity. The purpose of this scoping review is to summarize studies examining the effect and interaction of co-occurring metabolic or nutritional stressors and infectious diseases during gestation on DOHaD-related health outcomes. We identified nine studies in humans – four performed in the United States and five in LMICs. The most common outcome, also in seven of nine studies, was premature birth or low birth weight. We identified nine animal studies, six in mice, two in rats and one in sheep. The interaction between metabolic/nutritional exposures and infectious exposures had varying effects including synergism, inhibition and independent actions. No human studies were specifically designed to assess the interaction of metabolic/nutritional exposures and infectious diseases. Future studies of neonatal outcomes should measure these exposures and explicitly examine their concerted effect.

Dilation and abnormal tortuosity of retinal vessels are the hallmarks of severe retinopathy of prematurity (ROP) in premature infants. The stages of ROP are defined by vessel appearance at the interface between the vascular and avascular retinal areas. Deregulated signaling pathways involving hypoxia-inducible factors such as vascular endothelial growth factor (VEGF) are involved in the pathogenesis of ROP. VEGF-antagonists are increasingly being used as ‘off-label medication’ to treat this condition, with some success. We present Baby SM (female), who was born prematurely at 24 weeks gestation in a tertiary neonatal intensive care unit, and with a birth weight of 640 g. On screening at 35 weeks postmenstrual age (PMA), she was noted to have ROP, which became severe by 37 weeks PMA. She received one dose of intravitreal VEGF antagonist (Bevacizumab), resulting in a decrease in vessel tortuosity and dilation. However, repeat imaging at 4 weeks showed a re-emergence of vessel tortuosity. We believe the observed changes demonstrate an inherent retinal microvascular plasticity in premature neonates. With improved survival of extremely premature neonates and the availability of retinal imaging technology, we are now able to observe this plasticity.

Insufficient nutrition during the perinatal period causes structural alterations in humans and experimental animals, leading to increased vulnerability to diseases in later life. Japanese quail, Coturnix japonica, in which partial (8–10%) egg white was withdrawn (EwW) from eggs before incubation had lower birth weights than controls (CTs). EwW birds also had reduced hatching rates, smaller glomeruli and lower embryo weight. In EwW embryos, the surface condensate area containing mesenchymal cells was larger, suggesting that delayed but active nephrogenesis takes place. In mature EwW quail, the number of glomeruli in the cortical region (mm2) was significantly lower (CT 34.7±1.4, EwW 21.0±1.2); capillary loops showed focal ballooning, and mesangial areas were distinctly expanded. Immunoreactive cell junction proteins, N-cadherin and podocin, and slit diaphragms were clearly seen. With aging, the mesangial area and glomerular size continued to increase and were significantly larger in EwW quail, suggesting compensatory hypertrophy. Furthermore, apoptosis measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling analysis was higher in EwWs than in CTs on embryonic day 15 and postnatal day 4 (D4). Similarly, plasma glucocorticoid (corticosterone) was higher (P<0.01) on D4 in EwW quail. These results suggest that although nephrogenic activity is high in low-nutrition quail during the perinatal period, delayed development and increased apoptosis may result in a lower number of mature nephrons. Damaged or incompletely mature mesangium may trigger glomerular injury, leading in later life to nephrosclerosis. The present study shows that birds serve as a model for ‘fetal programming,’ which appears to have evolved phylogenetically early.

Stunting is a measure of overall nutritional status and is a major public health concern because of its association with child mortality and morbidity and later adult performance. This study examined the effects of pregnancy events, birth characteristics and infant risk exposure on stunting at age 2 years. The study, established in 1990 in Soweto, an urban South African township, included 1098 mother–infant pairs enroled in the Birth to Twenty Plus longitudinal birth cohort study. In total, 22% of children were stunted at age 2 years, with males at greater risk than females [24.8 v. 19.4%, odds ratio (OR)=1.38; 95% confidence interval (CI): 1.03, 1.83]. In unadjusted analysis, male sex, household socio-economic status (SES), overcrowding, maternal age, maternal education, single motherhood, ethnicity, birth weight, gestational age and duration of infant breastfeeding were all significantly associated with stunting. In multivariable analysis, higher birth weight was protective against stunting for both sexes. Higher maternal education was protective for females only (adjusted odds ratio (AOR)=0.35; 95% CI: 0.14, 0.87), whereas wealthier household SES protected males (AOR for richest SES group=0.39; 95% CI: 0.16, 0.92). In this and other similar settings, current stunting prevention efforts focussing on primarily providing targeted proximal interventions, such as food supplements, risk undermining the critical importance of addressing key distal determinants of stunting such as SES and maternal education.

Most nutritional studies on the development of children focus on mother–infant interactions. Maternal nutrition is critically involved in the growth and development of the fetus, but what about the father? The aim is to investigate the effects of paternal methyl-group donor intake (methionine, folate, betaine, choline) on paternal and offspring global DNA (hydroxy)methylation, offspring IGF2 DMR DNA methylation, and birth weight. Questionnaires, 7-day estimated dietary records, whole blood samples, and anthropometric measurements from 74 fathers were obtained. A total of 51 cord blood samples were collected and birth weight was obtained. DNA methylation status was measured using liquid chromatography-tandem mass spectrometry (global DNA (hydroxy)methylation) and pyrosequencing (IGF2 DMR methylation). Paternal betaine intake was positively associated with paternal global DNA hydroxymethylation (0.028% per 100 mg betaine increase, 95% CI: 0.003, 0.053, P=0.03) and cord blood global DNA methylation (0.679% per 100 mg betaine increase, 95% CI: 0.057, 1.302, P=0.03). Paternal methionine intake was positively associated with CpG1 (0.336% per 100 mg methionine increase, 95% CI: 0.103, 0.569, P=0.006), and mean CpG (0.201% per 100 mg methionine increase, 95% CI: 0.001, 0.402, P=0.049) methylation of the IGF2 DMR in cord blood. Further, a negative association between birth weight/birth weight-for-gestational age z-score and paternal betaine/methionine intake was found. In addition, a positive association between choline and birth weight/birth weight-for-gestational age z-score was also observed. Our data indicate a potential impact of paternal methyl-group donor intake on paternal global DNA hydroxymethylation, offspring global and IGF2 DMR DNA methylation, and prenatal growth.

Several studies have shown that maternal low-protein (LP) diet induces detrimental effects in cardiovascular system and oxidative stress in male animals. Additional studies suggested that female has lower incidence of cardiovascular disease. However until present data, the possible effects of estradiol on the undernutrition during gestational and lactation periods are not discussed. The present study was conducted to evaluate the effects of a maternal LP diet during gestational and lactation period on oxidative balance in the female rat hearts ventricles at two ages. Dams were fed with normal protein (NP) or a LP diet during the gestational and lactation period, and their female offspring were divided into age groups (22 or 122 days, corresponding to a low or high estrogen level) composing four experimental groups. Evaluating the nutritional effect showed an increase in oxidative stress biomarkers and decrease in enzymatic defense in LP-22D compared with NP-22D. In contrast, no changes were observed in malondialdehyde and carbonyls, but an increase in glutathione-S-transferase (GST) activity in the LP-122D compared with NP-122D. The global oxy-score in the LP-22D group indicated a predominance of oxidative damage when compared with NP-22D, while in LP-122D group the global oxy-score was restored to NP-122D levels. Evaluating the estradiol effect, our data show a significant decrease in oxidative stress with increase in CAT and GST activity, associated with increase in intracellular thiols. Our data suggest that in situation with low levels of estradiol, hypoproteic diet during gestation and lactation period has detrimental effects on heart, however when estradiol levels raise, the detrimental effects induced are mitigated.

Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.

Environmental enteropathy (EE) is a syndrome of altered small intestine structure and function hypothesized to be common among individuals lacking access to improved water and sanitation. There are plausible biological mechanisms, both inflammatory and non-inflammatory, by which EE may alter the cardiometabolic profile. Here, we test the hypothesis that EE is associated with the cardiometabolic profile among young children living in an environment of intense enteropathogen exposure. In total, 156 children participating in the Peruvian cohort of a multicenter study on childhood infectious diseases, growth and development were contacted at 3–5 years of age. The urinary lactulose:mannitol ratio, and plasma antibody to endotoxin core were determined in order to assess intestinal permeability and bacterial translocation. Blood pressure, anthropometry, fasting plasma glucose, insulin, and cholesterol and apolipoprotein profiles were also assessed. Extant cohort data were also used to relate biomarkers of EE during the first 18 months of life to early child cardiometabolic profile. Lower intestinal surface area, as assessed by percent mannitol excretion, was associated with lower apolipoprotein-AI and lower high-density lipoprotein concentrations. Lower intestinal surface area was also associated with greater blood pressure. Inflammation at 7 months of age was associated with higher blood pressure in later childhood. This study supports the potential for a relationship between EE and the cardiometabolic profile.

Prematurity is a risk factor for hypertension, vascular stiffness, nephron deficit and adult onset cardiorenal disease. The vascular tree and kidneys share morphogenic drivers that promote maturation in utero before 36 weeks of gestation. Vascular elastin accrual terminates after birth leaving collagen to promote vascular stiffness. Our objective was to determine if the histomorphometry of the umbilical artery, an extension of the aorta, parallels nephron mass across gestational age groups. From a cohort of 54 newborns, 32 umbilical cord specimens were adequate for evaluation. The umbilical cord was sectioned, stained with trichrome, and digitalized. Muscular and collagenous areas of the umbilical artery were measured in pixels using the Image J 1.48q software. Total kidney volume was measured by ultrasound and factored by body surface area (TKV/BSA). The umbilical artery total area was significantly greater in term v. preterm infants (9.3±1.3 v. 7.0±2.0 mm2; P<0.05) and increased with gestational age; while the percent muscular and collagen areas were independent of gestational age (R2=0.04; P=ns). Percent muscular area correlated positively with TKV/BSA (r=0.53; P=0.002); while an increase in collagen correlated inversely with kidney mass (r=−0.53; P=0.002). In conclusion, an enhanced % muscular area and presumed vascular elasticity was associated with increased renal mass in all infants. Umbilical artery histomorphometry provides a link between the intrauterine environment, vascular and kidney development.

Most individuals whose growth was restricted before birth undergo accelerated or catch-up neonatal growth. This is an independent risk factor for later metabolic disease, but the underlying mechanisms are poorly understood. This study aimed to test the hypothesis that natural and experimentally induced in utero growth restriction increase neonatal appetite and milk intake. Control (CON) and placentally restricted (PR) ewes carrying multiple fetuses delivered naturally at term. Outcomes were compared between CON (n=14) and PR (n=12) progeny and within twin lamb pairs. Lamb milk intake and feeding behaviour and ewe milk composition were determined using a modified weigh-suckle-weigh procedure on days 15 and 23. PR lambs tended to have lower birth weights than CON (−15%, P=0.052). Neonatal growth rates were similar in CON and PR, whilst heavier twins grew faster in absolute but not fractional terms than their co-twins. At day 23, milk protein content was higher in PR than CON ewes (P=0.038). At day 15, PR lambs had fewer suckling bouts than CON lambs and in females light twins had more suckling attempts than their heavier co-twins. Birth weight differences between twins positively predicted differences in milk intakes. Lactational constraint and natural prenatal growth restriction in twins may explain the similar milk intakes in CON and PR. Within twin comparisons support the hypothesis that prenatal constraint increases lamb appetite, although this did not increase milk intake. We suggest that future mechanistic studies of catch-up growth be performed in singletons and be powered to assess effects in each sex.

Placental transport of vitamin D and other nutrients (e.g. amino acids, fats and glucose) to the fetus is sensitive to maternal and fetal nutritional cues. We studied the effect of maternal calorific restriction on fetal vitamin D status and the placental expression of genes for nutrient transport [aromatic T-type amino acid transporter-1 (TAT-1); triglyceride hydrolase/lipoprotein uptake facilitator lipoprotein lipase (LPL)] and vitamin D homeostasis [CYP27B1; vitamin D receptor (VDR)], and their association with markers of fetal cardiovascular function and skeletal muscle growth. Pregnant sheep received 100% total metabolizable energy (ME) requirements (control), 40% total ME requirements peri-implantation [PI40, 1–31 days of gestation (dGA)] or 50% total ME requirements in late gestation (L, 104–127 dGA). Fetal, but not maternal, plasma 25-hydroxy-vitamin D (25OHD) concentration was lower in PI40 and L maternal undernutrition groups (P<0.01) compared with the control group at 0.86 gestation. PI40 group placental CYP27B1 messenger RNA (mRNA) levels were increased (P<0.05) compared with the control group. Across all groups, higher fetal plasma 25OHD concentration was associated with higher skeletal muscle myofibre and capillary density (P<0.05). In the placenta, higher VDR mRNA levels were associated with higher TAT-1 (P<0.05) and LPL (P<0.01) mRNA levels. In the PI40 maternal undernutrition group only, reduced fetal plasma 25OHD concentration may be mediated in part by altered placental CYP27B1. The association between placental mRNA levels of VDR and nutrient transport genes suggests a way in which the placenta may integrate nutritional cues in the face of maternal dietary challenges and alter fetal physiology.