Maternal treatment with dexamethasone (Dex) in threatening preterm delivery alters activities at the hypothalamic–pituitary–adrenal axis in the offspring. This alteration may interfere with reproductive function. The impact of gestational Dex exposure on male reproductive function of the offspring was investigated. A total of 25 pregnant rats randomly assigned to five groups (n=5) were treated with normal saline (control), Dex (100 μg/kg/day sc) during gestation days (GD) 1–7, 8–14, 15–21 and 1–21, respectively. Birth weight, anogenital distance (AGD), pubertal age, sperm parameters, hormonal profile and histopathology of testis and epididymis were determined in the F1 and F2 offspring. Results showed a significant increase (P<0.05) in pubertal age, serum corticosterone and gonadotropin-releasing hormone (GnRH) levels in the male offspring of DexGD 15–21 and 1–21 groups and a significant decrease (P<0.05) in serum testosterone, luteinizing hormone, birth weight and AGD at birth in the male F1 offspring. In the F2 offspring, there was a significant reduction (P<0.05) in serum corticosterone, testosterone, follicle-stimulating hormone and GnRH when compared with the control. Dex treatment at GD 15–21 and 1–21 significantly reduced (P<0.05) sperm motility and normal morphology in the F1 and F2 offspring. Maternal Dex treatment in rats during late gestation may disrupt sexual development markers in the F1 and F2 male offspring.

Cardiometabolic diseases exhibit changes in lipid biology, which is important as lipids have critical roles in membrane architecture, signalling, hormone synthesis, homoeostasis and metabolism. However, Developmental Origins of Health and Disease studies of cardiometabolic disease rarely include analysis of lipids. This short review highlights some examples of lipid pathology and then explores the technology available for analysing lipids, focussing on the need to develop imaging modalities for intracellular lipids. Analytical methods for studying interactions between the complex endocrine and intracellular signalling pathways that regulate lipid metabolism have been critical in expanding our understanding of how cardiometabolic diseases develop in association with obesity and dietary factors. Biochemical methods can be used to generate detailed lipid profiles to establish links between lifestyle factors and metabolic signalling pathways and determine how changes in specific lipid subtypes in plasma and homogenized tissue are associated with disease progression. New imaging modalities enable the specific visualization of intracellular lipid traffic and distribution in situ. These techniques provide a dynamic picture of the interactions between lipid storage, mobilization and signalling, which operate during normal cell function and are altered in many important diseases. The development of methods for imaging intracellular lipids can provide a dynamic real-time picture of how lipids are involved in complex signalling and other cell biology pathways; and how they ultimately regulate metabolic function/homoeostasis during early development. Some imaging modalities have the potential to be adapted for in vivo applications, and may enable the direct visualization of progression of pathogenesis of cardiometabolic disease after poor growth in early life.

The present study investigated the impact of a western diet during gestation and lactation on the anthropometry, serum biochemical, blood pressure and cardiovascular autonomic control on the offspring. Male Wistar rats were divided into two groups according to their mother’s diet received: control group (C: 18% calories of lipids) and westernized group (W: 32% calories of lipids). After weaning both groups received standard diet. On the 60th day of life, blood samples were collected for the analysis of fasting glucose and lipidogram. Cardiovascular parameters were measured on the same period. Autonomic nervous system modulation was evaluated by spectrum analysis of heart rate (HR) and systolic arterial pressure (SAP). The W increased glycemia (123±2 v. 155±2 mg/dl), low-density lipoprotein (15±1 v. 31±2 mg/dl), triglycerides (49±1 v. 85±2 mg/dl), total cholesterol (75±2 v. 86±2 mg/dl), and decreased high-density lipoprotein (50±4 v. 38±3 mg/dl), as well as increased body mass (209±4 v. 229±6 g) than C. Furthermore, the W showed higher SAP (130±4 v. 157±2 mmHg), HR (357±10 v. 428±14 bpm), sympathetic modulation to vessels (2.3±0.56 v. 6±0.84 mmHg2) and LF/HF ratio (0.15±0.01 v. 0.7±0.2) than C. These findings suggest that a western diet during pregnancy and lactation leads to overweight associated with autonomic misbalance and hypertension in adulthood.

Previous research has shown that childhood body size is associated with blood pressure in adulthood, and that early and rapid growth rates are correlated with adverse cardiovascular outcomes. Our objectives are to estimate associations between childhood body size growth parameters and adult blood pressure, and to examine the effect of early attainment of critical growth milestones on adult blood pressure, relative to normal or late attainment. Lifetime height and body mass index (BMI) measurements in childhood, and systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements in adulthood are taken from participants in the Fels Longitudinal Study. Childhood growth curves are estimated separately for stature and BMI using the Preece–Baines and third-degree polynomial models, respectively. Associations between the resulting parameter estimates and adult blood pressure are then examined using linear mixed models. Our findings show that the ages of achievement of the stature-based growth onset and peak velocity, as well as the age of achievement of the BMI-based adiposity rebound, are negatively associated with adult blood pressure, implying that early height or BMI growth can lead to increased blood pressure in adulthood. There were subtle differences in these relationships based on age and gender, and also between SBP and DBP. These results expand on the existing literature, showing that not only childhood body size, but also the timing of childhood growth can have a deleterious effect on adult cardiovascular health.

Rapid weight gain in infancy and low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA) at birth are associated with increased adiposity later in life. The association between placental LCPUFA delivery and weight gain in infancy is poorly understood. We sought to determine the relationships between maternal phenotype, placental fatty acid transporter expression and offspring growth patterns over the first 6 months. Placental tissue and cord blood were collected at term delivery from women with uncomplicated pregnancies. Offspring body composition measurements were recorded 1 day and 6 months after birth. Body mass index (BMI) z-scores were determined using World Health Organization 2006 reference data. Body phenotype patterns were compared among offspring who had an increase in BMI z-score and those who had a decrease. High skinfold thickness at birth and positive change in BMI z-scores during infancy were associated with low neonatal n-3 LCPUFA plasma levels (r=−0.46, P=0.046) and high saturated fatty acids levels (r=0.49, P=0.034). Growth of skinfolds over 6 months of age was associated with placental fatty acid transporter gene expression. Change in BMI z-score in the first 6 months of life correlated with arm muscle area growth, a measure of lean mass (r=0.62, P=0.003), but not with growth in skinfold thickness. Early infancy weight gain was associated with poor plasma LCPUFA status at birth, and fat deposition in infancy was related to changes in placental lipid handling. Thus, neonatal fatty acid profiles may influence the trajectory of infant growth and fat and lean mass deposition.

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.

Elevated birth weight is linked to glucose intolerance and obesity health-related complications later in life. No studies have examined if infant birth weight is associated with gene expression markers of obesity and inflammation in a tissue that comes directly from the infant following birth. We evaluated the association between birth weight and gene expression on fetal programming of obesity. Foreskin samples were collected following circumcision, and gene expression analyzed comparing the 15% greatest birth weight infants (n=7) v. the remainder of the cohort (n=40). Multivariate linear regression models were fit to relate expression levels on differentially expressed genes to birth weight group with adjustment for variables selected from a list of maternal and infant characteristics. Glucose transporter type 4 (GLUT4), insulin receptor substrate 2 (IRS2), leptin receptor (LEPR), lipoprotein lipase (LPL), low-density lipoprotein receptor-related protein 1 (LRP1), matrix metalloproteinase 2 (MMP2), plasminogen activator inhibitor-1 (PAI-1) and transcription factor 7-like 2 (TCF7L2) were significantly upregulated and histone deacetylase 1 (HDAC1) and thioredoxin (TXN) downregulated in the larger birth weight neonates v. controls. Multivariate modeling revealed that the estimated adjusted birth weight group difference exceeded one standard deviation of the expression level for eight of the 10 genes. Between 25 and 50% of variation in expression level was explained by multivariate modeling for eight of the 10 genes. Gene expression related to glycemic control, appetite/energy balance, obesity and inflammation were altered in tissue from babies with elevated birth weight, and these genes may provide important information regarding fetal programming in macrosomic babies.

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.

Despite the interest in the relationship of fetal exposures to adult cardiovascular disease, few studies have examined indicators of adult fatty liver disease as an outcome. Previous results are inconsistent, and indicate possible variation by sex. Adult liver enzymes [γ-glutamyl transferase (GGT), alanine transaminase (ALT) and aspartase transaminase (AST)] were measured in two cohort studies: the Bogalusa Heart Study (BHS; n=1803) and the Cardiovascular Risk in Young Finns (YF; n=3571) study, which also had ultrasound measures of liver fat (n=2546). Predictors of dichotomized (clinical cut-offs) and continuous (within the reference range) liver enzymes included low birthweight (<2500 g), macrosomia (>4000 g), small-for-gestational-age (birthweight <10th percentile for gestational age for population), large-for-gestational-age (>90th percentile), and preterm birth. Multiple logistic and linear regression were conducted, adjusted for medical, behavioral and socioeconomic indicators. Interactions with sex were also examined. In BHS, birth measures were not strongly associated with clinically high levels of liver enzymes, and within the reference range measures of reduced growth were associated with increased AST in women. In the YF study, at least one marker of reduced growth was associated with higher GGT, higher ALT and higher AST (in women). Probable fatty liver on ultrasound was associated with low birthweight (2.41, 1.42–4.09) and preterm birth (2.84, 1.70–4.76). These results suggest a link between birth parameters and adult fatty liver, but encourage consideration of population variation in these relationships.

Ilex paraguariensis (yerba mate) has a beneficial effect in the management of obesity. Here, we studied the effects of yerba mate on hypothalamic changes in leptin and insulin signalling, oxidative stress and liver morphology and metabolism in postnatal early overfeeding (EO) Wistar rats. To induce EO, the litter size was reduced to three pups per dam, and litters with 10 pups per dam were used as a control (10 litters each). On postnatal day (PN) 150, EO offspring were subdivided into EO and EO+mate groups (10 animals each), which were treated with water or mate tea [1 g/kg body weight (BW)/day, by gavage], respectively, for 30 days. The C offspring received water. On PN180, yerba mate treatment prevented BW gain and reduced total body fat, visceral fat and food intake in comparison with the EO group. Leptin and insulin signalling in the hypothalamus measured by Western blotting was reduced only in the EO group. Yerba mate treatment had a greater impact on insulin signalling normalization. In the liver, yerba mate treatment normalized antioxidant enzyme activities and, consequently, decreased lipid peroxidation, determined by malondialdehyde content. In addition, the steatosis level and the liver triglyceride content were also restored. Thus, for the first time, yerba mate was demonstrated to increase antioxidant defences and improve liver metabolism in adult rats that were overfed during lactation, possibly through improvements in the hypothalamic action of insulin. These findings may be important for the treatment of obesity-related disorders.

Research shows that stress in pregnancy has powerful and enduring effects on many facets of child development, including increases in behavior problems and neurodevelopmental disorders. Theory of mind is an important aspect of child development that is predictive of successful social functioning and is impaired in children with autism. A number of factors related to individual differences in theory of mind have been identified, but whether theory of mind development is shaped by prenatal events has not yet been examined. In this study we utilized a sudden onset flood that occurred in Queensland, Australia in 2011 to examine whether disaster-related prenatal maternal stress predicts child theory of mind and whether sex of the child or timing of the stressor in pregnancy moderates these effects. Higher levels of flood-related maternal subjective stress, but not objective hardship, predicted worse theory of mind at 30 months (n=130). Further, maternal cognitive appraisal of the flood moderated the effects of stress in pregnancy on girls’ theory of mind performance but not boys’. These results illuminate how stress in pregnancy can shape child development and the findings are discussed in relation to biological mechanisms in pregnancy and stress theory.

Intrauterine growth restriction (IUGR) and maternal stress during pregnancy are two compromises that negatively impact neurodevelopment and increase the risk of developing later life neuropsychiatric disorders such as schizophrenia, depression and behavioural disorders. Neurosteroids, particularly allopregnanolone, are important in protecting the developing brain and promoting many essential neurodevelopmental processes. Individually, IUGR and prenatal stress (PS) reduce myelination and neurogenesis within affected fetal brains, however less information is available on the combined effects of these two disorders on the term fetal brain. This study aimed to investigate how IUGR and PS impairs the neurosteroid pathway when combined using a guinea pig model, and how these then disrupt the neurodevelopment of the fetus. Uterine artery blood flow restriction was performed at GA30-35 to induce growth restriction, whilst PS was induced by exposure of the dam to a strobe light during gestation commencing GA40 and repeated every 5 days. Exposure in this model caused reductions in hippocampal CA1 MBP immunostaining of male fetuses in both IUGR alone and IUGR+PS paradigms but only by IUGR in the subcortical white mater, compared with control males. Plasma allopregnanolone was reduced by both stressors irrespective of sex, whereas GFAP or MAP2 expression were not affected by either stressor. Female neurodevelopment, as assessed by these markers, was unimpeded by these compromises. The addition of prenatal stress did not further compound these deficits.

It has been demonstrated that intrauterine growth restriction (IUGR) can program increase cardiometabolic risk. There are also evidences of the correlation between IUGR with low-grade inflammation and, thus can contribute to development of several cardiometabolic comorbidities. Therefore, we investigated the influence of IUGR on circulating mitochondrial DNA (mtDNA)/Toll-like receptor 9 (TLR9) and TNF-α expression in adult offspring. Considering that the aerobic training has anti-inflammatory actions, we also investigated whether aerobic training would improve these inflammatory factors. Pregnant Wistar rats received ad libitum or 50% of ad libitum diet throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to control, trained control, restricted and trained restricted. Aerobic training protocol was performed on a treadmill and after that, we evaluated circulating mtDNA, cardiac protein expression of TLR9, plasma and cardiac TNF-α levels, and left ventricle (LV) mass. We found that IUGR promoted an increase in the circulating mtDNA, TLR9 expression and plasma TNF-α levels. Further, our results revealed that aerobic training can restore mtDNA/TLR9 content and plasma levels of TNF-α among restricted rats. The cardiac TNF-α content and LV mass were not influenced either by IUGR or aerobic training. In conclusion, IUGR can program mtDNA/TLR9 content, which may lead to high levels of TNF-α. However, aerobic training was able to normalize these alterations. These findings evidenced that the association of IUGR and aerobic training seems to exert an important interaction effect regarding pro-inflammatory condition and, aerobic training may be used as a strategy to reduce deleterious adaptations in IUGR offspring.

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.

The 2nd--4th finger ratio (2D:4D) has been proposed as a potential indicator of greater androgen exposure during fetal development. Maternal periconceptional smoking may alter the homeostasis of fetal androgens, which could in turn result in differential development of 2D:4Ds in utero. The aim of the present study was to assess the effect of maternal periconceptional smoking (i.e. 1 year before through the first trimester of pregnancy) on the 2D:4D of children within The Maternal-Infant Research on Environmental Chemicals (MIREC) study. Maternal smoking history was obtained through questionnaires during the first trimester of pregnancy in 2001 women from 10 cities across Canada. The periconceptional smoking prevalence was 12%. A follow-up study was conducted to measure growth and development up to 5 years of age in a subsample of some 800 MIREC children (MIREC-CD Plus), and digital pictures of the ventral surface of both hands were obtained in mothers and children (2–5 years). The 2D:4D was calculated as the ratio of the 2nd and 4th fingers of each hand. Boys had lower mean 2D:4Ds compared with girls in both hands. Age and maternal 2D:4D were strong determinants of the children’s 2D:4D, however, the mean 2D:4D did not differ among children whose mothers had smoked during the periconceptional period compared with those who had not, irrespective of sex. In conclusion, we did not find an association between maternal periconceptional smoking and children’s 2D:4D, although the smoking prevalence was low.

As the resident macrophage of the central nervous system, microglia are thought to contribute to Alzheimer’s disease (AD) pathology through lack of neuroprotection. The role of immune dysfunction in AD may be due to disruption of regulatory signals for the activation of microglia that may occur early in development. We hypothesized that early toxicant exposure would systematically activate microglia, possibly reversing the pathological severity of AD. Offspring of a triple transgenic murine model for AD (3×TgAD) were exposed to a model neurotoxicant, lead acetate, from postnatal days (PND) 5–10. Our results indicated that female mice exposed to Pb had a greater and earlier incidence of amyloid burden within the hippocampus, coinciding with decreased markers of microglial activation at PND 50. Pb-exposed males had increased microglial activation at PND 50, as evidence by CD11b expression and microglial abundance, with no significant increase in amyloid burden at that time. There was greater amyloid burden at PND 90 and 180 in both male and female mice exposed to Pb compared with control. Together, these data suggest that activated microglia are neuroprotective against amyloid accumulation early in AD pathology, and that early exposure to Pb could increase susceptibility to later-life neurodegeneration. Likewise, females may be more susceptible to early-life microglial damage, and, subsequently, AD. Further investigation into the sex biased mechanisms by which microglial activation is altered by an early-life immune insult will provide critical insight into the temporal susceptibility of the developing neuroimmune system and its potential role in AD etiopathology.

This study was aimed to investigate associations between birth weight and multiple adiposity indicators in youth, and to examine potential mediating effects by biological maturation. This was a school-based study involving 981 Brazilian adolescents aged between 10 and 17 years. Birth weight was reported retrospectively by mothers. Maturation was estimated by age of peak height velocity. Adiposity indicators included body mass index (BMI), waist circumference and percent body fat estimated from triceps and subscapular skinfolds. Multilevel mediation analyses were performed using the Sobel test, adjusted for chronological age, gestational age, cardiorespiratory fitness and socio-economic status. Except for body fat in girls, biological maturation partly or fully mediated (P<0.05) positive relationships between birth weight with all other obesity indicators in both sexes with their respective values of indirect effects with 95% confidence intervals: BMI [boys: 0.44 (0.06–0.82); girls: 0.38 (0.13–0.64)], waist circumference [boys: 1.14 (0.22–2.05); girls: 0.87 (0.26–1.48)] and body fat [boys: 0.60 (0.13–1.07)]. To conclude, birth weight is associated with elevated obesity risk in adolescence and biological maturation seems to at least partly mediate this relationship.

Intrauterine growth restriction (IUGR) and fetal growth restriction (FGR) are pregnancy complications associated with morbidity in later life. Despite a growing body of evidence from current research on developmental origins of health and disease (DOHaD), little information is currently provided to parents on long-term metabolic, cardiovascular and neurologic consequences. As parents strongly rely on internet-based health-related information, we examined the quality of information on IUGR/FGR sequelae and DOHaD in webpages used by laypersons. Simulating non-clinicians experience, we entered the terms ‘IUGR consequences’ and ‘FGR consequences’ into Google and Yahoo search engines. The quality of the top search-hits was analyzed with regard to the certification through the Health On the Net Foundation (HON), currentness of cited references, while reliability of information and DOHaD-related consequences were assessed via the DISCERN Plus score (DPS). Overall the citation status was not up-to-date and only a few websites were HON-certified. The results of our analysis showed a dichotomy between the growing body of evidence regarding IUGR/FGR-related sequelae and lack of current guidelines, leaving parents without clear directions. Furthermore, detailed information on the concept of DOHaD is not provided. These findings emphasize the responsibility of the individual physician for providing advice on IUGR/FGR-related sequelae, monitoring and follow-up.