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.

Maternal nutrition is an environmental determinant for offspring growth and development, especially in critical periods. Nutritional imbalances during these phases can promote dysregulations in food intake and feeding preference in offspring, affecting body composition. The aim of this review is to summarize and discuss the effects of maternal high-fat diet (HFD) on offspring feeding behavior and body composition. A search was performed in the PUBMED, SCOPUS, Web of Science, and LILACS databases. Inclusion criteria were studies in rodents whose mothers were submitted to HFD that assessed outcomes of food or caloric intake on offspring and food preference associated or not with body weight or body composition analysis. At the end of the search, 17 articles with the proposed characteristics were included. In these studies, 15 articles manipulated diet during pregnancy and lactation, 1 during pregnancy only, and 1 during lactation only. Maternal exposure to a HFD leads to increased food intake, increased preference for HFDs, and earlier food independence in offspring. The offspring from HFD mothers present low birthweight but become heavier into adulthood. In addition, these animals also exhibited greater fat deposition on white adipose tissue pads. In conclusion, maternal exposure to HFD may compromise parameters in feeding behavior and body composition of offspring, impairing the health from conception until adulthood.

Epidemiological studies have demonstrated an association between low birthweight and a range of diseases in adult life including cardiometabolic and psychiatric diseases. One of the key mechanisms proposed to underlie early life ‘programming’ of disease is overexposure of the developing foetus to glucocorticoids. This review will explore the data from human studies that glucocorticoids are not only mediators of programming, but also targets of programming. Cohort studies of men and women of known birthweight have demonstrated that low birthweight is associated with high fasting cortisol levels. In healthy individuals and in people with type 2 diabetes who are at high cardiovascular risk, there is a similar association between high fasting cortisol and the metabolic syndrome. The high cortisol levels appear to be due to activation of the hypothalamic–pituitary–adrenal (HPA) axis though detailed studies to further explore central negative feedback sensitivity are required. The evidence in humans that glucocorticoids mediate programming is more scanty, though changes in maternal body composition, stress and anxiety levels and activity of the placental barrier enzyme 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) may all influence maternal HPA axis activity. Emerging studies are supportive that high maternal cortisol levels in humans and/or deficiencies placental 11β-HSD2 humans are associated with lower birthweight and adverse metabolic and neurocognitive outcomes in the offspring.

Intrauterine growth restriction (IUGR) is associated with a reduction in the numbers of nephrons in neonates, which increases the risk of hypertension. Our previous study showed that ouabain protects the development of the embryonic kidney during IUGR. To explore this molecular mechanism, IUGR rats were induced by protein and calorie restriction throughout pregnancy, and ouabain was delivered using a mini osmotic pump. RNA sequencing technology was used to identify the differentially expressed genes (DEGs) of the embryonic kidneys. DEGs were submitted to the Database for Annotation and Visualization and Integrated Discovery, and gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted. Maternal malnutrition significantly reduced fetal weight, but ouabain treatment had no significant effect on body weight. A total of 322 (177 upregulated and 145 downregulated) DEGs were detected between control and the IUGR group. Meanwhile, 318 DEGs were found to be differentially expressed (180 increased and 138 decreased) between the IUGR group and the ouabain-treated group. KEGG pathway analysis indicated that maternal undernutrition mainly disrupts the complement and coagulation cascades and the calcium signaling pathway, which could be protected by ouabain treatment. Taken together, these two biological pathways may play an important role in nephrogenesis, indicating potential novel therapeutic targets against the unfavorable effects of IUGR.

The study of very early pregnancy loss is impractical in the general population, but possible amongst infertility patients receiving carefully monitored treatments. We examined the association between fetal loss and the risk of birth defects in the surviving co-twin in a retrospective cohort study of infertility patients within an infertility clinic in South Australia from January 1986 to December 2002, linked to population registries for births, terminations and birth defects. The study population consisted of a total of 5683 births. Births from singleton pregnancies without loss were compared with survivors from (1) pregnancies with an empty fetal sac at 6–8 weeks after embryo transfer, (2) fetal loss subsequent to 8-week ultrasound and (3) multiple pregnancy continuing to birth. Odds ratios (OR) for birth defects were calculated with adjustment for confounders. Amongst infertility patients, the prevalence of birth defects was 7.9% for all twin pregnancies without fetal loss compared with 14.6% in pregnancies in which there had been an empty sac at ultrasound, and 11.6% for pregnancies with fetal loss after 6–8 weeks. Compared with singleton pregnancies without loss, the presence of an empty sac was associated with an increased risk of any defect (OR=1.90, 95% confidence intervals (CI)=1.09–3.30) and with multiple defects (OR=2.87, 95% CI=1.31–6.28). Twin pregnancies continuing to birth without loss were not associated with an overall increased prevalence of defects. We conclude that the observed loss of a co-twin by 6–8 weeks of pregnancy is related to the risk of major birth defects in the survivor.

The purpose of this study was to analyze the expression of the placenta-specific microRNA miR-517a in maternal serum and in placental tissue from low birth weight newborns and try to detect the effects of miR-517a expression on invasion potential of trophoblasts. Placental tissue and maternal serum were collected from both low birth weight newborns (n = 10) and normal birth weight newborns (n = 20). Expression of miR-517a was assessed in placenta and serum samples by real-time qRT-PCR. In addition, human trophoblast HTR8/SVneo cells were transfected with a miR-517a 2′-O-methyl oligonucleotide or a negative control RNA, and invasion was measured using transwell migration assays. Expression of miR-517a was significantly increased in placentas from low birth weight newborns (61.79 ± 23.06) in comparison with those of normal birth weight newborns (5.01 ± 1.97; P < 0.05). The expression of miR-517a was also increased in maternal serum isolated from the low birth weight newborn (25.78 ± 8.69) compared with the normal birth weight newborn (3.21 ± 1.07; P < 0.05). Overexpression of miR-517a significantly inhibited invasion of HTR8/SVneo cells (P < 0.05). These data indicate that miR-517a overexpression could potentially lead to low birth weight, likely through the inhibition of trophoblast invasion.

Prenatal development is highly plastic and readily influenced by the environment. Adverse conditions have been shown to alter organ development and predispose offspring to chronic diseases, including diabetes and hypertension. Notably, it appears that the changes in glucocorticoid hormones or glucocorticoid receptor (GR) levels in peripheral tissues could play a role in the development of chronic diseases. We have previously demonstrated that in vitro fertilization (IVF) and preimplantation embryo culture is associated with growth alterations and glucose intolerance in mice. However, it is unknown if GR signaling is affected in adult IVF offspring. Here we show that GR expression is increased in inbred (C57Bl6/J) and outbred (CF-1× B6D2F1/J) blastocysts following in vitro culture and elevated levels are also present in the adipose tissue of adult male mice. Importantly, genes involved in lipolysis and triglyceride synthesis and responsive to GR were also increased in adipose tissue, indicating that increased GR activates downstream gene pathways. The promoter region of GR, previously reported to be epigenetically modified by perinatal manipulation, showed no changes in DNA methylation status. Our findings demonstrate that IVF results in a long-term change in GR gene expression in a sex- and tissue-specific manner. These changes in adipose tissues may well contribute to the metabolic phenotype in mice conceived by IVF.

Growth restriction caused by postnatal undernutrition increases risk for cardiovascular disease in adulthood with the potential to induce arrhythmogenesis. Thus, the purpose was to determine if undernutrition during development produced arrhythmias at rest and when stressed with dobutamine in adulthood. Mouse dams were fed (CON: 20% protein), or low-protein (LP: 8%) diet before mating. A cross-fostering model was used where pups nursed by dams fed LP diet in early [EUN; postnatal day (PN) 1–10], late (LUN; PN11–21) and whole (PUN; 1–21) phases of postnatal life. Weaned pups were switched to CON diets for the remainder of the study (PN80). At PN80, body composition (magnetic resonance imaging), and quantitative electrocardiogram (ECG) measurements were obtained under 1% isoflurane anesthesia. After baseline ECG, an IP injection (1.5 µg/g body weight) of dobutamine was administered and ECG repeated. Undernutrition significantly (P<0.05) reduced body weight in LUN (22.68±0.88 g) and PUN (19.96±0.32 g) but not in CON (25.05±0.96 g) and EUN (25.28±0.9207 g). Fat mass decreased in all groups compared with controls (CON: 8.00±1.2 g, EUN: 6.32±0.65 g, LUN: 5.11±1.1 g, PUN: 3.90±0.25 g). Lean mass was only significantly reduced in PUN (CON: 17.99±0.26 g, EUN: 17.78±0.39 g, LUN: 17.34±0.33 g, PUN: 15.85±0.28 g). Absolute heart weights were significantly less from CON, with PUN having the smallest. ECG showed LUN had occurrences of atrial fibrillation; EUN had increases of 1st degree atrioventricular block upon stimulation, and PUN had increased risk for ventricular depolarization arrhythmias. CON did not display arrhythmias. Undernutrition in early life resulted in ventricular arrhythmias under stressed conditions, but undernutrition occurring in later postnatal life there is an increased incidence of atrial arrhythmias.

Although low birth weight (LBW) increases the risk for type 2 diabetes (T2DM), the relationship between high birth weight (HBW) and T2DM is less definitive and largely confined to North American Indigenous populations. We re-examined the relationship between LBW (<2500 g) and HBW (>4000 g) and both T2DM and gestational diabetes (GDM) among First Nations and non-First Nations women in Saskatchewan. We analyzed new data for female subjects from a 2001 case-control study that led to our hefty fetal phenotype hypothesis. Using survival analysis techniques and a validated algorithm for identifying diabetes in health care administrative data, we followed a 1950–1984 birth cohort of 2003 women until March 31, 2013. Cox regression analysis determined the time to occurrence of first episode of GDM and diagnosis of T2DM by birth weight and ethnicity. First Nations women with HBW demonstrated a greater risk for developing both T2DM [hazard ratios (HR) 1.568; 95% confidence interval (CI) 1.188, 2.069] and GDM (HR 1.468; 95% CI 1.016, 2.121) than those with normal birth weight (NBW). Non-First Nations women with LBW had a greater risk of developing GDM than those with NBW (HR 1.585; 95% CI 1.001, 2.512). HBW is a risk factor for GDM and T2DM among First Nations women. This is likely due to exposure of these women to their own mothers’ diabetic pregnancies or gestational impaired glucose tolerance. This inter-generational amplification of T2DM risk mediated through prenatal exposures appears to play a substantial role in the epidemic of T2DM among First Nations peoples.

The study aimed to evaluate the consequences of the consumption of a high-fructose diet (HFR; fructose was responsible for 45% of the energy from carbohydrates) by the mother, the father, or both on C57BL/6 adult male offspring. Non-consanguineous parents received the diet (HFR or control, C) from 8 weeks before mating until weaning (n=10 fathers and n=10 mothers on each diet). After weaning, only the C diet was offered to offspring. The groups were formed by one male randomly taken from each litter. The offspring groups were identified according to the mother’s diet (the first letter), then the father’s diet (the second letter), that is, C/C, C/HFR, HFR/C, HFR/HFR (n=10 per group). The parents exhibited the following characteristics: compared with those of the C group, the HFR parents had higher blood pressure (BP), enlarged liver, increased hepatic triacylglycerol content, hypercholesterolemia, hypertriglyceridemia, high plasma leptin and low adiponectin. The offspring exhibited the following characteristics: compared with the C/C group, the HFR/HFR group had high BP. The C/HFR, HFR/C and HFR/HFR showed elevated uric acid and leptin levels and diminished adiponectin. The HFR/HFR group showed liver inflammation (increased NFκB, SOCS3, JNK, TNF-α, IL1-β and IL6 levels). Likewise, SREBP-1c and FAS were upregulated. In conclusion, the consumption of a HFR by the mother and/or father is associated with adverse effects on liver metabolism in adult male offspring. When both mother and father are fed a HFR, the adverse effects on the offspring are more severe.

Receiving an education is essential for children living in poverty to fulfil their potential. Success in the early years of schooling is important as children who repeat grade one are particularly at risk for future dropout. We examined early life factors associated with grade repetition through logistic regression and explored reasons for repeating a grade through parent report. In 2012–2014 we re-enrolled children aged 7–11 years in rural KwaZulu-Natal who had been part of an early life intervention. Of the 894 children included, 43.1% had repeated a grade, of which 62.9% were boys. Higher maternal education (aOR 0.44; 95% CI 0.2–0.9) and being further along in the birth order (aOR 0.46; 95% CI 0.3–0.9) reduced the odds of grade repetition. In addition, maternal HIV status had the strongest effect on grade repetition for girls (aOR 2.17; 95% CI 1.3–3.8), whereas for boys, it was a fridge in the household (aOR 0.59; 95% CI 0.4–1.0). Issues with school readiness was the most common reason for repeating a grade according to parental report (126/385, 32.7%), while school disruptions was an important reason among HIV-exposed boys. Further research is needed to elucidate the pathways through which HIV affects girls’ educational outcomes and potentially impacts on disrupted schooling for boys. Our results also highlight the importance of preparation for schooling in the early years of life; future research could focus on gaining a better understanding of mechanisms by which to improve early school success, including increased quality of reception year and investigating the protective effect of older siblings.

Alcohol consumption around the time of conception is highly prevalent in Western countries. Exposure to ethanol levels during gestation has been associated with altered development of the mesolimbic reward pathway in rats and increased propensity to addiction, however the effect of exposure only around the time of conception is unknown. The current study investigated the effects of periconceptional alcohol exposure (PC:EtOH) on alcohol and palatable food preferences and gene expression in the ventral tegmental area (VTA) and the nucleus accumbens of the adult offspring. Rats were exposed to a liquid diet containing ethanol (EtOH) (12.5% vol/vol) or a control diet from 4 days before mating until 4 days after mating. PC:EtOH had no effect on alcohol preference in either sex. At 15 months of age, however, male PC:EtOH offspring consumed more high-fat food when compared with male control offspring, but this preference was not observed in females. Expression of the dopamine receptor type 1 (Drd1a) was lower in the VTA of male PC:EtOH offspring compared with their control counterparts. There was no effect of PC:EtOH on mRNA expression of the µ-opioid receptor, tyrosine hydroxylase (Th), dopamine receptor type 2 (Drd2) or dopamine active transporter (Slc6a3). These data support the hypothesis that periconceptional alcohol exposure can alter expression of key components of the mesolimbic reward pathway and heighten the preference of offspring for palatable foods and may therefore increase their propensity towards diet-induced obesity. These results highlight the importance of alcohol avoidance when planning a pregnancy.

While substantial evidence has identified low birth weight (LBW; <2500 g) as a risk factor for early life morbidity, mortality and poor childhood development, relatively little is known on the links between birth weight and economic outcomes in adulthood. The objective of this study was to systematically review the economics (EconLit) and biomedical literature (Medline) and estimate the pooled association between birth weight and adult earnings. A total of 15 studies from mostly high-income countries were included. On average, each standard deviation increase in birth weight was associated with a 2.75% increase in annual earnings [(95% CI: 1.44 to 4.07); 9 estimates]. A negative, but not statistically significant, association was found between being born LBW and earnings, compared to individuals not born LBW [mean difference: −3.41% (95% CI: −7.55 to 0.73); 7 estimates]. No studies from low-income countries were identified and all studies were observational. Overall, birth weight was consistently associated with adult earnings, and therefore, interventions that improve birth weight may provide beneficial effects on adult economic outcomes.

When the follicle reserve, which is developed solely during the fetal period, is depleted, women enter menopause. Intrauterine and childhood adverse conditions might affect the ovarian capacity by influencing follicle production in the first trimester, limiting the initial follicle pool or mediate an accelerated follicular loss thereafter. To investigate if adverse early life influences result in younger age at menopause, the following online databases were systematically searched: PubMed, EMBASE, CINHAL (EBSCO) and Cochrane library (Wiley) up to 1 January 2017. Eligibility, data extraction and quality assessment was independently performed by two researchers. A total of 5278 studies were identified, 11 studies were deemed eligible and included. Nine were cohort studies, 1 case–control study and 1 twin study. Due to the diversity of reported data and risk estimates we were unable to pool data or perform meta-analysis on pooled data. Prenatal and childhood exposure to famine was significantly associated to an earlier age at menopause in three studies. Mean differences in age at menopause varied from 4 months up to 1.7 years between famine exposed and unexposed women. Three studies described a significant association between a low weight at ages 1 or 2 and a younger age at menopause. A younger age at menopause was associated with a higher weight at birth in only one study and with a high ponderal index, a measure for fatness at birth in another study. None of the nine studies reporting on low birth weight and age at natural menopause find a significant association.

While birthweight of offspring is associated with pre-pregnancy body mass index (BMI) and later risk of obesity, its mediating effect between the association of maternal pre-pregnancy BMI and offspring’s childhood anthropometrics has rarely been investigated. This study aimed to examine whether offspring birthweight is a mediator in the association between pre-pregnancy BMI and offspring’s childhood anthropometrics. The study included 1,618 mother–child pairs from the Australian Longitudinal Study on Women’s Health and Mothers and their Children’s Health Study. Children’s anthropometrics [mean age 8.6 (s.d. =3.0) years] were calculated from the mothers’ self-reported child weight and height measures. G-computation was used to estimate the natural direct and indirect (via birthweight) effects of pre-pregnancy BMI. In the fully adjusted model for maternal sociodemographic and lifestyle factors, the natural direct effects of pre-pregnancy obesity on child BMI-for-age, height-for-age, weight-for-age and weight-for-height outcomes were, β (95% confidence interval, CI), 0.75 (0.55, 0.95), 0.13 (−0.07, 0.32), 0.62 (0.44, 0.80) and 0.57 (0.24, 0.90), respectively. The corresponding natural indirect effects were 0.04 (−0.04, 0.12), −0.01 (−0.09, 0.07), −0.01 (−0.08, 0.07) and 0.09 (−0.05, 0.23). Similar results were observed for pre-pregnancy overweight and pre-pregnancy BMI as a continuous scale. Most of the effect of pre-pregnancy obesity on childhood weight-related anthropometric outcomes appears to be via a direct effect, not mediated through offspring’s birthweight.

The term ‘developmental origins of health and disease’ (DOHaD) originally referred to delayed effects of altered maternal factors (e.g. smoking or poor nutrition) on the developing offspring, but it now also encompasses early life exposure to environmental chemicals, which can cause an unhealthy prenatal environment that endangers the fetus and increases its susceptibility to disease later in life. Prenatal exposure to the pharmaceutical diethylstilbestrol (DES) is a well-known DOHaD example as it was associated in the 1970s with vaginal cancer in daughters who were exposed to this potent synthetic estrogen before birth. Subsequently, numerous long-term effects have been described in breast and reproductive tissues of DES-exposed humans and experimental animals. Data reviewed suggest that the prenatal DES-exposed population should continue to be monitored for potential-increased disease risks as they age. Knowledge of sensitive developmental periods, and the mechanisms of DES-induced toxicities, provides useful information in predicting potential adverse effects of other environmental estrogens.

It is well established that high-dose alcohol consumption during pregnancy increases the risk for a plethora of adverse offspring outcomes. These include neurodevelopmental, cognitive and social deficits, as well as psychiatric illnesses, such as depression and anxiety. However, much less evidence is available on the effects of low- and early-dose alcohol exposure on mental health outcomes, regardless of the accumulating evidence that mental health outcomes should be considered in the context of the Developmental Origins of Health and Disease hypothesis. This review will discuss the evidence that indicates low-dose and early prenatal alcohol exposure can increase the risk of mental illness in offspring and discuss the mechanistic pathways that may be involved.

Chronic hypoxia during gestation induces greater occurrence of perinatal complications such as intrauterine growth restriction, fetal hypoxia, newborn asphyxia, and respiratory distress, among others. This condition may also cause a failure in the transition of the fetal to neonatal circulation, inducing pulmonary arterial hypertension of the neonate (PAHN), a syndrome that involves pulmonary vascular dysfunction, increased vasoconstrictor tone and pathological remodeling. As this syndrome has a relatively low prevalence in lowlands (~7 per 1000 live births) and very little is known about its prevalence and clinical evolution in highlands (above 2500 meters), our understanding is very limited. Therefore, studies on appropriate animal models have been crucial to comprehend the mechanisms underlying this pathology. Considering the strengths and weaknesses of any animal model of human disease is fundamental to achieve an effective and meaningful translation to clinical practice. The sheep model has been used to study the normal and abnormal cardiovascular development of the fetus and the neonate for almost a century. The aim of this review is to highlight the advances in our knowledge on the programming of cardiopulmonary function with the use of high-altitude newborn sheep as a translational model of PAHN.

Maternal physical activity induces brain functional changes and neuroplasticity, leading to an improvement of cognitive functions, such as learning and memory in the offspring. This study investigated the effects of voluntary maternal physical activity on the gene expression of the neurotrophic factors (NTFs): BDNF, NTF4, NTRK2, IGF-1 and IGF-1r in the different areas of mother’s brain, placenta and foetus brain of rats. Female Wistar rats (n = 15) were individually housed in voluntary physical activity cages, containing a running wheel, for 4 weeks (period of adaptation) before gestation. Rats were classified as inactive (I, n = 6); active (A, n = 4) and very active (VA, n = 5) according to daily distance spontaneously travelled. During gestation, the dams continued to have access to the running wheel. At the 20th day of gestation, gene expression of NTFs was analysed in different areas of mother’s brain (cerebellum, hypothalamus, hippocampus and cortex), placenta and the offspring’s brain. NTFs gene expression was evaluated using quantitative PCR. Very active mothers showed upregulation of IGF-1 mRNA in the cerebellum (36.8%) and NTF4 mRNA expression in the placenta (24.3%). In the cortex, there was a tendency of up-regulation of NTRK2 mRNA (p = 0.06) in the A and VA groups when compared to I group. There were no noticeable changes in the gene expression of NTFs in the offspring’s brain. Our findings suggest the existence of a developmental plasticity induced by maternal physical activity in specific areas of the brain and placenta representing the first investment for offspring during development.

Use of the herbicide atrazine (ATR) is banned in the European Union; yet, it is still widely used in the USA and Australia. ATR is known to alter testosterone and oestrogen production and thus reproductive characteristics in numerous species. In this proof of concept study, we examined the effect of ATR exposure, at a supra-environmental dose (5 mg/kg bw/day), beginning on E9.5 in utero, prior to sexual differentiation of the reproductive tissues, until 26 weeks of age, on the development of the mouse penis. Notably, this is the first study to specifically investigate whether ATR can affect penis characteristics. We show that ATR exposure, beginning in utero, causes a shortening (demasculinisation) of penis structures and increases the incidence of hypospadias in mice. These data indicate the need for further studies of ATR on human reproductive development and fertility, especially considering its continued and widespread use.