Recent advances in epigenetics have enhanced our knowledge of how environmental factors (UV radiation, drugs, infections, etc.) contribute to the development of autoimmune diseases (AID) in genetically predisposed individuals. Studies conducted in monozygotic twins discordant for AID and spontaneous autoimmune animal models have highlighted the importance of DNA methylation changes and histone modifications. Alterations in the epigenetic pattern seem to be cell specific, as CD4+ T cells and B cells are dysregulated in systemic lupus erythematosus, synovial fibroblasts in rheumatoid arthritis and cerebral cells in multiple sclerosis. With regard to lymphocytes, the control of tolerance is affected, leading to the development of autoreactive cells. Other epigenetic processes, such as the newly described miRNAs, and post-translational protein modifications may also be suspected. Altogether, a conceptual revolution is in progress, in AID, with potential new therapeutic strategies targeting epigenetic patterns.

Prenatal and early-life environmental exposures play a key role in the development of atopy and allergic disease. The Family Atherosclerosis Monitoring In earLY life Study is a general, population-based Canadian birth cohort that prospectively evaluated prenatal and early-life traits and their association with atopy and/or allergic disease. The study population included 901 babies, 857 mothers and 530 fathers. Prenatal and postnatal risk factors were evaluated through questionnaires collected during the antenatal period and at 1 year. The end points of atopy and allergic diseases in infants were evaluated through questionnaires and skin prick testing. Key outcomes included atopy (24.5%), food allergy (17.5%), cow’s milk allergy (4.8%), wheezing (18.6%) and eczema (16%). The association between infant antibiotic exposure [odds ratio (OR): 2.04, 95% confidence interval (CI): 1.45–2.88] and increased atopy was noted in the multivariate analysis, whereas prenatal maternal exposure to dogs (OR: 0.60, 95% CI: 0.42–0.84) and acetaminophen (OR: 0.68, 95% CI: 0.51–0.92) was associated with decreased atopy. This population-based birth cohort in Canada demonstrated high rates of atopy, food allergy, wheezing and eczema. Several previously reported and some novel prenatal and postnatal exposures were associated with atopy and allergic diseases at 1 year of age.

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.

The objective was to investigate the association between early and late maternal smoking during pregnancy on offspring body mass index (BMI). We undertook a retrospective cohort study using linked records from the Women’s and Children’s Health Network in South Australia. Among a cohort of women delivering a singleton, live-born infants between January 2000 and December 2005 (n=7658), 5961 reported not smoking during pregnancy, 297 reported quitting smoking during the first trimester of pregnancy, and 1400 reported continued smoking throughout pregnancy. Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance programme. The main outcome measure was age- and sex-specific BMI z-score. At 4 to 5 years, mean (s.d.) BMI z-score was 0.40 (1.05), 0.60 (1.07) and 0.65 (1.18) in children of mothers who reported never smoking, quitting smoking and continued smoking during pregnancy, respectively. Compared with the group of non-smokers, both quitting smoking and continued smoking were associated with an increase in child BMI z-score of 0.15 (95% confidence interval: 0.01–0.29) and 0.21 (0.13–0.29), respectively. A significant dose–response relationship was also observed between the number of cigarettes smoked per day on average during the second half of pregnancy and the increase in offspring BMI z-score (P<0.001). In conclusion, any maternal smoking in pregnancy, even if mothers quit, is associated with an increase in offspring BMI at 4 to 5 years of age.

Human development reportedly includes critical and sensitive periods during which environmental stressors can affect traits that persist throughout life. Controversy remains over which of these periods provides an opportunity for such stressors to affect health and longevity. The elaboration of reproductive biology and its behavioral sequelae during adolescence suggests such a sensitive period, particularly among males. We test the hypothesis that life expectancy at age 20 among males exposed to life-threatening stressors during early adolescence will fall below that among other males. We apply time-series methods to cohort mortality data in France between 1816 and 1919, England and Wales between 1841 and 1919, and Sweden between 1861 and 1919. Our results indicate an inverse association between cohort death rates at ages 10–14 and cohort life expectancy at age 20. Our findings imply that better-informed and more strategic management of the stressors encountered by early adolescents may improve population health.

We implemented six confounding adjustment methods: (1) covariate-adjusted regression, (2) propensity score (PS) regression, (3) PS stratification, (4) PS matching with two calipers, (5) inverse probability weighting and (6) doubly robust estimation to examine the associations between the body mass index (BMI) z-score at 3 years and two separate dichotomous exposure measures: exclusive breastfeeding v. formula only (n=437) and cesarean section v. vaginal delivery (n=1236). Data were drawn from a prospective pre-birth cohort study, Project Viva. The goal is to demonstrate the necessity and usefulness, and approaches for multiple confounding adjustment methods to analyze observational data. Unadjusted (univariate) and covariate-adjusted linear regression associations of breastfeeding with BMI z-score were −0.33 (95% CI −0.53, −0.13) and −0.24 (−0.46, −0.02), respectively. The other approaches resulted in smaller n (204–276) because of poor overlap of covariates, but CIs were of similar width except for inverse probability weighting (75% wider) and PS matching with a wider caliper (76% wider). Point estimates ranged widely, however, from −0.01 to −0.38. For cesarean section, because of better covariate overlap, the covariate-adjusted regression estimate (0.20) was remarkably robust to all adjustment methods, and the widths of the 95% CIs differed less than in the breastfeeding example. Choice of covariate adjustment method can matter. Lack of overlap in covariate structure between exposed and unexposed participants in observational studies can lead to erroneous covariate-adjusted estimates and confidence intervals. We recommend inspecting covariate overlap and using multiple confounding adjustment methods. Similar results bring reassurance. Contradictory results suggest issues with either the data or the analytic method.

Early life nutrition and growth are related to subsequent obesity risk in high-income countries. We investigated the association between nutrition and growth during infancy, and body composition at 10 years of age in 140 children selected from the Bone Health sub-study of the Birth-to-Twenty cohort from Soweto, Johannesburg, South Africa. Infant feeding and dietary data were collected during the first 12 months, and weight and height were measured at 1 and 2 years of age. At 10 years, anthropometry and dual-energy X-ray absorptiometry (DXA)-derived body composition were measured. Regression models were used to determine associations between independent and dependent variables at the 1% level of significance. A one z-score increase in birth weight was associated with a 1051 g increase in lean mass and a 0.22 increase in body mass index (BMI) z-score at the age of 10 years. After adjusting for confounders, stunting at age 1 year was associated with lower fat mass only at 10 years of age while at age 2 years, it was associated with lower lean mass only. Being underweight at one year of age was significantly associated with lower lean mass only. Weight-for-age (WAZ) change in the second year of infancy was a predictor of fat mass and BMI only. Body fatness at 10 years of age was positively associated with infant WAZ change rather than height-for-age change. There were no significant associations between infant dietary patterns, wasting and being underweight at age 2 years and pre-pubertal body composition. Further studies are needed to assess whether these associations continue during adolescence as pubertal development may be an important modifier of these associations.

Preterm birth and epicardial fat thickness (EFT) constitute novel risk factors for the onset of future adverse cardiovascular events. In total, 30 ex-extremely low birth weight (ex-ELBW) subjects (10 males, 20 females, aged 17–28) were enrolled and compared with 30 healthy peers. EFT was significantly higher (8.7±0.7 mm v. 5.6±0.9 mm; P<0.001) in ex-ELBW than in controls and was correlated with birth weight (r=−0.47, P=0.0009), gestational age (r=−0.39, P=0.03) and cardiac left ventricular mass (r=0.51, P=0.004). When excluding the influence of body mass index, birth weight was the sole remaining determinant of EFT, irrespective of gestational age (r=−0.37, P=0.04). The same findings when excluding the possible influence of blood pressure values on the cardiac structures (r=−0.40, P=0.028). In conclusion, EFT is significantly higher in former preterm subjects and is likewise associated with an increase in left ventricular mass. In view of the acknowledged correlation between the latter and an increased incidence of cardiovascular diseases, EFT appears to be an easy-to-measure tool capable of predicting the likely development of future adverse cardiovascular events in these subjects.

We examined developmental programming studies that reported sex-specific effects published between 2012 and 2014, and examined whether the authors reported a statistical approach to explicitly test whether the effect of treatment differed between the sexes, for example, a sex by treatment interaction term. Less than half of the studies that reported sex-specific effects described explicitly testing whether effects were indeed sex-specific; in most cases, an effect was considered ‘sex-specific’ if it was significant in one sex but not the other. This is not a robust approach, since significance in one sex and lack of significance in the other sex does not imply a significant difference between the sexes. However, sample size often limits statistical power to detect interactions. We suggest that if the effect is significant in only one sex, but the interaction term is not significant, alternative solutions would be to present the confidence intervals for the effect size for each sex, or using Bayesian approaches to calculate the probability that the effect sizes differ between the sexes. We present a simple example of a Bayesian analysis to illustrate that this approach is reasonably easy to implement and interpret.

The recognition of ‘fetal origins of adult disease’ has placed new responsibilities on the obstetrician, as antenatal care is no longer simply about ensuring good perinatal outcomes, but also needs to plan for optimal long-term health for mother and baby. Recently, it has become clear that the intrauterine environment has a broad and long-lasting impact, influencing fetal and childhood growth and development as well as future cardiovascular health, non-communicable disease risk and fertility. This article looks specifically at the importance of the developmental origins of ovarian reserve and ageing, the role of the placenta and maternal nutrition before and during pregnancy. It also reviews recent insights in developmental medicine of relevance to the obstetrician, and outlines emerging evidence supporting a proactive clinical approach to optimizing periconceptional as well as antenatal care aimed to protect newborns against long-term disease susceptibility.

Maternal high-fat diet consumption and obesity have been shown to program long-term obesity and lead to impaired glucose tolerance in offspring. Many rodent studies, however, use non-purified, cereal-based diets as the control for purified high-fat diets. In this study, primiparous ICR mice were fed purified control diet (10–11 kcal% from fat of lard or butter origin) and lard (45 or 60 kcal% fat) or butter (32 or 60 kcal% fat)-based high-fat diets for 4 weeks before mating, throughout pregnancy, and for 2 weeks of nursing. Before mating, female mice fed the 32 and 60% butter-based high-fat diets exhibited impaired glucose tolerance but those females fed the lard-based diets showed normal glucose disposal following a glucose challenge. High-fat diet consumption by female mice of all groups decreased lean to fat mass ratios during the 4th week of diet treatment compared with those mice consuming the 10–11% fat diets. All females were bred to male mice and pregnancy and offspring outcomes were monitored. The body weight of pups born to 45% lard-fed dams was significantly increased before weaning, but only female offspring born to 32% butter-fed dams exhibited long-term body weight increases. Offspring glucose tolerance and body composition were measured for at least 1 year. Minimal, if any, differences were observed in the offspring parameters. These results suggest that many variables should be considered when designing future high-fat diet feeding and maternal obesity studies in mice.

While fetal alcohol spectrum disorder (FASD) has primarily been thought of as a neurodevelopmental condition, research is beginning to highlight its ‘whole-body’ implications. Accordingly, the current study sought to provide a snapshot of potential health issues. Caregivers of children (median age of 12 years) with an FASD diagnosis were invited to participate in an online survey. Information relating to sample demographics, FASD status of the child and health outcomes were collected. The prevalence of health conditions reported in the FASD sample was compared against national prevalence data. Multiple linear regression utilising a stepwise approach was used to investigate potential predictors of the number of diagnosed health conditions. Survey data were from an international cohort (n = 197), with the majority of respondents based in Australia (40.2%) or the United States (27.7%). The most commonly reported diagnosed health conditions were eye conditions (44.7%), asthma (34.5%), heart conditions (34.0%) and skin conditions (27.4%). Binomial testing indicated the proportion of children diagnosed with these disorders was generally higher in the current FASD population, compared to national prevalence data. Indicators of metabolic dysfunction including diabetes and obesity were not significantly different compared to national prevalence data. Age of FASD diagnosis, existence of comorbid mental health conditions and the primary caregiver being in paid work were identified as being associated with the prevalence of diagnosed health conditions. Overall, the study has provided an up-to-date snapshot of health problems reported in a sample of children with FASD, confirming their increased risk of adverse health outcomes.

We assessed whether paternal demographic, anthropometric and clinical factors influence the risk of an infant being born large-for-gestational-age (LGA). We examined the data on 3659 fathers of term offspring (including 662 LGA infants) born to primiparous women from Screening for Pregnancy Endpoints (SCOPE). LGA was defined as birth weight >90th centile as per INTERGROWTH 21st standards, with reference group being infants ⩽90th centile. Associations between paternal factors and likelihood of an LGA infant were examined using univariable and multivariable models. Men who fathered LGA babies were 180 g heavier at birth (P<0.001) and were more likely to have been born macrosomic (P<0.001) than those whose infants were not LGA. Fathers of LGA infants were 2.1 cm taller (P<0.001), 2.8 kg heavier (P<0.001) and had similar body mass index (BMI). In multivariable models, increasing paternal birth weight and height were independently associated with greater odds of having an LGA infant, irrespective of maternal factors. One unit increase in paternal BMI was associated with 2.9% greater odds of having an LGA boy but not girl; however, this association disappeared after adjustment for maternal BMI. There were no associations between paternal demographic factors or clinical history and infant LGA. In conclusion, fathers who were heavier at birth and were taller were more likely to have an LGA infant, but maternal BMI had a dominant influence on LGA.

Intrauterine growth restriction (IUGR) is an important risk factor for development of hypertension, diabetes and the metabolic syndrome. Maternal low protein (LP) intake during rat pregnancy leads to IUGR in male and female offspring, although females may be resistant to the development of effect. Current evidence suggests that changes in the renin-angiotensin system (RAS) in utero contribute to this programmed hypertension, via sex-specific mechanisms. The previously orphaned G-protein coupled receptor (GPR91) was identified as a central player in the development of hypertension in adult mice, through a RAS-dependent pathway. However, whether the GPR91 pathway contributes to fetal programming is unknown. Furthermore, the nature of involvement of downstream modulators of the RAS including Gqα/11α and GαS has not been investigated in IUGR-LP rats. Therefore, we postulated that renal GPR91, in conjunction with RAS, is differentially impacted in a sex-specific manner from LP-induced IUGR rats. Pregnant Wistar rats were fed control (C, 20% protein) or LP (8% protein) diet until embryonic day 19 (E19) or postnatal d21. At E19, GPR91 protein and mRNA were increased in both male and female LP kidneys (P<0.05), whereas renin and angiotensin converting enzyme (ACE) were only increased in males (P=0.06 and P<0.05, respectively). On d21, AT1R and Gqα/11α were increased in LP males, while in LP females, AT2R protein was elevated and renin expression was decreased (P<0.05). This study demonstrates that in IUGR-LP rats, up regulation of GPR91 in fetal kidney is mirrored by increased ACE and renin in males. These in utero alterations, when combined with postnatal increases in AT1R-Gqα/11α specifically in male offspring, may predispose to the development of hypertension.

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.

Renin is essential for renal development and in adult kidneys vitamin D deficiency increases renin gene expression. We aimed to determine whether maternal vitamin D deficiency upregulates fetal renal renin expression, and if this is sustained. We also examined growth and the long-term renal effects in offspring on a normal diet. Female Sprague–Dawley rats in UVB-free housing were fed either vitamin D deficient chow (DEF) or normal chow from 4 weeks and mated with vitamin D replete males at 10 weeks. Fetuses were collected at E20 or dams littered and the pups were weaned onto normal chow. Kidney mRNA levels for renin, (pro)renin receptor [(P)RR], transforming growth factor β 1 (TGF-β1), and nephrin were determined in E20 fetuses and in male offspring at 38 weeks. Renal function was assessed at 33 weeks (24 h, metabolic cage) in both sexes. Renal mRNA expression was upregulated for renin in fetuses (P < 0.05) and was almost doubled in adult male offspring from DEF dams (P < 0.05). Adult males had reduced creatinine clearance, solute excretion and a suppressed urinary sodium-to-potassium ratio (P < 0.05). Female adult DEF offspring drank more and excreted more urine (P < 0.05) but creatinine clearance was not impaired. We conclude that maternal vitamin D depletion upregulates fetal renal renin gene expression and this persists into adulthood where, in males only, there is evidence of sodium retention and compromised renal function. Importantly these effects occurred despite the animals being on a normal diet from the time of weaning onwards.

In Australia, there are two distinct populations, each with vastly disparate health outcomes: Aboriginal and Torres Strait Islander People and non-Aboriginal Australians. Aboriginal Australians have significantly higher rates of health and socioeconomic disadvantage, and Aboriginal babies are also more likely to be born low birth weight or growth restricted. The Developmental Origins of Health and Disease (DOHaD) hypothesis advocates that a sub-optimal intrauterine environment, often manifested as diminished foetal growth, during critical periods of foetal development has the potential to alter the risk of non-communicable disease in the offspring. A better understanding of the role of the intrauterine environment and subsequent developmental programming, in response to both transgenerational and immediate stimuli, in Aboriginal Australians remains a relatively unexplored field and may provide insights into the prevailing health disparities between Aboriginal and non-Aboriginal children. This narrative review explores the role of DOHaD in explaining the ongoing disadvantage experienced by Aboriginal People in today’s society through a detailed discussion of the literature on the association between foetal growth, as a proxy for the quality of the intrauterine environment, and outcomes in the offspring including perinatal health, early life development and childhood education. The literature largely supports this hypothesis and this review therefore has potential implications for policy makers not only in Australia but also in other countries that have minority and Indigenous populations who suffer disproportionate disadvantage such as the United States, Canada and New Zealand.

Optimal early cognitive and emotional development are vital to reaching one’s full potential and represent our best chance to improve the mental health of the population. The developmental origins of health and disease (DOHaD) hypothesis posits that adverse perinatal exposures can alter physiology and increase disease risk. As physiological plasticity decreases with age, interventions applied during gestation may hold the most promise for reducing the impact of mental disorders across the lifespan. However, this vast clinical potential remains largely unrealized as the majority of human DOHaD research is observational in nature. The application of more rigorous experimental designs [e.g. Randomized Controlled Trials (RCTs)] not only represents a major step toward unlocking this potential, but are required to fully test the scientific validity of the DOHaD hypothesis as it pertains to mental illness. Here, we argue that the optimization of maternal diet and exercise during pregnancy represents our best chance to improve offspring neurodevelopment and reduce the burden of mental disorders. Follow-up studies of the offspring of pregnant women enrolled in new and existing RCTs of maternal gestational nutrition+exercise interventions are required to determine if acting during pregnancy can prevent and/or meaningfully reduce the prevalence and severity of mental disorders in the population.

Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress. We investigated the role of Nrf2a in larval steatosis following embryonic exposure to MEHP. Wild-type and nrf2a mutant (m) zebrafish embryos were exposed to 0 or 200 μg/l MEHP from 6 to either 96 (histology) or 120 hours post fertilization (hpf). At 120 hpf, exposures were ceased and fish were maintained in clean conditions until 15 days post fertilization (dpf). At 15 dpf, fish lengths and lipid content were examined, and the expression of genes involved in the antioxidant response and lipid processing was quantified. At 96 hpf, a subset of animals treated with MEHP had vacuolization in the liver. At 15 dpf, deficient Nrf2a signaling attenuated fish length by 7.7%. MEHP exposure increased hepatic steatosis and increased expression of peroxisome proliferator-activated receptor alpha target fabp1a1. Cumulatively, these data indicate that developmental exposure alone to MEHP may increase risk for hepatic steatosis and that Nrf2a does not play a major role in this phenotype.