Prenatal glucocorticoid overexposure has been shown to programme adult cardiovascular function in a range of species, but much less is known about the long-term effects of neonatal glucocorticoid overexposure. In horses, prenatal maturation of the hypothalamus–pituitary–adrenal axis and the normal prepartum surge in fetal cortisol occur late in gestation compared to other precocious species. Cortisol levels continue to rise in the hours after birth of full-term foals and increase further in the subsequent days in premature, dysmature and maladapted foals. Thus, this study examined the adult cardiovascular consequences of neonatal cortisol overexposure induced by adrenocorticotropic hormone administration to full-term male and female pony foals. After catheterisation at 2–3 years of age, basal arterial blood pressures (BP) and heart rate were measured together with the responses to phenylephrine (PE) and sodium nitroprusside (SNP). These data were used to assess cardiac baroreflex sensitivity. Neonatal cortisol overexposure reduced both the pressor and bradycardic responses to PE in the young adult males, but not females. It also enhanced the initial hypotensive response to SNP, slowed recovery of BP after infusion and reduced the gain of the cardiac baroreflex in the females, but not males. Basal diastolic pressure and cardiac baroreflex sensitivity also differed with sex, irrespective of neonatal treatment. The results show that there is a window of susceptibility for glucocorticoid programming during the immediate neonatal period that alters cardiovascular function in young adult horses in a sex-linked manner.

Epigenetic age acceleration (AA) has been associated with adverse environmental exposures and many chronic conditions. We estimated, in the NINFEA birth cohort, infant saliva epigenetic age, and investigated whether parental socio-economic position (SEP) and pregnancy outcomes are associated with infant epigenetic AA. A total of 139 saliva samples collected at on average 10.8 (range 7–17) months were used to estimate Horvath’s DNA methylation age. Epigenetic AA was defined as the residual from a linear regression of epigenetic age on chronological age. Linear regression models were used to test the associations of parental SEP and pregnancy outcomes with saliva epigenetic AA. A moderate positive association was found between DNA methylation age and chronological age, with the median absolute difference of 6.8 months (standard deviation [SD] 3.9). The evidence of the association between the indicators of low SEP and epigenetic AA was weak; infants born to unemployed mothers or with low education had on average 1 month higher epigenetic age than infants of mothers with high education and employment (coefficient 0.78 months, 95% confidence intervals [CIs]: −0.79 to 2.34 for low/medium education; 0.96, 95% CI: −1.81 to 3.73 for unemployment). There was no evidence for association of gestational age, birthweight or caesarean section with infant epigenetic AA. Using the Horvath’s method, DNA methylation age can be fairly accurately predicted from saliva samples already in the first months of life. This study did not reveal clear associations between either pregnancy outcomes or parental socio-economic characteristics and infant saliva epigenetic AA.

Prenatal exposure to mercury in utero causes abnormal foetal growth and adverse outcomes. DNA methylation is currently considered a possible mechanism through which this occurs. However, few studies have investigated the association between prenatal exposure to mercury and DNA methylation in detail. This study aimed to clarify the relationship between prenatal exposure to total mercury (Hg) and DNA methylation and its associations with sex-specific characteristics in male and female offspring. In a birth cohort study known as the Chiba study of Mother and Child Health, the DNA methylation status in cord tissue and Hg concentrations in cord serum were examined. A total of 67 participants (27 males and 40 females) were analysed based on Spearmanʼs correlations, adjusted by a false discovery rate of the sex of each offspring. Only one methylated locus was positively correlated with Hg concentrations in cord serum in male offspring, but not in female offspring, and was annotated to the haloacid dehalogenase-like hydrolase domain-containing protein 1 (HDHD1) gene on chromosome X. This locus was located in the intron of the HDHD1 gene body and is a binding site for the zinc finger protein CCCTC-binding factor. One of the other loci, located in HDHD1, was highly methylated in the group with higher mercury concentrations, and this locus was in the gene body of HDHD1. Our results suggest that prenatal exposure to Hg might affect the epigenetic status of male foetuses.

Polycyclic aromatic hydrocarbons (PAHs) may contribute to obesity. Childhood obesity is a strong predictor of adult obesity and morbidity; however, the relationship between PAHs and obesity in young children (e.g., aged 3–5) has not been studied. We examined the association between urinary PAH metabolites and measures of obesity in children. We analyzed data from 3667 children aged 3–18 years who participated in the Canadian Health Measures Survey (CHMS, 2009–2015). We ran separate multivariable linear models to estimate the association between quartiles of PAH metabolites and each of body mass index (BMI) percentile, waist circumference (WC), and waist-to-height ratio (WHtR) in the total population, as well as in the age subgroups 3–5, 6–11, and 12–18, adjusting for age, sex, ethnicity, education, income quintile, diet, creatinine, and exposure to environmental tobacco smoke. A multinomial logistic regression model estimated adjusted odds ratios for risk of central obesity. BMI, WC, and WHtR were positively associated with total PAH and naphthalene metabolites in the total population aged 3–18 and in age groups 6–11 and 12–18. In 3–5 year olds, WHtR, but not BMI, was significantly associated with total PAH, naphthalene, and phenanthrene metabolites. Overall, those in the highest quartile for naphthalene or total PAH metabolites had three times greater odds of having central obesity compared with those in the lowest quartile. Urinary PAH metabolites are associated with WHtR, an indicator of central obesity and predictor of health risks associated with obesity, in children as young as 3–5.

Maternal supraphysiological estradiol (E2) environment during pregnancy leads to adverse perinatal outcomes. However, the influence of oocyte exposure to high E2 levels on perinatal outcomes remains unknown. Thus, a retrospective cohort study was conducted to explore the effect of high E2 level induced by controlled ovarian stimulation (COH) on further outcomes after frozen embryo transfer (FET). The study included all FET cycles (n = 10,581) between 2014 and 2017. All cycles were categorized into three groups according to the E2 level on the day of the human Chorionic Gonadotropin trigger. Odds ratios (ORs) and their confidence intervals (CIs) were calculated to evaluate the association between E2 level during COH and pregnancy outcomes and subsequent neonatal outcomes. From our findings, higher E2 level was associated with lower percentage of chemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth as well as increased frequency of early miscarriage. Preterm births were more common among singletons in women with higher E2 level during COH (aOR1 = 1.93, 95% CI: 1.22–3.06; aOR2 = 2.05, 95% CI: 1.33–3.06). Incidence of small for gestational age (SGA) was more common in both singletons (aOR1 = 2.01, 95% CI: 1.30–3.11; aOR2 = 2.51, 95% CI: 1.69–3.74) and multiples (aOR1 = 1.58, 95% CI: 1.03–2.45; aOR2 = 1.99, 95% CI: 1.05–3.84) among women with relatively higher E2 level. No association was found between high E2 level during COH and the percentage of macrosomia or large for gestational age. In summary, oocyte exposure to high E2 level during COH should be brought to our attention, since the pregnancy rate decreasing and the risk of preterm birth and SGA increasing following FET.

There is an established link between birth parameters and risk of adult-onset cancers. The Developmental Origins of Health and Disease concept provides potential underlying mechanisms for such associations, including intrauterine exposure to endogenous hormones (androgens and estrogens), insulin-like growth factors, etc. However, there is conflicting evidence on the association between birth parameters and the cancer mortality risk. Therefore, we aimed to review and analyse the available data on the association linking birth weight and birth length with cancer mortality. Eleven studies were identified, published until April 2019. A significant association between birth weight and the prognosis of cancer (overall) was found (relative risk, RR 1.06, 95% confidence interval, CI: 1.01, 1.11), with low heterogeneity (I2 = 27.7%). In addition, higher birth weight was associated with poorer prognosis of prostate cancer (RR 1.21, 95% CI: 1.02, 1.44). However, the association of birth weight with breast cancer mortality risk in women was not significant (RR 1.16, 95% CI: 0.93, 1.44), which might be due to high statistical heterogeneity (I2 = 67.9%). Birth length was not associated with cancer mortality risk (RR 1.0, 95% CI: 0.90–1.11). It might be inferred that birth parameters are not associated with cancer mortality as strongly as with the risk of developing cancer. Also, the association between birth parameters and cancer mortality risk is not uniform and varies according to its subtypes, and study characteristics/design. This highlights the need for further prospective studies.

Early-life environmental and nutritional exposures are considered to contribute to the differences in cardiovascular disease (CVD) burden. Among sub-Saharan African populations, the association between markers of early-life exposures such as leg length and sitting height and CVD risk is yet to be investigated. This study assessed the association between leg length, sitting height, and estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk among Ghanaian-born populations in Europe and Ghana. We constructed sex-specific quintiles for sitting height and leg length for 3250 participants aged 40–70 years (mean age 52 years; men 39.6%; women 60.4%) in the cross-sectional multicenter Research on Diabetes and Obesity among African Migrants study. Ten-year risk of ASCVD was estimated using the Pooled Cohort Equations; risk ≥7.5% was defined as “elevated” CVD risk. Prevalence ratios (PR) were estimated to determine the associations between sitting height, leg length, and estimated 10-year ASCVD risk. For both men and women, mean sitting height and leg length were highest in Europe and lowest in rural Ghana. Sitting height was inversely associated with 10-year ASCVD risk among all women (PR for 1 standard deviation increase of sitting height: 0.75; 95% confidence interval: 0.67, 0.85). Among men, an inverse association between sitting height and 10-year ASCVD risk was significant on adjustment for study site, adult, and parental education but attenuated when further adjusted for height. No association was found between leg length and estimated 10-year ASCVD risk. Early-life and childhood exposures that influence sitting height could be the important determinants of ASCVD risk in this adult population.

Prenatal exposure to persistent organic pollutants (POPs) has been associated with the development of metabolic syndrome-related diseases in offspring. According to epidemiological studies, father’s transmission of environmental effects in addition to mother’s can influence offspring health. Moreover, maternal prenatal dietary folic acid (FA) may beneficially impact offspring health. The objective is to investigate whether prenatal FA supplementation can overcome the deleterious effects of prenatal exposure to POPs on lipid homeostasis and inflammation in three generations of male rat descendants through the paternal lineage. Female Sprague-Dawley rats (F0) were exposed to a POPs mixture (or corn oil) +/− FA supplementation for 9 weeks before and during gestation. F1 and F2 males were mated with untreated females. Plasma and hepatic lipids were measured in F1, F2, and F3 males after 12-h fast. Gene expression of inflammatory cytokines was determined by qPCR in epididymal adipose tissue. In F1 males, prenatal POPs exposure increased plasma lipids at 14 weeks old and hepatic lipids at 28 weeks old and prenatal FA supplementation decreased plasma total cholesterol at 14 weeks old. Prenatal POPs exposure decreased plasma triglycerides at 14 weeks old in F2 males. No change was observed in inflammatory markers. Our results show an impact of the paternal lineage on lipid homeostasis in rats up to the F2 male generation. FA supplementation of the F0 diet, regardless of POPs exposure, lowered plasma cholesterol in F1 males but failed to attenuate the deleterious effects of prenatal POPs exposure on plasma and hepatic lipids in F1 males.

Maternal pre-pregnancy weight has been related with young singletons’ cognitive and behavioral development, but it is not clear if it has an effect on temperament. We used a twin cohort to evaluate the association between maternal pre-pregnancy body mass index (BMI) and infants’ temperament. The mothers of 834 twins answered questions regarding their pre-pregnancy BMI and their 0- to 18-month-old children’s temperament using the Revised Infant Behavior Questionnaire. Three temperamental dimensions were examined: activity level, distress to limitation and duration of orienting. The relationship between maternal pre-pregnancy BMI and each temperamental component was investigated by means of multilevel mixed-effects linear regression analysis. We found no clear evidence of an association of maternal pre-pregnancy BMI with twins’ temperament. The development of temperament is influenced by a large number of factors, probably different from those influencing children’s emotional and behavioral development.

Maternal gut microbiota is thought to be one of the important factors in the developmental origins of health and disease (DOHaD) concept, but the effects of maternal gut microbiota on foetal growth are not well known. In this study, the association between maternal gut microbiota and foetal growth was investigated. Maternal and newborn information, as well as stool samples at the third trimester of pregnancy, were obtained from 51 mother–newborn pairs from the Chiba study of Mother and Child Health (C-MACH). Gut microbiota was analysed by 16S rRNA sequencing of stool samples and short-chain fatty acids (SCFAs) in stool were analysed by gas chromatography-tandem mass spectrometry. After adjustment for covariates, it was found that maternal gut microbial diversity had a positive association with head circumference in newborn males (Chao 1: adjusted r = 0.515, p = 0.029). Genus Parabacteroides and genus Eggerthella showed negative associations with newborn head circumference and weight, respectively in males (genus Parabacteroides: adjusted r = −0.598, p = 0.009, genus Eggerthella: adjusted r = −0.481, p = 0.043). On the other hand, genus Streptococcus showed a negative association with newborn height in females (adjusted r = −0.413, p = 0.040). In addition, hexanoate was involved in the association between maternal gut microbiota and newborn anthropometrics in the univariate analysis, but not in the multivariate analysis. These data suggest that maternal gut microbiota has sex-specific effects on foetal growth. Maternal gut microbiota is an important factor for optimal intrauterine growth.

This study examines the relationship between paternal height or body mass index (BMI) and birth weight of their offspring in a Japanese general population. The sample included 33,448 pregnant Japanese women and used fixed data, including maternal, paternal and infant characteristics, from the Japan Environment and Children’s Study (JECS), an ongoing nationwide birth cohort study. Relationships between paternal height or BMI and infant birth weight [i.e., small for gestational age (SGA) and large for gestational age (LGA)] were examined using a multinomial logistic regression model. Since fetal programming may be a sex-specific process, male and female infants were analyzed separately. Multivariate analysis showed that the higher the paternal height, the higher the odds of LGA and the lower the odds of SGA in both male and female infants. The effects of paternal BMI on the odds of both SGA and LGA in male infants were similar to those of paternal height; however, paternal height had a stronger impact than BMI on the odds of male LGA. In addition, paternal BMI showed no association with the odds of SGA and only a weak association with the odds of LGA in female infants. This cohort study showed that paternal height was associated with birth weight of their offspring and had stronger effects than paternal BMI, suggesting that the impact of paternal height on infant birth weight could be explained by genetic factors. The sex-dependent effect of paternal BMI on infant birth weight may be due to epigenetic effects.

Blood pressure (BP) tracks from childhood to adulthood, and early BP trajectories predict cardiovascular disease risk later in life. Excess postnatal weight gain is associated with vascular changes early in life. However, to what extent it is associated with children’s BP is largely unknown. In 853 healthy 5-year-old children of the Wheezing-Illnesses-Study-Leidsche-Rijn (WHISTLER) birth cohort, systolic (SBP) and diastolic BP (DBP) were measured, and z scores of individual weight gain rates adjusted for length gain rates were calculated using at least two weight and length measurements from birth until 3 months of age. Linear regression analyses were conducted to investigate the association between weight gain rates adjusted for length gain rates and BP adjusted for sex and ethnicity. Each standard deviation increase in weight gain rates adjusted for length gain rates was associated with 0.9 mmHg (95% CI 0.3, 1.5) higher sitting SBP after adjustment for confounders. Particularly in children in the lowest birth size decile, high excess weight gain was associated with higher sitting SBP values compared to children with low weight gain rates adjusted for length gain rates. BMI and visceral adipose tissue partly explained the association between excess weight gain and sitting SBP (β 0.5 mmHg, 95% CI −0.3, 1.3). Weight gain rates adjusted for length gain rates were not associated with supine SBP or DBP. Children with excess weight gain, properly adjusted for length gain, in the first three months of life, particularly those with a small birth size, showed higher sitting systolic BP at the age of 5 years.

The preconception, pregnancy and immediate postpartum and newborn periods are times for mothers and their offspring when they are especially vulnerable to major stressors – those that are sudden and unexpected and those that are chronic. Their adverse effects can transcend generations. Stressors can include natural disasters or political stressors such as conflict and/or migration. Considerable evidence has accumulated demonstrating the adverse effects of natural disasters on pregnancy outcomes and developmental trajectories. However, beyond tracking outcomes, the time has arrived for gathering more information related to identifying mechanisms, predicting risk and developing stress-reducing and resilience-building interventions to improve outcomes. Further, we need to learn how to encapsulate both the quantitative and qualitative information available and share it with communities and authorities to mitigate the adverse developmental effects of future disasters, conflicts and migrations. This article briefly reviews prenatal maternal stress and identifies three contemporary situations (wildfire in Fort McMurray, Alberta, Canada; hurricane Harvey in Houston, USA and transgenerational and migrant stress in Pforzheim, Germany) where current studies are being established by Canadian investigators to test an intervention. The experiences from these efforts are related along with attempts to involve communities in the studies and share the new knowledge to plan for future disasters or tragedies.

There is increasing evidence linking maternal diet and physical activity before and during pregnancy with offspring’s cardiovascular health. Although many studies examined this association, the evidence has not been reviewed systematically. We therefore undertook a systematic review to synthesize evidence examining the association of maternal diet and physical activity before and during pregnancy with offspring’s blood pressure and vascular health. We systematically searched the databases MEDLINE and EMBASE from inception to June 30, 2017. Eligibility screening, data extraction and quality assessment were performed by two independent reviewers. A total of 19 articles were included comprising three randomized controlled trials and 16 observational studies. Of the studies that examined the association of interest, 60% (three out of five studies) showed that high maternal carbohydrate intake was associated with higher offspring’s blood pressure. Maternal protein intake during pregnancy was negatively associated with offspring carotid intima-media thickness in two out of two studies. No consistent findings for maternal fatty acid intake were found. There were too few studies to draw conclusions on energy intake, fibre intake, protein/carbohydrate ratio, specific foods, dietary patterns and maternal physical activity. Heterogeneity in exposure and outcome assessment hampered pooling. Also, owing to the observational nature of most studies, causality cannot be established. Harmonization of valid exposure and outcome measurements, and the development of core outcome sets are needed to enable more robust conclusions.

Perimenopausal disorders (PDs) are prevalent and importantly affect quality of life among middle-aged women. Yet, very little is known about the developmental origins of these disorders. The objective of this study was to investigate the associations of birth characteristics with PDs. This cohort study is based on archived birth records for birth weight and gestational age, and followed prospectively in Swedish inpatient and outpatient registers for 8 years (n=3212). The main outcomes were menopausal and climacteric states (e.g. flushing, sleeplessness), perimenopausal bleeding and other PDs (e.g. atrophic vaginitis). Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) for three subtypes of PDs separately. During the follow-up, 218 women had PDs, among whom 125 had menopausal and climacteric states, 61 had perimenopausal bleeding and 58 had other PDs as first recorded disorder. Birth weight was linearly associated with incidence rate of menopausal and climacteric states [HR=1.66 per 1 kg increase, 95% confidence interval (95% CI)=1.14–2.41]. Gestational age (rather than birth weight) was associated with incidence rate of other PDs (HR=0.87 per 1 week increase, 95% CI=0.79–0.95). Neither birth weight nor gestational age was associated with perimenopausal bleeding. Similar results were found after adjustment for other early-life and adult socio-demographic characteristics. This observational study provides, for the first time, evidence regarding the developmental origins of PDs. Future research is required to investigate the underlying causal mechanisms, which may shed further light on the etiology of this class of disorders.

Evidence in support of the Developmental Origins of Health and Disease (DOHaD) hypothesis has reached the level where it can appropriately be used to inform practice. DOHaD informed interventions supporting primary noncommunicable disease risk reduction should target the pre- and periconceptional periods, pregnancy, lactation, childhood and adolescence. Such interventions are dependent on a health workforce (including dietitians, nurses, midwives, doctors, and nutrition teachers), that has a deep understanding of DOHaD concepts. This study assessed development of awareness of DOHaD concepts during undergraduate health professional training programs. Using a cross-sectional design, a standardized questionnaire was completed by Year 1–4 undergraduate students studying nutrition in Japan (n=309) and Year 1–3 nursing students in New Zealand (n=151). On entry to undergraduate study, most students had no awareness of the terms ‘DOHaD’ or ‘First 1000 Days’. While awareness reached 60% by Year 3 in courses that included DOHaD-related teaching, this remains inadequate. More than 95% of Year 1 undergraduates in both countries demonstrated an appreciation of associations between maternal nutrition and fetal health. However, awareness of associations between parental health status and/or nutritional environment and later-life health was low. While levels of awareness increased across program years, overall awareness was less than optimal. These results indicate evidence of some focus on DOHaD-related content in curricula. We argue that DOHaD principles should be one pillar around which health training curricula are built. This study indicates a need for the DOHaD community to engage with faculties in curriculum development.

It is now well accepted that exposure to adverse environmental conditions in utero can predispose a fetus to disease later in life. Using an avian model to study the programming of disease has a unique advantage as it allows isolation of the direct effects of adverse conditions on fetal physiology, without any confounding effects via the mother or placenta. However, experiments in avian models are limited by the lack of well-established surgical protocols for the adult bird, which we have established in this study. Surgery was performed on seven young adult Bovan Brown chickens (body weight 1617±214 g, mean±s.d.) in order to instrument them with femoral arterial and venous catheters and a femoral arterial flow probe. Isoflurane and lidocaine were both found to have depressive effects on chicken cardiovascular function. Optimised methods of anaesthesia, intraoperative monitoring, surgical approach, postoperative care, and experimentation are described. Chickens recovered rapidly from surgery without significant blood gas perturbation, and basal in vivo cardiovascular studies were performed following 5 days of recovery. These techniques allow detailed investigation of avian cardiometabolic function, permitting determination of the consequences in later life of direct environmental insults to fetal physiology, isolated from additional effects on maternal physiology and/or placental endocrinology.