The aim of this study was to observe the association between maternal undernutrition and metabolic risk indicators in newborns at birth. Fifty-nine expectant mothers between 28 and 40 weeks of gestation were included after obtaining their informed consent. Mothers were divided into undernourished, normally nourished and overnourished groups. A total of 54 deliveries were followed-up, and cord blood samples were collected. Metabolic status at birth was assessed by determining the cord blood concentrations of glucose, insulin and lipids and by measuring insulin resistance through homeostasis model assessment. Metabolic risk indicators in the offspring were compared following mothers’ nutrition status (under and normal nourished groups). We found that concentrations of glucose (5.31±2.01 v. 4.69±2.22 mmol/l, P=0.01), total cholesterol (2.51±1.52 v. 1.84±0.66 mmol/l, P=0.04), triglycerides (0.85±1.12 v. 0.34±0.24 mmol/l, P=0.00) and low-density lipoprotein (LDL)-cholestrol (1.26±0.93 v. 1.02±0.50 mmol/l, P=0.04) were significantly high in the offspring born to undernourished mothers. LDL-cholestrol remained significantly high in the undernourished group even after adjustment for potential confounders. Furthermore, a weak association was observed between maternal body fat mass with serum leptin (r=0.272, P=0.05) and maternal body mass Index with LDL-cholestrol in the cord blood (r=0.285, P=0.05). Our results showed that offspring of undernourished mothers had a relatively higher metabolic risk profile including LDL-cholestrol compared with normal nourished group, suggesting that maternal undernutrition may influence metabolic risk markers of the newborn at birth. We recommend that these results should be confirmed by a longitudinal study with a larger sample size.

Maternal overnutrition-induced fetal programming predisposes offspring to cardiovascular health issues throughout life. Understanding how these adverse cardiovascular effects are regulated at the maternal–fetal crosstalk will provide insight into the mechanisms of these cardiovascular diseases, which will help in further identifying potential targets for intervention. Here, we uncover a role of oxidative stress caused by prenatal overnutrition in governing cardiac damage. Mice exposed to maternal obesity showed remarkable pathological cardiomyocyte hypertrophy (p male < 0.001, Cohen’s d male = 1.77; p female < 0.001, Cohen’s d female = 1.94), increased collagen content (p male < 0.001, Cohen’s d male = 2.13; p female < 0.001, Cohen’s d female = 2.71), and increased levels of transforming growth factor β (TGF-β) (p male < 0.001, Cohen’s d male = 3.02; p female < 0.001, Cohen’s d female = 4.52), as well as left ventricular dysfunction in adulthood. To cope with increased oxidative stress in the myocardial tissue of offspring from obese mothers, we sought to decrease the effect of oxidative stress and prevent the development of these cardiovascular conditions with use of the antioxidant N-acetylcysteine during pregnancy. As predicted, after treatment with the antioxidant, there was greatly mitigated cardiomyocyte hypertrophy (p male < 0.001, Cohen’s d male = 1.31; p female < 0.001, Cohen’s d female = 0.82) and cardiac fibrosis, including decreased composition of collagen fibers (p male < 0.01, Cohen’s d male = 1.45; p female < 0.05, Cohen’s d female = 1.23) and reduced levels of TGF-β (p male < 0.05, Cohen’s d male = 1.83; p female < 0.01, Cohen’s d female = 3.81). We also observed improved left ventricle contractile function together with the alleviation of enhanced oxidative stress in the myocardial tissue of offspring. Collectively, these results established a crucial role of oxidative stress in prenatal overnutrition-associated ventricular remodeling and cardiac dysfunction. Our findings provided an important target for intervention of cardiovascular disease in overnutrition-related fetal programming.

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.

The maternal metabolic environment can be detrimental to the health of the offspring. In a previous work, we showed that maternal high-fat (HH) feeding in rabbit induced sex-dependent metabolic adaptation in the fetus and led to metabolic syndrome in adult offspring. As early development representing a critical window of susceptibility, in the present work we aimed to explore the effects of the HH diet on the oocyte, preimplantation embryo and its microenvironment. In oocytes from females on HH diet, transcriptomic analysis revealed a weak modification in the content of transcripts mainly involved in meiosis and translational control. The effect of maternal HH diet on the embryonic microenvironment was investigated by identifying the metabolite composition of uterine and embryonic fluids collected in vivo by biomicroscopy. Metabolomic analysis revealed differences in the HH uterine fluid surrounding the embryo, with increased pyruvate concentration. Within the blastocoelic fluid, metabolomic profiles showed decreased glucose and alanine concentrations. In addition, the blastocyst transcriptome showed under-expression of genes and pathways involved in lipid, glucose and amino acid transport and metabolism, most pronounced in female embryos. This work demonstrates that the maternal HH diet disrupts the in vivo composition of the embryonic microenvironment, where the presence of nutrients is increased. In contrast to this nutrient-rich environment, the embryo presents a decrease in nutrient sensing and metabolism suggesting a potential protective process. In addition, this work identifies a very early sex-specific response to the maternal HH diet, from the blastocyst stage.

Human health is strongly mediated by the gut microbiota ecosystem, which, in turn, depends not only on its state but also on its dynamics and how it responds to perturbations. Healthy microbiota ecosystems tend to be in criticality and antifragile dynamics corresponding to a maximum complexity configuration, which may be assessed with information and network theory analysis. Under this complex system perspective, we used a new analysis of published data to show that a children’s population with an industrialized urban lifestyle from Mexico City exhibits informational and network characteristics similar to parasitized children from a rural indigenous population in the remote mountainous region of Guerrero, México. We propose then, that in this critical age for gut microbiota maturation, the industrialized urban lifestyle could be thought of as an external perturbation to the gut microbiota ecosystem, and we show that it produces a similar loss in criticality/antifragility as the one observed by internal perturbation due to parasitosis by the helminth A. lumbricoides. Finally, several general complexity-based guidelines to prevent or restore gut ecosystem antifragility are discussed.

Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high-fat diet in utero, programed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat, n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat, n=12). Dams were fed the chow diet during the suckling period. At 28 days postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (P<0.001). There was no direct effect of prenatal diet on plasma triglycerides or cholesterol; however, transgenic ApoE*3 Leiden offspring displayed raised cholesterol when on an atherogenic diet compared with wild-type controls (P=0.031). Lesion size was correlated with plasma lipid parameters after adjustment for genotype, maternal diet and postnatal diet (R2=0.563, P<0.001). ApoE*3 Leiden mothers fed a MHF diet developed hypercholesterolemia (plasma cholesterol two-fold higher than in chow-fed mothers, P=0.011). The data strongly suggest that maternal hypercholesterolemia programs later susceptibility to atherosclerosis. This is consistent with previous observations in humans and animal models.

Little is known about the consequences of maternal copper (Cu) deficiency on the vascular function of offspring or on perpetuation of vascular effects to a second generation. We examined vascular functional responses in mesenteric arteries from Cu-deficient Sprague-Dawley rat dams and from offspring directly exposed to maternal Cu deficiency during development and lactation and perpetuation of the effects in a second generation of offspring. Dams were fed a diet with marginal (1 mg Cu/kg) or adequate (6 mg Cu/kg) Cu for 3 weeks before conception and throughout pregnancy and lactation periods. Half of the first generation (F1) litters were cross-fostered. At reproductive maturity, F1 pairs were bred within groups resulting in second generation (F2) offspring. At 9 weeks of age, mesenteric artery (200 μm) isometric tension was determined in response to vasoconstrictors and vasorelaxants using a small artery wire myograph. Cu deficiency did not alter the vascular function in dams. In F1 offspring, increased responsiveness to potassium chloride in male offspring was due to direct exposure to maternal Cu deficiency in the birth mother, while enhanced endothelium-dependent relaxation responses in female offspring resulted from postnatal exposure to maternal Cu deficiency. Increased endothelium independent and decreased endothelium-dependent relaxation responses were identified in F2 Cu-deficient male offspring. These data indicate that exposure to maternal Cu deficiency during critical windows of development alter the vascular function across two generations of offspring.

There is an accumulating data that shows relation between childhood adversity and vulnerability to chronic diseases as well as epigenetic influences that in turn give rise to these diseases. Asthma is one of the chronic diseases that is influenced from genetic regulation of the inflammatory biomolecules and therefore the hypothesis in this research was childhood adversity might have caused epigenetic differentiation in the asthma-related genes in the population who had childhood trauma. To test this hypothesis, the literature was systematically reviewed to extract epigenetically modified gene data of the adults who had childhood adversity, and affected genes were further evaluated for their association with asthma. PRISMA guidelines were adopted and PubMed and Google Scholar were included in the searched databases, to evaluate epigenetic modifications in asthma-related genes of physically, emotionally or sexually abused children. After retrieving a total of 5245 articles, 36 of them were included in the study. Several genes and pathways that may contribute to pathogenesis of asthma development, increased inflammation, or response to asthma treatment were found epigenetically affected by childhood traumas. Childhood adversity, causing epigenetic changes in DNA, may lead to asthma development or influence the course of the disease and therefore should be taken into account for the prolonged health consequences.

Accumulating evidence suggests that maternal overnutrition can result in a higher development risk of obesity and renal disease in the offspring’s adulthood. The present study tested different lipid levels in the maternal diet during pregnancy and lactation and its repercussions on the offspring of Wistar rats. Offspring of 1, 7, 30 and 90-d-old were divided into the following groups: Control (CNT) – offspring of dams that consumed a standard chow diet (3.5% of lipids); Experimental 1 (EXP1) – offspring of dams exposed to a high-fat diet (HFD) (28% of lipids); and Experimental 2 (EXP2) – offspring of dams exposed to a HFD (40% of lipids). Regarding maternal data, there was a decrease in the amount of diet ingested by EXP2. Daily caloric intake was higher in EXP1, while protein and carbohydrate intakes were lower in EXP2. While lipid intake was higher in the experimental groups, EXP1 consumed more lipids than EXP2, despite the body weight gain being higher in EXP2. Adult offspring from EXP1 presented higher blood glucose. Regarding morphometric analysis, in both experimental groups, there was an increase in the glomerular tuft and renal corpuscle areas, but an increase in the capsular space area only in EXP1. There was a decrease in the glomerular filtration rate (GFR) in EXP1, in contrast to an increase in GFR of EXP2, along with an increase in urinary protein excretion. In conclusion, the maternal HFDs caused significant kidney damage in offspring, but had different repercussions on the type and magnitude of recorded change.

With the advancement of medical technology, there are increasing opportunities for new-borns, infants, and pregnant women to be exposed to general anaesthesia. Propofol is commonly used for the induction of anaesthesia, maintenance of general intravenous anaesthesia and sedation of intensive-care children. Many previous studies have found that propofol has organ-protective effects, but growing evidence suggests that propofol interferes with brain development, affecting learning and cognitive function. The purpose of this review is to summarize the latest progress in understanding the neurotoxicity of propofol. Evidence from case studies and clinical studies suggests that propofol has neurotoxicity on the developing brain. We classify the findings on propofol-induced neurotoxicity based on its damage mechanism. We end by summarizing the current protective strategies against propofol neurotoxicity. Fully understanding the neurotoxic mechanisms of propofol can help us use it at a reasonable dosage, reduce its side effects, and increase patient safety.

Most human studies investigating the relationship between maternal diet in pregnancy and infant epigenetic state have focused on macro- and micro-nutrient intake, rather than the whole diet. This makes it difficult to translate the evidence into practical prenatal dietary recommendations.

To review the evidence on how the prenatal diet relates to the epigenetic state of infants measured in the first year of life via candidate gene or genome-wide approaches.

Following the PRISMA guidelines, this systematic literature search was completed in August 2020, and updated in August 2021 and April 2022. Studies investigating dietary supplementation were excluded. Risk of bias was assessed, and the certainty of results was analysed with consideration of study quality and validity.

Seven studies were included, encompassing 6852 mother-infant dyads. One study was a randomised controlled trial and the remaining six were observational studies. There was heterogeneity in dietary exposure measures. Three studies used an epigenome-wide association study (EWAS) design and four focused on candidate genes from cord blood samples. All studies showed inconsistent associations between maternal dietary measures and DNA methylation in infants. Effect sizes of maternal diet on DNA methylation ranged from very low (< 1%) to high (> 10%). All studies had limitations and were assessed as having moderate to high risk of bias.

The evidence presented here provides very low certainty that dietary patterns in pregnancy relate to epigenetic state in infants. We recommend that future studies maximise sample sizes and optimise and harmonise methods of dietary measurement and pipelines of epigenetic analysis.

The principles embodied by the Developmental Origins of Health and Disease (DOHaD) view of ‘life history’ trajectory are increasingly underpinned by biological data arising from molecular-based epigenomic and transcriptomic studies. Although a number of ‘omic’ platforms are now routinely and widely used in biology and medicine, data generation is frequently confounded by a frequency distribution in the measurement error (an inherent feature of the chemistry and physics of the measurement process), which adversely affect the accuracy of estimation and thus, the inference of relationships to other biological measures such as phenotype. Based on empirical derived data, we have previously derived a probability density function to capture such errors and thus improve the confidence of estimation and inference based on such data. Here we use published open source data sets to calculate parameter values relevant to the most widely used epigenomic and transcriptomic technologies Then by using our own data sets, we illustrate the benefits of this approach by specific application, to measurement of DNA methylation in this instance, in cases where levels of methylation at specific genomic sites represents either (1) a response variable or (2) an independent variable. Further, we extend this formulation to consideration of the ‘bivariate’ case, in which the co-dependency of methylation levels at two distinct genomic sites is tested for biological significance. These tools not only allow greater accuracy of measurement and improved confidence of functional inference, but in the case of epigenomic data at least, also reveal otherwise cryptic information.

The deleterious effects of adversity are likely intergenerational, such that one generation’s adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children’s behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

Low gestational weight gain (GWG) is a known risk factor of low birthweight. Although studies have previously examined the associations between GWG and birthweight, the period-specific effects of low GWG in each trimester remain unclear. This study aimed to quantify the trimester-specific direct effects of low GWG in Japanese women on birthweight. Using perinatal data from a cohort study, we analyzed pregnant women delivered at an obstetrics/gynecology hospital between October 2006 and May 2010. We focused on women with a pre-pregnancy body mass index (BMI) below 25 kg/m2. The exposure was low GWG. The gestation period was subdivided into trimesters, and the direct effects of low trimester-specific GWG on birthweight were estimated using marginal structural models. These models were guided by a direct acyclic graph that incorporated potential confounders, including pre-pregnancy BMI, age, smoking during pregnancy, height, and parity. We analyzed 563 women and their families. The mean cumulative GWG by the end of the first, second, and third trimesters was 0.9, 6.2, and 10.7 kg, respectively. Approximately 14.0% of the women gained total weight below the range recommended by Japanese Ministry of Health, Labour and Welfare. The direct effects of low GWG on birthweight were 65.9 g (95% confidence interval: 11.4, 120.5), −195.4 g (−263.4, −127.4), and −188.8 g (−292.0, −85.5) for the first, second, and third trimesters, respectively. Insufficient weight gain in the second and third trimesters had a negative impact on birthweight after adjusting for pre-pregnancy BMI and other covariates.

Either tobacco smoking or alcohol consumption during pregnancy sex-selectively increases susceptibility to drugs of abuse later in life. Considering that pregnant smoking women are frequently intermittent consumers of alcoholic beverages, here, we investigated whether a short-term ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to tobacco smoke aggravates susceptibility to nicotine in adolescent and adult mice. Swiss male and female mice were exposed to tobacco smoke (SMK; research cigarettes 3R4F, whole-body exposure, 8 h/daily) or ambient air during the gestational period and until the tenth postnatal day (PN). Ethanol (ETOH, 2 g/Kg, 25%, i.p.) or saline was injected in the pups every other day from PN2 to PN10. There were no significant differences in cotinine (nicotine metabolite) and ethanol serum levels among SMK, ETOH and SMK + ETOH groups. During adolescence (PN30) and adulthood (PN90), nicotine (NIC, 0.5 mg/Kg) susceptibility was evaluated in the conditioned place preference and open field tests. NIC impact was more evident in females: SMK, ETOH and SMK + ETOH adolescent females were equally more susceptible to nicotine-induced place preference than control animals. At adulthood, SMK and SMK + ETOH adult females exhibited a nicotine-evoked hyperlocomotor profile in the open field, with a stronger effect in the SMK + ETOH group. Our results indicate that ethanol exposure during the brain growth spurt, when combined to developmental exposure to tobacco smoke, increases nicotine susceptibility with stronger effects in adult females. This result represents a worsened outcome from the early developmental dual exposure and may predispose nicotine use/abuse later in life.

There is strong evidence that physical activity (PA) has an influence on physical performance in later life. Also, a small body size at birth has been associated with lower physical functioning in older age and both small and high birth weight have shown to be associated with lower leisure time physical activity. However, it is unknown whether size at birth modulates the association between PA and physical performance in old age. We examined 695 individuals from the Helsinki Birth Cohort Study born in Helsinki, Finland between 1934 and 1944. At a mean age of 70.7 years PA was objectively assessed with a multisensory activity monitor and physical performance with the Senior Fitness Test (SFT). Information on birth weight and gestational age was retrieved from hospital birth records. The study participants were divided in three birth weight groups, that is <3000 g, 3000–3499 g and ⩾3500 g. The volume of PA was significantly associated with the physical performance in all birth weight groups. However, the effect size of the association was large and significant only in men with a birth weight <3000 g (β 0.59; 95% confidence interval 0.37–0.81, P<0.001). Our study shows that the association between PA and physical performance is largest in men with low birth weight. Our results suggest that men with low birth weight might benefit most from engaging in PA in order to maintain a better physical performance.

Preterm birth (delivery <37 weeks of gestation) is associated with impaired glomerular capillary growth in neonates; if this persists, it may be a contributing factor in the increased risk of hypertension and chronic kidney disease in people born preterm. Therefore, in this study, we aimed to determine the long-term impact of preterm birth on renal morphology, in adult sheep. Singleton male sheep were delivered moderately preterm at 132 days (~0.9) of gestation (n = 6) or at term (147 days gestation; n = 6) and euthanised at 14.5 months of age (early adulthood). Stereological methods were used to determine mean renal corpuscle and glomerular volumes, and glomerular capillary length and surface area, in the outer, mid and inner regions of the renal cortex. Glomerulosclerosis and interstitial collagen levels were assessed histologically. By 14.5 months of age, there was no difference between the term and preterm sheep in body or kidney weight. Renal corpuscle volume was significantly larger in the preterm sheep than the term sheep, with the preterm sheep exhibiting enlarged Bowman’s spaces; however, there was no difference in glomerular volume between groups, with no impact of preterm birth on capillary length or surface area per glomerulus. There was also no difference in interstitial collagen levels or glomerulosclerosis index between groups. Findings suggest that moderate preterm birth does not adversely affect glomerular structure in early adulthood. The enlarged Bowman’s space in the renal corpuscles of the preterm sheep kidneys, however, is of concern and merits further research into its cause and functional consequences.

Individuals born small have an increased risk for developing type 2 diabetes. Altered food preferences in these subjects seem to play a role; however, limited evidence is available on the association between being born small-for-gestational-age (SGA) at term and food intake in adolescence. Alterations in leptin, ghrelin and dopamine levels are suggested mechanisms linking SGA with later food intake. From a large prospective Danish National Birth Cohort, we compared dietary intake of adolescents being born SGA with normal-for-gestational-age (NGA) adolescents. Intake of foods and nutrients was assessed by a validated food frequency questionnaire in a subsample of 15,607 14-year-old individuals born at term. SGA was defined by birth weight (BW) <10th percentile (n = 1470) and NGA as BW between 10 and 90th percentile (n = 14,137) according to sex and gestational age-specific BW standard curves. Girls born SGA had a 7% (95% CI: 3–12%, P = 0.002) higher intake of added sugar and a 2–8% lower intake of dietary fibre, vegetables, polyunsaturated fatty acids, and total n−6, compared with NGA girls (P < 0.05). Adjusting for parental socio-occupational status, maternal smoking and diet in pregnancy did not substantially change the differences in dietary intake, except from dietary fibre, which were no longer statistically significant. No significant differences in dietary intake between SGA and NGA boys were found. In summary, girls born SGA had an unfavourable dietary intake compared with NGA girls. These differences persisted after controlling for potential confounders, thus supporting a fetal programming effect on dietary intake in girls born SGA at term. However, residual confounding by other factors operating early in childhood cannot be excluded.

Birth weight and early growth have been associated with later blood pressure. However, not all studies consistently find a significant reduction in blood pressure with an increase in birth weight. In addition, the relative importance of birth weight and of other lifestyle and environmental factors is often overlooked and the association is rarely studied in adolescents. We investigated early life predictors, including birth weight, of adolescent blood pressure in the Gateshead Millennium Study (GMS). The GMS is a cohort of 1029 individuals born in 1999–2000 in Gateshead in Northern England. Throughout infancy and early childhood, detailed information were collected, including birth weight and measures of height and weight. Assessments of 491 returning participants at age 12 years included measures of body mass and blood pressure. Linear regression and path analysis were used to determine predictors and their relative importance on blood pressure. Birth weight was not directly associated with blood pressure at the age of 12. However, after adjustment for contemporaneous body mass index (BMI), an inverse association of standardized birth weight on systolic blood pressure was significant. The relative importance of birth weight on later systolic blood pressure was smaller than other contemporaneous body measures (height and BMI). There was no independent association of birth weight on blood pressure seen in this adolescent population. Contemporaneous body measures have an important role to play. Lifestyle factors that influence body mass or size, such as diet and physical activity, where interventions are directed at early prevention of hypertension should be targeted.