Protein restriction during early phases of body development, such as intrauterine life can favor the development of vascular disorders. However, it is not known if peripubertal protein restriction can favor vascular dysfunction in adulthood. The present study aimed to evaluated whether a protein restriction diet during peripubertal period favors endothelial dysfunction in adulthood. Male Wistar rats from postnatal day (PND) 30 until 60 received a diet with either 23% protein (CTR group) or with 4% protein (LP group). At PND 120, the thoracic aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in the presence or absence of: endothelium, indomethacin, apocynin and tempol. The maximum response (Rmax) and pD2 (-log of the concentration of the drug that causes 50% of the Rmax) were calculated. The lipid peroxidation and catalase activity were also evaluated in the aorta. The data were analyzed by ANOVA (one or two-ways and Tukey’s) or independent t-test; the results were expressed as mean ± S.E.M., p < 0.05. The Rmax to phenylephrine in aortic rings with endothelium were increased in LP rats when compared with the Rmax in CTR rats. Apocynin and tempol reduced Rmax to phenylephrine in LP aortic rings but not in CTR. The aortic response to the vasodilators was similar between the groups. Aortic catalase activity was lower and lipid peroxidation was greater in LP compared to CTR rats. Therefore, protein restriction during the peripubertal period causes endothelial dysfunction in adulthood through a mechanism related to oxidative stress.

Emerging evidence suggests that preterm-born individuals (<37 weeks gestation) are at increased risk of developing chronic health conditions in adulthood. This study compared the prevalence, co-occurrence, and cumulative prevalence of three female predominant chronic health conditions – hypertension, rheumatoid arthritis [RA], and hypothyroidism – alone and concurrently. Of 82,514 U.S. women aged 50–79 years enrolled in the Women’s Health Initiative, 2,303 self-reported being born preterm. Logistic regression was used to analyze the prevalence of each condition at enrollment with birth status (preterm, full term). Multinomial logistic regression models analyzed the association between birth status and each condition alone and concurrently. Outcome variables using the 3 conditions were created to give 8 categories ranging from no disease, each condition alone, two-way combinations, to having all three conditions. The models adjusted for age, race/ethnicity, and sociodemographic, lifestyle, and other health-related risk factors. Women born preterm were significantly more likely to have any one or a combination of the selected conditions. In fully adjusted models for individual conditions, the adjusted odds ratios (aORs) were 1.14 (95% CI, 1.04, 1.26) for hypertension, 1.28 (1.12, 1.47) for RA, and 1.12 (1.01, 1.24) for hypothyroidism. Hypothyroidism and RA were the strongest coexisting conditions [aOR 1.69, 95% CI (1.14, 2.51)], followed by hypertension and RA [aOR 1.48, 95% CI (1.20, 1.82)]. The aOR for all three conditions was 1.69 (1.22, 2.35). Perinatal history is pertinent across the life course. Preventive measures and early identification of risk factors and disease in preterm-born individuals are essential to mitigating adverse health outcomes in adulthood.

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.

Studies show associations between prenatal maternal stress (PNMS) and child autism, with little attention paid to PNMS and autism in young adulthood. The broad autism phenotype (BAP), encompassing sub-clinical levels of autism, includes aloof personality, pragmatic language impairment and rigid personality. It remains unclear whether different aspects of PNMS explain variance in different BAP domains in young adult offspring. We recruited women who were pregnant during, or within 3 months of, the 1998 Quebec ice storm crisis, and assessed three aspects of their stress (i.e., objective hardship, subjective distress and cognitive appraisal). At age 19, the young adult offspring (n = 33, 22F / 11M) completed a BAP self-report. Linear and logistic regressions were implemented to examine associations between PNMS and BAP traits. Up to 21.4% of the variance in BAP total score and in BAP three domains tended to be explained by at least one aspect of maternal stress, For example, 16.8% of the variance in aloof personality tended to be explained by maternal objective hardship; 15.1% of the variance in pragmatic language impairment tended to be explained by maternal subjective distress; 20.0% of the variance in rigid personality tended to be explained by maternal objective hardship and 14.3% by maternal cognitive appraisal. Given the small sample size, the results should be interpreted with caution. In conclusion, this small prospective study suggests that different aspects of maternal stress could have differential effects on different components of BAP traits in young adults.

Melatonin supplementation to obese mothers during gestation and lactation might benefit the pancreatic islet cellular composition and beta-cell function in male offspring adulthood. C57BL/6 females (mothers) were assigned to two groups (n = 20/each) based on their consumption in control (C 17% kJ as fat) or high-fat diet (HF 49% kJ as fat). Mothers were supplemented with melatonin (Mel) (10 mg/kg daily) during gestation and lactation, or vehicle, forming the groups (n = 10/each): C, CMel, HF, and HFMel. The male offspring were studied, considering they only received the C diet after weaning until three months old. The HF mothers and their offspring showed higher body weight, glucose intolerance, insulin resistance, and low insulin sensitivity than the C ones. However, HFMel mothers and their offspring showed improved glucose metabolism and weight loss than the HF ones. Also, the offspring’s higher expressions of pro-inflammatory markers and endoplasmic reticulum (ER) stress were observed in HF but reduced in HFMel. Contrarily, antioxidant enzymes were less expressed in HF but improved in HFMel. In addition, HF showed increased beta-cell mass and hyperinsulinemia but diminished in HFMel. Besides, the beta-cell maturity and identity gene expressions diminished in HF but enhanced in HFMel. In conclusion, obese mothers supplemented with melatonin benefit their offspring’s islet cell remodeling and function. In addition, improving pro-inflammatory markers, oxidative stress, and ER stress resulted in better glucose and insulin levels control. Consequently, pancreatic islets and functioning beta cells were preserved in the offspring of obese mothers supplemented with melatonin.

Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.

People commonly face adverse circumstances throughout life, which increases risk for psychiatric disorders, such as anxiety, depression, psychosis, and posttraumatic stress disorder (PTSD). Adversities may occur during different periods in life. Especially adversity during early periods has been suggested to put individuals at risk for adverse mental health outcomes. Here, we investigated whether timing of adversity during the prenatal period, childhood, or mid-to-late adulthood differentially impacted classification into late adulthood symptom profiles. We performed sex-stratified Latent Profile Analysis to identify latent profiles regarding anxious, depressive, psychotic, and PTSD symptoms in n = 568 Dutch famine birth cohort members (n = 294 women, n = 274 men, mean age(SD) = 72.9(0.8)). Cross-sectional late adulthood symptomatology, childhood traumatic maltreatment, and adulthood trauma were based on self-report questionnaires. Prenatal adversity was considered present when individuals were prenatally exposed to the 1944-45 Dutch famine. In both men and women we identified one anxious/depressive profile and three profiles with approximately equal severity of all symptom types within each profile, yet differentiating in overall severity (low, mild, high) between profiles. We additionally found a PTSD symptom profile in women. In men, logistic regression models showed significant associations between prenatal, childhood and adulthood adversity, and profile classification, with differential effects depending on timing and most profound effects of child maltreatment. In women, childhood and adulthood adversity significantly increased classification probability into almost all profiles, with no significant effect of prenatal adversity. These findings support a time-dependent and sex-specific impact of adversity during different periods across the lifespan on psychological health, with consequences into late adulthood.

Women with a history of preeclampsia (PE) have a greater risk of pulmonary arterial hypertension (PAH). In turn, pregnancy at high altitude is a risk factor for PE. However, whether women who develop PE during highland pregnancy are at risk of PAH before and after birth has not been investigated. We tested the hypothesis that during highland pregnancy, women who develop PE are at greater risk of PAH compared to women undergoing healthy highland pregnancies. The study was on 140 women in La Paz, Bolivia (3640m). Women undergoing healthy highland pregnancy were controls (C, n = 70; 29 ± 3.3 years old, mean±SD). Women diagnosed with PE were the experimental group (PE, n = 70, 31 ± 2 years old). Conventional (B- and M-mode, PW Doppler) and modern (pulsed wave tissue Doppler imaging) ultrasound were applied for cardiovascular íííassessment. Spirometry determined maternal lung function. Assessments occurred at 35 ± 4 weeks of pregnancy and 6 ± 0.3 weeks after birth. Relative to highland controls, highland PE women had enlarged right ventricular (RV) and right atrial chamber sizes, greater pulmonary artery dimensions and increased estimated RV contractility, pulmonary artery pressure and pulmonary vascular resistance. Highland PE women had lower values for peripheral oxygen saturation, forced expiratory flow and the bronchial permeability index. Differences remained 6 weeks after birth. Therefore, women who develop PE at high altitude are at greater risk of PAH before and long after birth. Hence, women with a history of PE at high altitude have an increased cardiovascular risk that transcends the systemic circulation to include the pulmonary vascular bed.

Experimental data on the effects of lifestyle interventions on fetal neurodevelopment in humans remain scarce. This study assessed the impact of a pregnancy nutrition+exercise intervention on offspring neurodevelopment at 12 months of age. The Be Healthy in Pregnancy (BHIP) randomized controlled trial (RCT) randomly assigned pregnant persons with stratification by site and body mass index (BMI) to bi-weekly nutrition counselling and high dairy protein diet, walking goal of 10,000 steps/day plus usual prenatal care (UPC; intervention group) or UPC alone (control group). This study examined a subset of these mothers (> 18 years, singleton pregnancy, BMI <40 kg/m2, and enrolled by ≤12 weeks gestation) and their infants (intervention = 42, control = 32), assessing cognition, language, motor, social-emotional, and adaptive functioning at 12 months using the Bayley Scales of Infant and Toddler Development third edition (BSID-III) as the outcome measure. We also examined if maternal factors (prepregnancy BMI, gestational weight gain (GWG)) moderated associations. Expressive language (MD = 9.62, 95% CI = (9.05–10.18), p = 0.03, ƞ2p = 0.07) and general adaptive composite (GAC) scores (MD = 103.97, 95% CI = (100.31–107.63), p = 0.04, ƞ2p = 0.06) were higher in infants of mothers in the intervention group. Effect sizes were medium. However, mean cognitive, receptive language, motor, and social-emotional scale scores did not differ between groups. A structured and monitored nutrition+exercise intervention during pregnancy led to improved expressive language and general adaptive behavior in 12-month-olds, but not cognitive, receptive language, motor, or socioemotional functioning. While these experimental data are promising, further research is needed to determine the clinical utility of nutrition+exercise interventions for optimizing infant neurodevelopment.

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.