Exposure to endocrine-disrupting chemicals during critical windows of development may lead to functional abnormalities in adulthood. Isoflavones are a flavonoid group of phytoestrogens that are recognized by their estrogenic activity and are highly abundant in soybean. Since the thyroid gland presents estrogen receptors and infants, toddlers and teenagers may consume isoflavones from soy-based infant formula and beverages as alternatives to animal milk, we propose to investigate the potential effects of relevant concentrations of soy isoflavones in the regulation of the hypothalamic–pituitary (HP) thyroid axis using peripubertal male rats as an experimental model. Thirty-two 23-day-old male rats were exposed to 0.5, 5, or 50 mg of soy isoflavones/kg from weaning to 60 days of age, when they were euthanized, and the tissues were collected to evaluate the mRNA expression of genes involved in the regulation of the HP thyroid axis and dosages of thyroid hormones (THs). Serum TSH concentrations were increased, while alterations were not observed in serum concentrations of triiodothyronine and thyroxine. Regarding mRNA gene expression, Mct-8 was increased in the hypothalamus, Mct-8, Thra1, and Thrb2 were decreased in the pituitary, and Nis and Pds were reduced in the thyroid. In the heart, Mct8 and Thrb2 were increased, and Thra1 was decreased. In the liver, Mct8, Thra1, and Thrb2 were decreased. These results suggest that the consumption of relevant doses of soy isoflavones during the peripubertal period in males may induce subclinical hypothyroidism, with alterations in the regulation of the HP thyroid axis, modulation of TH synthesis, and peripheral alterations in TH target organs.

Insulin-like growth factor 1 (IGF1) is a regulator of human growth during infancy and childhood, known to promote bone and muscle growth as well as lipid accumulation. This study aimed to investigate the effects of formula milk with or without IGF1 supplementation (in the form of pure IGF1 or bovine colostrum) on growth and body composition in infant cynomolgus macaques during the first 6 months of life. Three groups of infants were nursery-reared and received formula milk with or without IGF1 or bovine colostrum supplementation for 4 months, and a fourth group consisting of breast-fed infants was included for comparison (n=6 for each group). Ranked-based analysis of covariance was used to detect differences between adjusted means for sex. No differences in weight, height, fat mass, and fat-free mass could be detected between groups. However, bone mineral density (BMD) was significantly different between groups at the end of formula feeding. Infants that received bovine colostrum supplementation displayed higher mean BMD than infants of all other groups, with no differences between the latter three groups. In conclusion, our results suggest that supplementation with bovine colostrum can enhance BMD in formula-fed infants, an effect that apparently does not depend on IGF1. Bovine colostrum supplementation could be beneficial for long-term bone health in infants with suboptimal bone growth.

Low birthweight has been related to an increased risk of adult cardiovascular disease (CVD). Transgenerational studies have been used to investigate likely mechanisms underlying this inverse association. However, previous studies mostly examined the association of offspring birthweight with CVD risk factors among parents. In this study, we investigated the association between offspring birthweight and individual CVD risk factors, an index of CVD risk factors, and education in their parents, aunts/uncles, and aunts’/uncles’ partners. Birth data (Medical Birth Registry, Norway (MBRN) (1967–2012)) was linked to CVD risk factor data (the County Study, Age 40 Program, and Cohort Norway (CONOR)) for the parents, aunts/uncles, and their partners. For body mass index (BMI), resting heart rate (RHR), systolic blood pressure (SBP), total cholesterol (TC), triglycerides (TG), and a risk factor index, the associations were examined by linear regression. For smoking and education, they were examined by logistic regression. Low birthweight was associated with an unfavorable risk factor profile in all familial relationships. For each kg increase in birthweight, the mean risk factor index decreased by −0.14 units (−0.15, −0.13) in mothers, −0.11 (−0.12, −0.10) in fathers, and −0.02 (−0.05, −0.00) to −0.07 (−0.09, −0.06) in aunts/uncles and their partners. The association in mothers was stronger than fathers, but it was also stronger in aunts/uncles than their partners. Profound associations between birthweight and CVD risk factors in extended family members were observed that go beyond the expected genetic similarities in pedigrees, suggesting that mechanisms like environmental factors, assortative mating, and genetic nurturing may explain these associations.

The multifactorial etiology of pediatric cancer is poorly understood. Environmental factors occurring during embryogenesis can disrupt epigenetic signaling, resulting in several diseases after birth, including cancer. Associations between assisted reproductive technologies (ART), such as in vitro fertilization (IVF), and birth defects, imprinting disorders and other perinatal adverse events have been reported. IVF can result in methylation changes in the offspring, and a link with pediatric cancer has been suggested. In this study, we investigated the peripheral blood methylomes of 11 patients conceived by IVF who developed cancer in childhood. Methylation data of patients and paired sex/aged controls were obtained using the Infinium MethylationEPIC Kit (Illumina). We identified 25 differentially methylated regions (DMRs), 17 of them hypermethylated, and 8 hypomethylated in patients. The most significant DMR was a hypermethylated genomic segment located in the promoter region of LHX6, a transcription factor involved in the forebrain development and interneuron migration during embryogenesis. An additional control group was included to verify the LHX6 methylation status in children with similar cancers who were not conceived by ART. The higher LHX6 methylation levels in IVF patients compared to both control groups (healthy children and children conceived naturally who developed similar pediatric cancers), suggested that hypermethylation at the LHX6 promoter could be due to the IVF process and not secondary to the cancer itself. Further studies are required to evaluate this association and the potential role of LHX6 promoter hypermethylation for tumorigenesis.

Nonalcoholic fatty liver disease (NAFLD) involves changes in hepatic pathways, as lipogenesis, oxidative stress, endoplasmic reticulum (ER) stress, and macroautophagy. Maternal nicotine exposure exclusively during lactation leads to fatty liver (steatosis) only in the adult male offspring, not in females. Therefore, our hypothesis is that neonatal exposure to nicotine sex-dependently affects the signaling pathways involved in hepatic homeostasis of the offspring, explaining the hepatic lipid accumulation phenotype only in males. For this, between postnatal days 2 and 16, Wistar rat dams were implanted with osmotic minipumps, which released nicotine (NIC; 6 mg/Kg/day) or vehicle. The livers of offspring were evaluated at postnatal day 180. Only the male offspring that had been exposed to nicotine neonatally showed increased protein expression of markers of unfolded protein response (UPR), highlighting the presence of ER stress, as well as disruption of the activation of the macroautophagy repair pathway. These animals also had increased expression of diacylglycerol O-acyltransferase 1 and 4-hydroxynonenal, suggesting increased triglyceride esterification and oxidative stress. These parameters were not altered in the female offspring that had been neonatally exposed to nicotine, however they exhibited increased phospho adenosine monophosphate-activated protein kinase pAMPK expression, possibly as a protective mechanism. Thus, the disturbance in the hepatic homeostasis by UPR, macroautophagy, and oxidative stress modifications seem to be the molecular mechanisms underlying the liver steatosis in the adult male offspring of the nicotine-programming model. This highlights the importance of maternal smoking cessation during breastfeeding to decrease the risk of NAFLD development, especially in males.

Maternal periconceptional undernutrition (PCUN) affected fetal pancreatic maturation in late gestation lambs and impaired glucose tolerance in 10-month-old sheep. To examine the importance of the timing of maternal undernutrition around conception, a further cohort was born to PCUN ewes [undernourished for 61 d before conception (PreC), 30 d after conception (PostC), or 61 d before until 30 d after conception (PrePostC)], or normally fed ewes (Control) (n = 15–20/group). We compared glucose tolerance, insulin secretion, and sensitivity at 36 months of age. We also examined protein expression of insulin signalling proteins in muscle from these animals and in muscle from a fetal cohort (132 d of gestation; n = 7–10/group). Adult PostC and PrePostC sheep had higher glucose area under the curve than Controls (P = 0.07 and P = 0.02, respectively), whereas PreC sheep were similar to Controls (P = 0.97). PostC and PrePostC had reduced first-phase insulin secretion compared with Control (P = 0.03 and P = 0.02, respectively). PreC was similar to Control (P = 0.12). Skeletal muscle SLC2A4 protein expression in PostC and PrePostC was increased 19%–58% in fetuses (P = 0.004), but decreased 39%–43% in adult sheep (P = 0.003) compared with Controls. Consistent with this, protein kinase C zeta (PKCζ) protein expression tended to be increased in fetal (P = 0.09) and reduced in adult (P = 0.07) offspring of all PCUN ewes compared with Controls. Maternal PCUN alters several aspects of offspring glucose homeostasis into adulthood. These findings suggest that maternal periconceptional nutrition has a lasting impact on metabolic homeostasis of the offspring.

Neonatal undernutrition in rats results in short- and long-term behavioral and hormonal alterations in the offspring. It is not clear, however, whether these effects are present since the original insult or if they develop at some specific age later in life. Here, we assessed the ontogenetic profile of behavioral parameters associated with anxiety, exploration and memory/learning of Wistar rat offspring that were subjected to protein malnutrition during lactation. Dams and respective litters were separated into two groups: (1) protein-restricted (PR), which received a hypoproteic chow (8% protein) from birth to weaning [postnatal day (PN) 21]; (2) control (C), which received normoproteic chow. Offspring’s behaviors, corticosterone, catecholamines, T3 and T4 levels were assessed at PN21 (weaning), PN45 (adolescence), PN90 (young adulthood) or PN180 (adulthood). PR offspring showed an age-independent reduction in the levels of anxiety-like behaviors in the Elevated Plus Maze and better memory performance in the Radial Arm Water Maze. PR offspring showed peak exploratory activity in the Open Field earlier in life, at PN45, than C, which showed theirs at PN90. Corticosterone was reduced in PR offspring, particularly at young adulthood, while catecholamines were increased at weaning and adulthood. The current study shows that considerable age-dependent variations in the expression of the observed behaviors and hormonal levels exist from weaning to adulthood in rats, and that protein restriction during lactation has complex variable-dependent effects on the ontogenesis of the assessed parameters.

The aim of this study was to evaluate whether high-fat (HF) diet intake during puberty can program obesity as well as generate glucose imbalance and hepatic metabolic dysfunctions in adult life. Male Wistar rats were randomly assigned into two groups: rats fed standard chow (NF) and rats fed a HF from postnatal 30-day-old (PND30) until PND60. Then, both groups were fed a standard chow from PND60 until PND120. Euthanasia and samples collections occurred at PND120. HF animals were overweight (+11%) and had increased adiposity, hyperphagia (+12%), hyperglycaemia (+13%), hyperinsulinemia (+69%), and hypertriglyceridemia (+34%). Plasma glucose levels during intravenous glucose tolerance test (ivGTT) and intraperitoneal insulin tolerance test (ipITT) were also higher in the HF group, whereas Kitt was significantly lower (–34%), suggesting reduced insulin sensitivity. In the same sense, HF animals present pancreatic islets hypertrophy and high β-cell mass. HF animals also had a significant increase in blood glucose levels during pyruvate tolerance test, indicating increased gluconeogenesis. Hepatic morphology analyses showed an increase in lipid inclusion in the HF group. Moreover, PEPCK and FAS protein expression were higher in the livers of the HF animals (+79% and + 37%, respectively). In conclusion, HF during puberty causes obese phenotype leading to glucose dyshomeostasis and nonalcoholic fatty liver disease, which can be related to the overexpression of proteins PEPCK and FAS.

Maternal obesity and malnutrition during gestation and lactation have been recognized to increase the risk of obesity and metabolic disorders in the offspring across their lifespan. However, the gestational period during which malnutrition exerts a decisive effect is unclear. Brown adipose tissue (BAT) plays a critical role in energy metabolism owing to its high efficiency in oxidizing glucose and fatty acids. This study aimed to determine the impact of maternal high-fat diet (HFD) consumption only during pregnancy on BAT and energy metabolism in offspring mice. Dams were fed an HFD or a normal chow diet from embryonic day 2.5. HFD consumption during pregnancy induced glucose intolerance and hypertension in dams. In the offspring of HFD-fed dams, maternal HFD lowered fetal weight without affecting placental weight, whereas HFD consumption after birth exacerbated oxygen consumption and cold-induced thermogenesis at 12 months of age, accompanied by increased lipid droplet size in BAT. These data demonstrate that HFD consumption only during pregnancy exerts a long-lasting effect on BAT. Collectively, these findings indicate the importance of nutrition during pregnancy with respect to the energy metabolism of the offspring, and pregnant women should thus ensure proper nutrition during pregnancy to ensure normal energy metabolism in the offspring.

Sleep shortening during pregnancy may alter the mother’s environment, affecting the offspring. Thus, the present study evaluated the metabolic profile of female offspring from sleep-restricted rats during the last week of pregnancy. Pregnant Wistar rats were distributed into two groups: control (C) and sleep restriction (SR). The SR was performed 20 h/day, from 14th to 20th day of pregnancy. At 2 months, half of the offspring were subjected to ovariectomy (OVX); the others, to sham surgery. Studied groups were Csham, Covx, SRsham and SRovx. Cholesterol (HDL, LDL and C-total), triglycerides (TG) and glucose and insulin tolerance tests (GTT–ITT) were evaluated at 8 months. RSsham presented higher values of TG, while SRovx presented higher TG, LDL and C-total. Basal glucose concentration was increased in SRsham and SRovx. These data suggest that SR during pregnancy may be a risk factor for the development of diseases in adult female offspring.

Maternal diet during pregnancy has been associated with obesity among offspring. The extent to which trimester-specific dietary patterns are associated with markers of adiposity during adolescence remains unclear. We examined associations between prenatal diet patterns with adolescent offspring measures of adiposity and adipokines in 384 mother–adolescent dyads from the Mexico City ELEMENT cohort. Trimester-specific diet patterns were derived from principal component analysis of food frequency questionnaire data. Adolescent anthropometry and serum leptin and adiponectin were measured at 10–17 years. Three maternal diet patterns were identified: Prudent Diet (PD), high in fish and vegetables, the High Meat and Fat Diet (HMFD), high in pork and processed meats, and the Transitioning Mexican Diet (TMD), high in corn tortillas and sugar-sweetened beverages. Multiple linear regression was used to estimate sex-stratified associations among quartiles of diet patterns with adiposity and adipokines, adjusting for maternal marital status, education, and parity. First trimester TMD was associated with greater anthropometric measures and higher leptin in females, while third trimester HMFD was associated higher body fat percentage, triceps thickness, waist circumference, and leptin, but lower adiponectin among males. Contrary to expectation, there were positive associations between the trimester 1 PD pattern and anthropometric measurements in females, and for trimester 2 HMFD and TMD patterns with adipokines among males. Findings suggest maternal diet patterns may influence offspring adiposity markers during adolescence in a sex-specific manner.

This study aimed to investigate the association between maternal birth weight (MBW) with preterm delivery (PTD) in the Japanese population. To this end, a total of 78,972 Japanese pregnant women were included in a prospective birth cohort study. Multiple logistic regression and multinominal logistic regression models were applied to investigate the associations of MBW with PTD (delivery from 22 to < 37 weeks of gestation), early PTD (delivery from 22 to < 34 weeks), and late PTD (delivery from 34 to < 37 weeks). The results showed that MBW was inversely associated with PTD, early PTD, and late PTD (p-for-trend < 0.0001, 0.0014, and < 0.0001, respectively). The adjusted odds ratios per each 500 g of MBW decrease were 1.167 (95% confidence interval [CI]: 1.118–1.218) for PTD, 1.174 (95% CI: 1.070–1.287) for early PTD and 1.151 (95% CI: 1.098–1.206) for late PTD. The effect size of the association of MBW with early PTD was similar to that with late PTD. This study demonstrated for the first time an association of a low MBW with PTD, early PTD, and late PTD in a Japanese nationwide cohort.

One of the longstanding debates in life-course epidemiology is whether an adverse intrauterine environment, often proxied by birth weight, causally increases the future risk of cardiometabolic disease. The use of a discordant twin study design, which controls for the influence of shared genetic and environmental confounding factors, may be useful to investigate whether this relationship is causal. We conducted a discordant twin study of 120 monozygotic (MZ) and 148 dizygotic (DZ) twin pairs from the UK Biobank to explore the potential causal relationships between birth weight and a broad spectrum of later-life cardiometabolic risk factors. We used a linear mixed model to investigate the association between birth weight and later-life cardiometabolic risk factors for twins, allowing for both within-pair differences and between-pair differences in birth weight. Of primary interest is the within-pair association between differences in birth weight and cardiometabolic risk factors, which could reflect an intrauterine effect on later-life risk factors. We found no strong evidence of association in MZ twins between the within-pair differences in birth weight and most cardiometabolic risk factors in later life, except for nominal associations with C-reactive protein and insulin-like growth factor 1. However, these associations were not replicated in DZ twin pairs. Our study provided no strong evidence for intrauterine effects on later-life cardiometabolic risk factors, which is consistent with previous large-scale studies of singletons testing the potential causal relationship. It does not support the hypothesis that adverse intrauterine environments increase the risk of cardiometabolic disease in later life.

Animal and human data demonstrate independent relationships between fetal growth, hypothalamic-pituitary-adrenal axis function (HPA-A) and adult cardiometabolic outcomes. While the association between fetal growth and adult cardiometabolic outcomes is well-established, the role of the HPA-A in these relationships is unclear. This study aims to determine whether HPA-A function mediates or moderates this relationship. Approximately 2900 pregnant women were recruited between 1989-1991 in the Raine Study. Detailed anthropometric data was collected at birth (per cent optimal birthweight [POBW]). The Trier Social Stress Test was administered to the offspring (Generation 2; Gen2) at 18 years; HPA-A responses were determined (reactive responders [RR], anticipatory responders [AR] and non-responders [NR]). Cardiometabolic parameters (BMI, systolic BP [sBP] and LDL cholesterol) were measured at 20 years. Regression modelling demonstrated linear associations between POBW and BMI and sBP; quadratic associations were observed for LDL cholesterol. For every 10% increase in POBW, there was a 0.54 unit increase in BMI (standard error [SE] 0.15) and a 0.65 unit decrease in sBP (SE 0.34). The interaction between participant’s fetal growth and HPA-A phenotype was strongest for sBP in young adulthood. Interactions for BMI and LDL-C were non-significant. Decomposition of the total effect revealed no causal evidence of mediation or moderation.

Early life stress (ELS) and a Western diet (WD) promote mood and cardiovascular disorders, however, how these risks interact in disease pathogenesis is unclear. We assessed effects of ELS with or without a subsequent WD on behaviour, cardiometabolic risk factors, and cardiac function/ischaemic tolerance in male mice. Fifty-six new-born male C57BL/6J mice were randomly allocated to a control group (CON) undisturbed before weaning, or to maternal separation (3h/day) and early (postnatal day 17) weaning (MSEW). Mice consumed standard rodent chow (CON, n = 14; MSEW, n = 15) or WD chow (WD, n = 19; MSEW + WD, n = 19) from week 8 to 24. Fasted blood was sampled and open field test and elevated plus maze (EPM) tests undertaken at 7, 15, and 23 weeks of age, with hearts excised at 24 weeks for Langendorff perfusion (evaluating pre- and post-ischaemic function). MSEW alone transiently increased open field activity at 7 weeks; body weight and serum triglycerides at 4 and 7 weeks, respectively; and final blood glucose levels and insulin resistance at 23 weeks. WD increased insulin resistance and body weight gain, the latter potentiated by MSEW. MSEW + WD was anxiogenic, reducing EPM open arm activity vs. WD alone. Although MSEW had modest metabolic effects and did not influence cardiac function or ischaemic tolerance in lean mice, it exacerbated weight gain and anxiogenesis, and improved ischaemic tolerance in WD fed animals. MSEW-induced increases in body weight (obesity) in WD fed animals in the absence of changes in insulin resistance may have protected the hearts of these mice.

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.

Protein malnutrition during critical periods poses significant risks to reproductive health. Thus, this study aims to evaluate the immediate and delayed effects of a 30-day low-protein diet on the postnatal development of the male reproductive system. For so, male rats were fed a protein-deficient diet from postnatal day 30–60, followed by evaluations of testis, epididymis, and spermatozoa both at the end of the diet and after a 60-day recovery period. Testicular and epididymal weight was lowered in pubertal animals. Several histological alterations were found in the testis, such as acidophilic cells and vacuoles in the seminiferous epithelium, and sperm production was compromised. In the epididymis, the luminal compartment was diminished, and the stroma was enlarged both in the caput and cauda; in the cauda, the epithelial compartment was enlarged; the transit time of spermatozoa through this organ was diminished. Testosterone production was lowered. Spermatozoa’s motility, mitochondrial activation, and acrosomal integrity were impaired, and several alterations in morphology were observed. After the recovery period, testicular and epididymal weight was restored. Tissue remodulation was observed in the epididymis, but the spermatozoa’s transit time in this organ was not altered. Sperm and testosterone production, spermatozoa motility, mitochondrial activation, and acrosomal integrity were also restored. However, testicular histological alterations and spermatic morphological abnormalities were maintained in protein-restricted animals. Protein restriction during peripuberty impairs the reproductive maturation of pubertal Wistar rats, impairing testicular and epididymal function, with lasting effects even after dietary correction.