In The Pune Maternal Nutrition Study, vitamin B12 deficiency was seen in 65% of pregnant women, folate deficiency was rare. Maternal total homocysteine concentrations were inversely associated with offspring birthweight, and low vitamin B12 and high folate concentrations predicted higher offspring adiposity and insulin resistance. These findings guided a nested pre-conceptional randomised controlled trial ‘Pune Rural Intervention in Young Adolescents’. The interventions included: (1) vitamin B12+multi-micronutrients as per the United Nations International Multiple Micronutrient Antenatal Preparation, and proteins (B12+MMN), (2) vitamin B12 (B12 alone), and (3) placebo. Intervention improved maternal pre-conceptional and in-pregnancy micronutrient nutrition. Gene expression analysis in cord blood mononuclear cells in 88 pregnancies revealed 75 differentially expressed genes between the B12+MMN and placebo groups. The enriched biological processes included G2/M phase transition, chromosome segregation, and nuclear division. Enriched pathways included, mitotic spindle checkpoint and DNA damage response while enriched human phenotypes were sloping forehead and decreased head circumference. Fructose-bisphosphatase 2 (FBP2) and Cell Division Cycle Associated 2 (CDCA2) genes were under-expressed in the B12 alone group. The latter, involved in chromosome segregation was under-expressed in both intervention groups. Based on the role of B-complex vitamins in the synthesis of nucleotides and S-adenosyl methionine, and the roles of vitamins A and D on gene expression, we propose that the multi-micronutrient intervention epigenetically affected cell cycle dynamics. Neonates in the B12+MMN group had the highest ponderal index. Follow-up studies will reveal if the intervention and the altered biological processes influence offspring diabesity.

The aim of the study was to investigate any association between extrauterine growth restriction (EUGR) and intestinal flora of <30-week-old preterm infants. A total of 59 preterm infants were assigned to EUGR (n=23) and non-EUGR (n=36) groups. Intestinal bacteria were compared by using high-throughput sequencing of bacterial rRNA. The total abundance of bacteria in 344 genera (7568 v. 13,760; P<0.0001) and 456 species (10,032 v. 18,240; P<0.0001) was significantly decreased in the EUGR group compared with the non-EUGR group. After application of a multivariate logistic model and adjusting for potential confounding factors, as well as false-discovery rate corrections, we found four bacterial genera with higher and one bacterial genus with lower abundance in the EUGR group compared with the control group. In addition, the EUGR group showed significantly increased abundances of six species (Streptococcus parasanguinis, Bacterium RB5FF6, two Klebsiella species and Microbacterium), but decreased frequencies of three species (one Acinetobacter species, Endosymbiont_of_Sphenophorus_lev and one Enterobacter_species) compared with the non-EUGR group. Taken together, there were significant changes in the intestinal microflora of preterm infants with EUGR compared to preterm infants without EUGR.

Adults who had non-edematous severe acute malnutrition (SAM) during infancy (i.e., marasmus) have worse glucose tolerance and beta-cell function than survivors of edematous SAM (i.e., kwashiorkor). We hypothesized that wasting and/or stunting in SAM is associated with lower glucose disposal rate (M) and insulin clearance (MCR) in adulthood.

We recruited 40 nondiabetic adult SAM survivors (20 marasmus survivors (MS) and 20 kwashiorkor survivors (KS)) and 13 matched community controls. We performed 150-minute hyperinsulinaemic, euglycaemic clamps to estimate M and MCR. We also measured serum adiponectin, anthropometry, and body composition. Data on wasting (weight-for-height) and stunting (height-for-age) were abstracted from the hospital records.

Children with marasmus had lower weight-for-height z-scores (WHZ) (−3.8 ± 0.9 vs. −2.2 ± 1.4; P < 0.001) and lower height-for-age z-scores (HAZ) (−4.6 ± 1.1 vs. −3.4 ± 1.5; P = 0.0092) than those with kwashiorkor. As adults, mean age (SD) of participants was 27.2 (8.1) years; BMI was 23.6 (5.0) kg/m2. SAM survivors and controls had similar body composition. MS and KS and controls had similar M (9.1 ± 3.2; 8.7 ± 4.6; 6.9 ± 2.5 mg.kg−1.min−1 respectively; P = 0.3) and MCR. WHZ and HAZ were not associated with M, MCR or adiponectin even after adjusting for body composition.

Wasting and stunting during infancy are not associated with insulin sensitivity and insulin clearance in lean, young, adult survivors of SAM. These data are consistent with the finding that glucose intolerance in malnutrition survivors is mostly due to beta-cell dysfunction.

Prenatal hypoxia is a common complication of pregnancy and is associated with detrimental health outcomes, such as impaired cardiac and vascular function, in adult offspring. Exposure to prenatal hypoxia reportedly impacts the reproductive system of female offspring. Whether exposure to prenatal hypoxia influences pregnancy adaptations and outcomes in these female offspring is unknown. We hypothesised that prenatal hypoxia impairs uterine artery adaptations in pregnancies of the adult offspring. Pregnancy outcomes and uterine artery function were assessed in 14–16 weeks old non-pregnant and late pregnant (gestational day 20; term = 22 days) adult female offspring born to rats exposed to prenatal normoxia (21% oxygen) or hypoxia (11% oxygen, between days 15–21 of gestation). Compared with normoxia controls, prenatal hypoxia was associated with pregnant adult offspring having reduced placental weights in their litters, and uterine artery circumferential stress that increased with pregnancy. Overall, prenatal hypoxia adversely, albeit mildly, compromised pregnancies of adult offspring.

Mitochondrial dysfunction and resulting changes in adiposity have been observed in the offspring of animals fed a high fat (HF) diet. As iron is an important component of the mitochondria, we have studied the offspring of female rats fed complete (Con) or iron-deficient (FeD) rations for the duration of gestation to test for similar effects. The FeD offspring were ~12% smaller at weaning and remained so because of a persistent reduction in lean tissue mass. The offspring were fed a complete (stock) diet until 52 weeks of age after which some animals from each litter were fed a HF diet for a further 12 weeks. The HF diet increased body fat when compared with animals fed the stock diet, however, prenatal iron deficiency did not change the ratio of fat:lean in either the stock or HF diet groups. The HF diet caused triglyceride to accumulate in the liver, however, there was no effect of prenatal iron deficiency. The activity of the mitochondrial electron transport complexes was similar in all groups including those challenged with a HF diet. HF feeding increased the number of copies of mitochondrial DNA and the prevalence of the D-loop mutation, however, neither parameter was affected by prenatal iron deficiency. This study shows that the effects of prenatal iron deficiency differ from other models in that there is no persistent effect on hepatic mitochondria in aged animals exposed to an increased metabolic load.

Low birthweight rats due to fetal undernutrition sustain higher corticosterone levels when exposed to stress. This is due to the upregulated expression of the pituitary-specific Gas5, a long noncoding RNA (lncRNA) that acts as a glucocorticoid receptor decoy and then competitively inhibiting the binding of glucocorticoids to DNA. However, the mechanism of Gas5 lncRNA upregulation remains unclear. Therefore, using the fetal undernourished model, we identified the factors that regulated Gas5 lncRNA expression and examined their effect on subsequent generations. We found that the expression levels of miR-23 was significantly lower in low birth-weight rats compared with controls. The expression of miR-23 was significantly lower and the expression levels of Gas5 lncRNA were significantly higher in the pituitary gland of low birth-weight offspring of the F2 and F3 generations compared with controls. The methyl modulator intervention in lactating F0 maternal rats restored miR-23 and Gas5 lncRNA expressions not only in F1, F2 and F3 offspring. Moreover, the intervention reduced circulating corticosterone levels and gene expressions in the pituitary gland after restraint stress exposure. In conclusion, miR-23-mediated alterations of the stress response are inherited and restored by methyl modulator intervention during lactation.

The ability of “comfort-food” (CF) diet to revert long-term effects of early-life stress (ELS) is less well known. The objective of this study was to verify if the chronic exposure to CF diet in animals submitted to ELS could relief the stress response at behavioral, neuroendocrine, and neurobiochemical levels, via differences in glucocorticoid receptors expression in brain areas involved in the stress response. From the second day of life, litters of Wistar rats and their mothers were submitted to the reduced nesting material protocol (ELS). In adult life, ELS and a control group were exposed chronically to two diet schemes: standard rat chow only or both “CF” diet, containing fat (34%) and sugar (20%) and a diet similar to the standard diet. Anxiety-like behavior, neuroendocrine response stress, leptin, GR, SOCS-3, pSTAT3, and the abdominal fat were evaluated. The anxiety-like behavior results showed that ELS group when exposed to comfort food were not different from the others groups. Chronic exposure to CF diet induced an anxiety-like behavior in the control group. Groups chronically exposed to CF diet had lower levels of corticosterone over time independent of the neonatal group. The ELS group exposed to the “CF” diet had higher levels of hippocampal GR, lower levels of hypothalamic SOCS-3 and greater accumulation of abdominal fat. Chronic CF diet consumption is able to reduce corticosterone levels independent of the neonatal history, but is associated with anxiety-like behavior in animals without previous history of trauma. Metabolic disturbances like increased adiposity and altered SOCS-3 seem to be a result of multiple insults (neonatal trauma followed by chronic CF diet). We highlight that the Control-chow and ELS-chow data were previously published, and are included in this study for comparative analysis.

Clinical and experimental studies show an association between maternal periodontitis and adverse outcomes during gestation. On the other hand, there were no studies evaluating the impact of maternal periodontitis on the offspring. Thus, our objective was to investigate the repercussion of maternal periodontitis on the development of asthma in the offspring. Pregnant rats were submitted or not to periodontitis by ligature technique. Thirty days after birth, the puppies were sensitized and challenged with ovalbumin (OVA) in order to induce asthmatic response. Our results showed that maternal periodontitis reduced cellular infiltrate in the parenchyma of offspring, tracheal responsiveness, lung edema, and anti-OVA antibodies, without alter mucus as well as cytokines production. We concluded that periodontitis has relevant impact on the offspring’s immune system, blunting the response to allergic and inflammatory stimulus. This study shows the important role of oral health during pregnancy and opens possibilities for future studies in order to explain the effects of periodontitis during pregnancy in the offspring.

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.

Nutrition during the first 1000 days of life represents a window of opportunity to reduce the risk of metabolic dysfunctions later in life. Exclusive breastfeeding (EBF) and adequate introduction of solid foods are essential to promote metabolic and nutritional benefits. We evaluated the association of infant feeding practices from birth to 6 months (M) with adiposity indicators at 12 M. We performed a secondary analysis of 106 healthy term infants born from a cohort of healthy pregnant women. Type of breastfeeding (exclusive or nonexclusive), the start of complementary feeding (CF) (before (<4 M) or after (≥4 M)), and adiposity (body mass index – BMI, body mass index-for-age – BMI/A, waist circumference – WC, and waist circumference–length ratio – WLR) were evaluated at 12 M using descriptive statistics, mean differences, X2, and linear regression models. During the first 6 M, 28.3% (n = 30) of the infants received EBF. Early CF (<4 M) was present in 26.4% (n = 28) of the infants. Children who started CF < 4 M were less breastfed, received added sugars as the most frequently introduced food category, and showed higher BMI, BMI/A, WC, and WLR; those who consumed added sugars early (<4 M) had a higher WC. Starting CF < 4 M was the main factor associated with a higher WC at 12 M. Unhealthy infant feeding practices, such as lack of EBF, early CF, and early introduction of sugars, may be associated with higher adiposity at 12 M.

The Åland Islands were recently ranked as Finland’s healthiest region with lower prevalence of several non-communicable diseases compared with the national mean. We have compared birth characteristics of 1697 individuals born on the Åland Islands between 1937 and 1944 with contemporaneous data from the Helsinki Birth Cohort Study (HBCS; n=11,808). This is a first step towards a potential future analysis of Ålandic health from a life-course perspective. Mean birth weight and length were calculated for both cohorts. Birth weight was entered into a multiple linear regression model with sex, maternal age, marital status and birth year as predictors. Mean birth weight in the Åland cohort was 3499 g, 87 g (95% CI 62; 111) higher compared with the HBCS. Sex and maternal marital status were the strongest predictors of birth weight. More detailed studies are needed to explore the potential effects of this difference in average birth weight between cohorts.

Nutrition and the incidence of diseases during early life are considered environmental factors that determine people’s height when they become adults. While there is extensive literature focusing on the relationship between physical growth, general mortality and infant mortality rates, few studies analyse the impact of certain disease groups on the final height of historical populations. Using regional mortality rates by causes of death, the main objective of this study is to determine the onset of the disease environment during early life for populations born in Spain between 1916 and 1930, and its relationship with the stature reached at 21 years of age. A population-averaged model is performed on epidemic-infectious, gastrointestinal, and congenital diseases during the gestation period and first year of life. The disease burden in early life had a statistically significant negative effect on adult stature. These results support the premise that an improvement in the disease environment could lead to a greater number of short children surviving and therefore a decrease in the average height.

Although abundant evidence exists that adverse events during pregnancy lead to chronic conditions, there is limited information on the impact of acute insults such as sepsis. This study tested the hypothesis that impaired fetal development leads to altered organ responses to a septic insult in both male and female adult offspring. Fetal growth restricted (FGR) rats were generated using a maternal protein-restricted diet. Male and female FGR and control diet rats were housed until 150–160 d of age when they were exposed either a saline (control) or a fecal slurry intraperitoneal (Sepsis) injection. After 6 h, livers and lungs were analyzed for inflammation and, additionally, the amounts and function of pulmonary surfactant were measured. The results showed increases in the steady-state mRNA levels of inflammatory cytokines in the liver in response to the septic insult in both males and females; these responses were not different between FGR and control diet groups. In the lungs, cytokines were not detectable in any of the experimental groups. A significant decrease in the relative amount of surfactant was observed in male FGR offspring, but this was not observed in control males or in female animals. Overall, it is concluded that FGR induced by maternal protein restriction does not impact liver and lung inflammatory response to sepsis in either male or female adult rats. An altered septic response in male FGR offspring with respect to surfactant may imply a contribution to lung dysfunction.

Extremely premature birth is associated with a permanent disruption of energy metabolism. The underlying mechanisms are poorly understood. The oxidative stress induced by parenteral nutrition (PN) during the first week of life is suspected to reprogram energy metabolism in the liver. Full-term male Hartley guinea pigs (to isolate PN from prematurity) receiving PN enriched or not with glutathione (to isolate PN effects from PN-induced oxidative stress effects) or an Oral Nutrition (ON) during the first week of life were used. At 1 week (neonatal) and 16 weeks (adult), measurements of liver glutathione (GSH and GSSG) and activities of three key enzymes of energy metabolism (glucokinase (GCK), phosphofructokinase (PFK), and acetyl-CoA carboxylase (ACC)) were performed. Differences between groups were reported if p ≤ 0.05 (Analysis of Variance). At 1 week, compared to ON, PN induced higher GSSG (oxidative stress), higher GCK activity, and lower PFK and ACC activity, the glutathione supplement prevented all PN effects. At 16 weeks, early PN induced lower GSSG (reductive stress) and lower GCK activity, which was prevented by added glutathione, and higher ACC activity independent of glutathione supplement. ACC was negatively associated (r2 = 0.33) with GSSG. Increased nicotinamide adenine dinucleotide phosphate levels confirmed the glucose-6-phosphate accumulation at 1 week, whereas our protocol failed to document lipid accumulation at 16 weeks. In adult male guinea pigs, neonatal exposure to PN affected glutathione metabolism leading to reductive stress (lower GSSG) and an altered metabolic flow of glucose. Partial prevention with glutathione supplementation suggests that, in addition to peroxides, other factors of PN are involved.

Breastfeeding may reduce obesity risk, but this association could be confounded by breastfeeding families’ characteristics. We investigated if body composition differs at birth among infants who were either exclusively breast- or formula-fed. We hypothesized the two groups would differ in body composition, even at birth, prior to their post-natal feeding experience. Healthy primiparous carrying singleton pregnancy were recruited at 15 weeks’ gestation. PEA POD® measured body composition within 72 hours of delivery and infant feeding was prospectively captured. Out of the 1,152 infants recruited, 117 (10.2%) and 239 (20.7%) went on to be either exclusively breast- or formula-fed, respectively. Breastfed infants were heavier at birth, but their percentage fat mass (FM) was lower than that of exclusively formula-fed infants (covariate adjusted β = −1.91 percentage points of FM; 95% CI −2.82 to −1.01). Differences in intra-uterine exposures, irrespective of early diet, may partly explain an infant’s obesity risk.

Preterm birth, low birthweight, intrauterine growth retardation and small for gestational age are birth phenotypes that significantly contribute to life-long morbidity and mortality. This review examines the epidemiologic and biologic evidence of folic acid (FA) as a potential population-based intervention to curtail some adverse birth phenotypic expressions, and by extension, their later physical and neurodevelopmental consequences. We outlined a feto-placental adaptation categorization taking into account how prenatal insults may be encoded in fetal development, the adaptive success of the feto-placental response, and subsequent expression in the health of the fetus. Although there are plausible biological pathways that can be implicated, we found that the epidemiological evidence on the role of perinatal FA nutriture and fetal programming of adverse birth phenotypes is still inconclusive. Because biologic and epidemiological considerations alone do not suffice in deciphering the utility of FA in averting adverse birth phenotypes, we proposed a biopsychosocial model that takes into account multi-layered psychosocial contexts for improving subsequent research studies in this area.

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.

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.

Exposure to maternal hyperglycemia in utero has been associated with adverse metabolic outcomes in offspring. However, few studies have investigated the relationship between maternal hyperglycemia and offspring cortisol levels. We assessed associations of gestational diabetes mellitus (GDM) with cortisol biomarkers in two longitudinal prebirth cohorts: Project Viva included 928 mother–child pairs and Gen3G included 313 mother–child pairs. In Project Viva, GDM was diagnosed in N = 48 (5.2%) women using a two-step procedure (50 g glucose challenge test, if abnormal followed by 100 g oral glucose tolerance test [OGTT]), and in N = 29 (9.3%) women participating in Gen3G using one-step 75 g OGTT. In Project Viva, we measured cord blood glucocorticoids and child hair cortisol levels during mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In Gen3G, we measured hair cortisol at 5.4 (0.3) years. We used multivariable linear regression to examine associations of GDM with offspring cortisol, adjusting for child age and sex, maternal prepregnancy body mass index, education, and socioeconomic status. We additionally adjusted for child race/ethnicity in the cord blood analyses. In both Project Viva and Gen3G, we observed null associations of GDM and maternal glucose markers in pregnancy with cortisol biomarkers in cord blood at birth (β = 16.6 nmol/L, 95% CI −60.7, 94.0 in Project Viva) and in hair samples during childhood (β = −0.56 pg/mg, 95% CI −1.16, 0.04 in Project Viva; β = 0.09 pg/mg, 95% CI −0.38, 0.57 in Gen3G). Our findings do not support the hypothesis that maternal hyperglycemia is related to hypothalamic–pituitary–adrenal axis activity.