Diabetes predisposition is determined by pancreatic islet insulin secretion and insulin resistance. We studied female rat offspring exposed to low-protein maternal diet (50% control protein diet) in pregnancy and/or lactation at postnatal days 36, 110 and 450. Rats were fed either control 20% casein diet (C) or restricted diet (R – 10% casein) during pregnancy. After delivery, mothers received either C or R diet until weaning to provide four offspring groups: CC, RR, CR and RC (first letter denoting maternal pregnancy diet and the second lactation diet). Serum glucose, insulin and homeostatic model assessment (HOMA) were measured. Pancreatic islets were isolated and in vitro insulin secretion quantified in low glucose (5 mM) and high glucose (11 mM). Serum glucose, insulin and HOMA were similar in all groups at 36 and 110 postnatal days. HOMA was only higher in RR at 450 postnatal days. Only CC demonstrated differences in glucose sensitivity of β-cells to high and low doses at the three ages studied. At 36 days, RR, CR and RC and at 450 days RR and RC groups did not show glucose-stimulated insulin secretion differences between low and high glucose. Aging-associated glucose-stimulated insulin secretion loss was affected by maternal dietary history, indicating that developmental programming must be considered a major factor in aging-related development of predisposition to later-life dysfunctional insulin metabolism. Female offspring islets’ insulin secretion was higher than previously reported in males.

Poor nutrition during fetal development can permanently alter growth, cardiovascular physiology and metabolic function. Animal studies have shown that prenatal undernutrition followed by balanced postnatal nutrition alters deoxyribonucleic acid (DNA) methylation of gene promoter regions of candidate metabolic control genes in the liver. The aim of this study was to investigate whether methylation status of the proximal promoter regions of four candidate genes differed between individuals exposed to the Dutch famine in utero. In addition, we determined whether methylation status of these genes was associated with markers of metabolic and cardiovascular disease and adult lifestyle. Methylation status of the GR1-C (glucocorticoid receptor), PPARγ (peroxisome proliferator-activated receptor gamma), lipoprotein lipase and phosphatidylinositol 3 kinase p85 proximal promoters was investigated in DNA isolated from peripheral blood samples of 759 58-year-old subjects born around the time of the 1944–45 Dutch famine. We observed no differences in methylation levels of the promoters between exposed and unexposed men and women. Methylation status of PPARγ was associated with levels of high-density lipoprotein cholesterol and triglycerides as well as with exercise and smoking. Hypomethylation of the GR promoter was associated with adverse adult lifestyle factors, including higher body mass index, less exercise and more smoking. The previously reported increased risk of cardiovascular and metabolic disease after prenatal famine exposure was not associated with differences in methylation status across the promoter regions of these candidate genes measured in peripheral blood. The adult environment seems to affect GR and PPARγ promoter methylation.

Early life nutrition and growth are related to subsequent obesity risk in high-income countries. We investigated the association between nutrition and growth during infancy, and body composition at 10 years of age in 140 children selected from the Bone Health sub-study of the Birth-to-Twenty cohort from Soweto, Johannesburg, South Africa. Infant feeding and dietary data were collected during the first 12 months, and weight and height were measured at 1 and 2 years of age. At 10 years, anthropometry and dual-energy X-ray absorptiometry (DXA)-derived body composition were measured. Regression models were used to determine associations between independent and dependent variables at the 1% level of significance. A one z-score increase in birth weight was associated with a 1051 g increase in lean mass and a 0.22 increase in body mass index (BMI) z-score at the age of 10 years. After adjusting for confounders, stunting at age 1 year was associated with lower fat mass only at 10 years of age while at age 2 years, it was associated with lower lean mass only. Being underweight at one year of age was significantly associated with lower lean mass only. Weight-for-age (WAZ) change in the second year of infancy was a predictor of fat mass and BMI only. Body fatness at 10 years of age was positively associated with infant WAZ change rather than height-for-age change. There were no significant associations between infant dietary patterns, wasting and being underweight at age 2 years and pre-pubertal body composition. Further studies are needed to assess whether these associations continue during adolescence as pubertal development may be an important modifier of these associations.

The association of infants’ birth weight with maternal cardiovascular morbidity (CVD) and mortality substantiates the foetal origins hypothesis. Few studies to date have investigated grandparent–infant risk association. We prospectively examined this relationship in the Lifeways three-generation familial cohort, contrasting lineage and gender differences to understand mechanisms of intergenerational risk transmission. In 2001, a cohort of 1082 families was established at antenatal stage. A total of 539 families (n = 539 infants) had both a participating grandparent (n = 1054) and information on infants’ gestational age. At baseline, grandparents provided their diagnosed CVD status and 79% also underwent a cardiovascular risk factors assessment. In 2005, general practitioners provided an update for 61% grandparents. In 2010, a search of civil register confirmed 77 grandparental deaths in 539 families. Grandchildren's birth weight and grandparental cardiovascular risk factors associations were examined with linear regressions. Grandparental CVD associations were analysed using ANCOVA. Cox proportional hazard ratios (HR) were calculated for all-cause mortality associations. Models were adjusted for infants’, mothers’ and grandparents’ demographic, anthropometric and socio-behavioural characteristics, as appropriate. The paternal grandfathers’ (PGF) systolic blood pressure (mmHg) [β (95% CI) = 6.6 (0.8 – 12.5); P = 0.03] and paternal grandmothers’ serum triglycerides (mmol/l) [β (95% CI) = 78.8 (7.0 – 150.7); P = 0.03] were linearly predictive of infants’ birth weight, which was not observed for maternal grandparents. Mean birth weight for infants of maternal grandmothers with diabetes {−272.7 [(−499.7) − (−45.6)] g; P = 0.02} or stroke {−292.1 [(−544.5) − (−39.6)] g; P = 0.02} was lower than those without diabetes or stroke, a pattern not observed for paternal grandparents. Whereas PGFs’ mortality was significantly associated with infants’ high birth weight (⩾4000 g) [HR (95% CI) = 4.9 (1.2 – 19.9); P = 0.03], maternal grandparents’ mortality showed a converse pattern with infants’ low birth weight (<2500 g) [HR (95% CI) = 1.7 (0.4 – 8.2); P = 0.7], although not statistically significant. These findings suggest that intergenerational transmission of risk differs in maternal and paternal lines.

Advances in understanding the molecular basis of behavior through epigenetic mechanisms could help explain the developmental origins of child mental health disorders. However, the application of epigenetic principles to the study of human behavior is a relatively new endeavor. In this paper we discuss the ‘Developmental Origins of Health and Disease’ including the role of fetal programming. We then review epigenetic principles related to fetal programming and the recent application of epigenetics to behavior. We focus on the neuroendocrine system and develop a simple heuristic stress-related model to illustrate how epigenetic changes in placental genes could predispose the infant to neurobehavioral profiles that interact with postnatal environmental factors potentially leading to mental health disorders. We then discuss from an ‘Evo-Devo’ perspective how some of these behaviors could also be adaptive. We suggest how elucidation of these mechanisms can help to better define risk and protective factors and populations at risk.

Pregestational obesity is a significant risk factor for adverse pregnancy outcomes. Maternal obesity is associated with a specific proinflammatory, endocrine and metabolic phenotype that may lead to higher supply of nutrients to the feto-placental unit and to excessive fetal fat accumulation. In particular, obesity may influence placental fatty acid (FA) transport in several ways, leading to increased diffusion driving force across the placenta, and to altered placental development, size and exchange surface area. Animal models show that maternal obesity is associated with increased expression of specific FA carriers and inflammatory signaling molecules in placental cotyledonary tissue, resulting in enhanced lipid transfer across the placenta, dislipidemia, fat accumulation and possibly altered development in fetuses. Cell culture experiments confirmed that inflammatory molecules, adipokines and FA, all significantly altered in obesity, are important regulators of placental lipid exchange. Expression studies in placentas of obese–diabetic women found a significant increase in FA binding protein-4 expression and in cellular triglyceride content, resulting in increased triglyceride cord blood concentrations. The expression and activity of carriers involved in placental lipid transport are influenced by the endocrine, inflammatory and metabolic milieu of obesity, and further studies are needed to elucidate the strong association between maternal obesity and fetal overgrowth.

There is some evidence that perinatal factors, specifically birth weight (BW), may be related to the onset of prostate cancer (PRCA). This case–control study, nested within the Malmö Diet and Cancer Cohort Study, used archived birth record data from 308 incident PRCA cases diagnosed between 1991 and 2005, and 637 age-matched controls among 4781 men born (1923–1945) in Malmö and Lund, Sweden. We applied conditional logistic regression to examine the birth size–PRCA association, including tumour subtypes, adjusting for perinatal and adult factors. Compared with controls, cases had a non-significantly higher mean BW and were more likely to have high (>4000 g) BW (21% v. 18%), but did not differ in other birth size measures, nor in mean adult body mass index . We observed a non-linear association between BW and PRCA risk. Compared with BWs between 3000 and 3500 g (reference), the fully adjusted odds ratios (OR, 95% CI) were 0.55 (0.33–0.91) for <3000 g, 0.86 (0.61–1.22) for 3500–4000 g and 0.98 (0.64–1.50) for >4000 g. Among men with aggressive tumours, the reduction in risk for those with BWs <3000 g (OR 0.26, 95% CI 0.09–0.72) was stronger than the rate of risk for PRCA overall. Crude risk estimates were minimally attenuated when adjusted for gestational age, maternal age, birth order and adult factors. Birth length, head circumference and placental weight were not associated with prostate cancer. Our results indicate a protective effect of lower BW on risk of total and aggressive prostate cancer, rather than any direct effect of larger birth size.

Maternal protein restriction (MPR) during pregnancy impaired the reproduction of male offspring. We investigated, during the first wave of spermatogenesis, whether MPR exerts deleterious effects on germ cell proliferation and differentiation, as well as androgen receptor (AR) protein expression, which was used as a marker for Sertoli cell (SC) maturation. At the beginning of pregnancy (day 0), dams were fed a control diet (C: 20% casein) or a restricted isocaloric diet (R: 10% casein). After birth, four groups were established: CC, RR, CR and RC (first letter diet during pregnancy and second during lactation). Male offspring were studied at postnatal days 14, 21 and 36. At birth, pup body weight was unchanged. Body weight and testis weight were reduced in RR and CR groups at all ages evaluated. MPR delayed the germinal epithelium development at all ages evaluated. On performing Western blot and immunohistochemistry, AR expression was found to be lower in the three restricted groups. The results suggest that MPR during pregnancy and/or lactation delays SC maturation and germ cell differentiation, and affects intratubular organization. These changes might be responsible for the lower fertility rate at older ages.

Among US racial/ethnic minority women, we examined associations between maternal experiences of racial discrimination and child growth in the first 3 years of life. We analyzed data from Project Viva, a pre-birth cohort study. We restricted analyses to 539 mother–infant pairs; 294 were Black, 127 Hispanic, 110 Asian and 8 from additional racial/ethnic groups. During pregnancy, mothers completed the Experiences of Discrimination survey that measured lifetime experiences of racial discrimination in diverse domains. We categorized responses as 0, 1–2 or ⩾3 domains. Main outcomes were birth weight for gestational age z-score; weight for age (WFA) z-score at 6 months of age; and at 3 years of age, body mass index (BMI) z-score. In multivariable analyses, we adjusted for maternal race/ethnicity, nativity, education, age, pre-pregnancy BMI, household income and child sex and age. Among this cohort of mostly (58.2%) US-born and economically non-impoverished mothers, 33% reported 0 domains of discrimination, 33% reported discrimination in 1–2 domains and 35% reported discrimination in ⩾3 domains. Compared with children whose mothers reported no discrimination, those whose mothers reported ⩾3 domains had lower birth weight for gestational age z-score (β −0.25; 95% CI: −0.45, −0.04), lower 6 month WFA z-score (β −0.34; 95% CI: −0.65, −0.03) and lower 3-year BMI z-score (β −0.33; 95% CI: −0.66, 0.00). In conclusion, we found that among this cohort of US racial/ethnic minority women, mothers’ report of experiencing lifetime discrimination in ⩾ 3 domains was associated with lower fetal growth, weight at 6 months and 3-year BMI among their offspring.

The World Health Organization has identified substance use in the top 20 risk factors for ill health. Risks in pregnancy are compounded, with risk to the woman's health, to pregnancy progression and on both the foetus and the newborn. Intrauterine exposure can result in negative influences on offspring development, sometimes into adulthood. With effectively two patients, there is a clear need for antenatal screening. Biomarker reliability is limited and research efforts have been directed to self-report tools, often attempting to address potential lack of veracity if women feel guilty about substance use and worried about possible stigmatization. Tools, which assume the behaviour, are likely to elicit more honest responses; querying pre-pregnancy use would likely have the same effect. Although veracity is heightened if substance use questions are embedded within health and social functioning questionnaires, such tools may be too lengthy clinically. It has been proposed that screening only for alcohol and tobacco, with focus on the month pre-pregnancy, could enable identification of all other substances. Alternatively, the Revised Fagerstrom Questionnaire could be used initially, tobacco being highly indicative of substance use generally. The ASSIST V.3.0 is readily administered and covers all substances, although the pregnancy ‘risk level’ cut-off for tobacco is not established. Alcohol tools – the 4Ps, TLFB and ‘drug’ CAGE (with E: query of use to avoid withdrawal) – have been studied with other substances and could be used. General psychosocial distress and mental ill-health often co-exist with substance use and identification of substance use needs to become legitimate practice for obstetric clinicians.

Dietary protein restriction in pregnant females reduces offspring birth weight and increases the risk of developing obesity, type 2 diabetes and cardiovascular disease. Despite these grave consequences, few studies have addressed the effects of preconceptional maternal malnutrition. Here we investigate how a preconceptional low-protein (LP) diet affects offspring body mass and insulin-regulated glucose metabolism. Ten-week-old female mice (C57BL/6JBom) received either an LP or isocaloric control diet (8% and 22% crude protein, respectively) for 10 weeks before conception, but were thereafter fed standard laboratory chow (22.5% crude protein) during pregnancy, lactation and offspring growth. When the offspring were 10 weeks old, they were subjected to an intraperitoneal glucose tolerance test (GTT), and sacrificed after a 5-day recovery period to determine visceral organ mass. Body mass of LP male offspring was significantly lower at weaning compared with controls. A similar, nonsignificant, tendency was observed for LP female offspring. These differences in body mass disappeared within 1 week after weaning, a consequence of catch-up growth in LP offspring. GTTs of 10-week-old offspring revealed enhanced insulin sensitivity in LP offspring of both sexes. No differences were found in body mass, food intake or absolute size of visceral organs of adult offspring. Our results indicate that maternal protein restriction imposed before pregnancy produces effects similar to postconceptional malnutrition, namely, low birth weight, catch-up growth and enhanced insulin sensitivity at young adulthood. This could imply an increased risk of offspring developing lifestyle-acquired diseases during adulthood.

Epidemiological studies have demonstrated an association between low birthweight and a range of diseases in adult life including cardiometabolic and psychiatric diseases. One of the key mechanisms proposed to underlie early life ‘programming’ of disease is overexposure of the developing foetus to glucocorticoids. This review will explore the data from human studies that glucocorticoids are not only mediators of programming, but also targets of programming. Cohort studies of men and women of known birthweight have demonstrated that low birthweight is associated with high fasting cortisol levels. In healthy individuals and in people with type 2 diabetes who are at high cardiovascular risk, there is a similar association between high fasting cortisol and the metabolic syndrome. The high cortisol levels appear to be due to activation of the hypothalamic–pituitary–adrenal (HPA) axis though detailed studies to further explore central negative feedback sensitivity are required. The evidence in humans that glucocorticoids mediate programming is more scanty, though changes in maternal body composition, stress and anxiety levels and activity of the placental barrier enzyme 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) may all influence maternal HPA axis activity. Emerging studies are supportive that high maternal cortisol levels in humans and/or deficiencies placental 11β-HSD2 humans are associated with lower birthweight and adverse metabolic and neurocognitive outcomes in the offspring.

Epidemiological studies have suggested that the condition of recurrent pregnancy loss (RPL) may be multifactorial, with both genetic predisposition and environmental factors potentially involved in its pathogenesis. The aim of this study is to elucidate the associations between maternal folate, alcohol and energy metabolism-related gene polymorphisms and the risk of RPL. This case–control study, which involved 116 cases with two or more instances of RPL and 306 fertile controls, was performed in the city of Sapporo, Japan. The associations between eight single nucleotide polymorphisms of folate, alcohol and energy metabolism-related genes [methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), alcohol dehydrogenase 1B (ADH1B), aldehyde dehydrogenase 2 (ALDH2), beta-3-adrenergic receptor (ADRB3) and peroxisome proliferator-activated receptor gamma (PPARG)], and RPL were assessed. Without consideration of cigarette smoking or alcohol use, the risk of RPL significantly decreased in women with the MTHFR rs1801133 TT, MTR rs1805087 AG or ALDH2 rs671 AA genotype (P < 0.05). The risk of RPL associated with cigarette smoking and alcohol use decreased significantly in women carrying the MTHFR rs1801133 T allele [odds ratio (OR), 0.51; 95% confidence interval (CI), 0.27–0.95]. Similarly, the risk of RPL significantly decreased in women carrying the MTR rs1805087 G allele (OR, 0.44; 95% CI, 0.23–0.85). Our findings suggest that maternal gene polymorphisms related to folate metabolism may decrease the risk of RPL. Molecular epidemiological studies are needed to unequivocally elucidate the multifactorial effects of both genetic and environmental factors on human fecundity.

Early environmental influences on later-life health and mortality are well recognized in the doubling of life expectancy since 1800. To further define these relationships, we analyzed the associations between early-life mortality and both the estimated mortality level at age 40 and the exponential acceleration in mortality rates with age characterized by the Gompertz model. Using mortality data from 630 cohorts born throughout the 19th and early 20th century in nine European countries, we developed a multilevel model that accounts for cohort and period effects in later-life mortality. We show that early-life mortality, which is linked to exposure to infection and poor nutrition, predicts both the estimated cohort mortality level at age 40 and the subsequent Gompertz rate of mortality acceleration during aging. After controlling for effects of country and period, the model accounts for the majority of variance in the Gompertz parameters (about 90% of variation in the estimated level of mortality at age 40 and about 78% of variation in the Gompertz slope). The gains in cohort survival to older ages are entirely due to large declines in adult mortality level, because the rates of mortality acceleration at older ages became faster. These findings apply to cohorts born in both the 19th century and the early 20th century. This analysis defines new links in the developmental origins of adult health and disease in which effects of early-life circumstances, such as exposure to infections or poor nutrition, persist into mid-adulthood and remain evident in the cohort mortality rates from ages 40 to 90.

One of the major contributing factors to the continuous rise in obesity rates is the increase in caloric intake, which is driven to a large extent by the ease of access and availability of palatable high-fat, high-sugar ‘junk foods’. It is also clear that some individuals are more likely to overindulge in these foods than others; however, the factors that determine an individual's susceptibility towards the overconsumption of palatable foods are not well understood. There is growing evidence that an increased preference for these foods may have its origins early in life. Recent work from our group and others has reported that in utero and early life exposure to these palatable foods in rodents increased the offspring's preference towards foods high in fat and sugar. One of the potential mechanisms underlying the programming of food preferences is the altered development of the mesolimbic reward system, a system that plays an important role in driving palatable food intake in adults. The aim of this review is to explore the current knowledge of the programming of food preferences, a relatively new and emerging area in the DOHAD field, with a particular focus on maternal overnutrition, the development of the mesolimbic reward system and the biological mechanisms which may account for the early origins of an increased preference for palatable foods.

Maternal weight gain and pattern of weight gain during pregnancy influence the ultimate outcome of pregnancy. Pregravid body mass index (BMI), maternal dietary intake, maternal height and age all determine the weight gain during pregnancy. The study was taken up with an objective to observe maternal weight gain and its pattern in pregnancy in women from an upper income group and to find out their association with pregnancy outcome. 180 normal primiparous pregnant Indian women (20–35 years) from an upper income group were recruited between the 10th and 14th weeks of pregnancy and were followed up throughout their pregnancy to record total and trimester-wise weight gain. Neonatal birth weights were recorded. The results showed that mothers with high pregravid BMI gained more weight during pregnancy than the recommended weight gain; in addition, weight gain in the first trimester was significantly correlated with birth weight of the neonates (P = 0.019). Significant correlation was found between weight gain in the third trimester and birth weight of the neonate irrespective of maternal BMI. The rate of weight gain was significantly correlated with neonatal birth weights irrespective of maternal pregravid BMI (P = 0.022) and as per its categories (P = 0.027). Thus, overall it can be concluded that adequate maternal nutrition before and during pregnancy is important for adequate weight gain by the mother and can result in better outcome of pregnancy. The rate of weight gain is also an important contributing factor.

Maternal smoking during pregnancy and a low socioeconomic status (SES) lead to increased risks of adverse pregnancy outcome. Maternal education is often used as proxy for SES. We explored the programming of the insulin pathway genes IGF2 DMR (insulin growth factor 2 differentially methylated region), IGF2R (insulin growth factor 2 receptor) and INSIGF [the overlapping region of IGF2 and insulin (INS)] in the child through any periconception maternal smoking and education level. In 120 children at 17 months of age, methylation of DNA derived from white blood cells was measured. Periconception smoking and low education were independently associated with INSIGF methylation and showed a relative increase in methylation of +1.3%; P = 0.043 and +1.6%; P = 0.021. Smoking and low education showed an additive effect on INSIGF methylation (+2.8%; P = 0.011). There were no associations with IGF2 DMR and IGF2R methylation. Our data suggest that periconception maternal smoking and low education are associated with epigenetic marks on INSIGF in the very young child, this warrants further study in additional populations.