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.

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.

Poor fetal growth is associated with later-life changes in adult body composition and decrements in muscle strength and morphology. Few studies have investigated the association of poor fetal growth with whole-body exercise. The purpose of this study was to investigate the association of poor fetal growth with the maximal oxygen consumption (VO2max), lactate levels during exercise and the response to aerobic training. Thirty-six college-aged men and women (aged 20.8 ± 0.3 years), born to term (37–42 weeks gestation), were recruited to participate in an 8-week training program. Participants comprised two groups, high ponderal index (HIGHPI) and low ponderal index (LOWPI) (n = 18/group), identified as falling above and below the 10th percentile of the ponderal index (g/cm3)-for-gestational age distribution, respectively. The HIGHPI and LOWPI were matched pair-wise on age, sex, body mass index and pre-study physical activity patterns. The LOWPI and HIGHPI did not differ significantly before training, after training or with a change (Δ) in training VO2max (l/min or ml/min kg/fat-free mass (FFM)). However, LOWPI had significantly lower pre-training lactate levels at similar levels of relative work output (P = 0.016), and significantly smaller decreases in lactate at a fixed level of absolute work after training (P = 0.044). These differences were independent of pre-training aerobic fitness, the change in fitness with training, diet and fuel substrate choice. The lower lactate of untrained LOWPI subjects during exercise could reflect metabolic reprograming due to intrauterine growth restriction, or could be secondary to muscle morphological and/or fiber-type distribution changes that also associate with poor fetal growth.

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.

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.

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.

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.

A life-course approach to reduction of risk of non-communicable diseases (NCD) suggests that early-life interventions may be more effective than lifestyle modifications in middle age. Knowledge translation to develop understanding of the Developmental Origins of Health and Disease (DOHaD) within the community offers the potential to encourage informed diet and lifestyle choices supporting reduction of NCD risk in current and future generations. Many women do not make sustained dietary change before or during pregnancy, therefore appropriate nutritional behaviours need to be established prior to adulthood. This makes adolescence an appropriate stage for interventions to establish suitable dietary and lifestyle behaviours. Therefore, we engaged adolescents in a school-based educational intervention, and assessed the value of this in development of understanding of DOHaD concepts to support behaviour change that could lead to NCD risk reduction in the next generation. Modules of course work were written for 11–14 year olds and trialled in nine schools. Matched pre- and post-intervention questionnaire responses from 238 students and 99 parents, and post-intervention interviews evaluated the intervention. Understanding of a link between maternal diet during pregnancy and the health of the foetus in adulthood increased from 46% to 76% following intervention. Post-intervention evidence suggests the programme facilitated discussion of diet, lifestyle and DOHaD concepts in most families. The intervention was effective in improving understanding of DOHaD concepts and in some cases led to appropriate behaviour change. However, the sustainability of these changes remains to be determined through on-going evaluation of attitudes and behaviour within this cohort.

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.