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.

Stimulating the maternal immune system before or during pregnancy can dramatically improve morphologic outcome in mice that have been exposed to teratogens. For example, maternal immune stimulation in mice reduced craniofacial and palate defects, heart defects, digit and limb defects, tail malformations and neural tube defects caused by diverse teratogens that included chemical agents, hyperthermia, X-rays and diabetes mellitus. Several different procedures of immune stimulation were effective and included footpad injection with Freund's Complete Adjuvant, intraperitoneal (IP) injection with inert particles or attenuated Bacillus Calmette–Guerin, intrauterine injection with allogenic or xenogenic lymphocytes, or intravascular, intrauterine or IP injection with immunomodulatory cytokines. Limited information is available regarding mechanisms by which such immune stimulation reduces fetal dysmorphogenesis; however, cytokines of maternal origin have been suggested as effector molecules that act on the placenta or fetus to improve development. These collective data raise novel questions about the possibility of unrecognized maternal immune system regulatory activity in normal fetal development. This manuscript reviews the literature showing maternal immune protection against morphologic birth defects. Potential operating mechanisms are discussed, and the possibility is considered that a suppressed maternal immune system may negatively impact fetal development.

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.

The purpose of this investigation was to test the hypothesis that maternal exercise training during pregnancy enhances endothelial function in offspring at birth. Six-month-old gilts (n = 8) were artificially inseminated and randomized into exercise-trained (n = 4) and sedentary groups (n = 4). Exercise training consisted of 15 weeks of treadmill exercise. The thoracic aorta of offspring were harvested within 48 h after birth and vascular responsiveness to cumulative doses of endothelium-dependent (bradykinin: 10−11–10−6 M) and independent (sodium nitroprusside: 10−10–10−4 M) vasodilators were assessed using in vitro wire myography. Female offspring from the exercised-trained gilts had a significantly greater endothelium-dependent relaxation response in the thoracic aorta when compared with the male offspring and female offspring from the sedentary gilts. The results of this investigation demonstrate for the first time that maternal exercise during pregnancy produces an enhanced endothelium-dependent vasorelaxation response in the thoracic aortas of female offspring at birth.

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.

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.

The fetal or early origins of adult disease hypothesis states that environmental factors, particularly nutrition, act in early life to program the risks for chronic diseases in adult life. As eating habits can be linked to the development of several diseases including obesity, diabetes and cardiovascular disease, it could be proposed that persistent food preferences across the life-span in people who were exposed to an adverse fetal environment may partially explain their increased risk to develop metabolic disease later in life. In this paper, we grouped the clinical and experimental evidence demonstrating that the fetal environment may impact the individual's food preferences. In addition, we review the feeding preferences development and regulation (homeostatic and hedonic pathways, the role of taste/olfaction and the reward/pleasure), as well as propose mechanisms linking early life conditions to food preferences later in life. We review the evidence suggesting that in utero conditions are associated with the development of specific food preferences, which may be involved in the risk for later disease. This may have implications in terms of public health and primary prevention during early ages.

The term ‘developmental origins of health and disease’ (DOHaD) originally referred to delayed effects of altered maternal factors (e.g. smoking or poor nutrition) on the developing offspring, but it now also encompasses early life exposure to environmental chemicals, which can cause an unhealthy prenatal environment that endangers the fetus and increases its susceptibility to disease later in life. Prenatal exposure to the pharmaceutical diethylstilbestrol (DES) is a well-known DOHaD example as it was associated in the 1970s with vaginal cancer in daughters who were exposed to this potent synthetic estrogen before birth. Subsequently, numerous long-term effects have been described in breast and reproductive tissues of DES-exposed humans and experimental animals. Data reviewed suggest that the prenatal DES-exposed population should continue to be monitored for potential-increased disease risks as they age. Knowledge of sensitive developmental periods, and the mechanisms of DES-induced toxicities, provides useful information in predicting potential adverse effects of other environmental estrogens.

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.

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.

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.