Diethylstilbestrol (DES) is a non-steroidal estrogen that was commonly prescribed during pregnancy from the late 1940s to 1971. A potent endocrine disruptor, prenatal DES exposure has been linked with reproductive tract malformations, adverse pregnancy outcomes, cancer, infertility and earlier menopause. DES was used for years as a growth promoter in animal production. Some animal studies suggest that prenatal DES exposure is associated with obesity and metabolic disturbances. Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age (median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height. The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22], and RRs were 1.23 (CI: 1.07, 1.42) and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure. DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: −0.27, 1.66)]. This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity.

The Developmental Origins of Health and Disease (DOHaD) hypothesis refers to the concept that ‘malnutrition during the fetal period induces a nature of thrift in fetuses, such that they have a higher change of developing non-communicable diseases, such as obesity and diabetes, if they grow up in the current well-fed society.’ Epigenetics is a chemical change in DNA and histones that affects how genes are expressed without alterations of DNA sequences. Several lines of evidence suggest that malnutrition during the fetal period alters the epigenetic expression status of metabolic genes in the fetus and that this altered expression can persist, and possibly lead to metabolic disorders. Similarly, mental stress during the neonatal period can alter the epigenetic expression status of neuronal genes in neonates. Moreover, such environmental, stress-induced, epigenetic changes are transmitted to the next generation via an acquired epigenetic status in sperm. The advantage of epigenetic modifications over changes in genetic sequences is their potential reversibility; thus, epigenetic alterations are potentially reversed with gene expression. Therefore, we potentially establish ‘preemptive medicine,’ that, in combination with early detection of abnormal epigenetic status and early administration of epigenetic-restoring drugs may prevent the development of disorders associated with the DOHaD.

The critical period during which maternal hyperglycemia predisposes offspring to develop reproductive disorders in adult life is not known. The relationship between maternal hyperglycemia at different stages and reproductive functions of male offspring was investigated. A single intraperitoneal injection of alloxan (90 mg/kg body weight) was administered at gestation days (GD) 1, 8 and 15. Animals were subsequently given 10% glucose solution daily as drinking water until parturition. All male pups were sacrificed on the 63rd day of postnatal life. Birth weight, anogenital distance index (AGDi), testes descent day, preputial separation day, sperm profile, serum testosterone, luteinizing hormone and follicle-stimulating hormone levels and the histology of the testis were assessed. Data significance test was based on 95% confidence interval. GD1 pups showed a significant increase in mean birth weight, whereas GD8 pups and GD15 pups had significantly reduced birth weight as compared with control. AGDi was significantly increased in GD8 and GD15 pups. Testes descent and preputial separation in all the experimental groups were significantly earlier. There was a significant reduction in sperm count and viability in GD8 offspring. Sperm motility was reduced in all test groups. Testosterone level was reduced in all test groups. Histology of the testis showed varying degrees of pathologies. It was deduced from this study that maternal hyperglycemia caused alterations in reproductive functions in male offspring of Wistar rats irrespective of the period of gestation involved, although GD8 pups were most severely affected.

Physical inactivity and low birth weight (LBW) may lead to an increased risk for developing type 2 diabetes. The extent to which LBW individuals may benefit from physical exercise training when compared with those with normal birth weight (NBW) controls is uncertain. We assessed the impact of an outdoor exercise intervention on body composition, insulin secretion and action in young men born with LBW and NBW in rural India. A total of 61 LBW and 56 NBW healthy young men were recruited into the study. The individuals were instructed to perform outdoor bicycle exercise training for 45 min every day. Fasting blood samples, intravenous glucose tolerance tests and bioimpedance body composition assessment were carried out. Physical activity was measured using combined accelerometry and heart rate monitoring during the first and the last week of the intervention. Following the exercise intervention, the LBW group displayed an increase in physical fitness [55.0 ml (O2)/kg min (52.0−58.0)−57.5 ml (O2)/kg min (54.4−60.5)] level and total fat-free mass [10.9% (8.0−13.4)−11.4% (8.0−14.6)], as well as a corresponding decline in the ratio of total fat mass/fat-free mass. In contrast, an increase in total fat percentage as well as total fat mass was observed in the NBW group. After intervention, fasting plasma insulin levels, homoeostasis model assessments (HOMA) of insulin resistance (HOMA-IR) and insulin secretion (HOMA-IS), improved to the same extent in both the groups. In summary, young men born with LBW in rural India benefit metabolically from exercise training to an extent comparable with NBW controls.

Changes in anthropometrics often reflect changes in living conditions, and one’s characteristics at birth may be associated with future health. The aim of this study was to investigate the secular trends in maternal and neonatal anthropometrics in the Helsinki Birth Cohort Study. The study participants, thus, comprised all 13,345 live births recorded in Helsinki, Finland, between 1934 and 1944. Adult characteristics of the clinical subsample comprised of 2003 individuals, alive during 2003, were also analyzed. Linear Regression analysis with seasonal terms was applied to see whether clinically and statistically significant trends can be found in maternal age, height and body mass index (BMI) at pregnancy; gestational age, birth weight, ponderal index and sex ratio; and adult height, BMI and fat percentage. Statistically significant trends were found in maternal age and maternal BMI with abrupt changes between 1941 and 1944. Gestational age increased by an average of 0.11% per year (P<0.0001), and the proportion of premature births dropped from 7.9% in 1934 to 4.5% in 1944 (P<0.0001). In the clinical sample, a statistically significant, although small, average annual increase of 0.1% in adult heights was detected (P=0.0012 for men and P=0.0035 for women). In conclusion, although no significant changes were found in either neonatal or adult anthropometrics of babies born in Helsinki between 1934 and 1944, there were abrupt changes in the characteristics of their mothers.

David Barker established growth as a seminal link between early development and later health attainment and disease risk. This was nothing less than a paradigm shift in health and medicine, turning the focus of disease causality away from contemporary environmental influences to earliest growth as a time when functional anatomy and physiology sets in place critical structures and function for a lifetime.

Barker’s prodigious work investigated time- and place-specific interactions between maternal condition and exogenous environmental influences, focusing on how growth unfolds across development to function as a mechanistic link to ensuing health. Subsequent applications do not always attend to the specificity and sensitivity issues included in his original work, and commonly overlook the long-standing methods and knowledge base of auxology. Methodological areas in need of refinement include enhanced precision in how growth is represented and assessed. For example, multiple variables have been used as a referent for ‘growth,’ which is problematic because different body dimensions grow by different biological clocks with unique functional physiologies. In addition, categorical clinical variables obscure the spectrum of variability in growth experienced at the individual level. Finally, size alone is a limited measure as it does not capture how individuals change across age, or actually grow.

The ground-breaking notion that prenatal influences are important for future health gave rise to robust interest in studying the fetus. Identifying the many pathways by which size is realized permits targeted interventions addressing meaningful mechanistic links between growth and disease risk to promote health across the lifespan.

In rats, maternal exposure to restraint stress during pregnancy can induce abnormalities in the cardiovascular and central nervous systems of the offspring. These effects are mediated by long-lasting hyperactivation of the hypothalamic–pituitary–adrenal axis. However, little is known about the potential effects of stress during pregnancy on metabolic systems. We examined the effect of restraint stress in pregnant mice on the liver function of their offspring. The offspring of stressed mothers showed significantly higher lipid accumulation in the liver after weaning than did the controls; this accumulation was associated with increased expression of lipid metabolism-related proteins such as alanine aminotransferase 2 diglyceride acyltransferase 1, peroxisome proliferator-activated receptor gamma and glucocorticoid receptor. Additionally, we observed increased levels of 11β-hydroxysteroid dehydrogenase type 1, an intercellular mediator that converts glucocorticoid from the inactive to the active form, in the foetal and postnatal periods. These results indicate that restraint stress in pregnancy in mice induces metabolic abnormalities via 11β-hydroxysteroid dehydrogenase type 1-related pathways in the foetal liver. It is therefore possible that exposure to stress in pregnant women may be a risk factor for metabolic syndromes (e.g. fatty liver) in children.

The high prevalence of obesity is a major public health issue and contributes to the ‘double burden’ of disease in developing countries. Early exposure to poor nutrition may cause metabolic adaptations that, when accompanied by exposure to ‘affluent’ nutrition, may increase the risk for obesity and other metabolic disorders. The aim of this study was to determine differences in energy metabolism and nutritional status between normal-height and growth-retarded North Korean children living in South Korea. A total of 29 children were recruited and underwent measurements of resting energy expenditure (REE), respiratory quotient (RQ), anthropometrics and dietary intake. There was no difference in REE or any assessment of obesity between the growth-retarded and normal-height children. Children who were classified as growth retarded (HAZ<−1.0) or stunted (HAZ<−2.0) had a significantly higher RQ (β=0.036 or 0.060, respectively, P=0.018 or 0.016), independent of sex, age, fat-free mass, fat mass and food quotient, compared with children with normal height. The results from this study, the first from an Asian population, add to the growing body of literature suggesting that undernutrition early in life results in adaptations in energy metabolism that favor fat deposition, increasing the risk of stunted children becoming overweight or obese later in life. Continued research on this topic is warranted, given the continued rise in the prevalence of the double burden in transitional countries.

Excess consumption of added sugars, including sucrose and high fructose corn syrup (HFCS-55), have been implicated in the global epidemics of obesity and type 2 diabetes. This study aimed to investigate and compare the impact of maternal consumption of sucrose or HFCS-55 during pregnancy and lactation on the metabolic health of the dam and her offspring at birth. Female Albino Wistar rats were given access to chow and water, in addition to a sucrose or HFCS-55 beverage (10% w/v) before, and during pregnancy and lactation. Maternal glucose tolerance was determined throughout the study, and a postmortem was conducted on dams following lactation, and on offspring within 24 h of birth. Sucrose and HFCS-55 consumption resulted in increased total energy intake compared with controls, however the increase from sucrose consumption was accompanied by a compensatory decrease in chow consumption. There was no effect of sucrose or HFCS-55 consumption on body weight, however sucrose consumption resulted in increased adiposity and elevated total plasma cholesterol in the dam, while HFCS-55 consumption resulted in increased plasma insulin and decreased plasma non-esterified fatty acids (NEFA). Maternal HFCS-55 consumption was associated with decreased relative liver weight and plasma NEFA in the offspring at birth. There was no effect of either treatment on pup weight at birth. These findings suggest that both sucrose and HFCS-55 consumption during pregnancy and lactation have the potential to impact negatively on maternal metabolic health, which may have adverse consequences for the long-term health of the offspring.

Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women in the mid-1900s, is a potent endocrine disruptor. Prenatal DES exposure has been associated with reproductive disorders in women, but little is known about its effects on endogenous hormones. We assessed the association between prenatal DES exposure and reproductive hormones among participants from the Harvard Study of Moods and Cycles (HSMC), a longitudinal study of premenopausal women aged 36–45 years from Massachusetts (1995–1999). Prenatal DES exposure was reported at baseline (43 DES exposed and 782 unexposed). Early follicular-phase concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured at baseline and every 6 months during 36 months of follow-up. Inhibin B concentrations were measured through 18 months. We used multivariable logistic and repeated-measures linear regression to estimate odds ratios (OR) and percent differences in mean hormone values (β), respectively, comparing DES exposed with unexposed women, adjusted for potential confounders. DES-exposed women had lower mean concentrations of estradiol (pg/ml) (β=−15.6%, 95% confidence interval (CI): −26.5%, −3.2%) and inhibin B (pg/ml) (β=−20.3%, CI: −35.1%, −2.3%), and higher mean concentrations of FSH (IU/I) (β=12.2%, CI: −1.5%, 27.9%) and LH (IU/I) (β=10.4%, CI: −7.2%, 31.3%), than unexposed women. ORs for the association of DES with maximum FSH>10 IU/I and minimum inhibin B<45 pg/ml – indicators of low ovarian reserve – were 1.90 (CI: 0.86, 4.22) and 4.00 (CI: 0.88–18.1), respectively. Prenatal DES exposure was associated with variation in concentrations of FSH, estradiol and inhibin B among women of late reproductive age.

Evidence from both human and animal studies has shown that the prenatal and early postnatal environments influence susceptibility to chronic disease in later life and suggests that epigenetic processes are an important mechanism by which the environment alters long-term disease risk. Epigenetic processes, including DNA methylation, histone modification and non-coding RNAs, play a central role in regulating gene expression. The epigenome is highly sensitive to environmental factors in early life, such as nutrition, stress, endocrine disruption and pollution, and changes in the epigenome can induce long-term changes in gene expression and phenotype. In this review we focus on how the early life nutritional environment can alter the epigenome leading to an altered susceptibility to disease in later life.

Early development, throughout gestation and lactation, represents a period of extreme vulnerability during which susceptibility to later metabolic and cardiovascular injuries increases. Maternal diet is a major determinant of the foetal and newborn developmental environment; maternal undernutrition may result in adaptive responses leading to structural and molecular alterations in various organs and tissues, such as the brain and kidney. New nephron anlages appear in the renal cortex up to postnatal day 4 and the last anlages to be formed develop into functional nephrons by postnatal day 10 in rodents. We used a model of undernutrition in rat dams that were food-restricted during the first half of the lactation period in order to study the long-term effects of maternal diet on renal development, behaviour and neural hydromineral control mechanisms. The study showed that after 40% food restriction in maternal dietary intake, the dipsogenic responses for both water and salt intake were not altered; Fos expression in brain areas investigated involved in hydromineral homeostasis control was always higher in the offspring in response to isoproterenol. This was accompanied by normal plasma osmolality changes and typical renal histology. These results suggest that the mechanisms for the control of hydromineral balance were unaffected in the offspring of these 40% food-restricted mothers. Undernutrition of the pups may not be as drastic as suggested by dams’ restriction.

Previous studies have suggested an association between maternal smoking during pregnancy and asthma symptoms such as wheezing during childhood. However, few have evaluated this association in adolescence, especially in populations with high prevalence of wheezing as in Brazil. Using the 1993 Pelotas birth cohort, a longitudinal study set in southern Brazil of 5249 urban live births, we aimed to evaluate the association between maternal and the partner’s smoking during pregnancy and wheezing at 11 and 15 years of age. We evaluated smoking during pregnancy using number of cigarettes/day, and our main outcomes were as follows: wheezing in the last year and number of wheezing crises, at both 11 and 15 years of age, as well as persistent wheezing (having crises at 11 and 15 years of age) and medical asthma diagnosis at age 15. In addition, other socio-demographic variables were included as possible confounders and mediators of this association. We used Poisson regression models to evaluate crude and adjusted associations. Of the 5249 live births in 1993, 87.5% and 85.7% were followed-up to 11 and 15 years of age, respectively. Maternal smoking during pregnancy showed a dose-response association with number of wheezing crises at age 15 (P=0.023), presence of persistent wheezing (P=0.034) and asthma diagnosis (P=0.023). Partner’s smoking was not associated with any wheezing variables. Maternal smoking during pregnancy appears to exert an effect on respiratory morbidity of adolescents, evaluated by wheezing symptoms.

Several studies have shown that South Asian neonates have a characteristic thin–fat insulin-resistant phenotype. The aim of our study was to determine whether this phenotype is also present in South Asians who have migrated to a Western country (the Netherlands). South Asian and white Dutch pregnant women were included in our study. After delivery, cord blood was collected and neonatal anthropometry was measured within 72 h. Compared with white Dutch mothers, South Asian mothers were younger (28.5 v. 32.2 years, P<0.001) and had a higher prepregnancy body mass index (25.1 v. 23.0, P=0.001). Gestational age at delivery was on average 4 days shorter in South Asians (274.9 v. 278.8, P=0.001). To compare the two groups of neonates, we calculated sex- and gestation-specific s.d. scores using the values for mean and s.d. obtained from the white Dutch subjects as a reference. All measurements were smaller in South Asian neonates, except for those of the skinfolds. The largest difference was found in abdominal circumference (s.d. score 1.39, 95% CI −1.76 to −1.01). Triceps and subscapular skinfolds were similar in both groups (triceps s.d. score −0.34, 95% CI −0.88 to +0.20 and subscapular s.d. score −0.03, 95% CI −0.31 to +0.25). South Asian neonates had higher cord plasma levels of triglycerides (0.40 v. 0.36, P=0.614), glucose (5.4 v. 4.8, P=0.079) and insulin (6.3 v. 4.0, P=0.051). However, these differences were not statistically significant. After adjustment for birth weight, the difference in insulin became statistically significant (P=0.001). We therefore conclude that the thin–fat insulin-resistant phenotype is also present in South Asian neonates in the Netherlands.

The theory of developmental programming is supported by accumulating evidence, both observational and experimental. The direct application of the principles of developmental programming by clinicians to benefit pregnant women remains an area of limited attention. Examining a selection of inpatients at an obstetric referral center, I searched for situations in which clinical decision making could be driven by the principles of developmental programming. I also looked for situations in which the clinical research agenda could be dictated by these concepts. In the decision to undertake preventive measures to avoid preeclampsia, the offspring’s perspective may support more liberal application of calcium and aspirin. Consideration of the long-term health perspective of the offspring could drive choices in the management of obesity and diabetes in pregnancy. The administration of corticosteroids in women delivering by elective cesarean at term may have modest short-term benefits, but additional trials are necessary to investigate long-term offspring health. The offspring of women suffering hyperemesis gravidarum may benefit from nutritional therapy. The long-term health of the offspring could affect couples’ choice for IVF or expectant management. Applying the principles of developmental programming to the management of pregnant women could drive clinical decision making and is driving the clinical research agenda. Increasingly, developmental programming concepts are becoming an integral part of clinical practice, as well as determining the choice of outcomes in trials in obstetrics and fertility medicine. The presented cases underscore the need for more research to guide clinical practice.

Various environmental factors have been associated with the timing of eruption of primary dentition, but the evidence to date comes from small studies with limited information on potential risk factors. We aimed to investigate associations between tooth emergence patterns and pre-conception, pregnancy and postnatal influences. Dentition patterns were recorded at ages 1 and 2 years in 2915 children born to women in the Southampton Women’s Survey from whom information had been collected on maternal factors before conception and during pregnancy. In mutually adjusted regression models we found that: children were more dentally advanced at ages 1 and 2 years if their mothers had smoked during pregnancy or they were longer at birth; mothers of children whose dental development was advanced at age 2 years tended to have poorer socioeconomic circumstances, and to have reported a slower walking speed pre-pregnancy; and children of mothers of Asian ethnicity had later tooth development than those of white mothers. The findings add to the evidence of environmental impacts on the timing of the eruption of primary dentition in indicating that maternal smoking during pregnancy, socio-economic status and physical activity (assessed by reported walking speed) may influence the child’s primary dentition. Early life factors, including size at birth are also associated with dentition patterns, as is maternal ethnicity.

In vitro fertilization (IVF) and its subset intracytoplasmic sperm injection (ICSI), are widely used medical treatments for conception. There has been controversy over whether IVF is associated with adverse short- and long-term health outcomes of offspring. As with other prenatal factors, epigenetic change is thought to be a molecular mediator of any in utero programming effects. Most studies focused on DNA methylation at gene-specific and genomic level, with only a few on associations between DNA methylation and IVF. Using buccal epithelium from 208 twin pairs from the Peri/Postnatal Epigenetic Twin Study (PETS), we investigated associations between IVF and DNA methylation on a global level, using the proxies of Alu and LINE-1 interspersed repeats in addition to two locus-specific regulatory regions within IGF2/H19, controlling for 13 potentially confounding factors. Using multiple correction testing, we found strong evidence that IVF-conceived twins have lower DNA methylation in Alu, and weak evidence of lower methylation in one of the two IGF2/H19 regulatory regions and LINE-1, compared with naturally conceived twins. Weak evidence of a relationship between ICSI and DNA methylation within IGF2/H19 regulatory region was found, suggesting that one or more of the processes associated with IVF/ICSI may contribute to these methylation differences. Lower within- and between-pair DNA methylation variation was also found in IVF-conceived twins for LINE-1, Alu and one IGF2/H19 regulatory region. Although larger sample sizes are needed, our results provide additional insight to the possible influence of IVF and ICSI on DNA methylation. To our knowledge, this is the largest study to date investigating the association of IVF and DNA methylation.

We determined the protein expression of adipogenic transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) and its co-repressor and co-activator complexes in adipose tissue from the obese offspring of under- and over-nourished dams. Female rats were fed either a high-fat (60% kcal) or control (10% kcal) diet before mating, and throughout pregnancy and lactation (Mat-OB). Additional dams were 50% food-restricted from pregnancy day 10 to term [intrauterine growth-restricted (IUGR)]. Adipose tissue protein expression was analyzed in newborn and adult male offspring. Normal birth weight Mat-OB and low birth weight IUGR newborns had upregulated PPARγ with variable changes in co-repressors and co-activators. As obese adults, Mat-OB and IUGR offspring had increased PPARγ with decreased co-repressor and increased co-activator expression. Nutritionally programmed increased PPARγ expression is associated with altered expression of its co-regulators in the newborn and adult offspring. Functional studies of PPARγ co-regulators are necessary to establish their role in PPARγ-mediated programmed obesity.

The association between vitamin D and wheezing in early childhood is unclear. The primary objective of this study was to evaluate the association between vitamin D exposure, during both pregnancy and childhood, and early childhood wheezing. Secondary objectives were to evaluate the associations between vitamin D exposures and asthma and wheezing severity. We conducted a cohort study of children (0–5 years) recruited from 2008 to 2013 through the TARGet Kids! primary-care research network. Vitamin D exposures included maternal vitamin D supplement use during pregnancy, child vitamin D supplementation and children’s 25-hydroxyvitamin D (25(OH)D) concentrations. The outcomes measured were parent-reported childhood wheezing, diagnosed asthma and wheezing severity. Vitamin D supplement and wheezing data were available for 2478 children, and blood samples were available for 1275 children. Adjusted odds ratios (aOR) were estimated using logistic regression adjusted for age, sex, ethnicity, body mass index, birth weight, outdoor play, breastfeeding duration, daycare status, parental smoking and family history of asthma. Vitamin D supplementation during pregnancy was associated with lower odds of childhood wheezing (aOR=0.65; 95% CI: 0.46–0.93). In early childhood, neither 25(OH)D (aOR per 10 nmol/l=1.01; 95% CI: 0.96–1.06) nor vitamin D supplementation (aOR=1.00; 95% CI: 0.81–1.23) was associated with wheezing. No significant associations were observed with diagnosed asthma or wheezing severity. Vitamin D supplementation during pregnancy was associated with reduced odds of wheezing, but child vitamin D supplementation and childhood 25(OH)D were not associated with reduced wheezing. The timing of exposure may be important in understanding the association between vitamin D and childhood wheezing.