Aryeh D. Stein

Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome

Background: The manipulation of pregnancy diets in animals can lead to changes in DNA methylation with phenotypic consequences in the offspring. Human studies have concentrated on the effects of nutrition during early gestation. Lacking in humans is an epigenome-wide association study of DNA methylation in relation to perturbations in nutrition across all gestation periods. Methods: We used the quasi-experimental setting of the Dutch famine of 1944–45 to evaluate the impact of famine exposure during specific 10-week gestation periods, or during any time in gestation, on genome-wide DNA methylation levels at age ∼u200959 years. In addition, we evaluated the impact of exposure during a shorter pre- and post-conception period. DNA methylation was assessed using the Illumina 450k array in whole blood among 422 individuals with prenatal famine exposure and 463 time- or sibling-controls without prenatal famine exposure. Results: Famine exposure during gestation weeks 1–10, but not weeks 11–20, 21–30 or 31-delivery, was associated with an increase in DNA methylation of CpG dinucleotides cg20823026 (FAM150B), cg10354880 (SLC38A2) and cg27370573 (PPAP2C) and a decrease of cg11496778 (OSBPL5/MRGPRG) (Pu2009<u20095.9u2009×u200910−7, PFDRu2009<u20090.031). There was an increase in methylation of TACC1 and ZNF385A after exposure during any time in gestation (Pu2009<u20092.0u2009×u200910−7, PFDRu2009=u20090.034) and a decrease of cg23989336 (TMEM105) after exposure around conception. These changes represent a shift of 0.3–0.6 standard deviations and are linked to genes involved in growth, development and metabolism. Conclusion: Early gestation, and not mid or late gestation, is identified as a critical time-period for adult DNA methylation changes in whole blood after prenatal exposure to famine.

Maternal exposure to the dutch famine before conception and during pregnancy quality of life and depressive symptoms in adult offspring

Background: Gestational exposure to famine has been associated with several chronic diseases in adulthood, but few studies in humans have related prenatal famine exposure to health-related quality of life. We used the circumstances of the Dutch Famine of 1944–1945 (during which official rations were <900 kcal/day for 24 weeks) to assess whether exposure to famine prior to conception or at specified stages of pregnancy was related to self-reported health-related quality of life and depressive symptoms in adulthood. Methods: We studied 923 individuals, including persons born in western Holland between January 1945 and March 1946, persons born in the same 3 institutions in 1943 and 1947 and same-sex siblings of persons in series 1 or 2. Between 2003 and 2005 (mean age: 59 years), we assessed self-reported quality of life with the Short Form 36 questionnaire and derived mental and physical component scores. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression scale. Results: Mean mental and physical component scores were 52.4 (SD = 9.4) and 48.9 (9.0), respectively. The mean depression score was 11.6 (7.4). Age-, sex-, and schooling-adjusted estimates for mutually adjusted exposures were −2.48 for the mental component score with exposure before conception (95% confidence interval = −4.46 to −0.50) and 0.07 with exposure during pregnancy (−1.15 to 1.29). Adjusted estimates for the physical component score were 1.26 with exposure before conception (−0.67 to 3.19) and −0.73 with exposure during pregnancy (−1.94 to 0.48). Adjusted estimates for the depression score were 2.07 with exposure before conception (0.60 to 3.54) and 0.96 with exposure during pregnancy (0.09 to 1.88). There was no evidence of heterogeneity of effects by specific periods of pregnancy exposed to famine. Conclusions: A mothers exposure to famine prior to conception of her offspring was associated with lower self-reported measures of mental health and quality of life in her adult offspring.

Prenatal Docosahexaenoic Acid Supplementation and Infant Morbidity: Randomized Controlled Trial

OBJECTIVE: Long-chain polyunsaturated fatty acids such as docosahexaenoic acid (DHA) influence immune function and inflammation; however, the influence of maternal DHA supplementation on infant morbidity is unknown. We investigated the effects of prenatal DHA supplementation on infant morbidity. METHODS: In a double-blind randomized controlled trial conducted in Mexico, pregnant women received daily supplementation with 400 mg of DHA or placebo from 18 to 22 weeks gestation through parturition. In infants aged 1, 3, and 6 months, caregivers reported the occurrence of common illness symptoms in the preceding 15 days. RESULTS: Data were available at 1, 3, and 6 months for 849, 834, and 834 infants, respectively. The occurrence of specific illness symptoms did not differ between groups; however, the occurrence of a combined measure of cold symptoms was lower in the DHA group at 1 month (OR: 0.76; 95% CI: 0.58–1.00). At 1 month, the DHA group experienced 26%, 15%, and 30% shorter duration of cough, phlegm, and wheezing, respectively, but 22% longer duration of rash (all P ≤ .01). At 3 months, infants in the DHA group spent 14% less time ill (P < .0001). At 6 months, infants in the DHA group experienced 20%, 13%, 54%, 23%, and 25% shorter duration of fever, nasal secretion, difficulty breathing, rash, and “other illness,” respectively, but 74% longer duration of vomiting (all P < .05). CONCLUSIONS: DHA supplementation during pregnancy decreased the occurrence of colds in children at 1 month and influenced illness symptom duration at 1, 3, and 6 months.

Maternal undernutrition and the sex ratio at birth in Ethiopia: evidence from a national sample.

It has been suggested that maternal undernutrition results in facultative adjustment of the sex ratio at birth among humans, favouring females. We tested this hypothesis using data from the Demographics and Health Survey of Ethiopia for 2000. Our data provide at best limited support for the suggestion that maternal nutritional status is associated with the sex ratio at birth in humans.

DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood

DNA methylation mediates the association of prenatal famine exposure with higher adult BMI and serum triglyceride levels. Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342,596 cytosine-phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formal mediation analysis. DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing β cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-term metabolic health. The specific mechanism awaits elucidation.

Disability and self-rated health among older women and men in rural Guatemala: the role of obesity and chronic conditions.

Unprecedented population aging in poorer settings is coinciding with the rapid spread of obesity and other chronic conditions. These conditions predict disability and poor self-rated health and often are more prevalent in women than men. Thus, gender gaps in obesity and other chronic conditions may account for older womens greater disability and worse self-rated health in poor, rural populations, where aging, obesity, and chronic conditions are rapidly emerging. In a survey of 604 adults 50 years and older in rural Guatemala, we assessed whether gender gaps in obesity and other chronic conditions accounted for gender gaps in disability and self-rated health. Obesity strongly predicted gross mobility (GM) disability, and the number of chronic conditions strongly predicted all outcomes, especially in women. Controlling for gender gaps in body-mass index (BMI) and especially the number of chronic conditions eliminated gender gaps in GM disability, and controlling for gender gaps in the number of chronic conditions eliminated gender gaps in self-rated health. We recommend conducting longitudinal cohort studies to explore interventions that may mitigate adult obesity and chronic conditions among poor, rural older adults. Such interventions also may reduce gender gaps in later-life disability and self-rated health.

Parental childhood growth and offspring birthweight: pooled analyses from four birth cohorts in low and middle income countries.

Associations between parental and offspring size at birth are well established, but the relative importance of parental growth at different ages as predictors of offspring birthweight is less certain. Here we model parental birthweight and postnatal conditional growth in specific age periods as predictors of offspring birthweight.

Consumption of less than 10% of total energy from added sugars is associated with increasing HDL in females during adolescence: a longitudinal analysis.

Background Atherosclerotic changes associated with dyslipidemia and increased cardiovascular disease risk are believed to begin in childhood. While previous studies have linked added sugars consumption to low high‐density lipoprotein (HDL), little is known about the long‐term impact of this consumption. This study aims to assess the association between added sugars intake and HDL cholesterol levels during adolescence, and whether this association is modified by obesity. Methods and Results We used data from the National Heart Lung and Blood Institutes Growth and Health Study, a 10‐year cohort study of non‐Hispanic Caucasian and African‐American girls (N=2379) aged 9 and 10 years at baseline recruited from 3 sites in 1987‐1988 with biennial plasma lipid measurement and annual assessment of diet using a 3‐day food record. Added sugars consumption was dichotomized into low (0% to <10% of total energy) and high (≥10% of total energy). In a mixed model controlling for obesity, race, physical activity, smoking, maturation stage, age, and nutritional factors, low compared with high added sugar consumption was associated with a 0.26 mg/dL greater annual increase in HDL levels (95% CI 0.48 to 0.04; P=0.02). Over the 10‐year study period, the model predicted a mean increase of 2.2 mg/dL (95% CI 0.09 to 4.32; P=0.04) among low consumers, and a 0.4 mg/dL decrease (95% CI −1.32 to 0.52; P=0.4) among high consumers. Weight category did not modify this association (P=0.45). Conclusion Low added sugars consumption is associated with increasing HDL cholesterol levels throughout adolescence.

The 2D:4D digit ratio is not a useful marker for prenatal famine exposure: Evidence from the Dutch hunger winter families study

Objectives: Digit lengths, and in particular the ratio of the 2nd (2D) to 4th (4D) digit (2D:4D), are stable in adulthood and have been linked to characteristics thought to have developmental origins, but little research has focused on early life determinants of these measures. We examined whether exposure to acute famine during specific periods of gestation was associated with 2D, 4D or the 2D:4D ratio.

Early Life Growth Predicts Pubertal Development in South African Adolescents

Background: Given global trends toward earlier onset of puberty and the adverse psychosocial consequences of early puberty, it is important to understand the childhood predictors of pubertal timing and tempo. Objective: We examined the association between early growth and the timing and tempo of puberty in adolescents in South Africa. Methods: We analyzed prospectively collected data from 1060 boys and 1135 girls participating in the Birth-to-Twenty cohort in Soweto, South Africa. Height-for-age z scores (HAZs) and body mass index–for-age z scores (BMIZs) were calculated based on height (centimeters) and body mass index (kilograms per meter squared) at ages 5 y and 8 y. The development of genitals, breasts, and pubic hair was recorded annually from 9 to 16 y of age with the use of the Tanner sexual maturation scale (SMS). We used latent class growth analysis to identify pubertal trajectory classes and also characterized children as fast or slow developers based on the SMS score at 12 y of age. We used multinomial logistic regression to estimate associations of HAZ and BMIZ at ages 5 and 8 y with pubertal development. Results: We identified 3 classes for pubic hair development (for both girls and boys) and 4 classes for breast (for girls) and genital (for boys) development. In girls, both HAZ and BMIZ at age 5 y were positively associated with pubic hair development [relative risk ratio (RRR): 1.57, P < 0.001 and RRR: 1.51, P < 0.01, respectively], as was BMI at age 8 y (RRR: 2.06, P = 0.03); similar findings were observed for breast development. In boys, HAZ and BMIZ at age 5 y were positively associated with pubic hair development (RRR: 1.78, P < 0.001 and RRR: 1.43, P < 0.01, respectively); HAZ at age 5 y was associated with development of genitals (RRR: 2.19, P < 0.01). Conclusion: In boys and girls, both height and body mass index in early childhood predicted the trajectory of pubertal development. This may provide a tool to identify children at risk of early pubertal onset.