Developmental Origins Of Disease Research Articles

Prenatal exposure to polycyclic aromatic hydrocarbons and executive functions at school age: Results from a combined cohort study

BackgroundExecutive functions develop rapidly in childhood, enabling problem-solving, focused attention, and planning. Exposures to environmental toxicants in pregnancy may impair healthy executive function development in children. There is increasing concern regarding polycyclic aromatic hydrocarbons (PAHs) given their ability to transfer across the placenta and the fetal blood-brain barrier, yet evidence from epidemiological studies is limited. MethodsWe examined associations between prenatal PAH exposure and executive functions in 814 children of non-smoking mothers from two U.S. cohorts in the ECHO-PATHWAYS Consortium. Seven mono-hydroxylated PAH metabolites were measured in mid-pregnancy urine and analyzed individually and as mixtures. Three executive function domains were measured at age 8–9: cognitive flexibility, working memory, and inhibitory control. A composite score quantifying overall performance was further calculated. We fitted linear regressions adjusted for socio-demographics, maternal health behaviors, and psychological measures, and examined modification by child sex and stressful life events in pregnancy. Bayesian kernel machine regression was performed to estimate the interactive and overall effects of the PAH mixture. ResultsThe results from primary analysis of linear regressions were generally null, and no modification by child sex or maternal stress was indicated. Mixture analyses suggested several pairwise interactions between individual PAH metabolites in varied directions on working memory, particularly interactions between 2/3/9-FLUO and other PAH metabolites, but no overall or individual effects were evident. ConclusionWe conducted a novel exploration of PAH-executive functions association in a large, combined sample from two cohorts. Although findings were predominantly null, the study carries important implications for future research and contributes to evolving science regarding developmental origins of diseases.

Association of Above-Average Healthy Eating Index and Pregnancy Outcomes [ID: 1375493

INTRODUCTION: Nutritional health plays an important role in the intrauterine environment's effect on the developmental origins of disease. The Healthy Eating Index (HEI), a measure of dietary quality scaled 0–100 with 100 being ideal, has been shown to be poor on average in Americans. In a prospective cohort study of healthy pregnant individuals with a singleton gestation, we assessed dietary quality and its association with pregnancy outcomes. METHODS: Individuals completed their first study visit at a mean gestational age of 15 weeks, and three, 24-hour dietary recalls were obtained. Participants were dichotomized by HEI scores as above and at or below the U.S. average (>58 and ≤58). We assessed outcomes including gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), and large for gestational age (LGA >90th percentile). Statistical analysis was completed using two-sample t tests and Fisher's exact tests (P=.05). The study was IRB approved. RESULTS: Of the 67 participants included in the analysis, 45 (67%) had above average and 22 (33%) had below average HEI scores. The incidence of HDP was significantly lower among individuals with higher dietary quality (22.8% versus 4.4%, P=.03). Although the rates of GDM were not different between the two groups (15.6% versus 9.1%, P=.71), the proportion of LGA infants trended lower in those with higher HEI (4% versus 22%, P=.19). CONCLUSION: Our data suggest that higher dietary quality may lead to improved pregnancy outcomes and support the potential role of the HEI for further exploring these relationships in future research.

The Significance of Exposure to Pregestational Type 2 Diabetes in Utero on Fetal Renal Size and Subcutaneous Fat Thickness.

Objectives To determine the relationship between exposure to pregestational type 2 diabetes (T2D) and renal size and subcutaneous fat thickness in fetuses during routine obstetrical ultrasound. Methods This was a case-control study (January 1, 2019 to December 31, 2019). Routine obstetrical ultrasounds performed between 18 and 22 weeks' gestation at a tertiary-care fetal assessment unit were reviewed. “Cases” comprised ultrasounds of fetuses exposed to pregestational T2D in utero. The control group was assembled from ultrasounds of healthy controls. Postprocessing measurements of fetal renal size and abdominal wall thickness from stored images were performed by two independent observers, and findings were compared between groups. Results There were 54 cases and 428 ultrasounds of healthy controls. The mean maternal age of cases was 32.1 years (SD 6.2) compared to 33.2 years (SD 5.3) for healthy controls, and the majority of ultrasounds were performed in multiparous patients (83%). At the 18 to 22 week ultrasound, there was a significant reduction in renal size amongst fetuses exposed to maternal T2D in utero compared to controls; among cases, the mean renal width was 8.0 mm (95% CI 7.8–8.1) compared to 11.4 mm (95% CI 10.6–12.7) in controls (p < 0.0001); the mean renal thickness among cases was 8.1 mm (95% CI 7.9–8.2) compared to 11.5 mm (95% CI 10.7–12.9) in controls (p=0.001). There was no obvious difference in estimated fetal weight between groups, yet fetuses exposed to maternal T2D had increased subcutaneous abdominal wall fat thickness at this early gestational age (p=0.008). Conclusions Fetal renal size in cases exposed to pregestational T2D is significantly smaller compared to controls, and subcutaneous abdominal wall fat is significantly thicker. Given emerging evidence about the developmental origins of disease, further study is needed to correlate the association between fetal renal size and fat distribution in the fetus and the long-term risk of chronic renal disease and diabetes in these offspring.

Environmental epigenetic interaction of gametes and early embryos†.

In recent years, the developmental origins of diseases have been increasingly recognized and accepted. As such, it has been suggested that most adulthood chronic diseases such as diabetes, obesity, cardiovascular disease, and even tumors may develop at a very early stage. In addition to intrauterine environmental exposure, germ cells carry an important inheritance role as the primary link between the two generations. Adverse external influences during differentiation and development can cause damage to germ cells, which may then increase the risk of chronic disease development later in life. Here, we further elucidate and clarify the concept of gamete and embryo origins of adult diseases by focusing on the environmental insults on germ cells, from differentiation to maturation and fertilization.

Critical Windows of Exposure: why do they exist and what do they tell us?

BACKGROUND AND AIM: This is part of symposium 22 entitled “Innovative Methods for Identifying Perinatal Critical Windows with Mixtures” The concept of critical exposure windows is often equated with developmental origins of disease, although the concept is found in multiple disciplines such as cognitive sciences i.e. language development. In reality, critical exposure windows are the intersection of developmental biology and exposure science, in which time varying environments coincide with age varying biological development. METHODS: When time dependent environment and age dependent biological processes intersect, they create dose response curves that differ in slope uniquely from the slopes derived at other life stages. Critical exposure windows inform mechanisms as discovering them provides insights to both the biological effects of an environmental exposure and the complex age dependent processes that are being modified by that exposure. RESULTS:With regards to mixtures, consideration should also be given to the biological matrix in which exposures are measured, as the half lives and rates of excretions for different exposures vary in blood and urine and other tissues, creating potential biases in results. Variations of even a few months in exposure timing may also introduce bias if the life stage reflects accelerated growth and development (i.e. fetal life). CONCLUSIONS:Finally, from a public health perspective, knowing critical exposure windows means knowing when to intervene and has benefits to creating targeted interventions that are both more effective and more cost efficient. In this talk, we will discuss these issues and the developmental biology principles that underlie these phenomena, while also considering how time varying phenotype expression affects results. KEYWORDS: critical windows, developmental biology, exposure timing, bias

Human embryo research, stem cell-derived embryo models and invitro gametogenesis: Considerations leading to the revised ISSCR guidelines.

SummaryThe ISSCR Guidelines for Stem Cell Research and Clinical Translation were last revised in 2016. Since then, rapid progress has been made in research areas related to in vitro culture of human embryos, creation of stem cell-based embryo models, and in vitro gametogenesis. Therefore, a working group of international experts was convened to review the oversight process and provide an update to the guidelines. This report captures the discussion and summarizes the major recommendations made by this working group, with a specific emphasis on updating the categories of review and engagement with the specialized scientific and ethical oversight process.

Associations Between Maternal Nutrition in Pregnancy and Child Blood Pressure at 4–6 Years: A Prospective Study in a Community-Based Pregnancy Cohort

The intrauterine environment may influence offspring blood pressure, with effects possibly extending into adulthood. The associations between prenatal nutrition and offspring blood pressure, alone or in combination with other sociodemographic or behavioral factors, are unclear. To investigate the associations of maternal dietary patterns and plasma folate concentrations with blood pressure in children aged 4-6 years, and assess the potential effect modifications by child sex, maternal race, pre-pregnancy overweight or obesity, maternal smoking, and breastfeeding. Participants were 846 mother-child dyads from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Maternal nutrition was characterized by the Healthy Eating Index 2010 (HEI) scores and plasma folate concentrations in pregnancy. We calculated the systolic blood pressure (SBP) and diastolic blood pressure percentiles, incorporating sex, age, and height, and categorized children as either having high blood pressure (HBP; ≥90th percentile) or normal blood pressure. Linear regressions were performed to quantify the associations between maternal nutrition and continuous blood pressure percentiles, and Poisson regressions were used to estimate the incidence rate ratio (IRR) of binary HBP. We examined the effect modifications using interaction models. Mean HEI scores and folate concentrations were 60.0 (SD, 11.3) and 23.1ng/mL (SD, 11.1), respectively. Based on measurements at 1 visit, 29.6% of the children were defined as having HBP. Maternal HEI scores and plasma folate concentrations were not associated with child blood pressure percentiles or HBP in the full cohort. Among mothers self-identified as white, there was an inverse relationship between maternal HEI score and child SBP percentile (β, -0.40; 95%CI: -0.75 to -0.06). A maternal HEI score above 59 was associated with a reduced risk of HBP in girls (IRR, 0.53; 95% CI: 0.32-0.88). No modified associations by pre-pregnancy overweight or obesity, maternal smoking, or breastfeeding were indicated. We found little evidence for effects of maternal nutrition during pregnancy on childhood blood pressure, but detected sex- and race-specific associations. The study contributes to the evolving scientific inquiry regarding developmental origins of disease.

Early-Life Stress as a Probe to Study the Opioid System in Developing Rodents.

The developmental origins of disease or fetal programming model predict that early (intrauterine and/or postnatal) exposures to external insults of sufficient length and intensity may have enduring or lifelong consequences for physical and psychological health. The method described in this chapter considers an animal model to study the pathophysiological alterations connected to an HPA axis (hypothalamic-pituitary-adrenal) hyperactivity that are induced by an early-life stressful procedure involving the opioid system.

Developmental Origins of Disease

At any age one can become sick, however, it is pathetic when someone is born with a disease that too which is not expressed immediately. Such diseases show up weeks later and some years later. The causes of such diseases are multifactorial. In this mini-review, we are trying to focus on some important risk factors which should be considered before getting pregnant; in some genetic disorders, genetic analysis is important, even before pregnancy, for others prenatal diagnosis is recommended.

Reflections on the Catastrophic 2019–2020 Australian Bushfires

Reflections on the Catastrophic 2019–2020 Australian Bushfires

In utero exposure to endocrine disrupting chemicals, micro-RNA profiles, and fetal growth: a pilot study protocol.

Background: The developing fetus is particularly vulnerable to the effects of endocrine disrupting chemicals (EDCs). Molecular fingerprints of EDCs can be identified via microRNA (miRNA) expression profiles and may be etiologically implicated in the developmental origin of disease (DOHaD).Methods/design: This pilot study includes pregnant women at high risk (smoking at conception), and low risk (non-smoking at conception) for SGA birth (birthweight<10th percentile for gestational age). We have randomly selected 12 mothers (3 high-risk SGA birth, 3 low-risk SGA birth, 3 high-risk non-SGA birth, 3 low-risk non-SGA birth), with EDC measurements from gestational week 17. All offspring are female. We aim to test the stability of our samples (maternal serum, cord blood, placenta tissue), observe the differential expression of miRNA profiles over time (gestational weeks 17, 25, 33, 37, birth), and study the consistency between maternal EDC measures and miRNA expression profiles across our repeated measures.Expected impact of the study for Public Health: Results from this pilot study will inform the development of a larger cohort wide analysis, and will impact the current state of knowledge in the fields of public health, epigenetics, and the DOHaD.Significance for public healthThis research focuses on the developmental origin of disease with particular emphasis on maternal exposure to endocrine disrupting chemicals during pregnancy and fetal growth by examining microRNA profiles in maternal serum, placenta tissue, and cord blood. Pregnant mothers and offspring are the most vulnerable populations affected by environmental exposures including exposure to pesticides, metals, and contaminants in food. Results from our pilot study will inform a larger project proposal that will look not only at epigenetic modifications and fetal development, but also the epigenetic effects on longer term neurodevelopmental and metabolic outcomes in childhood and early adulthood.

Prenatal Adversity Modulates the Quality of Maternal Care Via the Exposed Offspring.

Adversities in pregnancy, including poor diet and stress, are associated with increased risk of developing both metabolic and mental health disorders later in life, a phenomenon described as fetal programming or developmental origins of disease. Predominant hypotheses proposed to explain this relationship suggest that the adversity imposes direct changes to the developing fetus which are maintained after birth resulting in an increased susceptibility to ill health. However, during pregnancy the mother, the developing fetus, and the placenta are all exposed to the adversity. The same adversities linked to altered offspring outcome can also result in suboptimal maternal care, which is considered an independent adverse exposure for the offspring. Recent key experiments in mice reveal the potential of prenatal adversity to drive alterations in maternal care through abnormal maternal-pup interactions and via alterations in placental signaling. Together, these data highlight the critical importance of viewing fetal programming holistically paying attention to the intimate, bidirectional, and reiterative relationship between mothers and their offspring.

Periconceptional environment and the developmental origins of disease

The concept emerging from Professor David Barker’s seminal research on the developmental origins of later-life disease has progressed in many directions since it was first published. One critical question being when during gestation might environment alter the developmental programme with such enduring consequences. Here, we review the growing consensus from clinical and animal research that the period around conception, embracing gamete maturation and early embryogenesis might be the most vulnerable period. We focus on four types of environmental exposure shown to modify periconceptional reproduction and offspring development and health: maternal overnutrition and obesity; maternal undernutrition; paternal diet and health; and assisted reproductive technology. These conditions may act through diverse epigenetic, cellular and physiological mechanisms to alter gene expression and cellular signalling and function in the conceptus affecting offspring growth and metabolism leading to increased risk for cardiometabolic and neurological disease in later life.

Bone Research Society Abstracts

Bone Research Society Abstracts

Developmental Origins of Disease: Emerging Prenatal Risk Factors and Future Disease Risk.

Many of the diseases and dysfunctions described in the paradigm of the developmental origins of health and disease have been studied in relation to prenatal nutrition or environmental toxicant exposures. Here, we selectively review the current research on four exposures-two nutritional and two environmental-that have recently emerged as prenatal risk factors for long-term health outcomes. Recent studies have provided strong evidence that prenatal exposure to (1) excessive intake of sugar-sweetened beverages, (2) unhealthy dietary patterns, (3) perfluoroalkyl substances, and (4) fine particulate matter, may increase risk of adverse health outcomes, such as obesity, cardiometabolic dysfunction, and allergy/asthma. Emerging prenatal nutritional factors and environmental toxicants influence offspring long-term health. More work is needed to identify the role of paternal exposures and maternal exposures during the preconception period and to further elucidate causality through intervention studies. The ubiquity of these emerging nutritional and environmental exposures makes this area of inquiry of considerable public health importance.

Birth-weight and Risk of Breast Cancer: A Systematic Review Study

Introduction: Observational studies have linked the risk of breast cancer to birth weight, however, findings are not consistent. Therefore, the objective of this study was to investigate and quantify the level of risk of breast cancer associated with birth-weight among women.&#x0D; Methodology: A systematic search of literature was conducted from 1990-2016 using the following databases: PUBMED, DH-Data, EMBASE, MEDLINE, PSYCINFO and GOOGLE SCHOLAR. 13 relevant articles were identified for the systematic review, out of which 5 were suitable for meta-analysis. The computer software Review Manager (RevMan) 5.2 was used for the meta-analysis.&#x0D; Results: Most of the studies reviewed reported significant increased risk of breast cancer among participants with high birth weight. There were indications that this relationship is more pronounced among premenopausal women. In addition, the meta-analysis further revealed that women with suboptimum birth-weight (&lt;3,500g) are at lesser risk of breast cancer when compared with optimum birth-weight 3,500g-4,500g (OR= 1.17 (95% CI 0.98, 1.39)); while optimum birth-weight (3,500g-4,500g) women are at lesser risk of breast cancer when compared with women with above-optimum birth-weight (&gt;4,500g) (OR=0.87 (95% CI 0.66, 1.15).&#x0D; Conclusion and Implications for Translation: This study revealed that the risk of breast cancer increases with increasing high birth weight especially among premenopausal women, thus suggesting early onset of breast cancer in this group. There is a clear relationship between high birth weight and risk of breast cancer; the developmental origin of health and diseases theory as postulated by Baker may be the strongest biological mechanism to explain this finding. Prevention programs through health education and early diagnosis strategies targeted at this group might be promising strategies to tackle global burden of breast cancer.&#x0D; Key words: • Breast cancer • Birth-weight • Level of risk • Developmental origin of disease • Systematic review&#x0D; Copyright © 2018 Ojeifo and Anjorin. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Birth weight and postnatal microbial exposures predict the distribution of peripheral blood leukocyte subsets in young adults in the Philippines

The immune system not only provides protection against infectious disease but also contributes to the etiology of neoplastic, atopic, and cardiovascular and metabolic diseases. Prenatal and postnatal nutritional and microbial environments have lasting effects on multiple aspects of immunity, indicating that immune processes may play important roles in the developmental origins of disease. The objective of this study is to evaluate the association between birth weight and the distribution of leukocyte (white blood cell) subsets in peripheral blood in young adulthood. Postnatal microbial exposures were also considered as predictors of leukocyte distribution. Participants (n=486; mean age=20.9 years) were drawn from a prospective birth cohort study in the Philippines, and analyses focused on the following cell types: CD4 T lymphocytes, CD8 T lymphocytes, B lymphocytes, natural killer cells, monocytes, granulocytes. Higher birth weight was a strong predictor of higher proportion of CD4 T lymphocytes (B=0.12, s.e.=0.041, P=0.003), lower proportion of CD8 T lymphocytes (B=-0.874, s.e.=0.364, P=0.016), higher CD4:CD8 ratio (B=1.964, s.e.=0.658, P=0.003), and higher B lymphocytes (B=0.062, s.e.=0.031, P=0.047). Measures of microbial exposure in infancy were negatively associated with proportions of B lymphocytes and granulocytes, and lower CD4:CD8 ratio. Leukocytes are the key regulators and effectors of innate and specific immunity, but the origins of variation in the distribution of cell type across individuals are not known. Our findings point toward nutritional and microbial exposures in infancy as potentially important determinants of immune-phenotypes in adulthood, and they suggest that leukocyte distribution is a plausible mechanism through which developmental environments have lasting effects on disease risk in adulthood.

Seeking genes responsible for developmental origins of health and disease from the fetal mouse liver following maternal food restriction.

Low birthweight resulting from a non-optimal fetal environment is correlated epidemiologically to a higher risk of adult diseases, and which has also been demonstrated using animal models for maternal undernutrition. In this study, we subjected pregnant mice to 50% food restriction (FR), and profiled gene expression and promoter DNA methylation genome-wide using the fetal livers. The fact that effect of food restriction is opposite between before and after birth encouraged us to hunt for genes that are expressed oppositely to adult calorie restriction (CR) using the maternal livers. Among oppositely regulated genes, we identified trib1 (tribbles homolog 1). Using genetically modified mice, trib1 has been shown to have a demonstrable contribution to a risk of hypertriglyceridaemia and insulin resistance. Our data showed that the trib1 expression and its promoter DNA methylation could be affected physiologically (by maternal nutrition), and therefore might be a strong candidate gene for developmental origins of adult diseases. Furthermore, lepr (leptin receptor) gene was downregulated by maternal FR, indicating its potential role in induction of obesity and diabetes. Gene expression as well as promoter DNA methylation profiling revealed that glucocorticoid receptor target genes were regulated by maternal FR. This supports previous studies that suggest an important role of fetal glucocorticoid exposure in the mechanism of developmental origins of diseases. Our transcriptomics profiling data also suggested that maternal FR impaired development of the immune system. An inventory of candidate genes responsible for developmental origins of health and disease is presented and discussed in this study.

Impact of gestational hyperglycemia on maternal and child health

To address the recent evidence regarding the association between hyperglycemia during pregnancy and adverse short-term and long-term outcome for both mothers and offspring. Recent data suggest a relationship between hyperglycemia during pregnancy and adverse short-term fetal outcomes, mainly those associated with excessive fetal growth. The degree of hyperglycemia plays an important role in risk stratification. Moreover, the long-term effect of hyperglycemia during pregnancy is expressed mainly as cardiometabolic morbidity and increased risk for the development of metabolic syndrome both maternal and in early adolescence. Alternation in DNA methylation and gene expression of metabolic pathways were found in association with hyperglycemia in utero, supporting the 'developmental origins of disease' hypothesis. The effect of hyperglycemia on the early life metabolic environment may contribute to the subsequent risk of cardiovascular or metabolic morbidity later in life. It is also a sign of future maternal metabolic alternation. Several future randomized trials, hopefully will help to determine if early intervention could decrease the risk for gestational diabetes and whether long term adverse outcome are preventable and importantly the association with degree of maternal hyperglycemia in pregnancy and future morbidity.

The Environment Within: Exploring the Role of the Gut Microbiome in Health and Disease

The human genome codes for approximately 23,000 genes,1 yet some experts have suggested that the total information coded by the human genome alone is not enough to carry out all of the body’s biological functions.2 A growing number of studies suggest that part of what determines how the human body functions may be not only our own genes, but also the genes of the trillions of microorganisms that reside on and in our bodies. The genomes of the bacteria and viruses of the human gut alone are thought to encode 3.3 million genes.3 “The genetic richness and complexity of the bugs we carry is much richer than our own,” says Jayne Danska, an immunologist at the Hospital for Sick Children Research Institute in Ontario, Canada. “They serve as a buffer and interpreter of our environment. We are chimeric organisms.” Figure 1 False-color scanning electron micrograph shows the surface of the colon mucosa with pink clusters of rod-shaped bacteria, possibly Escherichia coli, attached. The genomes of the bacteria and viruses of the human gut alone are thought to encode 3.3 million ... A role for gut microbes in gastrointestinal function has been well documented since researchers first described differences in the fecal bacteria of people with inflammatory bowel disease.4 The molecular mechanisms responsible for the gut microbiome’s impact on metabolism and diseases throughout the body remain largely unknown. However, researchers are beginning to decipher how the microorganisms of the human intestinal tract influence biological functions beyond the gut and play a role in immunological, metabolic, and neurological diseases.