Developmental Origins of Health and Disease: Who knows? Who cares?

Developmental origins of health and disease (DOHaD) is the study of how the early life environment can impact the risk of chronic diseases from childhood to adulthood and the mechanisms involved. Epigenetic modifications such as DNA methylation, histone modifications and non-coding RNAs are involved in mediating how early life environment impacts later health. This review is a summary of the Epigenetics and DOHaD workshop held at the 2016 DOHaD Society of Australia and New Zealand Conference. Our extensive knowledge of how the early life environment impacts later risk for chronic disease would not have been possible without animal models. In this review we highlight some animal model examples that demonstrate how an adverse early life exposure results in epigenetic and gene expression changes that may contribute to increased risk of chronic disease later in life. Type 2 diabetes and cardiovascular disease are chronic diseases with an increasing incidence due to the increased number of children and adults that are obese. Epigenetic changes such as DNA methylation have been shown to be associated with metabolic health measures and potentially predict future metabolic health status. Although more difficult to elucidate in humans, recent studies suggest that DNA methylation may be one of the epigenetic mechanisms that mediates the effects of early life exposures on later life risk of obesity and obesity related diseases. Finally, we discuss the role of the microbiome and how it is a new player in developmental programming and mediating early life exposures on later risk of chronic disease.

Preeclampsia: Exposing Future Cardiovascular Risk in Mothers and Their Children

Developmental Origin of Health and Disease (DOHaD) explains how the health of the mother influences the offspring’s risk of non-communicable diseases in later life. However, this remains underutilized in clinical practice. This study aimed to investigate the knowledge, attitude, and practice (KAP) of medical students, Obstetrics and Gynecology (O&G) and Pediatrics residents, toward DOHaD, identify potential barriers to DOHaD counseling, and translate DOHaD concepts into clinical practice. This cross-sectional study was conducted with a multi-section digital questionnaire, rated on a five-point Likert scale (1–5), with a higher score indicating better KAP. The scores between groups were compared using ANOVA. A total of 117 participants, comprising medical students (n = 75, 64.1 percent), O&G (n = 33, 28.2 percent) and Pediatric residents (n = 9, 7.7 percent), completed the questionnaire. The mean scores for the “Knowledge,” “Attitude” and “Practice” sections were 3.73 (standard deviation 0.82), 4.27 (0.59) and 3.03 (0.52), respectively. O&G residents scored higher for the “Practice” section than Pediatric residents (mean scores 3.17 vs. 2.16; p = .048). Overall, the participants demonstrated good knowledge and attitude, but poor practice toward DOHaD. Thus, there is a need to improve education and training for health care professionals, develop a structured implementation framework, and provide a transdisciplinary care continuum for mother and child.

The Developmental Origins of Health and Disease (DOHaD) framework aims to understand how early life exposures shape lifecycle health. To date, no comprehensive list of these exposures and their interactions has been developed, which limits our ability to predict trajectories of risk and resiliency in humans. To address this gap, we developed a model that uses text-mining, machine learning, and natural language processing approaches to automate search, data extraction, and content analysis from DOHaD-related research articles available in PubMed. Our first model captured 2469 articles, which were subsequently categorised into topics based on word frequencies within the titles and abstracts. A manual screening validated 848 of these as relevant, which were used to develop a revised model that finally captured 2098 articles that largely fell under the most prominently researched domains related to our specific DOHaD focus. The articles were clustered according to latent topic extraction, and 23 experts in the field independently labelled the perceived topics. Consensus analysis on this labelling yielded mostly from fair to substantial agreement, which demonstrates that automated models can be developed to successfully retrieve and classify research literature, as a first step to gather evidence related to DOHaD risk and resilience factors that influence later life human health.

The Developmental Origins of Health and Disease (DOHaD) framework aims to understand how environmental exposures in early life shape lifecycle health. Our understanding and the ability to prevent poor health outcomes and enrich for resiliency remain limited, in part, because exposure-outcome relationships are complex and poorly defined. We, therefore, aimed to determine the major DOHaD risk and resilience factors. A systematic approach with a 3-level screening process was used to conduct our Rapid Evidence Review following the established guidelines. Scientific databases using DOHaD-related keywords were searched to capture articles between January 1, 2009 and April 19, 2019. A final total of 56 systematic reviews/meta-analyses were obtained. Studies were categorized into domains based on primary exposures and outcomes investigated. Primary summary statistics and extracted data from the studies are presented in Graphical Overview for Evidence Reviews diagrams. There was substantial heterogeneity within and between studies. While global trends showed an increase in DOHaD publications over the last decade, the majority of data reported were from high-income countries. Articles were categorized under six exposure domains: Early Life Nutrition, Maternal/Paternal Health, Maternal/Paternal Psychological Exposure, Toxicants/Environment, Social Determinants, and Others. Studies examining social determinants of health and paternal influences were underrepresented. Only 23% of the articles explored resiliency factors. We synthesized major evidence on relationships between early life exposures and developmental and health outcomes, identifying risk and resiliency factors that influence later life health. Our findings provide insight into important trends and gaps in knowledge within many exposures and outcome domains.

The concept of Developmental Origins of Health and Disease (DOHaD), which has emerged over the past decades, links the state of health and disease in later life with environmental factors of the early life. It was the pioneer work of David J. Barker, Southampton University, United Kingdom, who proposed the fetal origins of adult disease hypothesis, also referred to as the “thrifty phenotype” hypothesis or Barker hypothesis, which states that an adverse fetal environmental, such as undernutrition, increases the risk of noncommunicable diseases (NCDs) in adulthood. At the beginning of this century, the DOHaD theory incorporated much broader concepts: not only were poor physical conditions in adulthood, such as disease suffering, strongly associated with the fetal and infant environment, but also the ability to maintain a healthy lifestyle. Currently, the belief that adverse fetal-childhood environments, such as undernutrition, stress, smoking, and chemical exposure due to growth restriction, increases the risk of NCDs in adulthood, such as cardiovascular disease, stroke, hypertension, type 2 diabetes, chronic kidney disease, osteoporosis, cancer, and psychiatric disorders, is widely accepted. In Europe and America, birth cohort studies are very popular because they enable the integration of data sharing and meta-analyses for genome-wide association studies, epigenome-wide association studies, exposome, Mendelian randomization, and early intervention studies. Recently, in Japan, the concept of preemptive medicine, which is a novel medical paradigm that advocates for presymptomatic diagnosis, prediction, or intervention at an early stage to prevent or delay disease onset, has been proposed. Therefore, interdisciplinary studies that focus on fetal and childhood developmental periods are highly recommended as a political strategy. In this chapter, I will introduce DOHaD cohort studies and interventions and discuss their statuses and perspectives.

The U.S. Developmental Origins of Health and Disease (DOHaD) meeting is an annual conference of primarily U.S. scientists who study early life programming of health and disease. The eighth annual symposium, entitled "Exploring Translational DOHaD Science: From Cells to Communities" was held at the Rizzo Conference Center in Chapel Hill, North Carolina, from October 14 to 16, 2024. The meeting was organized by US-DOHaD President Danielle Christifano and Vice President Kaela Varberg, and other Society Council Members. This year's meeting had record attendance, with 158 attendees from diverse disciplines, and featured 10 keynote speakers, 11 platform talks, and 84 poster presentations. Four major topics were covered: 1) Early nutrition and developmental outcomes, 2) Prenatal origins of child health, 3) Developmental impacts of toxicant exposures, and 4) Metabolic origins of health. Overall, the presented research highlighted the value of studying epigenetic effects of dietary and toxic exposures early in life. Various strategies emerged to address challenges facing the field, such as harnessing the power of nationwide longitudinal birth cohorts, new methods to integrate epigenetic and environmental data across various levels, and the emerging potential of organoids to identify the causal impact of early life exposures.

The prevalence of diabetes mellitus (DM) has been increasing dramatically worldwide, but the pathogenesis is still unknown. A growing amount of evidence suggests that an abnormal developmental environment in early life increases the risk of developing metabolic diseases in adult life, which is referred to as the “metabolic memory” and the Developmental Origins of Health and Disease (DOHaD) hypothesis. The mechanism of “metabolic memory” has become a hot topic in the field of DM worldwide and could be a key to understanding the pathogenesis of DM. In recent years, several large cohort studies have shown that shift workers have a higher risk of developing type 2 diabetes mellitus (T2DM) and worse control of blood glucose levels. Furthermore, a maternal high-fat diet could lead to metabolic disorders and abnormal expression of clock genes and clock-controlled genes in offspring. Thus, disorders of circadian rhythm might play a pivotal role in glucose metabolic disturbances, especially in terms of early adverse nutritional environments and the development of metabolic diseases in later life. In addition, as a peripheral clock, the gut microbiota has its own circadian rhythm that fluctuates with periodic feeding and has been widely recognized for its significant role in metabolism. In light of the important roles of the gut microbiota and circadian clock in metabolic health and their interconnected regulatory relationship, we propose that the “gut microbiota-circadian clock axis” might be a novel and crucial mechanism to decipher “metabolic memory.” The “gut microbiota-circadian clock axis” is expected to facilitate the future development of a novel target for the prevention and intervention of diabetes during the early stage of life.

This article traces evolving understandings of risk in pregnancy and early development by exploring 35 years of media reporting on the Developmental Origins of Health and Disease (DOHaD), an influential biomedical field. DOHaD transformed expert and lay understandings of risk by studying impacts of early life experiences on the risk of adult chronic disease. This article draws on a Discourse-Historical approach and uses the coverage of DOHaD as a case study to examine how understandings of risk have evolved and been mediated through language in the UK, US and Australian media. The analysis detects a major shift in the coverage. While reporting initially focused on some risks of early experiences for adult disease, with time the media identified a growing range of risks and harms for the future health of the foetus. The expansion of ideas of what constitutes a risk was associated with new attributions of blame, initially singling out mothers, but increasingly also grandmothers and fathers, as responsible for the health of future generations. These findings highlight the social and cultural context as well as discursive practices that brought about the expansion of the meaning of risk and blame in relation to early life development, pointing to widespread societal concerns about reproduction.

Developmental origins of health and disease (DOHaD) focuses on the earliest stages of human development, and provides a novel paradigm to complement other strategies for lifelong prevention of common chronic health conditions. The 3 International Congress on DOHaD, held in 2005, retained the most popular features from the first two biannual Congresses, while adding a number of innovations, including increased emphasis on implications of DOHaD for the developing world; programs for trainees and young investigators; and new perspectives, including developmental plasticity, influences of social hierarchies, effects of prematurity, and populations in transition. Emerging areas of science included, first, the controversial role of infant weight gain in predicting adult obesity, diabetes, and cardiovascular disease. Second, in the era of epidemic obesity, paying attention to the over-nourished fetus is as important as investigating the growth retarded one. Third, environmental toxins appear to have abroad range of long-lasting effects on the developing human. Fourth, epigenetic mechanisms could unite several strands of human and animal observations, and explain how genetically identical individuals raised in similar postnatal environments can nonetheless develop widely differing phenotypes. Improving the environment to which an individual is exposed during development may be as important as any other public health effort to enhance population health world wide.

Obesity and its complications are a global public health problem with increasing childhood prevalence. The developmental origins of health and disease (DOHaD) theory explain the maintenance of health or disease development throughout life, related to early life exposures. Although it arises from epidemiological observations, its support for epigenetics is strong. In this chapter, we address the importance of maternal diet in prenatal development, as well as the establishment of the infant microbiota and its postnatal regulating factors. According to the DOHaD theory, breastfeeding and other environmental factors are modulators or enhancers of the epigenetic mechanisms, which explain the increased incidence of noncommunicable diseases. We will discuss the molecular mechanisms related to the microbiota products, their effects on gene expression, and the pathophysiology of the disease. Finally, we will raise the areas of opportunity in childhood for preventive purposes, including the potential role of the use of prebiotics, probiotics, synbiotics, and postbiotics in early life.

Regression discontinuity design (RDD) is a quasi-experimental approach to study the causal effect of an exposure on later outcomes by exploiting the discontinuity in the exposure probability at an assignment variable cut-off. With the intent of facilitating the use of RDD in the Developmental Origins of Health and Disease (DOHaD) research, we describe the main aspects of the study design and review the studies, assignment variables and exposures that have been investigated to identify short- and long-term health effects of early life exposures. We also provide a brief overview of some of the methodological considerations for the RDD identification using an example of a DOHaD study. An increasing number of studies investigating the effects of early life environmental stressors on health outcomes use RDD, mostly in the context of education, social and welfare policies, healthcare organization and insurance, and clinical management. Age and calendar time are the mostly used assignment variables to study the effects of various early life policies and programs, shock events and guidelines. Maternal and newborn characteristics, such as age, birth weight and gestational age are frequently used assignment variables to study the effects of the type of neonatal care, health insurance, and newborn benefits, while socioeconomic measures have been used to study the effects of social and welfare programs. RDD has advantages, including intuitive interpretation, and transparent and simple graphical representation. It provides valid causal estimates if the assumptions, relatively weak compared to other non-experimental study designs, are met. Its use to study health effects of exposures acting early in life has been limited to studies based on registries and administrative databases, while birth cohort data has not been exploited so far using this design. Local causal effect around the cut-off, difficulty in reaching high statistical power compared to other study designs, and the rarity of settings outside of policy and program evaluations hamper the widespread use of RDD in the DOHaD research. Still, the assignment variables' cut-offs for exposures applied in previous studies can be used, if appropriate, in other settings and with additional outcomes to address different research questions.

Maternal long chain polyunsaturated fatty acid status and pregnancy complications

Conferencia clinicopatológica de la SEMI: Coordinadores: Dres. Ramón Pujol Farriols y Miguel Aranda Sánchez Hospital General Universitario Gregorio Marañón. Madrid 4 de abril de 2006

ABSTRACTExposure to environmental stressors during susceptible windows of development can result in negative health outcomes later in life, a concept known as the Developmental Origins of Health and Disease (DOHaD). There is a growing body of evidence that exposures to metals early in life (in utero and postnatal) increase the risk of developing adult diseases such as cancer, cardiovascular disease, non-alcoholic fatty liver disease, and diabetes. Of particular concern is exposure to the metalloid arsenic, a drinking water contaminant and worldwide health concern. Epidemiological studies of areas with high levels of arsenic in the drinking water, such as some regions in Chile and Bangladesh, indicate an association between in utero arsenic exposure and the development of adult diseases. Therefore, the need for experimental models to address the mechanism underlining early onset of adult diseases have emerged including the in utero and whole-life exposure models. This review will highlight the epidemiological events and subsequent novel experimental models implemented to study the impact of early life exposure to arsenic on the development of adult diseases. In addition, current research using these models will be discussed as well as possible underlying mechanism for the early onset of disease.Abbreviations: ALT: alanine aminotransferase; AMI: acute myocardial infarction; AST: aspartate aminotransferase; ATSDR: Agency for Toxic Substances and Disease Registry; CVD: cardiovascular disease; DMA: dimethylarsinate; DOHaD: Developmental Origins of Health and Disease; EPA: U.S. Environmental Protection Agency; ER-α: estrogen receptor alpha; HDL: high-density lipoprotein; HOMA-IR: homeostatic model assessment of insulin resistance; iAs: inorganic arsenic; LDL: low-density lipoprotein; MetS: metabolic syndrome; MMA: monomethylarsonate; NAFLD: non-alcoholic fatty liver disease; PND: postnatal day; ppb: parts per billion; ppm: parts per million; SAM: S-adenosylmethionine; USFDA: United States Food and Drug Administration