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Department of Cardiovascular Medicine, Kumamoto University, Kumamoto City, JapanInternational Research Center for Medical Science, Kumamoto University, Kumamoto City, Japan
Perinatal environment dramatically changes before and after birth.
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The Developmental Origin of Health and Disease (DOHaD) is the concept that non-communicable diseases are affected by the fetal period status.
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Much epidemiological evidence and genome-wide analyses support the DOHaD in the cardiovascular field.
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Hormonal effects, epigenetic modifications, and post-translational modifications are proposed to be involved as etiological factors.
Abstract
Numerous epidemiological and animal studies disclosed that birth weight is inversely associated with the incidence of the lifestyle-related disorders in adult life, such as cardiovascular disease, diabetes, and /or chronic kidney disease. Lower birth weight occurs in numerous undesired intrauterine environments including malnutrition, smoking, alcohol consumption, or stress. The Developmental Origin of Health and Disease (DOHaD) theory is based on the concept that the origins of lifestyle-related disease is formed at the time of fertilization, embryonic, fetal, and neonatal stages by the interrelation between genes and the environments (nutrition, stress, or environmental chemicals). Adult disease develops after delivery facing to abnormal environments such as over-nutrition, much stress, or lack of exercise. Disease develops through these two insults. This concept was first proposed as the “Barker Hypothesis.” David Barker had discovered the relation between the lower birth weight and the higher prevalence of ischemic heart disease mortality. Previous epidemiologic studies have found the people exposed to famine during early life had higher risks of cardiovascular diseases in adulthood. Yet, the exact mechanisms that permanently change the structure, physiology, and endocrine status of an individual across their lifespan following altered growth during fetal life are not entirely clear. Epidemiological studies including prospective cohort and observational analysis of the people exposed to malnutrition during fetal or infancy have disclosed the strong relation between the lower birth weight and the higher cardiovascular risks in adults. Recent progress of epigenetic studies unveiled strong genetic association. Hormonal regulation and epigenetic modifications have an important role for proper organ development and physiological functions. The molecular mechanism of predisposition is supposed to be the epigenetics modifications. Their dysregulation is related to the acquisition of the disease-susceptible trait. In this review, we overview the concept of DOHaD and introduce related clinical and basic research.
Most viviparous animals including humans have a placenta and a womb. They protect the fetus from the external environment to provide an optimal condition for fetal development. Abnormal maternal conditions, such as malnutrition or much mental stress, directly influence the fetal adaptation process. At birth, the ambient temperature and oxygen concentration change greatly, it is forced abruptly to adapt to the new environment that changes dramatically even in physiological conditions (Fig. 1).
Fig. 1Environmental transition during the perinatal period.
Poor prenatal environment in the womb increases the risk of cardiovascular disease in adults. British epidemiologist, David Barker (1938–2013) advocated the thrifty phenotype hypothesis from his landmark observations and following epidemiological data [
]. This concept started from the discovery of strong correlation between maternal undernutrition during pregnancy and increased risks of cardiovascular diseases in adults [
]. First, they found a strong geographical relation between infant mortality in 1921-25 and ischemic heart disease mortality rates in 1968-78 in England and Wales. In high neonatal mortality areas, people had faced a poor nutritional state and pregnant mothers were undernourished, so born children were at increased risk of neonatal death. Even if they survived, they had a high risk of developing ischemic heart disease in life. They supposed that poor nutrition in early life increases susceptibility to ischemic heart disease, and they demonstrated both men and women with the lowest weights at birth had the highest standardized mortality ratios from ischemic heart disease in the Hertfordshire study.
Many epidemiological and genome-wide studies have shown that the suboptimal perinatal environment influences susceptibility to later non-communicable diseases (NCDs) later in life. Now, Barker’s hypothesis has been expanded and is recognized as the Developmental Origins of Health and Diseases (DOHaD). However, its importance is not yet well recognized in the cardiovascular field. Here, we introduce the concept of DOHaD and adaptation mechanisms during the perinatal period.
In this review, we outline the concept of the DOHaD and noticeable human evidence. We also evaluate current research results and introduce the hypothesized underlying mechanisms in the programming of life-related adult diseases. Additionally, the concrete example of the adaptation mechanism through ketone body metabolism will be outlined.
The concept of developmental origins of health and diseases
Nutritional stress, such as undernutrition or hunger during pregnancy restricts fetal growth in the uterus. It is reported that approximately 16% of children born in the world are low birth weight infants who weigh less than 2,500 g UNICEF World Children's White Paper 2016 [
]. In Japan, the incidence of low birth weight infant has been high for long time. According to the demographic statistics of the Ministry of Health, Labor and Welfare, the proportion of low birth weight infants was 5.1% in the 1970s but then increased to 9.6% in 2006 and this high incidence has been unchanged until now (Fig. 2). The proportion has doubled in 30 years and is supposed to continue in future.
Fig. 2Proportion of low birth weight babies in Japan.
The DOHaD theory is based on the concept that lifestyle-related disorders in adults, such as ischemic heart disease, diabetes, and chronic kidney disease are affected by the nutritional state during the embryonic period. Barker and Osmond disclosed that high infant mortality and poor living conditions were related to the high risk of ischemic heart disease mortality [
]. First, they found a strong geographical relation between infant mortality in 1921-25 and ischemic heart disease mortality rates in 1968-78 in England and Wales. In the high neonatal mortality areas, people had faced a poor nutritional state and pregnant mothers were undernourished, so their born children were at increased risk of neonatal death. Even if they survived, they had a high risk of developing ischemic heart disease in later life. They supposed that poor nutrition in early life increases susceptibility to ischemic heart disease. Large-scale epidemiological studies have been conducted; the Nurses' health study I (NHS I), in the USA, reported that the risk of non-fatal adult cardiovascular disease was increased by approximately 30% for the birth weight 2267 g–2495 g and approximately 50% for the birthweight less than 2267 g compared with 3856 g–4536 g [
Various studies have also suggested the involvement of hypertension with birthweight. The Nurses' health study II (NHS II) enrolled more than 150,000 women and showed that the low birth weight female had an increased risk of hypertension [
]. The Northern Finland Birth Cohort 1966 surveyed the relation between birth weight and blood pressure at the age of 31 years old and showed that birth weight was inversely associated with blood pressure especially for males [
Several historical events, especially famine, have strongly influenced the birth weight. The Dutch Famine is one of the most well-known life-threatening famines caused in World War II. Dutch hunger winter occurred in the western Netherlands during 1944-1945. Food supply had been completely stopped with a one-month blockade by the German army occupation and following a harsh winter; after the release by the Allies, the area was supplied with abundant food. It was estimated that 18,000 people died from hunger. People were also exposed to extreme malnutrition, resulting in giving many low birth weight babies [
]. A follow-up study of the babies revealed that they showed decreased glucose tolerance later in life. Moreover, the study found significant association of low birth weight with elevated blood pressure [
]. The Biafran famine, another severe famine, was prompted by the Nigerian civil war (1967–1970). A cohort study of those survivors also indicated that the babies exposed to perinatal starvation were associated with elevated risks of hypertension, diabetes, or overweight [
In addition to in utero programming, there are also genetic factors that determine birth weight. Recently the association between the mother's own birth weight and the infant's birth weight was analyzed with an extended genome-wide association analysis [
]. If there is a genotype that reduces maternal birth weight, the offspring will have a lower birth weight even in a good intrauterine environment, and the offspring has an increased risk of developing future cardiovascular and metabolic disorders [
Although indirect, maternal and fetal genetic factors have been found to be closely linked to reduced birth weight, transmission of these genes to the fetus results in weight loss and increased blood pressure in the offspring [
From these findings of both of the genetic and the intrauterine environmental effects, lower birth weight is the obvious risk for cardiovascular diseases in adults.
Related mechanisms of DOHaD
Many epidemiological studies and genome-wide association studies provide evidence for DOHaD in cardiology. However, the underlying mechanisms are not completely understood. In this section, we introduce the proposed mechanisms and related research.
Hormonal effects
Functions of the hypothalamus, pituitary, and adrenal glands dramatically change during fetal development and their proper development is critical. These organs work in a coordinated manner via the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis regulates intrauterine homeostasis and plays a critical role in appropriate development of vital organs [
]. Prenatal stress changes the HPA axis, thereby causing excessive glucocorticoid expression, neurodevelopment, and causes excess glucocorticoid release in utero. The function of the HPA axis in utero and extra-uterine is also significantly involved in postnatal disease development. Prenatal stress changes regulating mechanisms of the HPA axis and causes the excess glucocorticoid release in utero also influences long-term and causes life-long effects [
]. Experimentally, prenatal overstress or exposure to glucocorticoids due to prenatal exposure to harmful environments alters offspring’s physiology and results in reduced birth weight. Subsequently, it has been shown to induce dysfunction of cardiovascular and metabolic homeostasis, and impairment of the HPA axis.
Placental 11 beta hydroxysteroid dehydrogenase type 2 (11 beta HSD2) deactivates maternal glucocorticoids. Decreased 11 beta HSD2 in the human placenta induces fetus exposed to much glucocorticoids in utero and correlates with reduced birth weight and increased blood pressure later in life. Similarly, in animal models, inhibition or knockout of placental 11 beta HSD2 reduces fetal birth weight. The result is a programming of hypersecretion of glucocorticoids. Its molecular mechanism involves epigenetic modifications, especially the tissue-specific intracellular glucocorticoid receptor (GR).
In growth-restricted murine model, leptin surge occurs prematurely and remodels HPA axis and generates prone trait of adiposity [
]. Status of DNA methylation and histone modification influences the birthweight and postnatal stage, such changes have an important role in tissue maturation [
]. A study by Einstein et al. on cord blood from neonates with intrauterine growth restriction revealed cytosine methylation dysregulation in comparison to control subjects [
]. Radford et al. showed that adult male mice exposed to undernutrition in utero had locus-specific hypomethylated sperm DNA. As a result, their offspring also exhibited transcriptional dysregulation, hypomethylation, and metabolic diseases [
These data point to the fact that the perinatal environmental stresses also might influence the epigenome status of the heart. Compared to other organs, cardiomyocytes have a unique feature as non-dividing cells. In the heart, both DNA methylation and histone modifications regulate cardiomyocyte development [
]. The heart is a highly differentiated organ and has vital functions throughout life. The process of DNA methylation of the cardiomyocyte formation and maturation is not yet fully understood. DNA and histones purified from healthy neonatal and adult myocardium, and myocardium with heart failure, have been analyzed. In the process of cardiomyocyte formation, specific regions are dynamically methylated and demethylated. In particular, the suppression of myocardial genes is mainly caused by DNA methylation and demethylation of H3K27me3, and the region has been partially elucidated. In addition, de novo methylation by DNA methyltransferase 3A / B causes suppression of the fetal heart genes, which contain essential components of cardiomyocytes. In heart failure cardiomyocytes, it partially mimics the neonatal methylation pattern. During postnatal growth of cardiomyocytes, DNA methylation changes much dynamically and regulates closely the function of cardiomyocytes. Perinatal stress might change the epigenetics of cardiomyocytes and ischemic heart disease might be induced in future.
Posttranslational modifications
Histone modification is a form of post-translational modification. Post-translational modifications include phosphorylation, acetylation, and ubiquitination and so on. Recently, we found that neonatal ketogenesis enhanced independent starvation; this reaction might be a nutritional adaptation mechanism (Fig. 3). Insufficient ketogenesis may lead to severe hepatosteatosis during the neonatal period and be related to non-communicable disease in adults. Moreover, insufficient ketogenesis affects the post-translational modifications through protein acetylation. In the case of mitochondria, hyperacetylation of mitochondrial proteins causes mitochondrial dysfunction. Therefore, impaired ketogenesis might be involved in the pathogenesis of DOHaD through post-translational modification [
Here, we have provided an overview of the concept of DOHaD and reported on clinical research. We have also introduced some studies, which relate to the etiology of DOHaD and the new concept of adaptation mechanism, neonatal ketogenesis. Further, we have reported direct evidence of the DOHaD, along with experimental evidence and clinical research that illuminates the underlying mechanisms.
Funding
A series of our studies is supported by the following grants: a Grant-in-Aid for Scientific Research (#19K08520 and #17K16014) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; a Grant for Basic Research of the Japanese Circulation Society (2018); a Grant from the Sumitomo Foundation (2018); a Grant from the Takeda Foundation (2019), Kumamoto University Challenging Research Projects (2019).
Disclosures
The authors declare no competing interests.
Acknowledgments
The authors thank Megumi Nagahiro and Saeko Tokunaga for their excellent technical support throughout the experiments.
References
Barker D.J.
Winter P.D.
Osmond C.
Margetts B.
Simmonds S.J.
Weight in infancy and death from ischaemic heart disease.
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