Early life, risk and blame: Developmental Origins of Health and Disease (DOHaD) in the news, 1988–2023

Editorial FocusEpigenetic changes in gene expression: focus on "The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction"Barbara T. AlexanderBarbara T. AlexanderPublished Online:01 Feb 2010https://doi.org/10.1152/ajpregu.00760.2009This is the final version - click for previous versionMoreSectionsPDF (180 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations the term epigenetics was first coined in 1942 by Waddington (20) to describe the interaction of genes with their environment during development that gives rise to a phenotype. Today, the term epigenetics is used when describing a phenotype that occurs in a manner outside conventional genetic interactions and refers to stable and heritable alterations in gene expression that do not involve a change in DNA sequence (9). DNA methylation is one type of epigenetic mechanism that serves as a postreplication modification and can occur in response to environmental influences (14). DNA methylation, which involves the modification of cytosines found in the dinucleotide sequence CpG (9), can activate or suppress transcription, is reversible (9), and plays a critical role in normal mammalian cell differentiation and development (14). DNA methylation is also implicated in the pathology of many age-related diseases, such as cancer (6), and, importantly, epigenetic modification of the genome can allow for stable transmission of gene activity to the next generation (9).Developmental origins of health and disease (DOHaD) refers to the process by which the phenotype of a fetus is altered in response to environmental influences (2). The DOHaD hypothesis originated from a geographical correlation of infant mortality and ischemic heart disease (2). Based on this study, Barker (2) proposed that adverse environmental influences during early development permanently alter the body's structure, function, and metabolism in ways that lead to an increased risk for adult cardiovascular and metabolic disease. Numerous epidemiological studies now validate this association, and numerous experimental studies have investigated potential mechanisms involved in the DOHaD (1); however, the exact link between fetal life and programmed adult disease remains unclear. Although the increased risk of adult health and disease observed in a fetus exposed to environmental stresses implicates epigenetic processes as a possible link (Figure 1), few studies have directly tested this hypothesis.Fig. 1.DNA methylation of a gene is a type of epigenetic process that can occur in response to adverse environmental influences. Changes in gene expression associated with an increased risk for adult disease occur in response to adverse environmental influences during critical periods of development. Thus, epigenetic processes may serve as a critical link between insults during fetal life and the increased risk for adult disease.Download figureDownload PowerPointThe rodent model of maternal low protein is well characterized as an experimental model of DOHaD (10). Protein is key for proper fetal growth (3) and a reduction in protein content from a range of 18% to 20% to a range of 9% to 12% in the maternal diet can lead to disproportionate fetal growth, hypertension, cardiovascular disease, and metabolic programming in low-protein offspring (1, 3, 10, 19). In addition, reductions in birth weight (3), cardiovascular dysfunction (19), and programmed alterations in methylation of hepatic gene promoters (4) can extend to the next generation. Thus, the mechanism by which maternal low protein leads to DOHaD may involve epigenetic effects mediated via altered DNA methylation of key genes linked to health and disease.Temporal alterations in lipid metabolism are noted in low-protein offspring; similar hepatic triglyceride and cholesterol content are observed at 1 mo of age (5) but increase in low-protein offspring with age relative to control (5). Hepatic lipid homeostasis is regulated by a number of nuclear receptors including the peroxisome proliferator-activated receptor-α (PPARα) and the liver X-receptor (LXR) (11). PPARα and LXR are activated by free fatty acids and cholesterol metabolites, respectively, and they modulate lipid homeostasis by activating target genes (8) that initiate the synthesis and uptake of cholesterol, fatty acids, and triglycerides (see Refs. 7 or 16 for a complete review). An earlier study by Lillycrop et al. (12) reported that a reduction in methylation of CpG dinucleotides in the PPARα nuclear receptor in 28-day-old offspring of low-protein dams is associated with an increase in expression of PPARα mRNA and its target gene, Acyl-CoA oxidase. Whether hypomethylation of the PPARα gene and increased gene expression persist into adulthood, and whether these changes in gene expression are associated with dysregulation of lipid metabolism are not addressed. However, these findings indicate that epigenetic regulation of the hepatic PPARα gene can occur in response to a fetal insult and suggests a potential link between adverse influences during fetal life and later adult health.Although epigenetic processes, such as changes in gene methylation, are known mediators of transcriptional activation and repression (9), whether the specific hypomethylation pattern of the PPARα gene induced by maternal low protein in offspring can directly influence PPARα gene expression was not determined in the previous study by Lillycrop et al. (12). van Straten et al. (17) utilize the DOHaD model of maternal low protein to demonstrate epigenetic modification of another nuclear receptor critical for lipid homeostasis, the LXR. In response to prenatal exposure to low protein, a specific pattern of hypermethylation of CpG dinucleotides in the fetal liver LXR alpha gene promoter was observed at embryonic day 19.5 (E19.5) in low-protein offspring and importantly, was associated with reduced expression of the fetal hepatic LXR alpha gene (17). In addition, expression of LXR alpha target genes, which contribute to cholesterol elimination, such as the ATP-binding cassette transporters ABCG5 and ABCG8, were also reduced (17). The causal relationship between the specific pattern of CpG hypermethylation of the LXR gene identified in this study and changes in LXR gene expression was directly tested in vitro by use of pharmacological and reporter gene expression assay methodologies (17). Notably, van Straten et al. observed that the specific hypermethylation pattern of the LXR gene induced in response to maternal low protein resulted in a reduction in gene expression in vitro (17). Thus, this study provides further evidence that epigenetic effects may serve as a critical link between the fetal response to a nutritional insult and later adult disease.However, the overall importance of epigenetic modification of a gene and the transmission of changes in gene expression into pathophysiological relevance is still not clear. In the current study by van Straten et al. (17) reduced expression of the fetal hepatic LXR gene and other genes involved in cholesterol excretion was associated with a decrease in fetal hepatic cholesterol content. In adult mice lacking the LXR alpha receptor, hepatic cholesterol is elevated in response to a dietary challenge of 2% cholesterol, suggesting that LXR alpha play a critical role in adult hepatic cholesterol homeostasis (7). Thus, suppression of fetal hepatic LXR alpha gene expression and its target genes was not associated with an increase in fetal hepatic cholesterol content. Cholesterol is critical for many processes during fetal development (15) and the fetus obtains its cholesterol from both endogenous and exogenous sources (21). Expression of rodent fetal hepatic LXR alpha peaks at E18 (15) and previous work by van Straten et al. demonstrate that LXR induced expression of hepatic ABCG5 and ABCG8 is functional in fetal mice (18). However, placental LXR and its target genes may also contribute to cholesterol homeostasis in the fetus (13), and therefore, the importance of programmed changes in the fetal hepatic LXR pathway on fetal lipid homeostasis is not yet clear. Additionally, whether programmed hypermethylation of the LXR alpha gene persists beyond fetal life is reversed, and/or contributes to changes in adult hepatic cholesterol content and later adult disease are important questions that remain to be tested.To conclude, the study by van Straten et al. (17) provides critical evidence that modulation of a gene by an epigenetic process, such as DNA methylation in response to fetal insult can alter gene expression. Whether these specific epigenetic modifications persist long term, contribute to later reprogramming of the LXR gene and its target genes, or contribute to an increased risk for adult disease is not yet known. Moreover, whether passage of an epigenetic modification to the next generation is of pathophysiological significance remains unanswered. Hypomethylation of the hepatic PPARα gene in offspring (F1) of maternal low-protein dams persists into adulthood (12) and is transmitted to the next generation (F2) (4). Yet, hypomethylation of the PPARα gene does not translate into an increase in PPARα gene expression in F2 offspring (4). Clearly, additional studies are required to comprehensively address the importance of transgenerational effects of epigenetic mechanisms in the DOHaD. Investigation of these parameters will be critical in determining the overall importance of epigenetic processes as a potential link between fetal responses to environmental influences, the programming of adult health and disease, and the heritable risk of disease in the next generation.GRANTSB. T. Alexander is supported by National Heart, Lung, and Blood Institute Grants HL-074927 and HL-51971.DISCLOSURESNo conflicts of interest are declared by the author.REFERENCES1. Alexander BT . Fetal programming of hypertension. Am J Physiol Regul Integr Comp Physiol 290: R1–R10, 2006.Link | ISI | Google Scholar2. Barker DJ . The origins of the development origins theory. J Intern Med 261: 412–417, 2007.Crossref | PubMed | ISI | Google Scholar3. Bertram CE , Hanson MA . Animal models and programming of the metabolic syndrome. Br Med Bull 60: 103–121, 2001.Crossref | PubMed | ISI | Google Scholar4. Burdge GC , Slater-Jefferies J , Torrens C , Phillips ES , Hanson MA , Lillycrop KA . Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 97: 435–439, 2007.Crossref | PubMed | ISI | Google Scholar5. Erhuma A , Salter AM , Sculley DV , Langtey-Evans SC , Bennett AJ . Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat. Am J Physiol Endocrinol Metab 292: E1702–E1714, 2007.Link | ISI | Google Scholar6. Esteller M . Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8: 286–298, 2007.Crossref | PubMed | ISI | Google Scholar7. Gabbi C , Warner M , Gustafsson JA . Liver X receptor B: emerging roles in the physiology and diseases. Mol Endocrinol 23: 129–136, 2009.Crossref | PubMed | Google Scholar8. Hong C , Tontonoz P . Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev 18: 461–467, 2008.Crossref | PubMed | ISI | Google Scholar9. Jaenisch R , Bird A . Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33, Suppl: 245–254, 2003.Crossref | PubMed | ISI | Google Scholar10. Langley-Evans SC . Fetal programming of cardiovascular function through exposure to maternal undernutrition. Proc Nutr Soc 60: 505–513, 2001.Crossref | PubMed | ISI | Google Scholar11. Li AC , Glass CK . PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res 45: 2161–2173, 2004.Crossref | PubMed | ISI | Google Scholar12. Lillycrop KA , Phillips ES , Torrens C , Hanson MA , Jackson AA , Burdge GC . Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br J Nutr 100: 278–282, 2008.Crossref | PubMed | ISI | Google Scholar13. Plösch T , van Straten EM , Kuipers F . Cholesterol transport by the placenta: placental liver X receptor activity as a modulator of fetal cholesterol metabolism? Placenta 28: 604–610, 2007.Crossref | PubMed | ISI | Google Scholar14. Reik W , Dean W , Walter J . Epigenetic reprogramming in mammalian development. Science 293: 1089–1093, 2001.Crossref | PubMed | ISI | Google Scholar15. Sakamoto A , Kawasaki T , Kazawa T , Ohashi R , Jiang S , Maejima T , Tanaka T , Iwanari H , Hamakubo T , Sakai J , Kodama T , Naito M . Expression of liver X receptor alpha in rat fetal tissues at different developmental stages. J Histochem Cytochem 55: 641–649, 2007.Crossref | PubMed | ISI | Google Scholar16. Steffensen KR , Gustafsson JA . Putative metabolic effects of the liver X receptor (LXR). Diabetes 53, Suppl 1: S36–S42, 2004.Crossref | PubMed | ISI | Google Scholar17. van Straten EME , Bloks VW , Huijkman NCA , Baller JFW , van Meer H , Lütjohann D , Kuipers F , Plösch T . The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction. Am J Physiol Regul Integr Comp Physiol (11 4, 2009). doi: 10.1152/ajpregu.00413.2009.PubMed | ISI | Google Scholar18. van Straten EM , Huijkman NC , Baller JF , Kuipers F , Plösch T . Pharmacological activation of LXR in utero directly influences ABC transporter expression and function in mice but does not affect adult cholesterol metabolism. Am J Physiol Endocrinol Metab 295: E1341–E1348, 2008.Link | ISI | Google Scholar19. Vehaskari VM , Woods LL . Prenatal programming of hypertension: lessons from experimental models. J Am Soc Nephrol 16: 2545–2556; 2005.Crossref | PubMed | ISI | Google Scholar20. Waddington CH . The epigenotype. Endeavour 1: 18–20, 1942.Google Scholar21. Wollett LA . Fetal lipid metabolism. Front Biosci 6: D536–D545, 2001.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: B. T. Alexander, Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216-4505 (e-mail: [email protected]umsmed.edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByDNA methylation as a regulator of intestinal gene expression15 February 2021 | British Journal of Nutrition, Vol. 126, No. 11Perinatal high methyl donor alters gene expression in IGF system in male offspring without altering DNA methylationFuture Science OA, Vol. 3, No. 1Sugared water consumption by adult offspring of mothers fed a protein-restricted diet during pregnancy results in increased offspring adiposity: the second hit effect14 October 2013 | British Journal of Nutrition, Vol. 111, No. 4Regulation of Early Human Growth: Impact on Long-Term Health18 November 2014 | Annals of Nutrition and Metabolism, Vol. 65, No. 2-3 More from this issue > Volume 298Issue 2February 2010Pages R272-R274 Copyright & PermissionsCopyright © 2010 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00760.2009PubMed19955491History Received 16 November 2009 Accepted 30 November 2009 Published online 1 February 2010 Published in print 1 February 2010 Metrics

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.

Developmental Origins of Health and Disease (DOHaD) considers the impact that the early life environment may have upon health and disease in later life. The most complete evidence within this field links birthweight with development of cardiovascular disease and type 2 diabetes in adulthood, with 10–20% higher risk of ischaemic heart disease and 19–30% higher risk of type 2 diabetes for every 1 kg lower birth weight.1, 2 As the combined burden of cardiovascular disease and diabetes accounts for 35% of all deaths worldwide,3 identification of risk factors, including those in early life, and the implementation of prevention and treatment strategies, is of clear relevance to public health. Health-care practitioners play crucial roles in the introduction of prevention and treatment strategies, and are well-placed to integrate early life risk factors into a life-span approach to healthcare. However, little is known about practitioners' recognition of and attitudes towards DOHaD; essential for translating research into practice. Accordingly, we examined the existing knowledge, acceptance and opinion of DOHaD principles in a cross-sectional survey of Australian healthcare practitioners. We targeted healthcare professionals with an important impact upon the early life environment. General practitioners, physicians, midwives, pharmacists, and dietitians were recruited through newsletters or emails sent by their representative professional associations and invited to complete an online survey. Almost all (98%) of the 208 respondents believed there was a link between early exposure and long-term risk of non-communicable disease, however only 49% recognised the term 'Developmental Origins of Health and Disease' or common synonyms. The association of birth weight with cardiovascular disease and type 2 diabetes was recognised by 57% and 82% of respondents, respectively. Fifty-one percent are giving professional advice regarding prevention of non-communicable disease related to early life exposure monthly or more frequently, despite only 25% describing themselves as confident when giving such advice. The vast majority (91%) would be comfortable recommending potential prevention strategies to reduce non-communicable disease related to early life exposure, with lifestyle modification and dietary supplements being the most frequently cited examples. Pregnant women and women planning pregnancy were the most frequently cited target groups for such prevention strategies. Our findings indicate that despite poor name recognition and knowledge of a specific key association, the general concepts of DOHaD are widely accepted by healthcare practitioners in Australia. This suggests that knowledge transfer may be required to facilitate the introduction of evidence-based targeted prevention and treatment strategies.

The hypothesis that environmental exposures in early life affect later health and risk for disease has been conceptualized as the Developmental Origin of Health and Disease (DOHAD).1 Several epidemiological studies linking nutritional status in childhood to later health gave rise to this hypothesis, which later was expanded to include intrauterine nutritional status and growth. The field is getting more attention as potential underlying physiological mechanisms are emerging. Epigenetics explains how gene expression may be altered without altering the DNA sequence, and provides a mechanistic explanation for the interaction between gene expression and environmental cues. Epigenetic modifications in the developing fetus may therefore link maternal health, including the pre-conception period, to lifetime health of the offspring. This has underscored the importance of healthier lifestyle, adequate nutrition, and physical and mental well-being among adolescents and women of fertile age.2 However, interventions have been difficult to evaluate in humans due to several inevitable confounding factors. Furthermore, developmental physiology is a complex field to explore, and caution is required, as interventions in pregnant women or adolescents may have future implications for the offspring that are unforeseen. The current evidence of DOHAD is based on combined data from several types of studies. The main body of evidence is generated from retrospective studies investigating different time periods, but not the entire lifespan from conception to old age. Perinatal outcomes are related to maternal health before or during pregnancy. Several such studies suggest an association between perinatal outcomes and the development of non-communicable diseases, such as diabetes, cancer and cardiovascular disease.1, 3 Importantly, studies of siblings and of abrupt changes in nutritional access link maternal health and nutritional status before or during pregnancy to the life course health of the offspring.4 On the other hand, prospective studies investigating the effect of the intrauterine environment for the offspring usually include pregnant women in the first or second trimester of pregnancy and report only early neonatal outcomes. The need for prospective longitudinal data across generations is being met by recent studies that recruit women before pregnancy and follow the offspring up to adolescence and reproductive age. Experimental data aiming to provide mechanistic understanding of phenotypic effects on fetal organ structure, growth and function suggest a causal effect of maternal diet, and metabolic or other types of stress on offspring outcomes in later life. Several studies have demonstrated that the composition and content of maternal diet (energy density, content of protein, antioxidant or methyl donors, etc.) may potentially have epigenetic effects on fetal phenotype.3 Experimental animal studies using in vitro fertilization and healthy surrogate mothers demonstrated altered phenotype in offspring when the gametes originated from nutritionally challenged mice.5 Moreover, human studies linking epigenetic traits to fetal exposure, searching for mechanistic links to later risk for disease, are emerging. Based on these observations, several large and well-designed interventional studies have been launched, aiming to improve maternal metabolic health during pregnancy, perinatal outcome and later risk of disease in the offspring. At first glance, the results have been somewhat disappointing, even when the interventions resulted in marked improvement of the maternal metabolic state.6 There are several potential explanations for this, illustrating the complexity of this intergenerational risk cycle. First, most of the studies started interventions well into the second trimester of pregnancy because approximately half of all pregnancies are unplanned and women of reproductive age are not frequent users of health services and are therefore less accessible through classical study recruitment strategies. Lifestyle changes are difficult to implement and it takes time to achieve planned goals. Thus, interventions in pregnancy may have been started too late to have a proper impact. Second, gametogenesis and early stages of embryogenesis are periods particularly susceptible for epigenetic alterations. In addition, maternal metabolic factors in early pregnancy probably affect placentation and thus placental function throughout pregnancy. In sum, the effect of an intervention depends both on the nature and the timing of the exposure. This is reflected in human observational studies demonstrating different effects of famine during early or late stages in pregnancy.4 Moreover, it is established that epigenetic patterns are tissue- and cell-specific and epigenetic changes in humans are not easily monitored due to the inaccessibility of adequate samples; in addition, data from experimental studies on animal are not directly transferable to humans. To complicate the picture even more, epigenetic modifications may be time-limited and reversible. Consequently, interventions may have other outcomes than expected or monitored and physiological conditioning may not necessarily result in measurable outcomes at birth or in early childhood. Indeed, follow up of children after interventional studies indicate that there might be effects on metabolic measurements in later childhood.7 Inversely, an outcome may be seemingly beneficial at birth but associated with later risk of disease. This is illustrated by the effects of bariatric surgery, where this exposure might have both positive (decreased risk of gestational diabetes and having large for gestational age fetus) and negative (shorter gestation and increased risk of having small-for-gestational age fetus) effects on neonatal outcomes.8 Interventional studies of micronutrient status and folate supplementation in human pregnancy revealed some important issues.9 First, an exposure (folate) may be beneficial at birth (higher birthweight in a population with frequent small for gestational age neonates) but may confer long-term risk (insulin resistance) in childhood. Second, it may be beneficial to some outcomes (neural tube defects), but not for others (insulin resistance). Third, the results are diverging depending on the population studied. Fourth, the effects may be influenced by other factors (such as vitamin A, homocysteine and vitamin B12 status). Fifth, the effects may be dependent on timing and dosage, eg both high and low folate status may confer risks. Finally, following the DOHAD concept, the time of observation from exposure to outcome is long and most studies will struggle to differentiate intrauterine effects from residual confounding from life itself. We inherit epigenetic marks not just from our life in utero, or early childhood, but also from the genome and postnatal environment. A mismatch between the pre- and postnatal environment is particularly linked to later disease. The epigenome is not a constant trait, but namely a way for cells, tissues and metabolic systems to adjust the genetic expression throughout life. In fact, the epigenome between monozygotic twins is increasingly different with age and diverse life exposures.3 Interventional generational studies have been launched and will provide us with important insight in the years to come.2 In summary, there are challenges that hamper the opportunities to study the concept of DOHAD mechanistically, and conclusions from interventional studies may not be transferable between different populations. Nevertheless, the sum of evidence, although fragmented, supports the DOHAD concept. The ideal studies needed to advise and survey the consequences of potential interventions must span generations and record even unforeseen outcomes. However, as a parallel to the global climate crisis, it is not a wise strategy to wait for more evidence before acting. Rather, the focus should be on the simplest and safest solutions. Targeted efforts to ensure good education, balanced nutrition and a healthy lifestyle in childhood and adolescence should be governmental priorities to promote healthy reproductive life and long-term health of the next generation.

Environmental factors affecting development through embryogenesis, pregnancy, and infancy impact health through all subsequent stages of life. Known as the Developmental Origins of Health and Disease (DOHaD) hypothesis, this concept is widely accepted among health and social scientists. However, it is unclear whether DOHaD‐based ideas are reaching the general public and/or influencing behaviour. This study thus investigated whether and under what circumstances pregnant people in Canada are familiar with DOHaD, and if DOHaD familiarity relates to eating behaviour. Survey responses from pregnant people from Hamilton, Canada, were used to assess respondents' knowledge of DOHaD (hereafter, DOHaDKNOWLEDGE) compared with their knowledge of more general pregnancy health recommendations (Pregnancy GuidelineKNOWLEDGE). The survey also characterized respondents' pregnancy diet quality and sociodemographic profiles. We fit two multiple, linear, mixed regression models to the data, one with DOHaDKNOWLEDGE score as the dependent variable and the other with diet quality score as the dependent. In both models, responses were clustered by respondents' neighbourhoods. Complete, internally consistent responses were available for 330 study‐eligible respondents. Relative to Pregnancy GuidelineKNOWLEDGE, respondents had lower, more variable DOHaDKNOWLEDGE scores. Additionally, higher DOHaDKNOWLEDGE was associated with higher socio‐economic position, older age, and lower parity, independent of Pregnancy GuidelineKNOWLEDGE. Diet quality during pregnancy was positively associated with DOHaDKNOWLEDGE, adjusting for sociodemographic factors. A subset of relatively high socio‐economic position respondents was familiar with DOHaD. Greater familiarity with DOHaD was associated with better pregnancy diet quality, hinting that translating DOHaD knowledge to pregnant people may motivate improved pregnancy nutrition and thus later‐life health for developing babies.

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.

BackgroundTo mitigate the growing burden of non-communicable diseases, doctors training to become paediatricians should be equipped with concepts and knowledge regarding Developmental Origins of Health and Disease (DOHaD).MethodsWe assessed the knowledge, attitudes, and practices (KAP) of medical officers, resident physicians, as well as junior and senior residents practising in the paediatric department of a tertiary women’s and children’s hospital. This was done through a cross-sectional online survey, with questions developed after focused group discussions with domain experts, and responses based on a 5-point Likert scale.ResultsA total of 95 physicians met the inclusion criteria, grouped into Medical Officers (MOs) and Registrars (REGs), and we received a 100% response rate. Results showed that few physicians (n = 22, 23.2%) knew the term DOHaD, and majority rated their colleagues to be inadequately informed (n = 84, 88.4%). Among the physicians, one third (n = 32, 33.7%) were not confident in their ability to counsel patients about initiating healthy feeding practices to prevent future metabolic diseases in their children. However, there was a readiness to be better equipped with DOHaD principles and knowledge, and 95.8% (n = 91) strongly acknowledged the physician’s responsibility to optimise early life determinants of cardiometabolic health.ConclusionIn conclusion, the findings suggest a poor translation of DOHaD concepts, indicating that bridging the gap between DOHaD research knowledge and clinical application represents an unmet need. These principles should be inculcated early in the professional training of all healthcare providers.

Phenotypic plasticity: historical context, theories and DOHaD.

The Developmental Origins of Health and Disease (DOHaD) framework has highlighted the role of maternal and paternal health on disease risk in offspring and across generations. Although adolescence is increasingly recognised as a key DOHaD window where interventions may have the greatest impact in breaking the cycle of non-communicable diseases, data around the recognition of this concept in adolescents remain limited. Previous work by our group found that the understanding of DOHaD-related concepts among adolescents in New Zealand was low, including some adolescents showing disagreement with key DOHaD concepts. This qualitative study aimed to explore DOHaD perspectives and understandings among a group of adolescents who responded to the survey using semi-structured focus groups and interviews (n = 12). Four core themes were identified: 1. knowledge of DOHaD and DOHaD-related terminology; 2. understanding different life course windows for DOHaD interventions; 3. recognising that DOHaD-related information needs to be accessible for adolescents; and 4. the importance of developing context-specific resources for adolescents. Adolescents in this study indicated that they had not heard of DOHaD or related terminology. Although the majority recognised that there were many important life stages for potential interventions, there was a strong emphasis on adolescence as a key window of opportunity. Adolescents suggested that more could be done in schools to help promote awareness and understanding of DOHaD-related concepts during the later years of schooling. The development of future resources needs to be contextually specific for adolescents to ensure increased uptake of information during this important developmental window.

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.

Epigenetics is likely to play a role in the mediation of the effects of genes and environment in risk for many non-communicable diseases (NCDs). The Developmental Origins of Health and Disease (DOHaD) theory presents unique opportunities regarding the possibility of early life interventions to alter the epigenetic makeup of an individual, thereby modifying their risk for a variety of NCDs. While it is important to determine how we can lower the risk of these NCDs, it is equally important to understand how the public's knowledge and opinion of DOHaD and epigenetic concepts may influence their willingness to undertake such interventions for themselves and their children. In this review, we provide an overview of epigenetics, DOHaD, NCDs, and the links between them. We explore the issues surrounding using epigenetics to identify those at increased risk of NCDs, including the concept of predictive testing of children. We also outline what is currently understood about the public's understanding and opinion of epigenetics, DOHaD, and their relation to NCDs. In doing so, we demonstrate that it is essential that future research explores the public's awareness and understanding of epigenetics and epigenetic concepts. This will provide much-needed information which will prepare health professionals for the introduction of epigenetic testing into future healthcare.

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

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) hypothesis derives from the epidemiological and basic/mechanistic health sciences. This well-supported hypothesis holds that environment during the earliest stages of life-pre-conception, pregnancy, infancy-shapes developmental trajectories and ultimately health outcomes across the lifespan. Evolutionary anthropologists from multiple subdisciplines are embracing synergies between the DOHaD framework and developmentalist approaches from evolutionary biology. Even wider dissemination and employment of DOHaD concepts will benefit evolutionary anthropological research. Insights from experimental DOHaD work will focus anthropologists' attention on biochemical/physiological mechanisms underpinning observed links between growth/health/behavioral outcomes and environmental contexts. Furthermore, the communication tools and wide public appeal of developmentalist health scientific research may facilitate the translation/application of evolutionary anthropological findings. Evolutionary Anthropology, in turn, can increase mainstream DOHaD research's use of evolutionary theory; holistic, longitudinal, and community-based perspectives; and engagement with populations whose environmental exposures differ from those most commonly studied in the health sciences.

Because the “Developmental Origins of Health and Disease (DOHaD)” hypothesis recently became widely known in a medical research area, fetal and childhood environment has been drawing more attention. In addition, based on the DOHaD, childhood growth trajectories, which are described by multilevel analysis, might be important in examining the effects of early-life environment. Therefore, it becomes more important to establish epidemiological evidence related to DOHaD from population-based birth cohort studies which include the study that uses the dataset from some public health activities. Moreover, it is also important to apply the findings from these studies to public health. In this chapter, some nationwide and local birth cohort studies and the results related to DOHaD from these studies are introduced. For instance, the association between maternal smoking status during pregnancy and birthweight from “Japanese Environment and Children’s Study” which is conducted by the Ministry of Environment, and childhood growth trajectories according to maternal smoking status during pregnancy from Project Koshu, are described.