Developmental Origins Of Health And Disease Paradigm Research Articles

Contribution of early nutrition on the development of malnutrition and allergic diseases in the first year of life: a study protocol for the Mother and Infant Cohort Study (MICOS)

BackgroundNutrition and environmental factors are essential for the education of the neonatal immune system. Epidemiological evidence has shown that malnutrition and allergic diseases that occur during early childhood share similar protective and risk factors. This paper describes the protocol of the Mother and Infant Cohort Study (MICOS), which aims to determine the contribution of early nutrition to the development of malnutrition and allergic diseases in infants’ first year of life.MethodsMICOS is a prospective cohort study conducted at selected government health clinics in two states, namely Selangor and Wilayah Persekutuan Kuala Lumpur, Malaysia. Women in their third trimester of pregnancy are recruited into the study and their infants will be followed-up at 3, 6, and 12 months of age. Information on prenatal factors including socio-demographic characteristics, obstetric history, pre-pregnancy body mass index, gestational weight gain, smoking, family history of allergic diseases, maternal dietary intake and sunlight exposure during pregnancy are obtained through face-to-face interviews. Postnatal factors including dietary intake, sun exposure, and anthropometric measurements of the mothers, as well as feeding practices, dietary intake, anthropometric measurements, and development of allergic diseases of the infants are assessed at each follow-up. Blood samples are collected from the mothers in the third trimester to determine 25-hydroxyvitamin D levels as well as from the infants at age 12 months to determine atopic sensitisation.DiscussionThe concept of developmental origins of health and disease (DOHaD) which emphasises on the role of early life environments in shaping future health and disease susceptibility in adulthood has gained a huge interest in recent years. The DOHaD paradigm has influenced many fields of research including malnutrition and allergic diseases. While findings from the developed countries remain controversial, such studies are scarce in developing countries including Malaysia. The present study will determine the cause and effect relationship between early nutrition and the development of malnutrition and allergic diseases in infants’ first year of life.

The significance of DOHaD for Small Island Developing States.

Small Island Developing States (SIDS) are island nations that experience specific social, economic and environmental vulnerabilities associated with small populations, isolation and limited resources. Globally, SIDS exhibit exceptionally high rates of non-communicable disease (NCD) risk and incidence. Despite this, there is a lack of context-specific research within SIDS focused on life course approaches to NCD prevention, particularly the impact of the early-life environment on later disease risk as defined by the Developmental Origins of Health and Disease (DOHaD) framework. Given that globalization has contributed to significant nutritional transitions in these populations, the DOHaD paradigm is highly relevant. SIDS in the Pacific region have the highest rates of NCD risk and incidence globally. Transitions from traditional foods grown locally to reliance on importation of Western-style processed foods high in fat and sugar are common. The Cook Islands is one Pacific SIDS that reports this transition, alongside rising overweight/obesity rates, currently 91%/72%, in the adult population. However, research on early-life NCD prevention within this context, as in many low- and middle-income countries, is scarce. Although traditional research emphasizes the need for large sample sizes, this is rarely possible in the smaller SIDS. In these vulnerable, high priority countries, consideration should be given to utilizing 'small' sample sizes that encompass a high proportion of the total population. This may enable contextually relevant research, crucial to inform NCD prevention strategies that can contribute to improving health and well-being for these at-risk communities.

[Does Malnutrition during Fetal Life Have a Potential to Be a Precipitating Factor for Developmental Disorders?]

The developmental origins of health and disease paradigm (DOHaD) is a concept that fetal environmental factors affect adult phenotypes. We performed experiments to evaluate the DOHaD theory in developmental disorders using mouse models. In vitro fertilization and embryo transfer techniques were used for mouse production. The AIN93G-control diet, which contains 20% protein (CD), 5% protein-restricted diet (PR), and PR with supplemental folic acid (FA) were provided as experimental diets to mothers. The body weights (BWs) of mothers and offspring, and the blood-clinical biochemistry results of mothers were examined. In addition, gene expression and genomic methylation in the brain of adult offspring and behavioral phenotypes of adult offspring were examined. Pregnant mothers that consumed the protein-restricted diets, namely, PR and FA, exhibited reduction in BW. The values of protein-related parameters determined by blood-clinical biochemistry decreased in the PR fed groups. The BWs of neonates and adult offspring did not change. The offspring exposed to maternal hyponutrition exhibited increased activity in the home cage and enhanced fear and anxiety-like behavior. The adult offspring of the PR-fed group and FA-fed groups exhibited different patterns of mRNA expression and genomic methylation in the brain. The maternal PR diet affected the progenies' behavioral phenotypes and epigenetic outcomes in the brain. However, the behavioral changes induced by maternal protein restriction were very slight. Hence, interactions between several genetic factors and environmental exposures such as maternal malnutrition may cause developmental and psychiatric disorders.

Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework.

Non-communicable diseases (NCDs) are a major cause of premature mortality. Recent studies show that predispositions for NCDs may arise from early-life exposure to low concentrations of environmental contaminants. This developmental origins of health and disease (DOHaD) paradigm suggests that programming of an embryo can be disrupted, changing the homeostatic set point of biological functions. Epigenetic alterations are a possible underlying mechanism. Here, we investigated the DOHaD paradigm by exposing zebrafish to subtoxic concentrations of the ubiquitous contaminant cadmium during embryogenesis, followed by growth under normal conditions. Prolonged behavioral responses to physical stress and altered antioxidative physiology were observed approximately ten weeks after termination of embryonal exposure, at concentrations that were 50–3200-fold below the direct embryotoxic concentration, and interpreted as altered developmental programming. Literature was explored for possible mechanistic pathways that link embryonic subtoxic cadmium to the observed apical phenotypes, more specifically, the probability of molecular mechanisms induced by cadmium exposure leading to altered DNA methylation and subsequently to the observed apical phenotypes. This was done using the adverse outcome pathway model framework, and assessing key event relationship plausibility by tailored Bradford-Hill analysis. Thus, cadmium interaction with thiols appeared to be the major contributor to late-life effects. Cadmium-thiol interactions may lead to depletion of the methyl donor S-adenosyl-methionine, resulting in methylome alterations, and may, additionally, result in oxidative stress, which may lead to DNA oxidation, and subsequently altered DNA methyltransferase activity. In this way, DNA methylation may be affected at a critical developmental stage, causing the observed apical phenotypes.

In utero origin of sex-related differences in future cardiovascular disease.

BackgroundThere are sex differences in the risk of development of cardiovascular disease (CVD). According to the developmental origins of health and disease paradigm (DOHaD), CVD originates in fetal life. This study examines fetal sex differences in cardiovascular development in utero.MethodsIn 1028 pregnant women, we assessed fetal circulation using pulsed wave Doppler examinations between 28 and 34 weeks gestation. To test associations between fetal sex and fetal circulation measurements, linear regression models were used adjusting for fetal size, gestational age, and fetal heart rate.ResultsA higher pulsatility index in the ductus venosus was observed in male fetuses compared to female fetuses (difference 0.02, 95 % CI 0.01; 0.05) with a lower E/A ratio of the tricuspid (difference −0.01, 95 % CI −0.03; −0.00) and mitral (difference −0.02, 95 % CI −0.03; −0.01) valves. This was mainly determined by differences in the E wave of the tricuspid and mitral valves (differences −1.02, 95 % CI −1.81; −0.24 and −1.28, 95 % CI −2.11; −0.46, respectively). Also in males, a lower peak systolic velocity was seen in the pulmonary artery (difference −1.33, 95 % CI −2.63; −0.03) with a similar lower trend regarding peak systolic velocity in the ascending aorta.ConclusionsMale fetuses exhibit an increased preload and reduced afterload conditions compared to females. While it is difficult to relate these measurements to exact cardiac function, our findings strongly suggest that the known differences in cardiovascular performance between the sexes already start in utero.

Developmental Origins of Health and Disease: Integrating Environmental Influences.

There are now robust data supporting the Developmental Origins of Health and Disease (DOHaD) paradigm. This includes human and animal data focusing on nutrition or environmental chemicals during development. However, the term DOHaD has not been generally accepted as the official term to be used when one is concerned with understanding the pathophysiological basis for how environmental influences acting during early development influence the risk of later noncommunicable diseases. Similarly, there is no global research or public health program built around the DOHaD paradigm that encompasses all aspects of environment. To better inform the global health efforts aimed at addressing the growing epidemic of chronic noncommunicable diseases of environmental origin, we propose a two-pronged approach: first, to make it clear that the current concept of DOHaD comprehensively includes a range of environmental factors and their relevance to disease occurrence not just throughout the life span but potentially across several generations; and second, to initiate the discussion of how adoption of DOHaD can promote a more realistic, accurate, and integrative approach to understanding environmental disruption of developmental programming and better inform clinical and policy interventions.

Impact of di-ethylhexylphthalate exposure on metabolic programming in P19 ECC-derived cardiomyocytes.

Di(2-ethylhexyl)phthalate (DEHP) is the most common plasticizer in plastic devices of everyday use. It is a ubiquitous environmental contaminant and primarily known to impair male gonadal development and fertility. Studies concerning the long-term effects of prenatal DEHP exposure on certain diseases [The Developmental Origins of Health and Disease paradigm (DOHaD) hypothesis] are scarce although it is proven that DEHP crosses the placenta. Rising environmental pollution during the last centuries coincides with an increasing prevalence of cardiovascular and metabolic diseases. We have investigated the effects of an early embryonic DEHP exposure at different developmental stages on cardiomyogenesis. We used an in-vitro model, the murine P19 embryonic carcinoma cell line (P19 ECC), mimicking early embryonic stages up to differentiated beating cardiomyocytes. P19 ECC were exposed to DEHP (5, 50, 100 µg ml(-1)) at the undifferentiated stage for 5 days and subsequently differentiated to beating cardiomyocytes. We analyzed the expression of metabolic (Pparg1, Fabp4 and Glut4), cardiac (Myh6, Gja1) and methylation (Dnmt1, Dnmt3a) marker genes by quantitative real-time PCR (qRT-PCR), beating rate and the differentiation velocity of the cells. The methylation status of Pparg1, Ppara and Glut4 was investigated by pyrosequencing. DEHP significantly altered the expression of all investigated genes. The beating rate and differentiation velocity were accelerated. Exposure to DEHP led to small but statistically significant increases in methylation of specific CpGs within Ppara and Pparg1, which otherwise were generally hypomethylated, but methylation of Glut4 was unaltered. Early DEHP exposure of P19 ECC alters the expression of genes associated with cellular metabolism and the functional features of cardiomyocytes.

The Peri/Postnatal Epigenetic Twins Study (PETS)

The Peri/postnatal Epigenetic Twins Study (PETS) is a longitudinal cohort of 250 pairs of Australian twins and their mothers, who were recruited mid-way through pregnancy from January 2007 to September 2009. The study is centered on the developmental origins of health and disease paradigm (DOHaD) in which an adverse intrauterine environment predisposes the individual to complex disease in later life by reducing growth in utero and adversely altering developmental plasticity. Data concerning diet and lifestyle were collected from mothers during pregnancy, and samples of plasma and serum taken at 28 weeks' gestation. We attended 75% of all births, at which time we collected multiple biological samples including placenta, cord blood, and neonatal cheek cells, the latter from 91% of pairs. Chorionicity was recorded and zygosity was determined by DNA testing where necessary. Approximately 40% of the twins are monozygotic, two-thirds of which are dichorionic. Twins were seen again at 18 months of age and repeat blood and cheek swabs taken where possible. Studies of gene expression and the epigenetic marks of DNA methylation have so far revealed that twins exhibit a wide range of epigenetic discordance at birth, that one-third of the epigenome changes significantly between birth and 18 months; shared (maternal) environment, genetic factors, and non-shared intrauterine environment contribute to an increasing proportion of epigenetic variation at birth, respectively, and affect tissues differently, and that within-pair birth weight discordance correlates with epigenetic discordance in genes associated with lipid metabolism, supporting an epigenetic mechanism for DOHaD.

How can the Developmental Origins of Health and Disease (DOHaD) hypothesis contribute to improving health in developing countries?

The relevance of nutrition during pregnancy and early infancy in defining short-term health and survival has been well established. However, the Developmental Origins of Health and Disease (DOHaD) paradigm provides a framework to assess the effect of early nutrition and growth on long-term health. This body of literature shows that early nutrition has significant consequences on later health and well-being. In this article, we briefly present the main consequences of malnutrition that affect human growth and development and consider how the DOHaD paradigm, with its evolutionary implications, might contribute to better addressing the challenge of improving nutrition. We examine how this paradigm is particularly appropriate in understanding the health and nutrition transition in countries that face the double burden of nutrition-related diseases (acute malnutrition coexisting with obesity and other chronic diseases). We focus on stunting (low height-for-age) to examine the short- as well as long-term consequences of early malnutrition with a life-course, transgenerational, and multidisciplinary perspective. We present current global and regional prevalence of stunting and discuss the need to reposition maternal and infant nutrition not only in health and nutrition intervention programs but also in consideration of the emerging research questions that should be resolved to better orient program and policy decisions.

Adult health outcomes and their implications for experiences of childhood nutritional stress in Jamaica

With insights from the developmental origins of health and disease paradigm (DOHaD), this study explores the impact of childhood nutritional stress on adult health outcomes in Jamaica. Jamaica experienced a lengthy period of political and economic instability beginning in the postcolonial period of the early 1960s. This study tests whether decreased government spending on public resources and limited access to imported food products during the early postcolonial period will be reflected in increased adiposity and body mass index among Jamaican adults. Ethnographic and anthropometric data were collected from individuals born between 1958 and 1988. Variability in health outcomes was assessed using Z-score values for body mass index and summed skinfold thickness measures. Age was employed as both a continuous and categorical independent variable. In partial correlation models controlling for economic status, body mass index values and summed skinfold thickness increased with age. Birth cohort and gender effects were also apparent. Women born between 1959 and 1968 had higher body mass index Z-score values than younger women. Both men and women born between 1959 and 1968 had significantly higher skinfold thickness measures than younger individuals. Individuals born between 1959 and 1968 were children during the immediate postcolonial era in Jamaica. Experiences of nutritional stress during critical developmental periods may have contributed to the observed age-related increases in adipose tissue and body mass index values. This study informs our understanding of the ways that fluctuations in the sociopolitical environment during development can mediate and contribute to poor adult health outcomes.