Developmental origins of health and disease (DOHaD) is an approach to medical research factors that can lead to the development of human diseases during early life development. These factors include the role of prenatal and perinatal exposure to environmental factors, such as undernutrition, stress, environmental chemical, etc. This approach includes an emphasis on epigenetic causes of adult chronic non-communicable diseases. As well as physical human disease, the psychopathology of the foetus can also be predicted by epigenetic factors.
Origin DOHaD has evolved into its modern understanding from several precursor concepts. In the 19th century the idea of "maternal impressions" was popular. Maternal impression is the idea that anything the mother did before giving birth could affect her offspring. Our modern understanding of DOHaD was developed by several studies by David Barker and his colleagues, which showed a strong relationship between infant mortality rates from 1921 to 1925 and ischemic heart disease rates from 1968 to 1978. This led to the fetal origins hypothesis of the origins of adult diseases, which proposed that this relationship was caused by differences in early life nutrition, with a supporting theory that birthweight is connected to the development of chronic disease.
During the Dutch Hunger Winter Famine (1944-1945) mothers were not able to receive the proper nutrition needed to healthily carry a baby. The babies who were born during this time developed diseases (such as heart disease, schizophrenia, and type 2 diabetes) at increased levels. Researchers were able to determine, decades after the famine, that the babies born during Dutch famine had an increase in methylation in some genes and a decrease in methylation in other genes compared to their siblings who were not born during the famine. The methylation levels explain why these individuals were predisposed to certain diseases. Data collected from the Dutch famine and similar events, such as the one at Leningrad, provided a reliable source of information to scientists studying DOHaD.
These studies in turn led to greater interest in the roles of developmental plasticity and early life environmental exposures in adult disease. The World Congress on Fetal Origins of Adult Disease held two meetings – one in 2001 and the other in 2003 – summarizing the new research in these areas. This congress later evolved into the International Society for Developmental Origins of Health and Disease.
Dutch hunger winter study Between 1944 and 1945, in the western regions of the Netherlands and in Amsterdam, a famine broke out due to a railway strike and German control limiting supplies. The people of these countries were receiving extremely limited calories (around 400-800 a day) which had an extreme effect on pregnant women and their children. Researchers began studying a cohort of middle-aged individuals whose mothers had been pregnant with them during the famine. The Dutch Hunger Winter study provided significant data to support the DOHaD. Further studies indicated that older people had a resilience to the effects of malnutrition on physical health in late life, but a higher vulnerability to socioeconomic stunting. Results concluded that the women with low caloric and nutritional intake during pregnancy had children that had greater rates of obesity as opposed to those who were not exposed to famine. This is conclusive with the DOHaD theory. The study goes on to investigate at what points in development DOHaD stood true. It is thought that exposure to famine in early gestational periods has a greater effect on the foetus, however, these theories are still under investigation.
Developmental plasticity
Thrifty phenotype hypothesis The thrifty phenotype hypothesis was proposed by C. Nicholas Hales and David Barker in a study published in 1992. This hypothesis suggested that poor growth during the fetal and infant stages can cause a development of type 2 diabetes later in life. Hales and Barker suggested that this poor growth was due to maternal malnutrition which leads to low birth weight. As previously stated, low infant birth weight usually leads to an increased risk of obesity which, if not acted on, can lead to type 2 diabetes.
The paper suggests that due to maternal malnutrition, infants can have lower birth weights. Since this is occurring during the plastic stage of development, this can cause the foetus to be "programmed" to conserve energy and store fat, thus leading to a lower metabolism. If there is a surplus of food during adulthood their body simply stores this abundance as more fat. This can then lead to not only diabetes but other metabolic diseases, too.
Responses of plasticity There are two different types of plasticity responses when dealing with human development. The first is an immediate adaptive response. This response will alter the development that is needed to survive if there have been changes in the environment. An example of this type of response is when oxygen deprivation causes a change in blood flow that would normally help with the expense of less critical tissues. Predictive adaptive response (PAR) is the second type of plasticity response. PARs are cues that happen in early life development that cause phenotype development to change that are normally adapted to environmental cues in later life. This can be a benefit only when the predicted and actual postnatal environment match.
Environmental mismatch hypothesis This is also referred to as the mismatch theory. Foetal malnutrition followed by excess nutrition in adults is a key example of environmental mismatches. This is very common among people born in impoverished societies. For pregnant women who are living in this type of circumstance the foetuses which are in utero are more likely to sense a low-protein condition and alter their development to survive. Therefore, the foetus will predict that getting food will be very difficult which then will set its metabolism for a "thrifty phenotype". By doing this it will use every calorie to its most efficient use for survival. This can be the same cause for a society with plenty of food available. The embryo will develop insulin resistance and enzyme levels will convert the food that is not being used into fat, which in later life can lead to obesity and diabetes. Overall the environmental mismatch hypothesis is an advantage for human development but not without some disadvantage in later life.
Mechanisms Epigenetic alterations of gene expression are closely related with developmental origins of the health and disease hypothesis. DNA methylation, histone modifications and non-coding RNAs are altered by the environment in the womb and potentially go on to produce higher rates of adult disease later in life.
DNA methylation The process of DNA methylation is the most studied epigenetic response as it relates to the developmental origins of health and disease. The methylation of chief regulatory cytosines changes the DNA's hydrophobicity and begins to inhibit interactions with transcription factors responsible for the expression of the gene. Certain metabolic disorders, cancer and neurodegenerative disorders can be attributed to DNA methylation events.
Histone modification Modifications of histones are important processes in developmental programming, with studies showing that maternal and paternal stress can induce histone modifications. These histone modifications alter phenotypes of organisms and can be the mechanism behind the predisposition of some metabolic disorders. Unbalanced diets increase the thioredoxin-interacting protein expressions causing blastocysts to form incorrectly because of altered histone methylation. High-fat diets are shown to alter histone methylation and acetylation and potentially lead to changes in gene expression within fetal adipose, liver, and skeletal muscle tissues.
Non-coding RNAs Recent studies have shown the importance in non-coding RNA's ability to regulate cell differentiation and organismal development. There are many types of non-coding RNA that are present and play a role in differentiating stem cells. There are many non-coding RNAs responsible for differentiating cells for human brain and muscle development. These RNA molecules have also been implicated in having a role in cardiovascular development. Long non-coding RNA called lncRNA Fendrr has shown to be an important regulator of heart development and it modifies chromatin and controls developmental signaling of genetically modified mice hearts. There is still a vast amount of research needed to fully understand this mechanism and its relation to DOHaD.
Examples
Cardiovascular disease In a study done by Barker, he found a strong connection between poor prenatal environments and increased possibilities of cardiovascular diseases in adults. He found a direct correlation between infant mortality in 1921-1925 and mortality rates in 1968-1978 because of heart diseases in England. In areas where pregnant mothers had to face poor nutritional states, their newborn children were at a high risk of death. If they survived the early stages of life, they developed a higher risk of cardiovascular diseases.
Studies on rats found that maternal nutrient restriction resulted in damage to the cardiac renin-angiotensin system (which regulates blood pressure and volume). Additionally, these studies have shown a decrease in the number of nephrons produced by the offspring of these mothers. These differences have been found to affect males and females differently, at least in the early stages. The exact mechanism of action is unknown but it is believed that it is epigenetic.
Metabolic diseases A study done at UC Irvine looked at the impact that maternal stress has on foetal development and overall foetal health. The researchers determined that a mother's stress and adverse pregnancy outcomes (APOs) related to the length of gestation and growth of the foetus along with impacts on the endocrine and immune systems of the foetus.
Early life influences, both prenatal and postnatal, have important effects on children later in life. It was determined that breastfed infants have significantly lower risks of obesity later in life than infants that were formula-fed.
Nutrition and growth during the early years of life can be related to the growth of diseases in humans later in their lives. For example, a study done in Jamaica showed that the blood pressure of children was associated with the mother's hemoglobin levels and body fat during pregnancy. Another example of this is shown in an article from the New England Journal of Medicine which took place during the Dutch famine. This study concluded that those who were in utero at the time of the famine were at a greater risk of obesity, hypertension, and heart disease than those who were born before or after the famine.
A maternal high-fat diet was used to help investigate how saturated fats cause unrestrained gestational weight gain and maternal obesity of offspring. When there is high-fat feeding during pregnancy, there are effects on the maternal metabolism and body composition. Some of the effects are insulin resistance, increased circulating lipids, increased adiposity, and hyperinsulinemia (high insulin in blood). When the fat intake was increased it started to adjust consumption of other macronutrients in the diet, which reduced the carbohydrate and protein consumption to match the increase of fatty acid. On another note, people who have obesity and a diet that is high in fat can develop a condition called dyslipidemia. It can lead to fibrosis of the liver, which is the cause for about 45% of deaths in the world.