Monthly Archives: October 2015

Effect of Environmental Factors During Pregnancy

The first 9 months of life are an essential period for the development of the body and for epigenetic changes to take place. The idea that the womb environment impacted on foetal programming began to be explored in the 1980s by David Barker, and this therefore became known as the ‘Barker Hypothesis’. He suggested that the prenatal environment is used as a sort of prediction of the environment in which the child will grow up, and therefore is used to prepare them for these sort of conditions.

Epigenetic modifications are ways in which gene expression is altered, without changes to the genetic code itself. DNA methylation (the addition of a methyl group at a specific point), microRNA expression, imprinting and histone modification are all ways in which the environment can actually alter our gene expression, and therefore impact on our lives. There are many ethical considerations that must be taken into account when studying these early stages of human life, so in many areas the research is limited and there is still probably much more to be discovered. This article will look at some factors involved with pregnancy that can influence the life of an infant.

Maternal Nutrition:

During the Dutch Hunger Winter in the Second World War, people received less than 30% of the normal calorie intake, due to a Nazi blockade of the Netherlands. Records of pregnant mothers, who suffered in this time, and their children, have been analysed and provide a unique study of the effects of starvation on developing infants. The records show that mothers who were in the first stages of pregnancy during the Dutch Hunger Winter gave birth to normal weight babies, but who had higher than average obesity rates and risk of mental health problems later in life. This fits with the ‘Barker Hypotheses’ as these children were prepared for a life in which food was scarce, although in reality this was not the case. Mothers who were in the later stages of pregnancy gave birth to smaller babies, who had lower than average obesity rates in later life. This could possibly suggest that a large amount of developmental programming concerning metabolism may already have been done by this stage. Effects of this period of starvation could also be observed in the grand children of these women, meaning that these changes appear to be heritable.
Studies of mice have found similar results, and have shown these changes to be due to DNA modifications, such as changes to the pattern of DNA methylation, not due to other factors such as the womb environment alone.
This evidence therefore suggests that the event of starvation of a pregnant mother can have effects on the infant, such as metabolic changes throughout their lifetime.

Nutrition around the time of conception
In rural Gambia, where people’s diet relies mainly on subsistence farming, there are fluctuations in food availability throughout the year. The area has a rainy and dry season each year, so the time of conception can easily be used to predict a typical diet of each woman at this point. In studying this region, researchers found that the maternal diet around the time of conception was linked to the level of DNA mehtylation of specific genes of the infants. This occurs because nutrients from the diet are required as a source of methyl groups, and also for the reactions by which methylation takes place. This means that the mother’s intake of nutrients, such as certain minerals and B-vitamins, can affect the genetic modifications taking place in her child.

Carbohydrate intake
Several studies have found low carbohydrate intake in mothers to be associated with epigenetic changes in infants. For example, Drake et al studied the impacts of a maternal diet lower in carbohydrate and higher in red meat, on the children involved. This study found that the diets lower in carbohydrate and higher in meat, correlated with a greater methylation of a specific DNA site and also higher BMI and waist circumference when the infants reached adulthood.

High calorie intake
A 2006 PubMed study by Villamor and Cnattingius found that a mother gaining weight between pregnancies increased the risk of the child becoming overweight, compared to their siblings. A study of macaques also found overnutrition of a mother during pregnancy to be associated with fatty liver disease and an average of double the percentage body fat of the infant. Several studies of rats have also found maternal overnutrition to be linked to increased appetite, high blood pressure, insulin resistance and increased body fat in offspring. It is thought that the appetite control differences in the offspring may be due to developmental programming changes that effect the concentrations of the hormones leptin and insulin.

Gestational Diabetes
There are many possible effects that gestational diabetes can have on the foetus, such as causing low blood sugar and mineral levels, jaundice and high birth weight. It can, however, also have effects on the child throughout its life, such as increased risk of obesity and developing type 2 diabetes. It is also possible that if gestational diabetes is poorly treated, that the mother’s body may start to break down fat and muscle tissue, rather than using glucose for energy. This causes ketones to be produced and there have been associations found suggesting these compounds are linked with learning disabilities throughout the child’s life.

Maternal Stress:

Studies have found prenatal stress to be linked with hyperactivity, inattention, emotional problems, lower levels of mental development and depression in the children. A study at Imperial College London found that higher levels of cortisol in the mother’s blood caused cortisol levels in the amniotic fluid to be higher. Environmental differences such as this, appear to cause changes to the developing brain of the foetus. These changes may even be structural differences, such as the smaller than average head circumference.
There is also evidence of epigenetic changes created due to the maternal stress. For example, the mother’s stress appears to effect the DNA methylation pattern in several of the infants cells, such as those related to sugar metabolism and T cells of the immune system. Although the impacts of this are largely unknown, it suggests that the children may be at a greater risk of diabetes, obesity and asthma.
Maternal stress also seems to be linked to increased methylation of the glucocorticoid receptor gene (NR3C1). This reduces its expression and means that a smaller amount of the receptor protein is produced. This is a receptor for cortisol in the infant’s brain, and is involved in a feedback mechanism which, in a healthy child, would reduce the amount of cortisol released. This can result in a greater stress-response in the child, and can increase the risk of depression.
A significant study in this area of research is that of children born following an ice storm in Canada, throughout which their pregnant mothers had been under intense stress. The 89 children involved were studied at 5 years old, and this study, published in 2008 found that higher stress levels of the mothers during pregnancy were associated with lower IQ, verbal IQ and language ability in the children. These children will continue to be studied to find out how they are affected later in life.

Alcohol Consumption:

The fact that alcohol consumption during pregnancy affects development is well known. This has been documented by many studies and a wide range of negative impacts have been found. For example, a 2012 study of prenatal alcohol exposure found that higher levels were associated with lower levels of attention and longer reaction time in 7 and 8 year old children. A previous study published in 2001 found a statistically significant association between alcohol exposure and reduction in the size of the frontal cortex. This area of the brain is involved with higher mental processes, such as thinking, decision making and planning, so underdevelopment can easily be linked to the observed effects of FAS. There are many different mechanisms that could explain how these effects are brought about. For example, greater oxidative stress, damage to mitochondria or glia cells, changes to growth factor activity and chemical messaging systems or altered gene regulation could all potentially cause cells to die. It is almost certain that multiple mechanisms occur to create FAS. More can be read about this from the National Institute on Alcohol Abuse and Alcoholism.

Maternal Smoking:

Exposing a foetus to tobacco constituents has been shown to be linked to reduced lung growth, infection of the respiratory tract, asthma and negative impacts on psychological development. Many substances, including nicotine and carbon monoxide, are carried in the mother’s blood and transferred to the developing baby via the placenta. Several of those substances can even be found in higher concentrations in the foetus than in the mother, such as nicotine, which can be 15% greater.
It is thought that these substances impact upon the foetus by creating epigenetic changes. For example, a 2010 PubMed study by Suter et al, found that maternal smoking was associated with greater levels of DNA methylation in several areas, affecting gene expression involved in development and growth, as well as possibly causing modifications to the placenta. Maternal smoking has also been found to by Maccani et al, to be associated with reduced amounts of a specific miRNA. MicroRNA are small, non-coding pieces of RNA, which pair up with mRNA, affecting translation of specific proteins. These two mechanisms begin to explain how it is possible for smoking to damage a developing child, however, many other processes may be involved.

Maternal Infection:

Infection during pregnancy is thought to be linked to a higher risk of neurological disorders, including autism. This effect would depend on the severity of infection of the mother, but it appears that proteins produced by the mother in her immune response may effect the infant’s brain, either directly or by effecting nutrient and oxygen supply via the placenta. This correlation has been found by several studies, for example, Atladottir et al in 2010, who found that hospital admission of a mother due to viral infection in the first trimester was associated with a three times greater risk of autism. When studying the total duration of pregnancy, however, they found no correlation.
For many types of virus, it is also holds true that infection early on in pregnancy presents a greater risk to the foetus. For example infection with rubella in the first 11 weeks of pregnancy is associated with a 90% risk of affecting the foetus, for example causing mental impairment, deafness, inflammation or cataracts. Other infections such as chickenpox or toxoplasmosis in pregnancy can also be extremely dangerous to the foetus.

Overall, it is clear that the time during pregnancy is crucial to a baby’s development, and can have long term consequences, affecting its whole life. There are many factors that can influence it’s development and genetic programming throughout this time, and little detail is known about most of these factors. There are also many more factors that would have an influence on the developing foetus. The more research that is carried out, the more we find out about the complexities of the genome and environment’s interaction. The extent to which conditions during pregnancy can effect a person’s life needs further exploration, and we so far can not know how many of the events of a mother’s life can influence the development of her child.

Sources used:
The Open University
Science Direct – Prenatal Stress
– Impact of prenatal stress, foetal alcohol exposure, or both on development
PubMed – Project Ice Storm
Frontiers in Genetics – developmental programming
American Psychological Association
The Epigenetics Revolution
The Lancet
American Journal of Obstetrics and Gynecology
National Institute on Alcohol Abuse and Alcoholics
Journal of the American Academy of Pediatrics
Autism Speaks
BioMed Central
US National Library of Medicine

Allergies on the Increase?

– Each year, in the UK, the number of allergy sufferers increases by 5%
– The incidence of hay fever in children in the UK has tripled in the past 30 years
– Initialy, this trend was only apparent for asthma and hay fever, however, food allergies are also now on the rise
– In the last decade, the number of cases of food allergies has doubled
– Since 1990, there has been a 500% increase in hospital admissions due to food allergies

Explaining this trend:

Is the rise due to increased awareness, or actually due to the development of allergies becoming more frequent?
It is true that awareness is increasing, and therefore a higher percentage of allergies are becoming diagnosed. However, there is a large amount of evidence suggesting that there is more to it than this. It seems that the incidence of allergy development is actually increasing too. The reason for this has been hotly debated.

A bit of background information:

The development of an allergy is determined by both genetic and environmental factors. The evidence for a genetic component can be clearly observed through the study of twins. A PubMed study published in 2000, found that 7% of fraternal twins shared the same peanut allergy, whereas 64% of identical twins shared this same allergy.
An allergy occurs when the immune system mistakingly identifies a harmless substance, such as a food protein or pollen, as a harmful pathogen, causing an immune response. There are 5 basic types of antibodies, one of which (IgE) is responsible for allergic reactions. Everybody has this antibody type, however, the lymphocyte should be able to distinguish between harmless proteins and those that are dangerous.
So why are allergies becoming more common? We know that this increase can not be due to genetic factors, as the rate of change is far too rapid. This indicates that there are environmental factors to blame. Genes can also be switched off or on as a result of environmental factors. This process, called epigenetics, could have a part to play in allergies. For example, infection by viruses can cause epigenetic changes, which are able to effect the bodies immune response. Several of the possible environmental causes for increasing allergies are discussed below:

‘Sunshine Hypothesis’
Lifestyle changes mean that children now spend a much higher percentage of their time indoors, reducing their sun exposure. Receiving sunlight is important to our bodies because 80% of our vitamin D is produced in the skin in UV light, and does not come directly from our diet. It is also known that using sunscreen with a protection factor of just 8, decreases the production of vitamin D by 98%. These changes explain why vitamin D deficiency has become far more common. Studies have repeatedly found that the prevalence of allergies is highest in westernised countries. In China, this correlation also holds true for cities that differ in level of westernisation. A possible explanation for this is that people in westernised areas generally spend a greater proportion of their time indoors, and generally have lower levels of vitamin D.
It is also known that vitamin D can have inhibitory effects on some of the T helper cells of the immune system, and therefore could be involved with allergic responses.

Pollution Hypothesis
Air pollution has become a major public health concern in recent decades. This pollution includes carbon dioxide, nitrogen dioxide, CFCs, ozone, sulphur dioxide and particles in suspension. There is strong evidence that pollutants are able to exacerbate existing allergies, such as asthma. For example, it has been shown that ozone immediately worsens dust mite allergies, and causes inflammation of the airways.
What is currently unknown, is whether this air pollution can actually induce the development of new allergies. Research into this has been carried out, for example a 2004 PubMed study by Gauderman et al found that the likelihood of developing asthma was higher in children who exercised in areas with high ozone concentrations. NO2 and exhaust particles have also been found to be associated with asthma development. However, this data is frustratingly inconsistent, as several studies have found no correlations. These different findings are thought to be due to differences in lifestyle factors of the participants, however, the exact reasons are unknown. Despite this uncertainty, possible mechanisms have been suggested to explain how pollution could cause the development of an allergy. For example, it has been shown that diesel exhaust particulates (DEPs) stimulate the epithelial cells of the airways to produce cytokines and chemokines, causing inflammation. This production is due to increases in transcription of the relevant genes. There are many other possible ways that pollution may effect inflammation and antioxidant pathways, meaning that the response to allergens could be affected.
It has also been suggested that climate change could affect allergies, as increasing temperatures change the distribution of allergens and can also alter the allergenic potential of pollen.

Diet Hypothesis
Processed foods are also under suspicion as a potential cause of allergy development. Our diets now contain far more processed foods, and are lacking in fruit and vegetables. It is a possibility that these diet changes have resulted in greater consumption of allergenic substances such as wheat. It is also possible that coming into contact with allergens at an early age could possibly increase the risk of developing an allergy. There has been some research into whether reduced omega-3 or antioxidant intake could be linked with allergy development. In some studies, diets low in oily fish have correlated with increased risk of asthma and allergies, but this evidence is inconsistent.

‘Hygiene Hypothesis’
It is well recognised that there is a correlation between high living standards and high frequency of allergic diseases. This high standard of living involves sanitation technology such as clean water and food supply as well as the use of antibiotics. Our lifestyle changes have resulted in the immune system coming into contact with fewer micro-organisms during childhood.
It is also known that children who have older siblings are less likely to develop allergies, and this likelihood also depends on the number of older siblings that they have. This link between birth order and vulnerability to allergies could be due to the fact that having more siblings around increases the number of germs that the child is exposed to. It is thought that in areas of the world where hygiene standards have greatly improved, the immune system is not fighting against as many pathogens, and this creates an imbalance which means we have a predisposition to the development of allergies. The imbalance that is created involves the quantities of T1 and T2 cells of the immune system. It is thought that people who have not come into contact with as many micro-organisms have fewer of the T1 response cells. T2 dominance is known to be associated with asthma, hay fever and other allergies. Therefore the micro-organisms that we have evolved with, could be essential to the development of our immune system.
The results of several animal studies have also given support to this hypothesis. For example, a German study published in December 2009 in the Journal of Experimental Medicine, found that exposing pregnant mice to barnyard micro-organisms, resulted in their offspring being resistant to allergies. The fact that children growing up on farms also have a reduced likelihood of developing allergies, suggests that this may also apply to humans.
As breast milk contains over 700 varieties of bacteria, I would also suggest that this could potentially have benefits to a baby’s immune system and affect the development of allergies. Therefore the use of formula milk is another factor that could be considered as it would reduce the natural exposure of infants to micro-organisms and therefore tie in with the ‘hygiene hypothesis’. This could then bring up questions about the significance of a mother’s diet during the breast feeding period, and whether this would affect the development of allergies in the infant.

Overall, it appears that there is no certainty as to why the frequency of allergies is increasing in developed countries. There is, however, compelling evidence to suggest that environmental factors associated with our changing lifestyles are causing changes to our immune response. There is a growing body of evidence to support the ‘hygiene hypothesis’, but it is also possible that other factors, such as dietary changes and pollution could be contributing to this apparent trend.

Sources used:
Live Science – food allergies
British Society for immunology
Science Direct – Immunobiology 2007
Biomed Central
National Geographic
Korean Journal International Medicine